<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>An evaluation of the EFSA’s dietary
reference values (DRVs), Part 1
Dietary reference values for vitamins and minerals for adults
No. 2018/19A, The Hague, September 18, 2018
Background document to:
Voedingsnormen voor vitamines en mineralen voor volwassenen
No. 2018/19, The Hague, September 18, 2018
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<pre>                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 2 of 179
contents
01 Introduction                                      4         12 Vitamin E (alpha-tocopherol)                                       68
02 Vitamin A (retinol and carotenes)                  8         13 Vitamin K1 (phylloquinone)                                         73
03 Thiamin (vitamin B1)                             15         14 Biotin                                                             79
04 Riboflavin (vitamin B2)                          22         15 Choline                                                            83
05 Niacin (vitamin B3)                              27         16 Calcium                                                            88
06 Pantothenic acid (vitamin B5)                    33         17 Chromium (III)                                                     95
07 Vitamin B6                                       37         18 Copper                                                             98
08 Folate                                            43         19 Fluoride                                                         104
09 Vitamin B12 (cobalamin)                          50         20 Iodine                                                           108
10 Vitamin C (ascorbic acid)                        55         21 Iron                                                             114
11 Vitamin D (ergocalciferol and cholecalciferol)   61         22 Magnesium                                                        121
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<pre>                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 3 of 179
23 Manganese                                        126              References                                                     164
24 Molybdenum                                       130              Annexes                                                        169
                                                                      A      Types of reference values and their definitions          170
25 Phosphorus                                       134              B      List of abbreviations                                    172
                                                                      C      Overview of the 2018 and 2014 reference values for
26 Potassium                                        139                     the Netherlands                                          175
27 Selenium                                         143
28 Zinc                                             149
29 Summary                                          154
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<pre>chapter 01 | Introduction                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 4 of 179
01
introduction
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<pre>chapter 01 | Introduction                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 5 of 179
This report serves as the background document for the Health Council              States of America and Canada) were established earlier. Furthermore,
advisory report on micronutrient requirements of adults4, which has been          and importantly, EFSA´s reports on dietary reference values provide a
prepared by the Council’s Committee on Nutrition. It describes the                thorough and transparent evaluation of the scientific evidence, and were
evaluation of reference values per nutrient. The advisory report gives            established by panels consisting of scientific experts from member states,
recommendations based on the outcome of these evaluations. The                    including the Netherlands. The EFSA reports on micronutrients were
evaluations cover the reference values for healthy adults except for              published in the period 2014-2018 (the final report has not yet been
pregnant and lactating women. These values for pregnant women and                 published) and can be considered to be the most recently available, thus
lactating women as well as for infants and for children, will be evaluated        the use of these reports as the point of departure for updating the
and presented separately. This background document has been prepared              scientific background of the Dutch reference values was assumed to be
by a working group of the Committee on Nutrition.                                 sufficient. This is also the reason why the Committee did not carry out an
                                                                                  update of the literature.
1.1 EFSA’s dietary reference values are used as the point of
       departure                                                                  1.2 EFSA’s reference values are accepted unless there are
The point of departure of this evaluation of the Dutch reference values                 objections
was to adopt EFSA’s dietary reference values5-32 for use in the                   To determine whether there were objections against the use of EFSA’s
Netherlands, unless there were major objections against these values.             reference values in the Netherlands, the Committee identified three key
The Health Council considers that harmonisation of reference values               questions:
across the EU is preferable. Reference values refer to populations
comprising people with a broad range of characteristics, dietary habits and       1. Should EFSA’s reference values be rejected based on a specific
lifestyles, and generally, on this population level, there are no, or only           nutritional context in the Netherlands that differs from (the rest of)
small differences between countries. A differentiation of reference values           Europe?
between European countries will seldom be required for physiological              The nutritional context or policy in the Netherlands may differ from the
reasons. Note that reference values for larger geographical region (e.g. for      European context on which EFSA’s reference values are based, and this
the Scandinavian countries, the German-speaking countries, the United             may require the use of other reference values in the Netherlands. Note
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<pre>chapter 01 | Introduction                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 6 of 179
that EFSA’s dietary reference values were used as the point of departure          values which has been used in the Netherlands since 2014,33 based
for the evaluation, because the Committee anticipated that the nutritional        mainly on the Dutch34-36 and Scandinavian37 reports. Two reports covered
context or policy in the Netherlands would rarely give rise to the rejection      groups of European countries: the Scandinavian countries37 and the
of EFSA’s dietary reference values.                                               German-speaking countries,38 and thus required harmonisation with
                                                                                  several European countries. Two other reports aimed to establish values
2. Do (part of) EFSA’s reference values differ 10% or more from the 2014          for large geographical areas: the IOM reports for the United Stated of
    values for the Netherlands?                                                   America and Canada;2,39-43 and the report by WHO/FAO which is used in
The Committee considered that if EFSA’s reference values were close to            many countries all over the world.44 The latter report is primarily used in
the values currently used in the Netherlands, switching to EFSA’s values          non-Western areas and, therefore, the WHO/FAO reference values may
would have no, or only limited implications, and this would diminish              deviate from the reference values for Western countries.
possible objections against the use of EFSA’s values in the Netherlands.          The Committee considered that objections should be based on scientific
Note that, in these cases, the Committee still describes and evaluates the        evidence. This implies that if there is a lack of scientific evidence on
scientific basis of EFSA’s reference values, so that for all nutrients the        requirements, there is also no evidence to substantiate objections against
report summarizes the evidence on which the reference values are based.           EFSA’s reference values. These reference values were then accepted for
                                                                                  use in the Netherlands, because there is no scientific evidence available
3. Are there objections against the scientific basis used by EFSA for this        to define more evidence-based reference values than EFSA has done.
    specific nutrient?                                                            The advisory report will, however, specify which of the reference values
The Committee evaluated the research and argumentation that EFSA                  for the Netherlands are based on limited knowledge of requirements.
used to establish the reference values for each nutrient; in the report, this
is referred to as the evaluation of the scientific basis of EFSA’s reference      1.3 Evaluation steps taken for each nutrient
values for the nutrient considered. The evaluation was carried out by             Chapters 2 to 28 describe the evaluation of reference values per nutrient.
comparing EFSA’s reference values and their scientific basis5-32 with the         Each chapter starts with a schedule presenting the answers to the three
reference values in five (sets of) reports which were considered most             questions described in paragraph 1.2. Thereafter, the evaluation and
relevant for this evaluation. The first set of reports is the compilation of      argumentation which the Committee used to reach the conclusion is
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<pre>chapter 01 | Introduction                                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 7 of 179
described in more detail, before the conclusion itself is presented. Each of                            Population intake data for the NL were used as background information by
these chapters consists of four paragraphs:                                                             the Committee. If EFSA’s reference value(s) differ from the reference
                                                                                                        value used in the Netherlands since 2014, and are adopted by the
 Paragraph 1     The first paragraph presents a table with the reference values in the EFSA report
                 and in the five (sets of) reports which are used for comparison; the table only
                                                                                                        Committee for use in the Netherlands, this has implications for the
                 comprises the reports with reference values for the nutrient in question. Note         implementation and use of the reference values. For instance, on a
                 that the reports use different names for the different types of reference values
                 (Annex A).                                                                             population level, even if intake levels stay the same, the risk of insufficient
                 The percentual differences between EFSA’s values and the values in the other
                 five (sets of) reports are described.                                                  intakes will appear to increase or decrease, simply as a result of a change
 Paragraph 2     The second paragraph provides an explanation for the observed differences
                                                                                                        of reference values. The National Institute for Public Health and the
                 between the reports regarding the research and argumentation used to establish
                 the reference values. This step provided the Committee with more insight into          Environment (RIVM) described the habitual intake of Dutch adults aged
                 assumptions, uncertainties and points of discussion related to the derivation of
                 the reference values. The Committee describes the information as provided in the       18-50 years, based on the Dutch National Food Consumption Survey
                 reports; the original publications were only consulted if considered necessary.
                 In this second paragraph, the Committee also describes whether organisations
                                                                                                        2007-2010, and compared these intakes with the Dutch reference values
                 differentiated between subgroups according to sex and/or age, and if available,        used from 2014, and with EFSA’s reference values. The results were
                 the argumentation for these choices. This is relevant, because the choices
                 regarding these subgroups are not consistent between the reports and may               available for the Committee during the evaluation of the reference values
                 impact the resulting reference values. If the reports use different expression units
                 for their reference values, this is also described in the second paragraph.            and used as background information. The findings are published by the
 Paragraph 3     The third paragraph describes the Committee’s conclusion on the scientific basis       RIVM simultaneously with the present advisory report.45 Intake data in
                 of EFSA’s reference values for the nutrient considered. In this paragraph the
                 Committee interprets and evaluates the information provided in the second              themselves provide no information on the requirements for a nutrient and,
                 paragraph, and in addition, the information from studies described by EFSA on
                 the direct relationship between the intake of the nutrient and the occurrence,         therefore, these data were not used by the Committee as an argument for
                 correction or prevention of clinical signs of deficiency. The latter studies generally
                                                                                                        accepting or rejecting reference values.
                 do not form the basis of the actual reference values, but do provide relevant
                 background information for interpreting the relevance of the reference values for
                 health.
                 In this third paragraph, the Committee also presents a textbox with background
                 information on the function of the nutrient, the occurrence of deficiencies and the
                 clinical symptoms of insufficient intakes.
 Paragraph 4     The fourth and final paragraph in each chapter presents a summary of the main
                 findings, the conclusion by the Committee and the reference values
                 recommended for use in the Netherlands.
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<pre>chapter 02 | Vitamin A (retinol and carotenes)         An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 8 of 179
02
vitamin A
(retinol and carotenes)
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 9 of 179
                                                 Vitamin A                                                   2.1 Overview and comparison of values
                                                                                                             Table 1. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected
         based on a specific nutritional context in the                                 YES                  values are based
       Netherlands that differs from (the rest of) Europe?
                                                                                                               Report                 PRI/RDA/AI/RI               AR                 CVb          Main criterion
                                                                                                                                      (μg RE or RAEa/day)         (μg/day)           (%)
                                                                                                                                      Type ♂           ♀          ♂       ♀
                                                                                                               EFSA 201516            PRI     750     650         570 490            15%          Factorial approach based on the
                                NO                                                                                                                                                                average intake needed to
                                                                                                                                                                                                  establish adequate liver stores of
                                                                                                                                                                                                  20 μg/g liver tissue.
                                                                                                               NCM 201437             RI      900     700         600 500            25/20%       Factorial approach
      Are there objections against EFSA’s scientific basis                                                     = HCNL 201433                                                                      NCM adopted IOM.
                        for this nutrient?                                                                     DACH 201538            AI      1,000 800           600 600            33/12%c      Not clearly specified.
                                                                                                               IOM 2001    41
                                                                                                                                      RDA     900     700         625 500            20%          Factorial approach based on the
                                                                                                                                                                                                  average intake needed to
                                                                                                                                                                                                  establish adequate liver stores of
                                             YES                                                                                                                                                  20 μg/g liver tissue.
                                                                                                               WHO/FAO                RI      600     19-65       300 19-65          50/23%       Based on values derived for
                                                                                                               200444                                 yr: 500            yr: 270                  prevention of (sub)clinical
                                                                                                                                                      >65 yr:            >65 yr:                  deficiency in late infancy, AR 4.8
                     Do (part of) EFSA's reference values differ 10% or                                                                               600                300                      and RI 9.3μg RE/kg/day (AR/RI
      NO                                                                                YES
                      more from the 2014 values for the Netherlands?                                                                                                                              are supported by additional
                                                                                      PRI ♂                                                                                                       data); WHO/FAO 1988 was
                                                                                                                                                                                                  maintained.
                                                                                                             a
                                                                                                                RE = retinol equivalent; RAE = retinol activity equivalent. The difference is described and discussed in paragraph
                                                     PRI ♀                                                      1.2 under the header “The assumed efficiency of the conversion of carotenes to retinol, or the unit of expression
                                              NO
                                                     ARs                                                        of the reference values: RE versus RAE.”
                                                                                                             b
                                                                                                                If the coefficient of variation was not specified in the report, it was calculated as
                                                                                                                100% x [ ( PRI/RI/RDA - AR ) / 2 ] / AR.
                                                                                                             c
                                                                                                                DACH assumes that the CV of women is lower than the CV of men, considering that their average plasma
           No objections against the use of                   Major objection against the use of                concentration is lower (DACH refers to Heseker et al., 1994).
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                          An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 10 of 179
Table 1 shows that NCM, IOM and especially DACH use higher values               Sex differences
than EFSA’s PRIs (+14%, +14% and +29%), whereas WHO/FAO uses a                  All reports established different values for men and women. This
lower value (-21%).                                                             difference results from the difference in reference body weights between
                                                                                men and women (see Table 2).
2.2 Explanation of differences between reports
This evaluation focuses on the difference between EFSA and IOM,                 The assumed efficiency of the conversion of carotenes to retinol, or
because:                                                                        the unit of expression of the reference values: RE versus RAE
• NCM adopted the IOM approach and values.                                      The reports use different conversion factors for carotenes: EFSA and
• The DACH approach is not clearly specified.                                   DACH express their reference values in retinol equivalents (RE) and thus
• The WHO/FAO-values are based on the extrapolation of estimates for            assume a more efficient conversion of carotenes to retinol in comparison
   infants to adults, which implies more uncertainty compared to methods        to HCNL, NCM, IOM, and WHO/FAO (Table 3). The EFSA Panel notes
   based on estimates in adults.                                                that there are large uncertainties in establishing equivalency ratios from
The ARs of EFSA and IOM were estimated using a factorial method in              the whole diet of large populations. In 1993, the Scientific Committee of
which six estimates (“factors”) are multiplied. Table 2 compares the values     Food used retinol equivalents (RE). The EFSA Panel considers that
of all six factors and presents the evaluation of the differences by the        current evidence is insufficient to support a change.
Committee in the right column.
                                                                                Table 3. Differences between reports regarding the efficiency of the conversion of
                                                                                carotenes to retinol
Differences between older and younger adults                                                                Unit of expression of dietary reference value
EFSA, NCM, DACH and IOM set equal reference values for older and                                            Retinol equivalents    Retinol activity     Other conversion
                                                                                                            (RE)                   equivalents (RAE)    factors
younger adults and WHO/FAO does so for men. WHO/FAO’s value for                  Reports using the          EFSA, DACH             HCNL, NCM, IOM       WHO/FAO
                                                                                 conversion factor
older women (600 μg RE/d) differs from their value for younger women
                                                                                 Amounts equivalent to 1 μg
(500 μg RE/d), but this difference is not explained in the WHO/FAO report.       retinol :
                                                                                 • β-carotene               6 μg = 1 μg RE         12 μg = 1 μg RAE     14 μg = 1 μg RAE
                                                                                 • Other carotenes          12 μg = 1 μg RE        24 μg = 1 μg RAE     28 μg = 1 μg RAE
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 11 of 179
Table 2. Comparison of the factorial approaches of EFSA and IOM
 Factor     Wording used by EFSA for          EFSA’s estimate of this        Wording used by IOM for this         IOM’s estimate of this factor        Evaluation of the difference
            this factor                       factor                         factor
 Factor 1   target liver concentration        20 μg retinol/g liver          minimum acceptable liver reserve     20 μg retinol/g liver                No difference: EFSA and IOM both use the target liver
                                                                                                                                                       concentration suggested by Olson et al. (1987).
 Factor 2   body / liver retinol stores ratio x 1.25             (10:8)      ratio of total body: liver vitamin A x 1.1              (10:9)            EFSA notes that human data are scarce and range between
                                                                             reserves                                                                  1.1 and 2.4 (40-90% of whole body retinol is in the liver).
                                                                                                                                                       EFSA uses 1.25 (80% in the liver), IOM uses 1.11 (90% in
                                                                                                                                                       the liver). IOM’s value represents the lowest point of the
                                                                                                                                                       range of estimates; EFSA also uses a low value, but not the
                                                                                                                                                       lowest. As data are scarce, the Committee prefers EFSA’s
                                                                                                                                                       value.
 Factor 3   liver / body weight ratio         x 0.024            (2.4%)      liver / body weight ratio            x 0.03             (1:33)            The Committee accepts EFSA’s value, because it is based
                                                                                                                                                       on an update of literature.
 Factor 4   fractional catabolic rate of      x 0.007            (0.7% per   percent of body vitamin A stores     x 0.005            (0.5%             The Committee accepts EFSA’s value, because it is based
            retinol                                              day)        lost when ingesting a vitamin                           per day)          on an update of literature.
                                                                             A-free diet
 Factor 5   1 / efficiency of body storage    x2                 (100%/ 50%) 1 / efficiency of storage of         x 2.5              (100%/ 40%)       The Committee prefers EFSA’s over IOM’s interpretation of
            of ingested retinol               Assuming that – with adequate  ingested retinol                     Data from Bangladeshi adults with the publication by Haskell et al. (1997), and therefore
                                              liver stores – 80% of body                                          ≥20 μg retinol/g liver indicate an   accepts EFSA’s value. EFSA corrected Haskell’s estimate by
                                              stores are found in the liver,                                      average efficiency of storage of     for the ratio of total body over liver retinol stores, whereas
                                              EFSA corrects the estimate by                                       ingested retinol of 42% in the liver IOM did not. Note that in this study, RAE-intake was almost
                                              Haskell et al. to 52%                                               (Haskell et al., 1997).              exclusively retinol (dietary RAE intake was low:
                                                                                                                                                       approximately 100 μg RAE/day).
            Product of factors 1-5 x 103      8.4                            Product of factors 1-5 x 103         8.25                                 Multiplication by 103 is needed for the conversion to
                                              ♂                   ♀                                               ♂                   ♀                microgram retinol (activity)equivalents per kilogram
                                                                                                                                                       (instead of per gram) body weight.
 Factor 6   reference body weight (kg)        x 68.1              x 58.5     reference body weight (kg)           x 76                x 61             EFSA’s reference body weights are relatively low for use in
                                                                                                                                                       the Netherlands: on average, Dutch adults are taller than
                                                                                                                                                       European adults.
            Product of factors 1-6 x 103      572                 491        Product of factors 1-6 x 103         627                 503              AR/EAR is calculated by multiplication of the estimates of six
                                                                                                                                                       factors.
 AR         EFSA’s AR                         570                 490        IOM’s EAR                            625                 500              AR/EAR-values are rounded.
            Coefficient of variation (CV)     15%                 15%        Coefficient of variation (CV)        20%                 20%              The Committee has no objections against EFSA’s coefficient
                                                                                                                                                       of variation. The coefficients of variation are based on expert
                                                                                                                                                       judgement rather than scientific research.
            1.3 x AR                          744                 638        1.4 x EAR                            878                 704              PRI is calculated as ( 1 + 2xCV/100 ) x AR/EAR.
 PRI        EFSA’s PRI                        750                 650        IOM’s RDA                            900                 700              PRI/RDA-values are rounded.
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 12 of 179
2.3 Conclusion on the scientific basis of EFSA’s reference                              the case of vitamin A, one study is relevant in this respect: Sauberlich et al.
       values                                                                           (1974) induced visual abnormalities in 8 apparently healthy men by feeding
                                                                                        them a low-retinol diet, and reported that these abnormalities were
The Committee agrees with EFSA’s estimates for five of the six factors of               corrected by a retinol intake of 300 μg retinol per day and that cutaneous
the factorial method (see the right column of Table 2). However, the                    lesions were prevented at an intake of 600 µg/d. The Committee notes that
reference body weights used by EFSA (factor 6) are relatively low for the               the proposed AR for men (615 μg/day) corresponds with the intake level
Netherlands. On average, Dutch adults are taller than European adults.                  reported to be associated with prevention of deficiency symptoms in men,
The factorial method implies that the reference values are proportional to              and thus appears to be relevant for health maintenance.
body weight. Table 4 shows the impact on AR and PRI, using EFSA’s
versus HCNL’s reference weights. The Committee prefers to use EFSA’s                    Table 5. Vitamin A intake levels associated with the occurrence, correction or
                                                                                        prevention of deficiencies, as described by EFSA
method, but to replace EFSA’s reference weights by the reference weights
                                                                                         Clinical manifestation                    Associated intake       Subjects EFSA’s reference
used by HCNL. The resulting values differ only slightly from HCNL 2014                   Abnormalities in adaptation to dark and   Up to 771 days on       8 adult  Sauberlich et al.
                                                                                         in electroretinographic patterns          retinol deficient diets men      Vitamin A
(AR♂ +2.5%, AR♀ +5%, PRI♂ -11%, PRI♀ -3%).                                                                                         (0-23 µg/d)                      metabolism and
                                                                                         Correction of abnormalities in adaptation 300 µg retinol/d                 requirements in the
                                                                                         to dark and in electroretinographic       4-5 µg/kg body                   human studied with
Table 4. Effect of HCNL’s higher reference weights on the average requirements and                                                                                  the use of labelled
                                                                                         patterns                                  weight/d
population reference intake estimates using EFSA’s method                                Prevention of deficiency symptoms such    600 µg retinol/d                 retinol. Vitamins and
                                                                                         as electroretinographic anomalies and                                      Hormones 1974; 32,
                          Reference body     Average requirement  Population reference
                                                                                         changes in the eyes and the skin                                           251-275.
                          weight (kg)        (μg/day)             intake (μg/day)
                          ♂         ♀        ♂          ♀         ♂           ♀
 EFSA                     68.1      58.5     570        490       750         650
 EFSA’s method, but using 73.5      62.5     615        525       800         680       Conclusion regarding the assumed efficiency of the conversion of
 HCNL’s reference
 weights35,36                                                                           carotenes to retinol, or the unit of expression of the reference values:
                                                                                        RE versus RAE
In this paragraph the Committee also compares these proposed ARs with                   IOM and Melse-Boonstra et al.46 report that the results of a substantial
intake levels associated with the occurrence, correction or prevention of               number of studies carried out over the last decade provide support for the
deficiencies, based on studies described in the EFSA report (Table 5). In
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 13 of 179
use of RAE instead of RE as the unit of expression. The Committee                                          2.4 Summary and conclusion
prefers the use of RAE as the unit of expression.
                                                                                                           Table 6. Summary of the evaluation of EFSA’s AR and PRI values for vitamin A
Note that the unit of expression does not influence the outcome of EFSA’s                                    Main findings, used for the conclusion
factorial method leading to the AR, because EFSA’s factorial method                                          Aspect                         Conclusion                Comment
                                                                                                             EFSA’s ARs compared            Slightly lower            Note that, after upward correction of EFSA’s ARs
estimates the retinol requirements: the estimates of factors 1, 2, 4 and 5 in                                to HCNL 2014’s                                           using the higher reference weights of (taller) Dutch
                                                                                                             (=NCM’s) ARsa                                            adults, the corrected ARs are slightly higher than
Table 2 relate mainly or exclusively to retinol (not to carotenes), whereas the                                                                                       HCNL 2014’s (=NCM’s) ARs.
estimates of both remaining factors (factor 3: the liver to body weight ratio;                               EFSA’s PRIs compared Lower, especially in                Note that, after upward correction of EFSA’s PRIs
                                                                                                             to HCNL’s (=NCM’s) RIs men                               using the higher reference weights of (taller) Dutch
and factor 6: reference body weight) are unrelated to retinol or carotenes.                                                                                           adults, the corrected PRI for men is still about 10%
                                                                                                                                                                      lower than HCNL 2014’s (=NCM’s) RI, whereas the
The choice regarding the efficiency of the conversion of carotenes to retinol                                                                                         corrected PRI for women is almost equal to HCNL
                                                                                                                                                                      2014’s (=NCM’s) RI.
is a separate issue, unrelated to the factorial method. Therefore, the
                                                                                                             Scientific basis of            Objections                The Committee has no objections against EFSA’s
outcome of the factorial method can be expressed in μg RAE/day.                                              EFSA’s ARs                                               factorial method, based on sufficient liver stores, but
                                                                                                                                                                      considers that higher reference weights should be
                                                                                                                                                                      used for the Netherlands. Sauberlich et al. (1974)
                                                                                                                                                                      estimated that an intake of 600 μg/day is associated
                                                                                                                                                                      with the prevention of deficiency symptoms in men.
                                                                                                                                                                      The proposed ARs (615 μg/day) is close to this value.
   Background information – a summary of the information provided by the EFSA report –                       EFSA’s AR and PRI are          The Committee             The choice between RE and RAE does not influence
   on the function of the nutrient, the occurrence of clinical deficiency and deficiency                     expressed in retinol           prefers retinol           the outcome of the factorial method. Therefore, the
                                                                                                             equivalents (RE)               activity equivalents      outcome of the factorial method can be expressed in
   symptoms
                                                                                                                                            (RAE)                     μg RAE/day.
   Vitamin A is an essential nutrient as humans do not have the capability for de novo synthesis of          Other findings
   compounds with vitamin A activity. Vitamin A is involved in the visual cycle in the retina and the        Aspect                         Conclusion                Comment
                                                                                                             Differentiation between        Not applied by EFSA Consistent with most of the other reports evaluated.
   systemic maintenance of growth and integrity of cells in body tissues.
                                                                                                             younger and older                                        (Note that WHO/FAO does differentiate for women,
   Vitamin A deficiency occurs in low income countries, specifically India and Bangladesh.
                                                                                                             adults                                                   but not for men).
   Symptoms of vitamin A deficiency involve several functions, such as:                                      Differentiation between        Applied by EFSA           Consistent with the other reports evaluated. The
   •   vision (the most specific clinical consequence is xerophthalmia)                                      men and women                                            differentiation is based on body weights.
   •   immunity                                                                                            a
                                                                                                              HCNL 2014 served as a temporary update of the Dutch reference values which had not been updated in the
   •   reproduction.                                                                                          Netherlands since 1992. HCNL 2014 refers to a compilation of reference values from different reports that use a
                                                                                                              different terminology for the reference values (see Appendix C). The terminology used for the HCNL 2014
   Vitamin A deficiency has also been related to:
                                                                                                              reference values (EAR or AR; RDA or RI or PRI; AI or RI) is determined by the report from which the HCNL 2014
   •   worsening of low iron status, resulting in vitamin A deficiency anaemia                                reference values originate: if this is an HCNL report, the HCNL terminology is used; with values originating from
   •   follicular hyperkeratosis.                                                                             other reports, such as the NCM report for vitamin A, the terminology of that report is used. For vitamin A, the
                                                                                                              terms AR and RI are used for the HCNL 2014 reference values, because these reference values originate from
                                                                                                              the NCM report.
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<pre>chapter 02 | Vitamin A (retinol and carotenes)                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 14 of 179
The Committee agrees largely with EFSA’s factorial method of setting the
reference values, but objects to one of the six factors EFSA used in the
factorial method. Vitamin A is one of the few nutrients for which the
method of establishing the reference values implies a proportional effect
of the reference weights on the reference values. The Committee
considers that higher reference weights should be used for the
Netherlands, because Dutch adults are relatively tall. The resulting values
are presented in Table 7.
The retinol supply to the body is established not only by the intake of
retinol, but also by the intake of carotenes which are converted to retinol in
the body. The Committee does not support EFSA’s choice regarding the
conversion factors for carotenes (EFSA expresses the reference values as
retinol equivalents) but recommends expressing the reference values as
retinol activity equivalents instead.
Table 7. AR and PRI for vitamin A, recommended for the Netherlands
                                      Men >18 years       Women >18 years
 Average requirement (AR) using       615 μg RAE/day      525 μg RAE/day
 EFSA’s factorial method but applying
 HCNL’s reference weights
 Population reference intake (PRI)    800 μg RAE/day      680 μg RAE/day
 using EFSA’s factorial method but
 applying HCNL’s reference weights
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<pre>chapter 03 | Thiamin (vitamin B1)                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 15 of 179
03
thiamin (vitamin B1)
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<pre>chapter 03 | Thiamin (vitamin B1)                                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 16 of 179
                                                  Thiamin                                                     3.1 Overview and comparison of values
                                                                                                              Table 8 presents an overview of reference values and criteria.
         Should EFSA's reference values be rejected
                                                                                                              EFSA and NCM express the reference values in mg/MJ, whereas HCNL,
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?                                                    DACH, IOM and WHO/FAO express the reference values in mg/day.
                                                                                                              NCM’s RI in mg/MJ is 20% higher than EFSA’s PRI; NCM’s AR is 40%
                                                                                                              higher than EFSA’s AR. Note that NCM uses values in mg/MJ as the
                                NO                                                                            starting point, but present values in mg/day in their summarising table.
                                                                                                              A comparison of EFSA with HCNL, DACH, IOM and WHO/FAO is only
                                                                                                              possible after conversion of EFSA’s values to mg/d (EFSA presents values
      Are there objections against EFSA’s scientific basis
                        for this nutrient?                                                                    in mg/d for four age groups and four physical activity levels in an annexa).
                                                                                                              For men, the RI/RDA-values by DACH, IOM and WHO/FAO equal the
                                                                                                              average of EFSA’s PRI-values converted to mg/day; HCNL’s RDA is 8%
                                             YES
                                                                                                              lower and NCM’s RI is 17% higher. For women, the RDA/RI-values by
                                                                                                              HCNL, NCM, IOM and WHO/FAO are 18% higher and the value by DACH
      NO
                     Do (part of) EFSA's reference values differ 10% or
                                                                                        YES                   is 10% higher than the average of EFSA’s PRI-values converted to mg/
                      more from the 2014 values for the Netherlands?
                                                                                                              day.
                                              NO
           No objections against the use of                   Major objection against the use of
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands         a
                                                                                                                In EFSA’s appendix, values in mg/d are presented for the age groups 18-29, 30-39, 40-49 and 50-59 years for
                                                                                                                four different physical activity levels (PALs). The average of these values are used for the comparison with HCNL,
                                                                                                                IOM and WHO/FAO. At a PAL value of 1.4, the recommended intakes in the four age groups ranged between
                                                                                                                0.9-1.0 mg/d (♂) and 0.8 mg/d (♀), at a PAL-value of 1.6 these ranges were 1.1 mg/d (♂) and  0.9 mg/d (♀), at a
                                                                                                                PAL-value of 1.8 these ranges were 1.2-1.3 mg/d (♂) and  1.0 mg/d (♀), and at a PAL-value of 2.0 these ranges
                                                                                                                were 1.3-1.4 mg/d (♂) and  1.1 mg/d (♀). The values averaged over age groups and PAL-levels were 1.2 mg/day
                                                                                                                for men and 0.9 mg/day for women.
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<pre>chapter 03 | Thiamin (vitamin B1)                                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 17 of 179
Table 8. Overview of the reference values for adults and the criteria on which these values are based
  Report                         PRI/RAD/AI/RI                                                                    AR                                              CV              Main criterion
                                 Type            mg/MJ              mg/day                                        mg/MJ                 mg/d                      (%)
  EFSA 2016    9
                                PRI              0.1                (♂ 1.2)                                       0.072                 (♂ 0.9)                   20%             AR is based on data from depletion-repletion studies
                                                                    (♀ 0.9)                                                             (♀ 0.6)                                   showing that 0.072 mg/MJ is associated with:a
                                                                                                                                                                                  • αETKb <1.15
                                                                                                                                                                                  • low urinary thiamin excretion
                                                                                                                                                                                  • ~0.09 mg/24h
                                                                                                                                                                                  • restoration of baseline ETKAc.
  HCNL 200036                   RDA              (♂ 0.10-0.11)      1.1                                           (♂ 0.07-0.08.2)       0.8                       20%             AR is based on:
  = HCNL 201433                                  (♀ 0.13)                                                         (♀ 0.9)                                                         • urinary thiamin excretion
                                                                                                                                                                                  • αETK and ETKA.
  NCM 201437                    RI               0.12               Age d           ♂            ♀                0.1                   ♂e 1.2    ♀ 0.9           10% 6           Criteria are not clear. NCM refers to NCM 2004, WHO/
                                                                    18-30 yr        1.4          1.1                                                                              FAO 2004, DACH 2015; IOM 1998 and Sauberlich
                                                                    31-60 yr        1.3          1.1                                                                              1979.
                                                                    >61 yr          1.2          1.0
  DACH 201538                   RDA              (0.13)             19-24 yr        1.3          1.0              0.11                                            10%             AR is based on adequate urinary thiamin excretion.
                                                                    25-50 yr        1.2          1.0
                                                                    51-64 yr        1.2          1.0
                                                                    > 65 yr         1.1          1.0
  IOM 199842                    RDA                                 ♂1.2                                          (0.07)                ♂1.0                      10%             AR is based on:
                                                                    ♀1.1                                                                ♀0.9                                      • low urinary thiamin excretion
                                                                                                                                                                                  • αETK and ETKA
  WHO/FAO 200444                AI                                  ♂1.2                                                                                                          Criteria are not clear. At least partly based on
                                                                    ♀1.1                                                                                                          Sauberlich et al., 1979.
a
   EFSA notes that, in comparison to 0.072 mg/MJ, an intake of >0.14 mg/MJ was associated with a sharp increase in urinary thiamin excretion and only slight changes in transketolase activity, indicating tissue saturation.
b
   The erythrocyte transketolase activity coefficient (αETK) is a functional marker of thiamin status. It represents the degree to which ETKA rises in response to addition of thiamin diphosphate (TDP). αETK can discriminate low ETKA due
   to thiamin deficiency from low ETKA due to a lack of the apoenzyme. A value of αETK <1.15 is generally considered to reflect an adequate thiamin status.
c
   The erythrocyte transketolase activity (ETKA) is a functional marker of thiamin status. It represents the basal value of the enzyme erythrocyte transketolase, without stimulation by thiamin diphosphate (TDP).
d
   NCM presents these RI-values per age group in Table 1.3 of their report, not in the summarising table at the beginning of their Chapter 19 on thiamin.
e
   NCM presents these AR-values (age group not specified) in the summarising table at the beginning of their Chapter 19 on thiamin.
f
   CV calculated as 100% x [ ( PRI/RI/RDA - AR ) / 2 ] / AR.
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<pre>chapter 03 | Thiamin (vitamin B1)                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 18 of 179
3.2 Explanation of differences between reports                                 urinary thiamin excretion. Note that DACH uses a higher average
                                                                               requirement in mg/MJ because their value is based on adequate instead
Difference in the unit of expression (mg/MJ versus mg/day)                     of low urinary excretion. EFSA also refers to the depletion-repletion study
EFSA expresses the reference values in mg/MJ instead of mg/day which           by Kraut et al. (1966; n=6) and to publications providing supporting
is consistent with NCM. Although HCNL, DACH, IOM and WHO/FAO                   evidence.
express the reference values in mg/day, they derive the reference values       Note that EFSA and HCNL use a coefficient of variation of 20% to
from estimates in mg/MJ. Therefore, the Committee agrees with EFSA’s           calculate PRI/RDA from AR, whereas DACH and IOM use a coefficient of
use of mg/MJ as the unit of expression.                                        variation of 10%.
Note that for the conversion of requirements in mg/MJ to mg/d, EFSA (in
appendices) and DACH used average energy requirements, whereas                 Differences between older and younger adults
HCNL used average energy intake. IOM does not specify whether they             EFSA and NCM use one value in mg/MJ for all groups. Because of the
used energy intake or energy requirement.                                      lower energy intake/requirement of older compared to younger adults,
The Committee concludes that the reference value in mg per MJ refers to        values converted to mg/day are lower for older than for younger adults.
energy intake rather than energy requirement, because the unit of              DACH also distinguished between age groups, with lower reference
expression is mainly based on the positive relationship between thiamin        values in mg/day for older compared to younger adults. The reference
requirement and energy intake in the controlled experiment by Sauberlich       values set by HCNL, IOM and WHO/FAO do not differ between older and
et al. (1979), who studied intake levels from 0.003 to >0.14 mg/MJ.            younger adults.
This evaluation focuses only on EFSA, HCNL, DACH and IOM, because:             Sex differences
• The NCM-criteria are unclear.                                                EFSA, NCM, DACH and IOM assume that the thiamin requirement in mg/
• The WHO/FAO-criteria are unclear.                                            MJ is equal for all groups. As a result, values converted to mg/day differ
The reports by EFSA, HCNL, DACH and IOM are all based primarily on             between men and women according to the differences in energy
the depletion-repletion study by Sauberlich et al. (1979; n=7) with criteria   requirement. HCNL assumed that the thiamin requirement in mg/MJ is
based on achieving an adequate status (αETK and ETKA) at low levels of         higher for women (0.09 mg/MJ) than for men (0.07-0.08 mg/MJ), with the
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<pre>chapter 03 | Thiamin (vitamin B1)                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 19 of 179
result that reference values expressed in mg/day are equal for women and
men. The issue of whether or not to differentiate the requirement in mg/MJ       Background information – a summary of the information provided by the EFSA report –
between men and women is not explicitly discussed by EFSA.                       on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                 symptoms in adults
                                                                                 Free thiamin functions as the precursor for TDP, which acts as a coenzyme for enzymes
3.3 Conclusion on the scientific basis of EFSA’s reference                       involved in carbohydrate and branched-chain amino acid metabolism, and in energy-yielding
       values                                                                    reactions.
                                                                                 Thiamin deficiency occurs in populations with:
The Committee agrees with EFSA’s derivation of the AR and PRI, which is
                                                                                 •   diets low in thiamin (diets mainly consisting of milled white cereals, e.g. polished rice, white
largely in line with the reports by HCNL and IOM.                                    wheat flour)
                                                                                 •   diets rich in thiaminase (thiaminase is abundant in some raw or fermented fish, ferns and
Table 9 shows that clinical signs of deficiency have been induced by
                                                                                     insects).
feeding apparently healthy subjects a low-thiamin diet with intakes up to        In Western countries, it occurs in specific risk groups:
                                                                                 •   alcoholism
0.05 mg/MJ, and that in one study this intake level of 0.05 mg/MJ was
                                                                                 •   drug abuse
associated with the correction of unspecific symptoms of deficiency. The         •   after bariatric surgery or gastrectomy
                                                                                 •   chronic gastrointestinal and liver disorders.
Committee notes that EFSA’s AR provides a margin above this intake
                                                                                 Symptoms include:
level.                                                                           •   beriberi, with mostly neurological and cardiovascular manifestations
                                                                                 •   peripheral neuritis
The Committee has no objections against the scientific basis used by
                                                                                 •   cardiac insufficiency
EFSA to derive the AR.                                                           •   tendency for oedemas
                                                                                 which may be accompanied by:
                                                                                 •   extreme fatigue
                                                                                 •   irritability
                                                                                 •   forgetfulness, poor coordination
                                                                                 •   gastrointestinal disturbances, constipation,
                                                                                 •   laboured breathing
                                                                                 •   loss of appetite and weight loss.
                                                                                 Thiamin deficiency also can lead to:
                                                                                 •   Wernicke’s encephalopathy (ocular abnormalities, ataxia, disturbances of consciousness)
                                                                                 •   Korsakoff’s syndrome (psychosis) resulting in amnesia, disorientation and often
                                                                                     confabulation.
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<pre>chapter 03 | Thiamin (vitamin B1)                                                          An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 20 of 179
Table 9. Thiamin intake levels associated with the occurrence or correction of                     3.4 Summary and conclusion
deficiencies, as described by EFSA
 Clinical manifestation associated     Associated intake         Subjects/     EFSA’s              Table 10. Summary of the evaluation of EFSA’s AR and PRI values for thiamin
 with deficiency                                                 Specific      reference
                                                                                                    Main findings, used for the conclusion
 Unspecific subjective symptoms        After 30 days intake of   5 out of 8    Ziporin et al.,
                                                                                                    Aspect              Conclusion                  Comment
 (e.g. general malaise, headache,      0.110-0.180 mg/day        healthy young 1965a,b
                                                                                                    EFSA’s ARs          Not applicable, because     Using the average of EFSA’s values converted to
 nausea) and physical symptoms         (0.009-0.015 mg/MJ).      men (age not
                                                                                                    compared to         EFSA uses a different       mg/day (appendix in EFSA’s report), EFSA’s ARs
 (sinus tachycardia at rest,           Symptoms disappeared      specified)
                                                                                                    HCNL’s EARs         expression unit (mg/MJ)     appear to differ little from HCNL’s EARs.
 diminution of muscle strength and     after 12 days repletion
                                                                                                                        than HCNL
 tendon reflexes)                      with 0.540-0.610 mg/day
                                       (0.046-0.052 mg/MJ).                                         EFSA’s PRIs         Not applicable, because     Using the average of EFSA’s values converted to
                                                                                                    compared to         EFSA uses a different       mg/day (appendix in EFSA’s report), EFSA’s PRIs
 Deficiency symptoms in relation to a 0.05 mg/MJ (0.5 mg/day     Not specified Williams et al.,
                                                                                                    HCNL’s RDAs         expression unit (mg/MJ)     appear to differ little from HCNL’s RDAs.
 thiamin intake                        for women and 0.6 mg/                   1942; Foltz et al.,
                                                                                                                        than HCNL
                                       day for men) for 2-8                    1944; Wood et
                                       weeks.                                  al., 1980            Scientific basis of No objections               EFSA uses the same biochemical parameters of
                                                                                                    EFSA’s AR                                       function and status as HCNL and IOM. Clinical
 Anorexia and a marked impairment      0.042 mg/MJ               2 healthy     Williams et al.,
                                                                                                                                                    signs of deficiency were reported at intakes up to
 of mental and physical health                                   subjects      1942
                                                                                                                                                    0.05 mg/MJ. EFSA’s AR (0.072 mg/MJ) provides
 Clinical symptoms suggestive of       0.052 mg/MJ               2 healthy     Williams et al.,
                                                                                                                                                    a margin above this level. Although most of the
 thiamin deficiency                                              subjects      1943
                                                                                                                                                    other evaluated reports express the reference
 An impairment of metabolism of a      Long-term intake of 0.045 Not specified Horwitt et al.,                                                      values in mg/day, these values are consistently
 glucose test dose after 30 months     mg/MJ                                   1948; Horwitt and                                                    based on estimates in mg/MJ.
 without specific signs of deficiency,                                         Kreisler, 1949
                                                                                                    Other findings
 associated with a decline in urinary
                                                                                                    Aspect              Conclusion                  Comment
 excretion of thiamin down to 0.015
 mg/day after 20 months                                                                             Differentiation     Not applied by EFSA         The values expressed in or converted to mg/d by
                                                                                                    between younger     (but EFSA’s reference value EFSA, NCM and DACH are lower in older
                                                                                                    and older adults    is in mg/MJ)                compared to younger adults.
                                                                                                                                                    HCNL, IOM and WHO/FAO do not differentiate
                                                                                                                                                    between younger and older adults.
                                                                                                    Differentiation     Not applied by EFSA         The values expressed in or converted to mg/d by
                                                                                                    between men and     (but EFSA’s reference value EFSA, NCM, DACH, IOM and WHO/FAO are
                                                                                                    women               is in mg/MJ)                lower for women than for men.
                                                                                                                                                    HCNL 2014 used the same value in mg/day for
                                                                                                                                                    women and men.
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<pre>chapter 03 | Thiamin (vitamin B1)                                          An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 21 of 179
The Committee has no objections against the scientific basis of EFSA’s
reference values, or EFSA’s PRIs and ARs and recommends accepting
these values (Table 11) in the Netherlands.
Table 11. AR and PRI for thiamin, recommended for the Netherlands
                                             Men and women >18 years
 Average requirement (AR)                    0.072 mg per MJ energy intake
 Population reference intake (PRI)           0.1 mg per MJ energy intake
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<pre>chapter 04 | Riboflavin (vitamin B2)                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 22 of 179
04
riboflavin (vitamin B2)
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<pre>chapter 04 | Riboflavin (vitamin B2)                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 23 of 179
                                                 Riboflavin                                                    4.1 Overview and comparison of values
                                                                                                               Table 12. Overview of the reference values for adults and the criteria on which these
          Should EFSA's reference values be rejected                                                           values are based.
          based on a specific nutritional context in the                                 YES
        Netherlands that differs from (the rest of) Europe?                                                     Report       PRI/RDA/AI/RI (mg/d)      AR (mg/d) CV Main criterion
                                                                                                                             Type  ♂              ♀    ♂    ♀      (%)
                                                                                                                EFSA 20177,a
                                                                                                                             PRI   1.6            1.6  1.3  1.3    10  Status and function parameters:
                                                                                                                                                                       the intake at which urinary
                                                                                                                                                                       riboflavin sharply increases (the
                                 NO
                                                                                                                                                                       riboflavin intake associated with
                                                                                                                                                                       the inflection point in the urinary
                                                                                                                                                                       riboflavin excretion curve); in line
                                                                                                                                                                       with EGRAC1 <1.3.
       Are there objections against EFSA’s scientific basis                                                     HCNL 200036  RDA   1.5            1.1  1.1  0.8    18c Status and function parameters:
                         for this nutrient?                                                                     = HCNL                                                 urinary riboflavin, intake at which it
                                                                                                                201433                                                 sharply increases, and EGRAC
                                                                                                                                                                       <1.3.
                                                                                                                NCM 201437   RI    18-30 yr  1.6d 1.3  1.4e 1.1        The values in NCM’s previous
                                              YES                                                                                  31-60 yr  1.5  1.2                  (2004) report: AR = 0.12 mg/MJ
                                                                                                                                   61-74 yr  1.4  1.2                  and RI = 0.14 mg/MJ (CV 10%)
                                                                                                                                   >75 yr    1.3  1.2                  are maintained and applied to both
                                                                                                                                                                       children and adults. The values are
                      Do (part of) EFSA's reference values differ 10% or                                                                                               based on older studies in which
       NO                                                                                YES
                       more from the 2014 values for the Netherlands?                                                                                                  riboflavin status was assessed
                                                                                       PRI ♀                                                                           using primarily urinary excretion of
                                                                                        ARs
                                                                                                                                                                       riboflavin and to a lesser extent
                                                                                                                                                                       using the EGRAC (NCM mentions
                                                                                                                                                                       two ranges of cut-off values for
                                               NO     PRI ♂
                                                                                                                                                                       EGRAC:1.2-1.25 and 1.3-1.4).
                                                                                                                DACH 201538  RI    19-50 yr 1.4   1.1  1.1  0.9    10  AR = 0.12 mg/MJ and RI = 0.14
                                                                                                                                   >51 yr    1.3  1.0                  mg/MJ, based on EGRAC<1.2
                                                                                                                                                                       and/or 24u urinary riboflavin
            No objections against the use of                   Major objection against the use of                                                                      excretion >120 μg/day.
      EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands
                                                                                                                                                                       (Marginal deficiency: EGRAC
                                                                                                                                                                       1.2-1.4 and/or 24u urinary
                                                                                                                                                                       excretion 40-119 μg/day.
                                                                                                                                                                       Deficiency: EGRAC >1.4 and/or
                                                                                                                                                                       24u urinary excretion <40 μg/day).
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<pre>chapter 04 | Riboflavin (vitamin B2)                                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 24 of 179
  Report            PRI/RDA/AI/RI (mg/d)                   AR (mg/d) CV Main criterion
                                                                          (%)
                                                                                                                       the relationship between riboflavin and energy requirements, whereas
                    Type      ♂                    ♀       ♂    ♀
  IOM 199842        RDA       1.3                 1.1     1.1   0.9       10    Function parameter: requirement        EFSA’s values are not.
                                                                                at normal EGRAC level (normal
                                                                                varied between studies, with           NCM and DACH base their reference values on requirements in mg/MJ,
                                                                                cut-off values ranging between 1.2
                                                                                                                       resulting in lower reference values for older versus younger adults and for
                                                                                and 1.4).
  WHO/FAO           RI        1.3                 1.1                           Status parameters: tissue              women versus men. HCNL and IOM base the difference between their
  200444                                                                        saturation & urinary excretion.
                                                                                                                       values for men and women on the relationship of riboflavin to energy
a
   EFSA uses ‘total riboflavin’ for the sum of three dietary components (free riboflavin, and both biologically active
   derivates FMN and FAD). ‘Free riboflavin’ refers only to the first of these components.                             requirements.
b
   EGRAC = Erythrocyte Glutathione Reductase Activation Coefficient: the ratio of the activity of Erythrocyte
   Glutathione Reductase, measured in-vitro with, and without, addition of the cofactor flavin adenine dinucleotide    In contrast to the reports used for comparison, EFSA uses the same value
   (FAD).
c
   CV not presented by HCNL, but calculated as 100% x [ ( PRI/RI/RDA - AR ) / 2 ] / AR.                                (mg/day) for men and women and for younger and older adults. The EFSA
d
   NCM presents these RI-values in mg/d per age group in Table 1.3 of their report.
e
   NCM presents the AR-values in mg/d in the summarising table at the start of Chapter 20 on riboflavin.               Panel does note that several (but not all) studies indicate that an increase
                                                                                                                       of physical activity appears to lower the riboflavin status (EGRAC
Table 12 presents an overview of reference values and criteria.                                                        increases and/or the urinary excretion of riboflavin decreases), suggesting
Almost all RI/RDA-values for men in the evaluated reports are between                                                  a higher riboflavin requirement with increased energy expenditure.
6% and 19% lower than EFSA’s PRI for men. The one exception is NCM’s                                                   However, because of several limitations in these studies,a the EFSA Panel
RI for young (18-30 years) adult men, which equals EFSA’s PRI for men.                                                 notes that there is a lack of experimental data showing a clear quantitative
All RI/RDA-values for women in the evaluated reports are between 19%                                                   relationship between riboflavin status biomarkers (urinary excretion of
and 31% lower than EFSA’s PRI for women.                                                                               riboflavin and EGRAC) and energy expenditure (or physical activity).
                                                                                                                       EFSA based their AR (1.3 mg/day) on four studies estimating the mean
4.2 Explanation of differences between reports                                                                         riboflavin intakes associated with the inflection pointsb in the urinary excretion
The reports base their ARs for riboflavin on the same biochemical
parameters of status (urinary riboflavin excretion) and function (EGRAC).                                              a
                                                                                                                         Only one of these studies reported TEE in a small number of subjects over a very wide range (8.3-19.6 MJ/day)
                                                                                                                         although mean TEE did not differ during the different experimental periods in which riboflavin intake was
All reports present the reference values in the unit mg/day. However, the                                                changed. The EFSA Panel considers this a strong limitation. The Panel also notes the lack of information on the
                                                                                                                         method of measurement of riboflavin intake in some of the studies, the particular aim of some of the studies (i.e.
values in the reports used for comparison are (at least partly) based on
                                                                                                                         weight management studies in overweight or obese women), their short duration or small sample size, and the
                                                                                                                         high variability in the characteristics of the subjects (e.g. large range of BMIs).
                                                                                                                       b
                                                                                                                         Inflection point: the riboflavin intake level at which urinary riboflavin rises sharply.
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<pre>chapter 04 | Riboflavin (vitamin B2)                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 25 of 179
curves. In these studies, the differences between the estimates for men and     compared to younger adults, based on the lower energy requirement of
women, as well as the differences between the estimates for younger and         older adults (NCM and DACH base their values on a riboflavin
older adults were small and there was overlap between the ranges:               requirement of 0.12 mg/MJ).
• two studies in men, one in 66 men and another in 73 men (estimated
   inflection points were at riboflavin intakes of 1.3 mg/d, range 1.1-1.6;     Sex differences
   Horwitt et al., 1950) and 1.4 mg/d, range 1.3-1.5; Guo et al., 2016),        As explained earlier in this paragraph, EFSA concluded that the available
• one study in 4 older men and 10 older women (estimated inflection             evidence did not support a difference according to sex, based on the
   points were at riboflavin intakes of 1.1 mg/d, range 1.1-1.3; Boisvert       observation that estimates from two larger studies in men (Horwitt 1950,
   et al.,1993), and                                                            n=66, Guo 2016, n=73) were similar to the estimate from one small study
• one study in 14 younger women (estimated inflection points were at            in women (Brewer 1946, n=14).
   riboflavin intakes between 1.3 and 1.5 mg/d, range 1.3-1.6; Brewer           The reports used for comparison have set lower reference values for
   et al., 1946).                                                               women compared to men.
EFSA calculated the AR for adults from the mean riboflavin intakes              HCNL, NCM, DACH and IOM based the difference between their values
associated with the inflection points, weighted for the number of subjects      for men and women solely on the assumed relationship between riboflavin
in each study. EFSA considered that information on the variability in the       and energy requirements.
requirement was absent, but the potential effect of physical activity and of
MTHFR 677TT genotype on riboflavin requirement was covered by the               4.3 Conclusion on the scientific basis of EFSA’s reference
data in the four studies. Therefore, a CV of 10% was assumed to be                    values
sufficient, resulting in a PRI of 1.6 mg/day.                                   The scientific basis of EFSA’s reference values is described in paragraph
                                                                                4.2. EFSA furthermore reports that, based on several studies, clinical
Differences between older and younger adults                                    signs of deficiency appear to occur at intakes up to 0.6 mg/d, whereas no
EFSA, HCNL, IOM and WHO/FAO use the same reference values in mg/                deficiency has been reported at intakes within the range of 0.8-1.1 mg/day
day for younger and older adults, and appear to agree that the available        (Table 13). The Committee notes that the EFSA’s AR for adults (1.3 mg/
research indicates that, at older age, the riboflavin requirement is not        day) provides a margin above this intake level. The Committee has no
lower than at younger age. NCM and DACH set lower values for older              objections against the scientific basis of EFSA’s reference values.
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<pre>chapter 04 | Riboflavin (vitamin B2)                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 26 of 179
Table 13. Riboflavin intake levels associated with the occurrence, correction or                              4.4 Summary and conclusion
prevention of deficiencies, as described by EFSA
 Clinical manifestation         Associated intake     Subjects/        EFSA’s reference                       Table 14. Summary of the evaluation of EFSA’s AR and PRI values for riboflavin
 associated with                                      specific                                                 Main findings, used for the conclusion
 deficiency                                           group
                                                                                                               Aspect                          Conclusion     Comment
 Signs of deficiency (not       <0.5-0.6 mg/day       Men and          Sebrell et al., 1941; Williams et al.,
                                                                                                               EFSA’s ARs compared to          Higher         EFSA’s AR compared to HCNL’s EAR is 20%
 specified by EFSA)             several months        women            1943; Keys et al., 1944;
                                                                                                               HCNL’s EARs                                    higher for men and 60% higher for women.
 Skin lesions                   0.55 mg/day           3 adult men      Horwitt et al., 1950
                                                                                                               EFSA’s PRIs compared to         Higher,        EFSA’s PRI compared to HCNL’s RDA is 5% higher
 No signs of deficiency         0.8 mg/day            Not specified    Sebrell et al., 1941; Williams et al.,  HCNL’s RDAs                     especially in  for men and 45% higher for women.
                                                                       1943; Keys et al., 1944; Horwitt et                                     women
                                                                       al., 1950; Bamji 1969
                                                                                                               Scientific basis of EFSA’s AR   No objections  All reports use EGRAC (cut-off values vary
 No signs of deficiency         1.0-1.1 mg/day for 6 Chinese men       Guo et al., 2016                                                                       between 1.2 and 1.4) and/or 24-hour urinary
                                weeks (control        (18-22 yr)                                                                                              riboflavin excretion. EFSA’s AR (1.3 mg/d) provides
                                group)                                                                                                                        a margin above the intake associated with
                                                                                                                                                              deficiency (0.6 mg/day).
                                                                                                               Other findings
    Background information – a summary of the information provided by the EFSA report –                        Aspect                          Conclusion     Comment
    on the function of the nutrient, the occurrence of clinical deficiency and deficiency                      Differentiation between         Not applied by Consistent with most of the reports used for
    symptoms in adults                                                                                         younger and older adults        EFSA           comparison.
                                                                                                               Differentiation between men     Not applied by Not consistent with the reports used for
    Riboflavin is the integral part of the coenzymes FAD and FMN that act as the cofactors of                  and women                       EFSA           comparison, which all differentiate between men
    flavoprotein enzymes involved in a variety of reactions. FAD and FMN act as proton carriers in                                                            and women.
    redox reactions involved in energy metabolism, metabolic pathways and the formation of some
    vitamins and coenzymes. In particular, riboflavin is involved in the metabolism of niacin and
    vitamin B6.
                                                                                                              The Committee has no objections against the scientific basis of EFSA’s
    Riboflavin deficiency has been reported in populations from both developed and developing                 reference values, or EFSA’s AR and PRI and recommends accepting
    countries, and is most often accompanied by other nutrient deficiencies.
    Symptoms are unspecific, take several months to develop and are unreliable to assess
                                                                                                              these values (Table 15) in the Netherlands.
    adequacy or inadequacy. They include, e.g.:
    •   sore throat                                                                                           Table 15. AR and PRI for riboflavin, recommended for the Netherlands
    •   hyperaemia
                                                                                                                                                                     Men and women >18 years
    •   oedema of the pharyngeal and oral mucous membranes
                                                                                                               Average requirement (AR) in mg/d                      1.3 mg/d
    •   cheilosis
                                                                                                               Population reference intake (PRI) in mg/d             1.6 mg/d
    •   glossitis (magenta tongue)
    •   seborrhoeic dermatitis, skin lesions including angular stomatitis
    •   normochromic normocytic anaemia characterised by erythroid hypoplasia and
        reticulocytopenia.
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<pre>chapter 05 | Niacin (vitamin B3)                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 27 of 179
05
niacin (vitamin B3)
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<pre>chapter 05 | Niacin (vitamin B3)                                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 28 of 179
                                                     Niacin                                                    5.1 Overview and comparison of values
          Should EFSA's reference values be rejected
                                                                                                               Table 16 presents an overview of reference values and criteria.
          based on a specific nutritional context in the                                 YES
        Netherlands that differs from (the rest of) Europe?                                                    EFSA, NCM and DACH express the reference values in mg NE/MJ,a
                                                                                                               whereas HCNL, IOM and WHO/FAO express the reference values in mg
                                                                                                               NE/day.
                                 NO                                                                            EFSA, NCM and DACH use the same PRI/RDA/AI/RI (1.6 mg/MJ) and the
                                                                                                               same AR (1.3 mg/MJ). NCM and DACH (but not EFSA) add that, at lower
                                                                                                               energy intakes, the PRI/RDA/AI/RI is 13 mg NE per day.
       Are there objections against EFSA’s scientific basis
                         for this nutrient?                                                                    Only after conversion of EFSA’s values to mg/d (which EFSA presents in
                                                                                                               an appendix), is a comparison with HCNL, IOM and WHO/FAO possible.
                                                                                                               For this comparison, the average of EFSA’s converted PRI-values is
                                              YES
                                                                                                               used.b The RDAs/RIs of HCNL, IOM and WHO/FAO appear to differ little
                                                                                                               from the average of EFSA’s converted PRI-values. HCNL’s RDAs are 6%
       NO
                      Do (part of) EFSA's reference values differ 10% or
                                                                                         YES                   (♂) and 7% (♀) lower; the RDAs/RIs by IOM and WHO/FAO are 11%
                       more from the 2014 values for the Netherlands?
                                                                                                               lower than (♂) and equal to (♀) EFSA’s average value in mg/d.
                                               NO
            No objections against the use of                   Major objection against the use of
      EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands         a
                                                                                                                 NCM and DACH also present reference values in milligrams per day based on one level of energy intake.
                                                                                                               b
                                                                                                                 In EFSA’s appendix, values in mg/d are presented for different age groups and four different PAL-values. The
                                                                                                                 average of these values are used for the comparison with HCNL, IOM and WHO/FAO. At a PAL value of 1.4,
                                                                                                                 EFSA´s values averaged over the four age groups were 15 mg/d (♂) and 12 mg/d (♀), at a PAL-value of 1.6 the
                                                                                                                 averages were 17 mg/d (♂) and 14 mg/d (♀), at a PAL-value of 1.8 the averages were 19 mg/d (♂) and 15 mg/d
                                                                                                                 (♀), and at a PAL-value of 2.0 the averages were 21 mg/d (♂) and 17 mg/d (♀). The values averaged over age
                                                                                                                 groups and PAL-levels were 18 mg/day for men and 14 mg/day for women.
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<pre>chapter 05 | Niacin (vitamin B3)                                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 29 of 179
Table 16. Overview of the reference values for adults and the criteria on which these values are based; values in bold are reference values presented in the reports, values in
italics are calculated by the committee to enable a comparison to be made between reports
  Report                    PRI/RDA/AI/RI                                                          AR                                            CV (%)        Main criterion
                            Type     mg NE/MJ          mg NE/day                                   mg NE/MJ         mg NE/day
                                                       Age range              ♂      ♀                              ♂              ♀
  EFSA 2014   24
                            PRI      1.6               (averaged 1            ~18 ~14)             1.3                                           10%           Preformed niacin or tryptophan2 required to restore “normal”
                                                                                                                                                               urinary excretion of NMN and 2-Pyr.3
  HCNL 200036 =             RDA                                               17     13                            12              9             ~20% 4        Urinary excretion of NMN > 1.0 mg/d.
  HCNL 201433
  NCM 201437                RI       1.65              NCM Chapter 22:        18     15            1.3             15              12            ~10%c         Urinary excretion of niacin metabolites.
                                                       NCM Table 1.3:                                                                                          In absence of new data, NCM 2004 value of 1.6 NE/MJ is
                                                       18-30 yr               19     15                                                                        maintained.
                                                       31-60 yr               18     14
                                                       61-74 yr               16     13
                                                       >75 yr                 15     13
  DACH 201538               RDA      1.6               19-24 yr               16     13            1.3                                           10%           DACH adopted the value used by EFSA 2014, NCM 2014, UK
                                                       25-50 yr               15     12                                                                        2009 and WHO/FAO 2004. Values in mg/d are achieved using
                                                       51-50 yr               15     11                                                                        the average energy requirements at a PAL-value of 1.4.
                                                       >65 yr                 14     11
  IOM 200141                RDA                                               16     14                            12              11            15%           Urinary NMN excretion > 1.0 mg/d (no pellagra signs; the
                                                                                                                                                               metabolites are not excreted until requirement is met).
  WHO/FAO 200444            AI                         ♂ 16; ♀ 14                                                                                              Not explicitly described.
a
   Averages for the 4 age groups between 18 and 50 years and 4 Physical Activity Levels (PAL-values) which EFSA presents in an appendix.
b
   Niacin can be synthesised in the human body from the indispensable amino acid tryptophan. Approximately 60 mg of tryptophan yields 1 mg of niacin defined as 1 mg niacin equivalent (NE).
c
   NMN = N-methylnicotinamide; 2-Pyr = N-methyl-2-pyridone-5-carboxamide.
d
   CV calculated as 100% x [ ( PRI/RI/RDA – AR ) / 2 ] / AR.
e
   NCM notes that at energy intakes below 8 MJ/d the RI is 8 mg NE/day (instead of 1.6 mg NE/MJ).
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<pre>chapter 05 | Niacin (vitamin B3)                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 30 of 179
5.2 Explanation of differences between reports                                 set by HCNL, IOM and WHO/FAO are expressed in mg/d and do not differ
EFSA, HCNL, NCM and IOM base the AR on biochemical parameters of               between older and younger adults.
status: the intake required for “normal” urinary excretion of niacin
metabolites. After conversion to mg/day, there appears to be agreement         Sex differences
on the reference values for niacin equivalents (see 5.1). EFSA refers to       EFSA, NCM and DACH assume that the niacin requirement in mg/MJ is
three studies involving a total of 30 adults.                                  equal for all groups; note that NCM and DACH specified reference values
                                                                               both in mg/MJ and in mg/day. Their values converted to mg/day differ
Difference in the unit of expression (mg/MJ versus mg/day)                     between men and women according to the differences in energy
EFSA, NCM and DACH express the reference values in mg/MJ, because              requirement. Values by HCNL, IOM and WHO/FAO are in mg/day, but
studies of niacin requirements are presented in relation to energy intake,     these reference values show corresponding differences between men and
based on the known biochemical function of niacin in energy metabolism.        women.
HCNL, IOM and WHO/FAO express the reference values in mg/day,
considering that there is insufficient experimental evidence on the effect of  5.3 Conclusion on the scientific basis of EFSA’s reference
energy intake on niacine requirements. However, these organisations did               values
set lower reference values for women than for men based on the function        The Committee agrees with EFSA’s method of setting the reference
of niacin in energy metabolism. The Committee has no objections against        values for niacin, because EFSA and the reports for comparison use the
EFSA’s use of mg/MJ as the unit of expression.                                 same biochemical parameters of status. EFSA notes that signs of pellagra
                                                                               have been reported at intakes of up to 1 mg NE/MJ (Table 17). The
Differences between older and younger adults                                   Committee notes that EFSA’s AR (1.3 mg/MJ) provides a margin above
EFSA, NCM and DACH set one value in mg/MJ for all groups; note that            this intake level.
NCM and DACH specified reference values both in mg/MJ and in mg/day.           The Committee has no objections against the scientific basis of EFSA’s
Their values converted to mg/day differ between younger and older adults       reference values.
according to the differences in energy requirements. The reference values
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<pre>chapter 05 | Niacin (vitamin B3)                                                          An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 31 of 179
Table 17. Niacin intake levels associated with the occurrence, correction or prevention
of deficiencies, as described by EFSA                                                                Background information – a summary of the information provided by the EFSA report –
 Clinical manifestation    Associated intake   Subjects/Specific group EFSA’s reference              on the function of the nutrient, the occurrence of clinical deficiency and deficiency
 associated with                                                                                     symptoms in adults
 deficiency
 3 out of 5 subjects       about 0.94 mg NE/MJ 5 women with             Goldsmith et al. (1952)      The function of niacin is as the precursor of the nicotinamide nucleotide coenzymes NAD and
 developed pellagra                            psychoneurosis (aged                                  NADP, which are involved in oxidation/reduction reactions and associated with both catabolic
 after 50-60 d. 2 out of 2                     25-54 years).                                         and anabolic processes.
 subjects did not                                                                                    Niacin deficiency (pellagra) appears in populations in India and parts of China and Africa with:
 develop pellagra after                                                                              •   diets low in both niacin and the amino acid tryptophan (diets mainly consisting of corn or
 40-42 d
                                                                                                         maize).
 2 out of 10 subjects      0.94-0.99 mg NE/MJ  9 women and one man      Goldsmith et al. (1955)
                                                                                                     In Western countries, niacin deficiency (pellagra) occurs in specific groups with conditions or
 developed pellagra                            (aged 26-60 years, some
                                                                                                     diseases interfering with niacin intake, absorption and/or metabolism, e.g.:
 after 80 d                                    of whom were psychiatric
                                               or neurology patients).                               •   chronic alcohol abuse
 Signs of pellagra in      Approx 0.9-1 mg     Comparison of data on    Horwitt et al. (1956)        •   anorexia nervosa
 ‘some subjects’           NE/MJ               niacin and tryptophan    mentioned this finding       •   gastrointestinal diseases characterised by malabsorption or disturbances in tryptophan
                                               requirements (n=15       referring to three other         metabolism.
                                               subjects, followed up to studies                      Symptoms of pellagra:
                                               87 weeks) with those                                  •   photosensitive dermatitis (pigmented rash that develops symmetrically in areas exposed to
                                               (n=20) from two other
                                                                                                         sunlight)
                                               similar publications
                                                                                                     •   skin lesions
                                               (Frazier and Friedemann,
                                               1946; Goldsmith et al.,                               •   tongue and mouth soreness
                                               1952) and an                                          •   vomiting
                                               unpublished source.                                   •   diarrhea
 Subjects did not show     1.06 mg NE/MJ       40 male psychiatric      Horwitt et al. (1956)        •   depression
 signs of pellagra after   (n=~15)             patients (aged ≥30 years                              •   dementia
 37 wk                                         except for one subject)                               •   if untreated: death from multiorgan failure.
                                               followed up to 87 weeks.
                                                                                                     Early symptoms are usually non-specific and include weakness, loss of appetite, fatigue,
                                                                                                     digestive disturbances, abdominal pain, irritability.
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<pre>chapter 05 | Niacin (vitamin B3)                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 32 of 179
5.4 Summary and conclusion                                                                           EFSA expresses the reference values in a different unit compared to
                                                                                                     HCNL, but the differences appear to be small. The Committee has no
Table 18. Summary of the evaluation of EFSA’s AR and PRI values for niacin                           objections against the scientific basis of EFSA’s reference values, or
 Main findings, used for the conclusion
 Aspect                  Conclusion              Comment                                             EFSA’s AR and PRI and recommends accepting these values (Table 19)
 EFSA’s ARs compared     Not applicable, because Using the average of EFSA’s values converted to     in the Netherlands.
 to HCNL’s EARs          EFSA uses a different   mg/day (appendix in EFSA’s report), EFSA’s ARs
                         expression unit (mg/MJ) appear to be similar to HCNL’s EARs.
                         than HCNL                                                                   Table 19. AR and PRI for niacin, recommended for the Netherlands
 EFSA’s PRIs             Not applicable, because Using the average of EFSA’s values converted to
 compared to HCNL’s      EFSA uses a different   mg/day (appendix in EFSA’s report), EFSA’s PRIs                                                  Men and women >18 years
 RDAs                    expression unit (mg/MJ) appear to be <10% higher than HCNL’s RDAs.           Average requirement (AR)                    1.3 mg NE/MJ energy intake
                         than HCNL                                                                    Population reference intake (PRI)           1.6 mg NE/MJ energy intake
 Scientific basis of     No objections           The biochemical parameters of status on which
 EFSA’s AR                                       EFSA based the reference values are consistent
                                                 with the reports used for comparison. Clinical
                                                 signs of deficiency are reported at intakes of up
                                                 to 1 mg/MJ. EFSA’s AR (1.3 mg/MJ) provides a
                                                 margin above this level.
 Other findings
 Aspect                  Conclusion              Comment
 Differentiation between Not applied by EFSA     EFSA, NCM and DACH are consistent. HCNL,
 younger and older       (but EFSA’s reference   IOM and WHO/FAO use a different unit (mg/day)
 adults                  value is in mg/MJ)      and do not differentiate between younger and
                                                 older women.
 Differentiation between Not applied by EFSA     Consistent with all reports used for comparison.
 men and women           (but EFSA’s reference
                         value is in mg/MJ)
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<pre>chapter 06 | Pantothenic acid (vitamin B5)             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 33 of 179
06
pantothenic acid
(vitamin B5)
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<pre>chapter 06 | Pantothenic acid (vitamin B5)                                                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 34 of 179
                                             Pantothenic acid                                                 6.1 Overview and comparison of values
                                                                                                              Table 20. Overview of the criteria on which the PRI/RDA/RI/AI for adults are based
          Should EFSA's reference values be rejected                                                           Report        AI (mg/d) Main criterion
          based on a specific nutritional context in the                                 YES                   EFSA 2014  23
                                                                                                                             5         Approximate midpoint of the observed median/mean intakes; there are
        Netherlands that differs from (the rest of) Europe?
                                                                                                                                       no signs of insufficiencies.
                                                                                                               HCNL 200036   5         Habitual intakes in populations (1-7 mg/d); there are no signs of
                                                                                                               = HCNL                  insufficiencies.
                                                                                                               201433                  Intake balancing excretion (4 mg/d; 8 young women).
                                 NO                                                                            DACH 201538   6         Intake in Germany (range 3.1-4.5 mg/d) and USA (♀4.1 mg/d; ♂6.2
                                                                                                                                       mg/d); there are no signs of insufficiencies.
                                                                                                                                       At intake < 4 mg/d, blood levels are within the normal range.
                                                                                                               IOM 199842    5         The approximate midpoint of habitual intakes (4-7 mg/d); there is no
                                                                                                                                       evidence suggesting that this range of intake is inadequate.
       Are there objections against EFSA’s scientific basis
                         for this nutrient?                                                                                            Intake balancing excretion (4 mg/d; 8 young women).
                                                                                                               WHO/FAO       5         Observed median/mean intakes in adolescents (4-8 mg/d) and adults
                                                                                                               200444                  (4-7 mg/d).
                                                                                                                                       Studies in adolescents suggest that intakes of less than 4 mg/day were
                                              YES                                                                                      sufficient to maintain blood and urinary pantothenate.
                                                                                                              Table 20 presents an overview of reference values and criteria. Note that
       NO
                      Do (part of) EFSA's reference values differ 10% or
                                                                                         YES                  NCM 2012 did not provide recommended intakes for pantothenic acid,
                       more from the 2014 values for the Netherlands?
                                                   AI                                                         due to lack of sufficient evidence.37
                                                                                                              EFSA, HCNL, IOM and WHO/FAO use the same AI of 5 mg/d for all
                                               NO                                                             adults. DACH has set a higher AI (+20% relative to EFSA’s value).
                                                                                                              6.2 Explanation of differences between reports
            No objections against the use of                   Major objection against the use of
       EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands        The AIs in all reports are based on observed median/mean intakes,
                                                                                                              because there are no signs of insufficiencies.
                                                                                                              IOM and HCNL additionally state that intake balances the urinary excretion
                                                                                                              at an intake of 4 mg/d. DACH mentions that intakes below 4 mg/day
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<pre>chapter 06 | Pantothenic acid (vitamin B5)                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 35 of 179
appear to be sufficient to maintain blood pantothenate in adolescents.         6.3 Conclusion on the scientific basis of EFSA’s reference
(Note that DACH does not explain why their AI for adults is set at 6 mg/d.)           values
The EFSA Panel considers that urinary and blood pantothenate are not           EFSA’s based the AI for pantothenic acid on median and mean intakes of
suitable for deriving the AR for pantothenic acid, because their variability   pantothenic acid, consistent with the reports used for comparison,
characteristics and their ability to discriminate between pantothenic acid     because pantothenic acid deficiency is rare.
insufficiency and adequacy are not well known, and no cut-off values for       EFSA provides no information on pantothenic acid intake levels
these biomarkers have been established.                                        associated with the occurrence, correction or prevention of deficiencies.
EFSA uses European intake data to set the reference value. These data          The Committee has no objections against the scientific basis of EFSA’s
were collected between 1996 and 2010 in Austria, France, Germany,              reference values, but notes that median and mean intakes may
Hungary, Ireland, Poland and Portugal. EFSA mentions: “In adult men and        substantially exceed requirements; deficiencies have not been reported in
women below about 65 years, mean/median intakes of 3.2 to 6.3 mg/day           healthy subjects on normal diets.
were reported. Data from France, Germany and Ireland indicated median
intakes between 4.2 mg/day and 6.3 mg/day in men and between 3.3 and              Background information – a summary of the information provided by the EFSA report –
5.2 mg/day in women, while data in Austria, Hungary and Portugal                  on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                  symptoms in adults
indicated mean intakes of 4.0 to 5.4 mg/day in men and 3.2 to 4.7 mg/day
                                                                                  Pantothenic acid is a component of coenzyme A (CoA) and acyl-carrier proteins and serves in
in women. In older men and women, mean/median intakes of 2.2 to 6.0
                                                                                  acyl-group activation and transfer, which is essential for fatty acid synthesis and oxidative
mg/day were reported. Data from France, Germany and Ireland indicated             degradation of fatty acids and amino acids. Humans cannot synthesise pantothenic acid and
                                                                                  depend on its dietary intake. Pantothenic acid is ubiquitous in food.
median intakes ranging from 4.2 to 6.0 mg/day in men and from 3.6 to 5.2
                                                                                  Pantothenic acid deficiency is rare and EFSA provides no information on pantothenic acid intake
mg/day in women, while data in Austria, Hungary, Poland and Portugal              levels at which deficiencies are or are not reported. Deficiency symptoms have been described in:
                                                                                  •   subjects on a pantothenic acid antagonist
indicated mean intakes of between 2.6 to 4.7 mg/day in men and between
                                                                                  •   subjects on a pantothenic acid-deficient diet.
2.2 and 4.4 mg/day in women.”                                                     Symptoms include:
                                                                                  •   mood changes
                                                                                  •   sleep disturbances
Differences between older and younger adults and sex differences                  •   neurological disturbances
                                                                                  •   cardiac disturbances
All reports set one value for men and women aged >18 years.
                                                                                  •   gastrointestinal disturbances.
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<pre>chapter 06 | Pantothenic acid (vitamin B5)                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 36 of 179
6.4 Summary and conclusion                                                                         EFSA’s AI for pantothenic acid equals the HCNL’s AI. EFSA’s AI is based on
                                                                                                   the approximate midpoint of observed median/mean intakes in European
Table 21. Summary of the evaluation of EFSA’s AI value for pantothenic acid                        countries (other than the Netherlands), which is assumed to be adequate
 Main findings, used for the conclusion
 Aspect                        Conclusion          Comment                                         because no signs of deficiency are reported. Pantothenic acid deficiency is
 EFSA’s AI compared to         Difference 0%       Consistent with HCNL                            rare and has not been reported in healthy subjects on normal diets, so that
 HCNL’s AI 2014
 Scientific basis of EFSA’s AI No objections       EFSA’s AI is based on median and mean           the adequate intake may substantially exceed requirements. However, there
                                                   intakes, consistent with the reports used for
                                                   comparison. The Committee notes that these      is no evidence available to define a more evidence-based AI.
                                                   intakes may substantially exceed
                                                                                                   Therefore, the Committee has no objections against the scientific basis of
                                                   requirements.
 Other findings                                                                                    EFSA’s AI, or EFSA’s AI for adults (Table 22).
 Aspect                        Conclusion          Comment
 Differentiation between       Not applied by EFSA Consistent with the reports used for            Table 22. AI for pantothenic acid, recommended for the Netherlands
 younger and older adults                          comparison.
                                                                                                                                             Men and women >18 years
 Differentiation between men   Not applied by EFSA Consistent with the reports used for
                                                                                                    Adequate intake (AI)                     5 mg/day
 and women                                         comparison.
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<pre>chapter 07 | Vitamin B6                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 37 of 179
07
vitamin B6
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<pre>chapter 07 | Vitamin B6                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 38 of 179
                                                    Vitamin B6                                                     7.1 Overview and comparison of values
                                                                                                                   Table 23. Overview of the reference values for adults and the criteria on which these
            Should EFSA's reference values be rejected                                                             values are based
             based on a specific nutritional context in the                                YES
          Netherlands that differs from (the rest of) Europe?                                                        Report      Age         PRI/RDA/AI/RI          AR (mg/d)       CV      Main criterion
                                                                                                                                 group       (mg/d)                                 (%)
                                                                                                                                             Type ♂         ♀       ♂       ♀
                                                                                                                     EFSA        >18 yr      PRI      1.7 1.6       1.5     1.3     10      Status parameter: plasma pyridoxal
                                                                                                                     201610                                                                 5’-phosphate (PLP)a >30 nmol/L; AR
                                   NO
                                                                                                                                                                                            for women is based on data in women,
                                                                                                                                                                                            and then extrapolated to men via
                                                                                                                                                                                            allometric scaling (there are few data
                                                                                                                                                                                            on men).
         Are there objections against EFSA’s scientific basis                                                        HCNL        19-50 yr    RDA      1.5 1.5       1.1     1.1     20      Status parameter: PLP >20 nmol/L.
                           for this nutrient?                                                                        200335      >50 yr      RDA      1.8 1.5       1.3     1.1     20      Note: if protein intake >150 g/d,
                                                                                                                     = HCNL                                                                 vitamin B6 requirements increase by
                                                                                                                     201433                                                                 0.01-0.02 mg per gram of extra
                                                                                                                                                                                            protein.
                                                YES                                                                  NCM         18-60 yr    RI       1.5 1.2       1.3     1.0     10      The AR is based on the recommended
                                                                                                                     201437      >60 yr      RI       1.5 1.3                               B6 intake of 0.015 mg vitamin B6 per
                                                                                                                                                                                            g protein (as 0.01 mg/g protein is
                                                                                                                                                                                            associated with PLP >20 nmol/L). The
                        Do (part of) EFSA's reference values differ 10% or                                                                                                                  value in mg/d is calculated using
         NO                                                                                YES
                          more from the 2014 values for the Netherlands?                                                                                                                    protein intakes of 15 energy % for
                                                                                    PRI♂ 19-50 yr                                                                                           younger adults and 18 energy% for
                                                                                          ARs
                                                                                                                                                                                            older adults, and the average energy
                                                                                                                                                                                            requirements.
                                                         PRI♀ 19-50yr                                                DACH        19-64 yr    AI       1.5 1.2       -       -       -       The AI is based on the recommended
                                                 NO
                                                         PRIs >50yr
                                                                                                                     201538      >64 yr      AI       1.4 1.2       -       -       -       B6 intake of 0.02 mg per gram protein,
                                                                                                                                                                                            using the recommended protein
                                                                                                                                                                                            intake.
                                                                                                                     IOM         19-50 yr    RDA      1.3 1.3       1.1     1.1     10      Status parameters: excretion
               No objections against the use of                   Major objection against the use of                 199842      >50 yr      2        1.7 1.5       1.4     1.3     10      tryptophan catabolites (no target levels
        EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands
                                                                                                                                                                                            given); plasma PLP >20 nmol/L.
                                                                                                                     WHO/        19-50 yr    RI       1.3 1.3       -       -       -       Status parameter: plasma PLP >20
 Vitamin B6 is the preferred name for a group of substances in food, including pyridoxine (PN), pyridoxal (PL) and   FAO         >50 yr      RI       1.7 1.5                               nmol/l. No AR or CV mentioned.
 pyridoxamine (PM), and their respective phosphorylated forms, pyridoxine 5’-phosphate (PNP), pyridoxal              200444
 5’-phosphate (PLP), and pyridoxamine 5’-phosphate (PMP). The metabolically active forms are PLP and PMP.
                                                                                                                   a
                                                                                                                      Plasma pyridoxal 5’-phosphate (PLP) is the predominant active form of vitamin B6 that functions as a coenzyme
                                                                                                                      in various metabolic reactions. (The other active form is pyridoxamine 5’- phosphate or PMP.)
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<pre>chapter 07 | Vitamin B6                                                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 39 of 179
Table 23 shows that, in contrast to the reports used for comparison, EFSA                                             The ARs by EFSA, HCNL, IOM and WHO/FAO are based on a
does not set different reference values for older adults.                                                             biochemical parameter of status. The differences result from the higher
For younger men, the RDA/RI/AI values in all reports used for comparison                                              cut-off value for plasma pyridoxal 5’-phosphate (PLP) used by EFSA (30
are between 12% and 24% lower than EFSA’s PRIs.                                                                       nmol/l) in comparison to HCNL, IOM and WHO/FAO (20 nmol/l).
For older men, EFSA’s PRI equals the values set by IOM and WHO/FAO,                                                   • EFSA (2016) based the cut-off value of 30 nmol/l on one study in young
HCNL’s value is 6% higher, whereas NCM’s RI and DACH’s AI are 12%                                                         adults published in 2013, indicating that mean PLP values below 30
and 18% lower.                                                                                                            nmol/L (mean PLP decreased from 53 to 22 nmol/L) were associated
The RDA/RI/AI values for both younger and older women in the reports                                                      with effects on biochemical parameters: amino acid, lipid, and organic
used for comparison are between 6% and 25% lower than EFSA’s PRIs.                                                        acid profiles in plasma.c
Note that HCNL used a larger coefficient of variation than EFSA and IOM                                               • IOM (1998) stated that results from a large number of studies involving
(20% versus 10%). Therefore the difference between the ARs are larger                                                     various population groups (IOM provides 7 references) included
than the difference between the PRIs/RDAs.                                                                                substantial proportions of individuals with plasma PLP concentrations
                                                                                                                          below 30 nmol/L, with no confirming clinical or other data to suggest B6
7.2 Explanation of differences between reports                                                                            deficiency. IOM mentions that other investigators have proposed a
NCM’s AR and DACH’s AI are based on protein requirements, assuming                                                        cut-off value of 20 nmol/L for plasma PLP as an index of adequacy
that the vitamin B6 requirements linearly increase with protein intake.a                                                  (IOM refers to Lui et al., J Lab Clin Med 1985; 106: 491-7) and notes
EFSA, HCNL, IOM and WHO/FAO do not support this assumption.b The                                                          that this more conservative cut-off of 20 nmol/L is not accompanied by
Committee prefers reference values based on the biochemical parameter                                                     observable health risks but allows a moderate safety margin to protect
of status, rather than on protein requirements.                                                                           against the development of signs or symptoms of deficiency. IOM
                                                                                                                          selected the cut-off value of 20 nmol/L as the basis for the EAR, but
a
  NCM uses the reference value for energy intake and the assumption that the diet provides 15 energy% protein in
  younger adults and 18 energy% protein in older adults. DACH uses the reference value for protein intake.
b
  EFSA considers that, within the range of observed intakes in Europe, there is insufficient evidence supporting the
  relationship between vitamin B6 requirement and protein intake. HCNL and IOM conclude that the relationship of      c
                                                                                                                        23 young adult men and women (20-40 years) consumed a diet with <0.5 mg of vitamin B6 per day for 4 weeks
  vitamin B6 requirements with protein intake is not linear and – given the habitual range of protein intake - does     and mean plasma PLP decreased from 53 to 22 nmol/L. Two publications describe the results: Gregory et al.
  not have to be considered in establishing vitamin B6 reference values. WHO/FAO states that, despite the               (2013) report a variety of biochemical changes in amino acid profiles. Da Silva et al. (2013) report effects on the
  involvement of PLP with many enzymes affecting amino acid metabolism, there seems to be only a slight effect of       profiles of one-carbon and tryptophan metabolites. The Committee notes that these outcomes all are related to
  dietary proteins on vitamin B6 status.                                                                                biochemical parameters rather than to clinical signs of deficiency.
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<pre>chapter 07 | Vitamin B6                                                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 40 of 179
    mentions that “its use may overestimate the B6 requirement for health                                       In the reports by HCNL, IOM and WHO/FAO a lower cut-off value for
    maintenance of more than half the group”. The key references used by                                        plasma PLP (20 nmol/L) is used, compared with the EFSA report (30
    EFSA were not available at the publication of the IOM report.                                               nmol/L). For men, this results in a lower AR for younger versus older men
                                                                                                                in all three reports. Based on the available research in each group, HCNL
Note that HCNL applied a higher CV (20%) than EFSA and IOM (10%) to                                             set the same AR for older and younger women, whereas IOM and WHO/
calculate the RDA from the AR. HCNL used this higher CV because of                                              FAO set a lower AR for younger versus older women.
uncertainty on the requirements.
                                                                                                                Sex differences
Difference between older and younger adults                                                                     EFSA concludes that for men, reliable data to determine the requirements
EFSA bases the AR on the intake level sufficient to maintain a plasma                                           are not available. Therefore, EFSA extrapolates the AR for men from the
PLP concentration of 30 nmol/L in 50% of each group of women. For                                               AR for women using metabolic weight, defined as (body weight)0.75,
younger women, the level was estimated to be 1.2 mg of vitamin B6 per                                           resulting in a higher value for men than for women.
day, based on the linear regression analysis by Hansen et al. (2001).a This                                     IOM and HCNL base their EAR for younger men on the available studies
reference was published after the IOM report. For older women, the level                                        in men, resulting in younger adults having the same AR for men and
was estimated to be 1.3 mg of vitamin B6 per day, based on other                                                women. IOM notes that it is difficult to derive a precise EAR for younger
references.b When setting the reference values, EFSA uses the higher                                            men because most studies have identified the vitamin B6 intake that
estimate for older women (+0.1 mg/d for older compared to younger                                               restores biomarkers to baseline values in all subjects which may be
women) for all women as a conservative approach and because the                                                 considerably higher than the intake level needed for health, and because,
difference is small.                                                                                            in most studies, the levels of vitamin B6 tested appear to have been in
                                                                                                                excess of the average requirement. HCNL also mentions that research in
                                                                                                                younger men is limited.
a
  The study by Hansen et al. (2001) is based on the combined data of 44 women (mean age about 20–30 years
  according to studies) participating in 6 intervention studies (5 references).
b
  EFSA based the estimate for older women on a depletion/repletion study in 2 women, an intervention study
  comparing 29 younger and 26 older adults, and several cross-sectional studies.
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<pre>chapter 07 | Vitamin B6                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 41 of 179
7.3 Conclusion on the scientific basis of EFSA’s reference                       Table 24. Vitamin B6 intake levels associated with the occurrence, correction or
                                                                                 prevention of deficiencies, as described by EFSA
       values
                                                                                  Clinical manifestation               Associated intake                  Subjects/      Reference
EFSA’s cut-off value for plasma PLP is 30 nmol/L, based on one study              associated with deficiency                                              Specific group
                                                                                  Abnormal electroencephalogram        Depletion diet for (maximum)       2 out of 8     Kretsch et al.,
showing biochemical effects after reducing the average plasma PLP to 22           within 12 days in 2 women            28 days: <0.05 mg B6/day           young women    1991 and 1995
nmol/L. The Committee notes that this cut-off value is not based on               The electroencephalogram was         Repletion with 0.5 mg B6/day
                                                                                  quickly normalised
evidence regarding clinical effects, and that 22 nmol/L is closer to 20 than
to 30 nmol/L. The Committee therefore considers that this study does not
provide sufficient basis for the cut-off value of 30 nmol/L.
Therefore, the Committee has objections against the scientific basis of              Background information – a summary of the information provided by the EFSA report –
EFSA’s reference values.                                                             on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                     symptoms in adults
                                                                                     The metabolically active forms PLP and PMP act as cofactors for more than 100 enzymes
The Committee prefers the cut-off value for plasma PLP used by HCNL, IOM
                                                                                     involved primarily in amino acid metabolism, but also in one-carbon reactions, glycogenolysis
and WHO/FAO (20 nmol/L), because it is based on the absence of                       and gluconeogenesis, haem synthesis, niacin formation and other functions (lipid metabolism,
                                                                                     neurotransmitter synthesis and hormone action).
symptoms of deficiency.
                                                                                     Vitamin B6 deficiency is rare and has only been reported:
EFSA presents some evidence on vitamin B6 intake levels associated with              •   In the USA in the early 1950s, in young infants who consumed infant formula low in vitamin
                                                                                         B6.
the occurrence, correction or prevention of deficiencies (Table 24). In eight
                                                                                     •   IOM 1998: “in adults … clinical symptoms of B6 deficiency have been observed only in
young women, the depletion period with an intake of lower than 0.05 mg/day               controlled studies during depletion with very low levels of B6 and have never been seen at
                                                                                         intakes of 0.5 mg/day or greater”.
within 12 days resulted in abnormalities in the electroencephalograms of two
                                                                                     Symptoms:
women; increasing the intake to 0.5 mg/day quickly reversed these                    •   hypochromic microcytic anaemia
                                                                                     •   neurological abnormalities (hyperirritability, convulsive seizures and abnormal
deficiency symptoms. The Committee notes that the AR-values for young
                                                                                         electroencephalograms)
women in the HCNL report (1.1 mg/day) provides a substantial margin above            •   eczema
                                                                                     •   seborrhoeic dermatitis
this intake level associated with the correction of deficiency (0.5 mg/day).
                                                                                     •   cheilosis
The Committee has no objections against the scientific basis of HCNL’s               •   glossitis
                                                                                     •   angular stomatitis.
reference values.
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<pre>chapter 07 | Vitamin B6                                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 42 of 179
7.4 Summary and conclusion                                                                          The Committee has objections against the scientific basis of EFSA’s ARs,
                                                                                                    because the evidence for the use of the cut-off value for plasma PLP of 30
Table 25. Summary of the evaluation of EFSA’s AR and PRI values for vitamin B6
 Main findings, used for the conclusion
                                                                                                    nmol/L is insufficient. The Committee prefers the lower cut-off value for
 Aspect              Conclusion          Comment                                                    plasma PLP used by HCNL, IOM and WHO/FAO (PLP >20 nmol/L), which
 EFSA’s ARs          Differences >10%    For men aged 19-50 yr and all women aged >19 yr,
 compared to                             EFSA’s AR is approximately 35% and 20% higher              is associated with absence of deficiency signs.
 HCNL’s EARs                             than HCNL’s EAR. For men aged >50 yr, EFSA’s AR
                                         is around 15% higher than HCNL’s EAR.
 EFSA’s PRIs         Differences partly  For men aged 19-50 yr, EFSA’s PRI is approximately         The Committee has objections against EFSA’s PRI and AR for adults and
 compared to         >10%                15%. For all adult women EFSA’s PRI is 7% higher
 HCNL’s RDAs                             than HCNL’s RDA; EFSA’s PRI for men aged >50 yr is         recommends maintaining HCNL’s reference values (Table 26).
                                         5% lower than HCNL’s RDA.
 Scientific basis of Objections          The Committee considers that there is insufficient         Table 26. AR and PRI for vitamin B6, recommended for the Netherlands
 EFSA’s ARs                              evidence for the use of EFSA’s relatively high cut-off
                                                                                                                                       Men                            Women
                                         value for plasma PLP. In young women, a correction
                                                                                                                                       18-50 years >50 years          >18 years
                                         of deficiency was reported with an intake of 0.5 mg/
                                         day, which is much lower than both EFSA’s AR (1.3           Average requirement (AR)          1.1 mg/d    1.3 mg/d           1.1 mg/d
                                         mg/day) and the 2003 Dutch AR (1.1 mg/day).                 Population reference intake (PRI) 1.5 mg/d    1.8 mg/d           1.5 mg/d
 Other findings
 Aspect              Conclusion          Comment
 Differentiation     Not applied by EFSA Not consistent with the reports used for comparison:
 between younger                         all differentiate between younger and older adults for
 and older adults                        either men, or women or both.
 Differentiation     Applied by EFSA     Consistent with DACH and NCM, although the basis
 between men and                         for the differentiation differs (metabolic weight versus
 women                                   protein requirements). HCNL, IOM and WHO/FAO
                                         differentiate between older men and older women, but
                                         not between younger men and younger women.
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<pre>chapter 08 | Folate                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 43 of 179
08
folate
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<pre>chapter 08 | Folate                                                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 44 of 179
                                                         Folate                                                       8.1 Overview and comparison of values
                                                                                                                      Table 27. Overview of the PRI/RDA/RI and AR values for adults and the criteria on
              Should EFSA's reference values be rejected                                                              which these values are based, in dietary folate equivalents (DFE)a
              based on a specific nutritional context in the                                    YES
           Netherlands that differs from (the rest of) Europe?
                                                                                                                        Report       Age             PRI/RDA/AI/RI        AR        CVa        Main criterion
                                                                                                                                     group           Type     (μg/d)      (μg/d)    (%)
                                                                                                                        EFSA         >14 yr          PRI      330         250       15%        Serum folate (>10 nmol/L) and erythrocyte
                                                                                                                        201426                                                                 folate (>340 nmol/L), both cut-off values are
                                                                                                                                                                                               associated with lowest plasma
                                      NO                                                                                                                                                       homocysteine.
                                                                                                                        HCNL         >18 yr          RDA      300         200       25%        Serum folate (>7 nmol/L); erythrocyte
                                                                                                                        200335                                                                 folate (>300 nmol/L); plasma homocysteine
                                                                                                                        = HCNL                                                                 (<15 μmol/L). The high CV (25%) is chosen
          Are there objections against EFSA’s scientific basis                                                          201433                                                                 so that the RDA also covers the higher
                              for this nutrient?                                                                                                                                               requirement of persons with the
                                                                                                                                                                                               TT-genotype for the 5,10-methylenetetra-
                                                                                                                                                                                               hydrofolate reductase.
                                                                                                                        NCM          Reproduc-       RI       ♂ 300;      200       25%        Serum folate (>7 nmol/L); erythrocyte folate
                                                   YES                                                                  201437       tive age                 ♀ 400                            (>317 nmol/L); plasma homocysteine (<12
                                                                                                                                     range                                                     μmol/L). RI for all women in reproductive
                                                                                                                                     Older           RI       300         200       25%        age is 100 μg/d higher than RI for men and
                                                                                                                                                                                               older women, because of the possibility of
                          Do (part of) EFSA's reference values differ 10% or                                                                                                                   unplanned pregnancies.
          NO                                                                                    YES
                            more from the 2014 values for the Netherlands?                                              DACH         >12 yr          RDA      300         220       15%        Serum folate (>10 nmol/L); erythrocyte
                                                                                           PRI & AR                     201538,47                                                              folate (>340 nmol/L); plasma homocysteine
                                                                                                                                                                                               (<12 μmol/L, secondary criterion).
                                                                                                                        IOM          >18 yr          RDA      400         320       10%        Serum folate (>7 nmol/L); erythrocyte folate
                                                                                                                        199842                                                                 (>305 nmol/L, based on the absence of
                                                    NO
                                                                                                                                                                                               hypersegmented neutrophils in the blood
                                                                                                                                                                                               and on indicators chromosome damage);
                                                                                                                                                                                               plasma homocysteine (<14/16 μmol/L).
                                                                                                                        WHO/         >18 yr          RDA      400         320       10%        WHO/FAO accepted the IOM values.
                No objections against the use of                     Major objection against the use of                 FAO
          EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands               200444
                                                                                                                      a
                                                                                                                         If the coefficient of variation was not specified in the report, it was calculated as
                                                                                                                         100% x [ ( PRI/RI/RDA - AR ) / 2 ] / AR.
 Folate is one of the B-vitamins. Previously, folate was also called – dependent on the country – vitamin B11
 or vitamin B9, but folate is internationally the preferred name. Folic acid is the synthetic form of folate,
 also known as pteroylmonoglutamic acid (PGA), which is used in dietary supplements and foodstuffs
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<pre>chapter 08 | Folate                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 45 of 179
Table 27 shows that HCNL’s RDA, DACH’s RI as well as the NCM’s RI for         the small study by O’Keefe et al. (1995),a whereas HCNL and NCM do not
men and older women are 9% lower than EFSA’s PRI. NCM’s RI for                take this publication into account because other key references indicate
women in the reproductive age range, IOM’s RDA and WHO/FAO’s RI are           that lower intake levels are sufficient.b,c The Committee prefers the
21% higher than EFSA’s PRI.                                                   AR-value of HCNL and NCM (200 μg/d), which is based on more data
                                                                              than the IOM-value.
8.2 Explanation of differences between reports                                EFSA and DACH use the same cut-off values for serum and erythrocyte
This evaluation focuses on the difference between EFSA, HCNL, NCM,            folate, but the AR by DACH (220 μg/d) is somewhat lower than EFSA’s AR
DACH and IOM, because the WHO/FAO-criteria are not clear.                     (250 μg/d).
All reports base the ARs on the same biochemical parameters of status,        The coefficient of variation (CV) used to calculate the PRI from the AR
but EFSA and DACH use higher cut-off values for the biomarkers than the       varies substantially between the reports: the CV used by HCNL and NCM
other organisations:                                                          is the highest (25%), the CV used by EFSA and DACH is 15%, the CV
• Serum folate cut-off values were 10 nmol/l (EFSA and DACH) or 7             used by IOM and WHO/FAO is the lowest (10%).
   nmol/L (HCNL, NCM and IOM).
• Erythrocyte folate cut-off values were 340 nmol/l (EFSA and DACH),
   317 nmol/L (NCM) or 300/305 nmol/L (HCNL and IOM).
                                                                              a
                                                                                O’Keefe et al. (1995) studied 3 groups with 5-6 subjects each. IOM’s AR is the intake level in the group with the
Although HCNL, NCM and IOM use the same cut-off values for serum and            lowest supplemental level: 3 of the 5 subjects in this group had a low erythrocyte folate (<362 nmol/L) and a low
                                                                                serum folate (<7 nmol/L) at the end of the 70-day period on the experimental diets.
erythrocyte folate, the AR set by HCNL and NCM (200 μg/d) is                  b
                                                                                HCNL based the average requirement of 200 μg/d mainly on the publications of Milne et al. (1983; n=40) and
                                                                                Sauberlich et al. (1987; n=10). NCM based the average requirement of 200 μg/d on the study by Sauberlich et al.
substantially lower than IOM’s AR (320 μg/d). The difference is the result      (1987) and several additional studies.
                                                                              c
                                                                                Note that IOM’s AR (320 μg/d) is even higher than the ARs of EFSA and DACH (EFSA: 250 μg/d and DACH: 220
of the publications used to set the AR. IOM gives the greatest weight to        μg/d) which are based on higher cut-off values for serum and erythrocyte folate. EFSA bases the average
                                                                                requirement for adults of 250 μg folate per day on the results of the study by Kauwell et al. (2000; n=32), which is
                                                                                in agreement with the publications of Milne et al. (1983) and Sauberlich et al. (1987). EFSA mentions that folate
                                                                                intakes in the latter two studies have probably been underestimated.
                                                                                DACH bases their average requirement of 220 μg/d on Milne et al. (1983), Sauberlich et al. (1987) and Herbert
                                                                                (1962; n=3), but adds 10% to the estimate of 200 μg/d in order to take into account a certain underestimation of
                                                                                the folate content of foods due to analytical limitations.
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<pre>chapter 08 | Folate                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 46 of 179
Differences between older and younger adults                                   Approaches regarding the prevention of neural tube defects in infants
EFSA, HCNL, DACH, IOM and WHO/FAO do not differentiate the                     by folic acid
reference values between younger and older adults, based on the                The use of a supplement containing 400 micrograms of folic acid per day
available research.                                                            from at least four weeks prior to conception until eight weeks after
NCM does not differentiate the reference values between younger and            conception (when the neural tube has closed) lowers the chance of having
older men. However, for women in the reproductive age range, NCM does          a child with a neural tube defect by at least 50% (estimates range
differentiate between women in the reproductive age and older women,           36-72%).48,49
based on the role of folic acid in the prevention of neural tube defects.      Countries use different approaches to achieve this preventive effect of
NCM’s RI for women in the reproductive age is 400 μg/d, which is 100           folic acid against neural tube defects in infants:
μg/d higher than the RI for older women (and all adult men). Note that the     • In the Netherlands, women who wish to conceive are advised to use a
approach regarding the prevention of neural tube defects in infants with           supplement containing 400 μg/d of folic acid, starting at least four
folic acid differs between countries; this is described and discussed below.       weeks prior to conception until eight weeks after conception.49
                                                                               • Other countries such as the USA and Canada use – additionally to the
Sex differences                                                                    advise to use a folic acid supplement – mandatory fortification of staple
EFSA, HCNL, DACH, IOM and WHO/FAO do not differentiate the                         foodstuffs with folic acid. A disadvantage of such fortification is the
reference values between men and women, based on studies in men and                resulting higher proportion of individuals with excessively high intakes
studies in women.                                                                  of folic acid in all groups and especially in children.
NCM does not differentiate the reference values between older men and          • NCM set the RI for women in the reproductive age range at a 100 μg/d
older women. However, NCM’s RI for women in the reproductive age                   higher level than the RI for men in the same age range and for older
range is 100 μg/d higher than their RI for men in this age range. Note that        men and women. NCM writes: “Women of reproductive age represent a
the approach regarding the prevention of neural tube defects in infants            specific challenge because there is convincing evidence that an
with folic acid differs between countries; this is described and discussed         adequate supply of folate before and up to 12 weeks after conception
below.                                                                             reduces the risk of NTD. However, far from all pregnancies are
                                                                                   planned. Therefore, an RI of 400 μg/d for all women of reproductive
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<pre>chapter 08 | Folate                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 47 of 179
   ages should provide adequate folate supply to women experiencing           8.3 Conclusion on the scientific basis of EFSA’s reference
   unplanned pregnancies.”37                                                        values
From these three approaches to achieve this preventive effect of folic acid   The cut-off values for serum folate and erythrocyte folate used by HCNL,
against neural tube defects in infants, only NCM’s approach involves the      NCM and IOM are associated with the prevention of clinical deficiency
dietary reference values and should be considered within the context of       (megaloblastic anaemia). The higher cut-off values used by EFSA and
this report. Both other approaches (supplementation, either in combination    DACH are based on lowering the plasma homocysteine concentration.
with the mandatory fortification of staple foodstuffs or not) concern         The Committee considers that the clinical relevance of the lowering of
implementation policies instead of dietary reference values, and therefore    plasma homocysteine is unclear.
are beyond the scope of this report.                                          Therefore, the Committee has objections against the scientific basis of
NCM’s RI is not based on evidence regarding the folate requirement of all     EFSA’s reference values.
women in the childbearing age, but aims at a subgroup of these women:         The Committee prefers the cut-off values for serum and erythrocyte folate
those who are going to be pregnant. The RI is set at a higher level than      used by HCNL, NCM and IOM. In paragraph 8.2, the Committee
NCM’s RI for other adults, in order to improve the folate status in women     concluded that the AR-value set by HCNL and NCM (200 μg/d) are based
who will experience an unplanned pregnancy and in women who are not           on more data than the higher AR-value set by IOM (320 μg/d).
reached by information campaigns on folic acid supplementation around         The Committee has no objections against the scientific basis of HCNL’s
conception.                                                                   reference values
The Committee considers that the evaluation of implementation strategies      EFSA did not describe publications on studies relating specific intake
requires a broader perspective, and prefers that dietary reference values     levels to the occurrence, correction or prevention of deficiency signs, but
are based on evidence regarding the requirements of the whole group.          EFSA does mentions that NCM (2004) and the UK Department of Health
Therefore, the Committee does not support NCM’s RI.                           (1991) associate intakes of 100 μg/day and 150-200 μg/day, respectively,
                                                                              with the absence of deficiency (Table 28). The Committee notes that the
                                                                              proposed AR (200 μg/day) corresponds with (or is higher than) intake
                                                                              levels associated with prevention of deficiency symptoms.
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<pre>chapter 08 | Folate                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 48 of 179
Table 28. Folate intake levels associated with the prevention of deficiencies, as
described by EFSA                                                                                Background information – a summary of the information provided by the EFSA report –
 Clinical manifestation associated with deficiency            Associated Subjects EFSA’s         on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                              intake              reference      symptoms in adults
 NCM 2004 set a lower level of intake of 100 μg DFE/day,      100 μg              NCM 2004
 based on the minimum intake needed to prevent folate         DFE/day                            Folate functions as a cofactor or cosubstrate in numerous one-carbon transfer reactions that are
 deficiency anaemia (Herbert et al., 1962), daily losses from                                    important for the synthesis of RNA and DNA, amino acid interconversions and the process of
 stores while on a virtually folate-free diet (Zalusky and
                                                                                                 methylation. Different folate forms are involved in specific reactions, but all of them are finally
 Herbert, 1961) and the excretion in urine in well-nourished
                                                                                                 metabolised to THF.
 individuals (Herbert, 1987a).
                                                                                                 Folate deficiency does occur in Western populations, but EFSA does not provide further
 The UK COMA (DH, 1991) considered the folate                 150-200 μg Canadian UK COMA
 concentration of autopsied liver samples, the prevalence of  DFE/day    subjects (DH, 1991)     information on this.
 8-10% of low red blood cell folate concentrations                                               Symptoms:
 (<150 μg/mL) and the absence of overt signs of clinical and                                     •   hypersegmentation of neutrophils (five to six lobes instead of two to four; this is a specific
 haematological folate deficiency in Canadian subjects on                                            sign)
 folate intakes of 150-200 μg/day (Hoppner et al., 1977;                                         •   megaloblastic anaemia (this is a sign of folate deficiency, but it can also occur as a result of
 Hoppner and Lampi, 1980).
                                                                                                     vitamin B12 deficiency alone)
                                                                                                 •   lowering of granulocyte and platelet counts with the advancement of anaemia
                                                                                                 •   megaloblastosis can affect the epithelial cells of the entire gastrointestinal tract and can
                                                                                                     impair the absorption of folate and further exacerbate the deficiency state.
                                                                                                 Folate deficiency has also been associated with (usually mild) forms of:
                                                                                                 •   irritability
                                                                                                 •   forgetfulness.
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<pre>chapter 08 | Folate                                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 49 of 179
8.4 Summary and conclusion                                                                       The Committee has objections against the scientific basis of EFSA’s
                                                                                                 dietary reference values, because it considers that the evidence for the
Table 29. Summary of the evaluation of EFSA’s AR and PRI values for folate
equivalents                                                                                      use of EFSA’s relatively high cut-off values for serum and erythrocyte
 Main findings, used for the conclusion                                                          folate is insufficient. The Committee prefers to use the lower cut-off values
 Aspect                         Conclusion          Comment
                                                                                                 used by HCNL, NCM and IOM, which are associated with the prevention
 EFSA’s ARs compared to         Difference >10%     EFSA’s AR is 25% higher than HCNL’s
 HCNL’s (=NCM’s) EARs                               EAR.                                         of clinical deficiency. The AR-value of HCNL and NCM (200 μg/d) is based
 EFSA’s PRIs compared to        Difference >10%     EFSA’s PRI is 10% higher than HCNL’s
 HCNL’s (=NCM’s) RDAs                               RDA.                                         on more data than the IOM’s AR (320 μg/d). The Committee does not
 Scientific basis of EFSA’s AR  Objections          EFSA and the reports used for comparison
                                                                                                 support NCM’s RI for women in the reproductive age range, because this
                                                    base the AR on the intake required to
                                                    maintain a cut-off value for serum and       value aims specifically at the subgroup of women who are going to be
                                                    erythrocyte folate. However, EFSA uses
                                                    relatively high cut-off values. The          pregnant. It has no objections against the scientific basis of HCNL’s
                                                    Committee prefers the cut-off values used
                                                    by HCNL.
                                                                                                 dietary reference values.
 Other findings                                                                                  The Committee has objections against EFSA’s PRI and AR for adults and
 Aspect                         Conclusion          Comment
 Differentiation between        Not applied by EFSA Consistent with the reports used for
                                                                                                 recommends maintaining HCNL’s reference values (Table 30).
 younger and older adults                           comparison.
 Differentiation between men    Not applied by EFSA Consistent with the reports used for         Table 30. AR and PRI for folate equivalents recommended for the Netherlands
 and women                                          comparison.                                                                                               Men and womena >18 years
                                                                                                   Average requirement (AR)                                   200 μg/day
                                                                                                   Population reference intake (PRI)                          300 μg/day
                                                                                                 a
                                                                                                    Note that women who wish to conceive are advised to use a supplement containing 400 μg/d of folic acid, starting
                                                                                                    at least four weeks prior to conception until the eighth week of pregnancy, in addition to these reference values.
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<pre>chapter 09 | Vitamin B12 (cobalamin)                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 50 of 179
09
vitamin B12
(cobalamin)
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<pre>chapter 09 | Vitamin B12 (cobalamin)                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 51 of 179
                                                Vitamin B12                                                    9.1 Overview and comparison of values
                                                                                                               Table 31. Overview of the reference values for adults and the criteria on which these
          Should EFSA's reference values be rejected                                                           values are based
          based on a specific nutritional context in the                                 YES
        Netherlands that differs from (the rest of) Europe?
                                                                                                                 Report         PRI/RDA/AI/RI          AR         CV        Main criterion
                                                                                                                                Type        (μg/d)     (μg/d)     (%)
                                                                                                                 EFSA           AI          4          -          -         Four status/function parameters: serum holoTC
                                                                                                                 201515                                                     & cobalamin, MMA & tHcy and in consideration
                                                                                                                                                                            of observed intakes in several EU countries.
                                 NO
                                                                                                                 HCNL           RDA         2.8        2.0        20%       Factorial method: requirement is intake needed
                                                                                                                 200335                                                     to compensate 0.2% daily loss of body store in
                                                                                                                 = HCNL                                                     liver of 0.5 mg, at absorption rate 50%: AR = 2
                                                                                                                 201433                                                     μg/d.
       Are there objections against EFSA’s scientific basis                                                      NCM 201437 RI              2.0        1.4        15%       Prevention of haematological abnormalities: In
                         for this nutrient?                                                                                                                       (20%1)    20 patients with pernicious anaemia, an
                                                                                                                                                                            intramuscular 0.5-2.0 μg/d normalised and
                                                                                                                                                                            maintained haematological status, and 0.5-1.0
                                                                                                                                                                            μg was sufficient for most subjects. Because
                                              YES                                                                                                                           these patients are unable to reabsorb B12 from
                                                                                                                                                                            bile, healthy individuals need somewhat less.
                                                                                                                                                                            In NNR 2004, AR was estimated to be 0.7 μg/d.
                                                                                                                                                                            At absorption rate of 50%, AR = 1.4 μg/d.
                      Do (part of) EFSA's reference values differ 10% or                                         DACH           RDA         3.0        2.0        25%a      Prevention of haematological abnormalities
       NO                                                                                YES
                       more from the 2014 values for the Netherlands?                                            201538                                                     and status parameter: Plasma cobalamin
                                                                                         AI                                                                                 concentration and haematological parameters.
                                                                                                                 IOM 199842     RDA         2.4        2.0        10%       Factorial method: 1) estimate intramuscular
                                                                                                                                                                            requirement for adequate hematological status
                                                                                                                                                                            (stable Hb, normal MCV & reticulocyte
                                               NO
                                                                                                                                                                            response): 1.5 μg/d; 2) subtract losses via bile:
                                                                                                                                                                            0.5 μg/d; 3) correct for bioavailability: 50%.
                                                                                                                                                                            Result: EAR = 2.0 μg/d.
                                                                                                                 WHO/FAO        RI          2.4        2.0        10%       WHO/FAO adopted IOM 1998.
            No objections against the use of                   Major objection against the use of                200444
      EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands         a
                                                                                                                  CV calculated as 100% x [ ( PRI/RI/RDA – AR ) / 2 ] / AR.
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<pre>chapter 09 | Vitamin B12 (cobalamin)                                                                         An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 52 of 179
Table 31 presents an overview of reference values and criteria. EFSA set                                              • The cross-sectional study by Bor et al. (2010), providing information on
an AI for vitamin B12, whereas the reports used for comparison set an AR                                                   biomarker levels in quintiles of estimated vitamin B12 intake (Table 32).
and PRI. The RDAs/RIs in these other reports are substantially lower than                                             • The findings in the placebo-group of the intervention study by Pentieva
EFSA’s AI: HCNL -30%; NCM -50%; DACH -25%; IOM and WHO/FAO                                                                 et al. (2012), which provides information on biomarker levels at the
-40%. The coefficients of variation used in the reports used for comparison                                                average background vitamin B12 intake of 4 μg/day.c
to calculate the RDA/RI from AR ranged between 10% and 25%.                                                           The EFSA Panel concludes that data on the dose–response relationships
                                                                                                                      between vitamin B12 intake and biochemical parameters, considered
9.2 Explanation of differences between reports                                                                        together, are limited. The available findings provide consistent evidence
This paragraph focuses on the differences between EFSA and HCNL,                                                      that a vitamin B12 intake of 4 μg/day is associated with adequate levels of
NCM and IOM, because DACH does not clearly describe how they arrived                                                  all four biomarkers, indicating an adequate vitamin B12 status. EFSA
at the reference values, and WHO/FAO adopted the reference values of                                                  added that the observed (average) intakes of adults in several EU
IOM. EFSA’s AI is based on biochemical parameters of status and                                                       countries range between 4.2 and 8.6 μg/day.
function; the ARs of HCNL and IOM are based on a factorial method, and                                                HCNL and IOM both established an AR of 2.0 μg/day, based on the
the AR of NCM on the prevention of haematological abnormalities.                                                      factorial method.
                                                                                                                      EFSA did explore the factorial approach, but rejected this method,
EFSA uses four biomarkers to establish the AI. This combination of                                                    considering that – depending on the assumptions used – the estimates
biomarkers is required, because of the limitations of each individual                                                 ranged widely (5-15 μg/day). The Committee notes that even the lowest of
biomarker and uncertainties with respect to the cut-off values.a EFSA                                                 EFSA’s factorial estimates are substantially higher than HCNL’s and IOM’s
bases the AI on twob studies:                                                                                         AR. The main reason is, that EFSA’s factorial method aimed at maintaining
                                                                                                                      body stores of 2 and 3 mg, which is the average body content in healthy
a
  Paragraph 2.4.6 of EFSA report: “The Panel considers that serum holoTC is the most specific and therefore the
  first ranked biomarker to characterise adequate cobalamin status. In addition, the Panel considers that cut-off
  values of reference ranges for these biomarkers have not yet been clearly defined.”                                 c
                                                                                                                        The intervention study by Pentieva et al. (2012) provided data in 231 UK subjects with an average background
b
  In paragraph 5.1.1.3 of EFSA report a third study is described: the Norwegian observational study by                  vitamin B12 intake of 4 μg/day, receiving either placebo or a vitamin B12 supplement with 3.4, 12.7 or 46.1 μg/
  Vogiatzoglou et al. (2009). EFSA Panel does not use this study for setting the AI, because it provides information    day; this study provides no information on intakes below 4 μg/day. In the placebo group (approximately 60
  on biomarker-levels only for intakes >5 μg/day, i.e. for the mean daily vitamin B12 intakes in four groups: middle-   subjects), mean values for plasma holoTC, cobalamin, MMA and tHcy were adequate (note that mean MMA was
  aged men (7.3 μg/day) and women (5.5 μg/day), and older men (6.9 μg/day) and women (5.1 μg/day). In all               220 nmol/L and was thus within the range of proposed upper limits: 210 to 450 nmol/L). In all three groups using
  groups, the average biomarker levels were adequate.                                                                   vitamin B12 supplements, the levels of all four biomarkers were adequate.
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<pre>chapter 09 | Vitamin B12 (cobalamin)                                                                         An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 53 of 179
adults, whereas HCNL and IOM aimed at maintaining body stores of 0.5                                                 9.3 Conclusion on the scientific basis of EFSA’s reference
mg, which is the lowest body content in individuals with no haematological                                                    values
symptoms of vitamin B12 deficiency.                                                                                  The Committee notes that, in the study by Bor et al. (2010), adequate levels
NCM’s AR of 1.4 μg/day refers to the intake associated with the                                                      of all four biomarkers were reported at a vitamin B12 intake of 4.2 μg/day,
maintenance of a normal haematological status.                                                                       but also at an intake of 2.8 μg/day (Table 32), so that these findings appear
                                                                                                                     to comply with an AI of 2.8 μg/day. The study by Pentieva et al. (2012) is not
Differences between older and younger adults and sex differences                                                     suitable for assessing the adequacy of intakes below 4 μg/day, because the
None of the reports differentiate the reference values between younger                                               average background vitamin B12 intake was 4 μg/day. Although the intake of
and older adults or between men and women. There are insufficient data                                               4 μg/day is associated with adequate levels of the four biomarkers, the
to differentiate between men and women.                                                                              evidence presented indicates that a lower intake than 4 μg/day may also be
                                                                                                                     adequate. EFSA does not present evidence that the AI of 4 μg/day would
Table 32. EFSA’s information with respect to cut-off values for the four biochemical
                                                                                                                     provide additional health benefits, in comparison to an intake of 2 μg/day.
parameters used to set the AIa
                                                                                                                     Therefore, the Committee has objections against the scientific basis of
  Biochemical                Information provided in the EFSA report
  parameters                 Ranges of parameter         Results in the reference by Bor et al., 201050              EFSA’s AI.a
  considered by              cut-off values for          Parameter level at observed              Intake above
  EFSA to set the AI         vitamin B12                 intakesb                                 which the
                                                                                                                     The EFSA report does not present publications relating vitamin B12 intake
                             insufficiency               Intake 2.8 μg/d      Intake 4.2 μg/d     parameter          levels with the occurrence, correction or prevention of vitamin B12
                                                                                                  levelled off
  Serum holotrans-           Range of lower limits:      50 pmol/L            65 pmol/L           4 μg/d             deficiency, but EFSA does mention that intakes of 1.5-2 μg/day seem to
  cobalamin (holoTC)         11-48 pmol/L.
                                                                                                                     represent a minimum requirement for maintenance of a normal
  Serum cobalamin            Range of lower limits:      325 pmol/L           350 pmol/L          7 μg/d
                             134-178 pmol/L.                                                                         haematological status, and is associated with body stores of 1-2 mg. Note
  Serum methylmalonic Range of upper limits:             210 nmol/L           200 nmol/L          3-7 μg/d
  acid (MMA)                 210-450 nmol/L.                                                                         that NCM associated an intake level of 1.4 μg/day with the maintenance of
  Plasma total               Frequently used upper 8 μmol/L                   7 μmol/L            4-7 μg/d
                                                                                                                     a normal haematological status.
  homocysteine (tHcy)        limit: tHcy >15 μmol/L
a
   The study by Bor et al. (2010) comprised 300 USA men and women. Biomarker values were reported for quintiles
   of B12 intake, each comprising around 60 subjects.
b
   Two intake levels are the most relevant here (quintiles 2 and 3) and are therefore reported. Quintile 2: median
   intake 2.8 μg/d (range 2.1-3.4 μg/d). Quintile 3: median intake 4.2 μg/d (range 3.4-5.3 μg/d).
                                                                                                                     a
                                                                                                                       Note that the NCM report mentions that cross-sectional population studies have shown that biochemical
                                                                                                                       indicators of vitamin B12 status are stabilised at intakes of about 4-10 μg/d among adults, but that it is unclear
                                                                                                                       whether intakes in this range are associated with long-term benefits.
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<pre>chapter 09 | Vitamin B12 (cobalamin)                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 54 of 179
HCNL’s AR (2 μg/day) is based on the factorial method aimed at                                            9.4 Summary and conclusion
maintaining the lowest body content in individuals with no haematological
                                                                                                          Table 33. Summary of the evaluation of EFSA’s AI values for vitamin B12
symptoms of vitamin B12 deficiency. The Committee has no objections                                        Main findings, used for the conclusion
                                                                                                           Aspect                    Conclusion           Comment
against the scientific basis of HCNL’s AR.                                                                 EFSA’s AI compared to     Differences >10%     EFSA’s AR is 40-45% higher than HCNL’s RDA.
                                                                                                           HCNL’s RDA 2003
                                                                                                           Scientific basis of       Objections           The evidence EFSA uses to establish their AI
                                                                                                           EFSA’s AI                                      indicates that lower intakes may also be
  Background information – a summary of the information provided by the EFSA report – on                                                                  adequate, based on the biomarker levels used by
  the function of the nutrient, the occurrence of clinical deficiency and deficiency symptoms                                                             EFSA as the scientific basis.
  in adults                                                                                                Other findings
                                                                                                           Aspect                    Conclusion           Comment
  In humans, two reactions are known to require cobalamin as coenzyme. One is the conversion of            Differentiation between   Not applied by EFSA  Consistent with the reports used for comparison.
  methylmalonyl-CoA to succinyl-CoA. The other is the transmethylation of homocysteine to                  younger and older adults
  methionine by methionine synthase; cobalamin and folate are both required and interact in this           Differentiation between   Not applied by EFSA  Consistent with the reports used for comparison.
  reaction.                                                                                                men and women
  In Western populations, vitamin B12 deficiency may occur in vegans, in older adults with atrophic
  gastritis or pernicious anemia (resulting in malabsorption of cobalamin bound to food), and in          The Committee has objections against the scientific basis of EFSA’s AI and
  people with Imerslund-Gräsbeck syndrome.                                                                thus against EFSA’s AI, because a lower intake may be sufficient to achieve
  Symptoms:
  •   megaloblastic anaemia (this is a sign of vitamin B12 deficiency, but it can also occur as a         EFSA’s cut-off values for biomarkers, and EFSA presents no evidence that
      result of folate deficiency alone; the onset occurs later in cobalamin deficiency)                  their relatively high AI would provide additional health benefits.
  •   neurological dysfunction (including myelopathy, neuropathy and neuropsychiatric
      abnormalities, and less often optic nerve atrophy; due to progressive demyelinating lesions of      The Committee has no objections against the scientific basis of HCNL’s
      the white matter in the spinal cord and brain). Clinical cerebral features are associated with      AR. This factorial method is related to the prevention of deficiency.
      mental symptoms, such as irritability, memory disturbances, depression. In severe deficiency
      or advanced stages, a dementia-like illness, frank psychosis with hallucinations and paranoia       HCNL’s AR is consistent with the AR in most of the reports used for
      may occur.                                                                                          comparison, although NCM set an even lower AR (1.4 μg/day).
                                                                                                          The Committee has objections against EFSA’s AI for adults, and
                                                                                                          recommends maintaining HCNL’s reference values (Table 34).
                                                                                                          Table 34. AR and PRI for vitamin B12, recommended for the Netherlands
                                                                                                                                                         Men and women >18 years
                                                                                                           Average requirement (AR)                      2.0 μg/day
                                                                                                           Population reference intake (PRI)             2.8 μg/day
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<pre>chapter 10 | Vitamin C (ascorbic acid)                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 55 of 179
10
vitamin C
(ascorbic acid)
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<pre>chapter 10 | Vitamin C (ascorbic acid)                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 56 of 179
                                                Vitamin C                                                     10.1 Overview and comparison of values
                                                                                                              Table 35. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected                                                           values are based
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?                                                     Report    PRI/RDA/AI/RI  AR      CV      Main criterium
                                                                                                                         (mg/d)         (mg/d)
                                                                                                                         Type ♂     ♀   ♂    ♀
                                                                                                               EFSA      PRI    110 95  90   80 10      In healthy, non-smoking men, an intake of 90 mg/d
                                                                                                               201329                                   (AR♂) balances metabolic losses at a saturated
                                NO
                                                                                                                                                        body pool of 1.5 gram (metabolic losses 50 mg/d),
                                                                                                                                                        taking into account that urinary losses are 25% of
                                                                                                                                                        intake and absorption is 80% of intake. The AR for
                                                                                                                                                        women is extrapolated from the AR for men by
      Are there objections against EFSA’s scientific basis                                                                                              isometric scaling (linear with body weight).
                        for this nutrient?                                                                     NCM       RI     75  75  60   50 ♂12,5% Status parameter: plasma ascorbate concentration
                                                                                                               201437                           ♀25%    of 32 μmol/L is associated with a lowered risk of
                                                                                                               = HCNL                                   chronic diseases. Pharmacokinetic data indicate
                                                                                                               201433                                   that such concentration corresponds to a body pool
                                             YES                                                                                                        of 1.0 -1.2 g, and to an intake of 60 mg/d in men
                                                                                                                                                        and 50 mg/d in women. This is close to the intake
                                                                                                                                                        at which vitamin C begins to be excreted in the
                                                                                                                                                        urine.
                     Do (part of) EFSA's reference values differ 10% or                                                                                 The CV for women was assumed to be double that
      NO                                                                                YES
                      more from the 2014 values for the Netherlands?                                                                                    for men, to ensure adequate non-haem iron
                                                                                   PRIs & ARs                                                           absorption.
                                                                                                               DACH      RDA    110 95  91   77 10      As EFSA.
                                                                                                               201538,51
                                                                                                               IOM 20002 RDA    90  75  75   60 10      Status parameter: neutrophil ascorbate
                                              NO
                                                                                                                                                        concentration at near-maximal level (80%),
                                                                                                                                                        because of its relationship with antioxidant
                                                                                                                                                        protection.
                                                                                                               WHO/FAO   RI     45  45  25-30   25-40% Maintenance of a body content of 0.9 g vitamin C,
           No objections against the use of                   Major objection against the use of               200444                                   assuming an absorption efficiency of 85%, and a
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands                                                   catabolic rate of 2.9%. The body content of 0.9
                                                                                                                                                        gram is halfway between tissue saturation (1.5 g),
                                                                                                                                                        and the point at which clinical signs of scurvy
                                                                                                                                                        appear (0.3-0.4 g)
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<pre>chapter 10 | Vitamin C (ascorbic acid)                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 57 of 179
Table 35 shows that EFSA’s PRI equals the RDA by DACH. The values by                                          plasma ascorbate concentration of about 45-50 μmol/L.b Taking a
IOM, NCM and WHO/FAO are lower (-20%, -27% and -56% relative to                                               conservative approach, and based on the fact that a complete set of data
EFSA’s PRIs).                                                                                                 was only available in men, the EFSA Panel selected metabolic losses of
                                                                                                              50 mg/day, an absorption of 80% and a urinary excretion of 25% of the
10.2 Explanation of differences between reports                                                               vitamin C intake and calculated that an intake of 90 mg vitamin C per day,
The scientific basis for the reference values for vitamin C varies                                            on average, is required to balance daily losses in men.c
substantially between the reports. The ARs by EFSA, DACH and WHO/                                             The EFSA Panel notes that women reach the plasma concentration of 50
FAO are based on the metabolic losses at a certain body pool of vitamin                                       μmol/L with a slightly lower intake of vitamin C compared to men. No data
C; EFSA and DACH aim at a saturated body pool (1.5 gram), whereas                                             on metabolic losses were available for women, and therefore, EFSA set
WHO/FAO aims at a body pool of 0.9 gram. NCM’s reference values are                                           the AR for women by extrapolating the AR for men, using isometric scaling
based on a plasma ascorbic acid concentration of 32 μmol/L, which is                                          (linear with the reference body weights of 68.1 for men and 58.5 for
associated with a body pool of 1.0-1.2 gram. IOM’s ARs are based on the                                       women).d
neutrophil ascorbate concentration. In this paragraph the methods are                                         Assuming a CV of 10%, PRIs of 110 and 95 mg vitamin C per day are
described in more detail.                                                                                     derived for men and women, respectively. EFSA notes that in almost all
                                                                                                              healthy men, the intake of 110 mg/day is associated with a plasma
The EFSA Panel decided to determine the AR for vitamin C in healthy                                           ascorbate concentration above 50 μmol/L.
adults from the vitamin C intake that balances metabolic vitamin C losses
and maintains fasting plasma ascorbate concentrations at about 50                                             DACH follows the same line of reasoning as EFSA, resulting in the same
μmol/L. In healthy non-smokinga men aged 20-45 years the maximum                                              reference values as EFSA.
metabolic losses of vitamin C were estimated to be about 3.0% of a
saturated body pool of 1.5 gram: 40-50 mg/day, corresponding to a
                                                                                                              b
                                                                                                                EFSA mentions that vitamin C intakes above 200 mg/day progressively elevate the plasma concentration to a
                                                                                                                plateau of 70-80 μmol/L or even above, at the expense of a dramatic increase in urinary excretion.
                                                                                                              c
                                                                                                                 AR for men (mg/d) = 50 mg/d / ((80%-25%)/100) = 50 mg/d / 0.55 = 91 mg/d, rounded to 90 mg/d.
a
  EFSA notes that smokers have higher metabolic losses compared to non-smokers at similar vitamin C intakes.  d
                                                                                                                 AR for women (mg/d) = 91 mg/d x (58.5/68.1) = 78 mg/d, rounded to 80 mg/d.
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<pre>chapter 10 | Vitamin C (ascorbic acid)                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 58 of 179
NCM set the AR at the vitamin C intake required to achieve a plasma             Thus, IOM extrapolated the AR for men to the AR for women, based on
ascorbate concentration of 32 μmol/L, which is associated with a body pool      body weight differences.
of 1-1.2 g. NCM notes that a concentration of 23 nmol/L and a body pool of
0.9 mg would be sufficient to prevent scurvy. NCM uses the higher cut-off       WHO/FAO bases their reference values on the body content of 0.9 gram,a
value of 32 mmol/L to set the AR. This is the unweighted mean of the            which is halfway between tissue saturation (1.5 g), and the point at which
cut-off points in eight population studies associated with clearly lowered      clinical signs of scurvy appear (0.3-0.4 g). WHO/FAO notes that the last
risk to mortality from chronic diseases, such as cancer and cardiovascular      signs of deficiency have disappeared when the body content reaches
diseases. NCM’s cut-off point for plasma ascorbate concentration                about 1.0 gram.
corresponds with intakes of 60 g/d in men and 50 g/d in women.                  WHO/FAO’s RI is based on the 97.5th percentile of the catabolic rate of
NCM notes that women have slightly higher plasma vitamin C                      4.1%, which was calculated as the estimated mean catabolic rate (2.9%)
concentrations for a given level of intake, and therefore, NCM’s AR for         plus two times the estimated standard deviation (0.6%). The 97.5th
women is slightly lower than NCM’s AR for men. However, NCM’s                   percentile of metabolic losses is then calculated to be 37 mg, which is
RI-values are equal for men and women, because NCM uses a higher                4.1% of the body content of 0.9 gram. Using an assumed absorption
coefficient of variation for women than for men in order to ensure              efficiency of 85%, WHO/FAO establishes the recommended intake of 45
adequate non-haem iron absorption in women (25% and 12.5%,                      mg per day.
respectively).                                                                  WHO/FAO notes that turnover studies in women were not available.
                                                                                Requirements in women are expected to be lower than in men because of
IOM based the AR on the vitamin C intake required to achieve a neutrophil       the smaller body size, however, in depletion-repletion studies plasma
ascorbate concentration at near-maximal level (80%), which would be             ascorbic acid concentrations fell more rapidly in women than in men.
relevant for antioxidant protection. As no similar data were available for      Therefore, to be prudent, WHO/FAO uses the RI for men also for women.
women, IOM assumed that women have a lower requirement due to their
smaller lean body mass, total body water, and body size. IOM notes that
this assumption was supported by the finding that women maintain higher
plasma ascorbate concentrations than men at a given vitamin C intake.           a
                                                                                  Note that the WHO/FAO report does describe the relationship between vitamin C intake and plasma ascorbic
                                                                                  acid, but does not use this for setting the AR and RI.
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<pre>chapter 10 | Vitamin C (ascorbic acid)                                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 59 of 179
WHO/FAO calculated the AR-range of 25-30a mg/day by interpolation                                              The Committee notes that research in women is insufficient for an
between 10 mg/day, which is the minimal intake to prevent against scurvy,                                      evidence-based choice between the EFSA/DACH/IOM approach and the
and the RI of 45mg/day.                                                                                        more prudent approach of NCM and WHO/FAO.
Differences between older and younger adults                                                                   10.3 Conclusion on the scientific basis of EFSA’s reference
None of the reports differentiate the reference values between younger                                               values
and older adults.                                                                                              The EFSA Panel considers that a saturated body pool (1.5 gram) and a
                                                                                                               plasma ascorbate concentration of 50 nmol/L is indicative of an adequate
Sex differences                                                                                                vitamin C status at which the different functions of vitamin C in the body
All organisations consistently note that the reference values for women                                        can be fulfilled, but does not provide evidence that this provides more
cannot be based on research in women, because the required studies are                                         health benefits than the maintenance of a smaller body pool or lower
not available for women. EFSA, DACH and IOM differentiate between                                              plasma ascorbate concentrations.
men and women based on the difference in reference weights for men                                             The Committee has objections against the scientific basis of EFSA’s
and women.                                                                                                     reference values.
Both NCM and WHO/FAO use the RI for men also for women, based on
different arguments. NCM uses the same RI for men and women, to                                                NCM’s AR-values are based on a plasma ascorbate concentration of 32
ensure adequate non-haem iron absorption in women (note that NCM’s                                             nmol/L, which in turn is based on the cut-off points in eight population
AR is lower for women than for men, based on the difference in reference                                       studies associated with lowered risk to mortality from chronic diseases.
body weights). WHO/FAO uses the same RI and AR for men and women,                                              The vitamin C intake associated with the prevention of deficiency is 10
as a prudent approach, because in depletion-repletion studies plasma                                           mg/day (Table 36).
ascorbic acid concentrations fell more rapidly in women than in men.                                           The Committee has no objections against the scientific basis of NCM’s
                                                                                                               reference values.
a
   Using the body content of 0.9 gram and the assumed average catabolic rate of 2.9%, the average metabolic
  losses were estimated to be 26 mg/d (2.9% of 0.9 gram). With an assumed absorption efficiency of 85%, the
  average requirement (after rounding) would be 30 mg per day.
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<pre>chapter 10 | Vitamin C (ascorbic acid)                                                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 60 of 179
                                                                                                          10.4 Summary and conclusion
    Background information – a summary of the information provided by the EFSA report –
    on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                                          Table 37. Summary of the evaluation of EFSA’s AI values for vitamin C
    symptoms
                                                                                                           Main findings, used for the conclusion
                                                                                                           Aspect                    Conclusion              Comment
    Vitamin C has a number of biochemical and physiological functions in the body which are largely
                                                                                                           EFSA’s ARs compared       Differences >10%         EFSA’s AR is 50% and 60% higher than HCNL’s
    dependent on its ability to provide reducing equivalents in various biochemical reactions. Vitamin
                                                                                                           to HCNL’s (=NCM’s)                                 (=NCM’s) ARs for men and women, respectively.
    C is an enzyme cofactor for biochemical reactions catalysed by monooxygenases, dioxygenases            ARs
    and mixed function oxygenases. Vitamin C plays an important role in the biosynthesis of                EFSA’s PRIs compared      Differences >10%         EFSA’s PRI is 45% and 25% higher than HCNL’s
    collagen and the synthesis of carnitine. Vitamin C is a cofactor in the conversion of dopamine to      to HCNL’s (=NCM’s) RIs                             (=NCM’s) RI, for men and women, respectively.
    noradrenaline, is involved in the metabolism of cholesterol to bile acids, and has various other       Scientific basis of       Objections               EFSA does not provide evidence that a saturated
    effects in the body.                                                                                   EFSA’s ARs                                         body pool (1.5 gram) and plasma ascorbate
    The EFSA report does not provide information on the occurrence of vitamin C deficiency. The                                                               concentrations > 50 nmol/L provide more health
    IOM report2 notes that scurvy is rare in developed countries, but is occasionally seen in                                                                 benefits than the maintenance of a smaller body
                                                                                                                                                              pool and lower plasma ascorbate concentrations.
    individuals who consume few fruits and vegetables, have peculiar or restricted diets, or in those
                                                                                                           Other findings
    who abuse alcohol or drugs.
                                                                                                           Aspect                    Conclusion              Comment
    Symptoms of vitamin C deficiency:
                                                                                                           Differentiation between   Not applied by EFSA      Consistent with the reports used for comparison.
    •   Scurvy, characterised by symptoms related to connective tissue defects that result from a
                                                                                                           younger and older adults
        weakening of collagenous structures (tooth loss, joint pain, bone and connective tissue
                                                                                                           Differentiation between   Applied by EFSA          Consistent with the reports used for comparison.
        disorders, and poor wound healing).                                                                men and women
    •   Depression, hypochondria and mood changes are frequently associated with scurvy and
        may be related to deficient dopamine hydroxylation.
                                                                                                          The Committee has objections against the scientific basis of EFSA’s
    •   Early or prescorbutic symptoms also include fatigue, lethargy, anaemia, aching joints, and
        muscle weakness.                                                                                  reference values. There is insufficient evidence for using a saturated body
                                                                                                          pool of vitamin C and plasma ascorbate concentrations > 50 nmol/L as the
                                                                                                          basis for setting the reference values.
Table 36. Vitamin C intake level associated with the prevention of deficiencies, as                       The Committee recommends maintaining HCNL’s reference values, which
described by EFSA
                                                                                                          are the reference values presented in the NCM report (Table 38).
 Clinical manifestation     Associated          Subjects/       EFSA’s reference
 associated with            intake              Specific
 deficiency                                     group                                                     Table 38. AR and PRI for vitamin C, recommended for the Netherlands.
 No scurvy                  10 mg/d             5 adult men     Baker et al., 1971; Levine, 1986; Weber                                               Men >18 years                 Women >18 years
                                                                et al., 1996; Burri & Jacob, 1997          Average requirement (AR)                   60 mg/d                       50 mg/d
                                                                                                           Population reference intake (PRI)          75 mg/d                       75 mg/d
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<pre>chapter 11 | Vitamin D (ergocalciferol and cholecalciferol) An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 61 of 179
11
vitamin D (ergocalciferol
and cholecalciferol)
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<pre>chapter 11 | Vitamin D (ergocalciferol and cholecalciferol)                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 62 of 179
                                                 Vitamin D                                                    11.1 Overview and comparison of values
                                                                                                              Table 39. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected                                                           values are based
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?
                                                                                                               Report        Age group AR/RI/RDA        AR     CV (%) Main criterion
                                                                                                                                       Type (μg/d)      (μg/d)
                                                                                                               EFSA 20168    ≥1 yr      AI    15a                     Serum 25(OH)D2 >50 nmol/L
                                                                                                               HCNL 201234   0-69 yr    AI    10a                     Serum 25(OH)D >30 nmol/L, and
                                NO                                                                             = HCNL 201433                                          taking into account that (1) there
                                                                                                                                                                      are no signs that everyone in this
                                                                                                                                                                      group requires vitamin D
                                                                                                                                                                      supplementation and (2) that in
                                                                                                                                                                      Dutch people with lighter skin
      Are there objections against EFSA’s scientific basis                                                                                                            types, the average vitamin D
                        for this nutrient?
                                                                                                                                                                      production is 7 μg/day, and the
                                                                                                                                                                      average dietary intake is 3 μg/day.
                                                                                                                                                                      There is convincing evidence that
                                                                                                                             >70 yr     RDA 20a         10            daily supplementation with 10 to 20
                                             YES                                                                                                                      μg vitamin D in combination with
                                                                                                                                                                      (in most studies 1 g/d) calcium
                                                                                                                                                                      reduces the risk of bone fractures.
                                                                                                               NCM 201437    1-74 yr    RI    10c (20a) 7.5c   17%d   Serum 25(OH)D >50 nmol/L
                     Do (part of) EFSA's reference values differ 10% or                                                      >75 yr     RI    20                      Serum 25(OH)D >50 nmol/L and
      NO                                                                                YES
                      more from the 2014 values for the Netherlands?                                                                                                  convincing evidence on a
                                                                                        AIs                                                                           protective effect of vitamin D on
                                                                                                                                                                      bone health, total mortality, and the
                                                                                                                                                                      risk of falling, mainly seen for
                                              NO                                                                                                                      combined supplementation with
                                                                                                                                                                      vitamin D and calcium.
                                                                                                               DACH 201538   >1 yr      AI    20a                     Serum 25(OH)D >50 nmol/L.
                                                                                                               IOM 2011 39
                                                                                                                             1-70 yr    RDA 15   a
                                                                                                                                                        10 a
                                                                                                                                                               25% d
                                                                                                                                                                      AR: serum 25(OH)D >40 nmol/L
                                                                                                                                                                      RDA: serum 25(OH)D >50 nmol/L
           No objections against the use of                   Major objection against the use of                             >70 yr     RDA 20a         10a    50%d   At high age there is more
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands
                                                                                                                                                                      variability, therefore although AR is
                                                                                                                                                                      the same, RDA is higher.
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<pre>chapter 11 | Vitamin D (ergocalciferol and cholecalciferol)                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 63 of 179
  Report              Age group AR/RI/RDA                  AR         CV (%)   Main criterion
                                     Type (μg/d)           (μg/d)
                                                                                                                      However, the NCM report is an exception: NCM’s primary RI value refers
  WHO/FAO             <50 yr         AI      5a                                Serum 25(OH)D >27 nmol/L,              to conditions of normal cutaneous vitamin D synthesis. NCM does
  200444              51-65 yr       AI      10a                               based on IOM 1997.
                      >65 yr         AI      15a                               Factors declining with age: skin       mention that the recommended intake for people with little or no sun
                                                                               synthesis (linear decrease as the
                                                                               skin thins from 20 y), rate of
                                                                                                                      exposure is 20 μg/d. Note that the latter value is used for the comparison
                                                                               activation to the hormonal form of     with other reports, so that the comparison of reports which is presented
                                                                               vitamin D, response of target
                                                                               tissues (e.g. bone).                   below, refers consistently to conditions of minimal cutaneous vitamin D.
a
   Under conditions of minimal cutaneous vitamin D synthesis. In the presence of endogenous cutaneous vitamin D
   synthesis, the requirement for dietary vitamin D is lower or may even be zero.
b
   Serum 25(OH)D concentration is the main form of vitamin D in the blood circulation. It is used as a biomarker of
   vitamin D status in adult and children populations. It reflects the amount of vitamin D attained from both         Comparison of the values for conditions with minimal cutaneous
   cutaneous synthesis and dietary sources.
c
   The RI set by NCM applies to conditions of normal cutaneous vitamin D synthesis. In the text NCM mentions that
                                                                                                                      vitamin D synthesis
   the recommended intake for people with little or no sun exposure is 20 μg/d.
                                                                                                                      Younger adults: Table 39 shows that, under conditions of minimal
d
   CV calculated as 100% x [ ( RDA/RI - AR ) / 2 ] / AR.
                                                                                                                      cutaneous vitamin D synthesis, EFSA’s AI equals IOM’s RDA, but HCNL
Cutaneous vitamin D synthesis                                                                                         and WHO/FAO use a lower AI/RI (-33% and -67%), whereas NCM and
In most people, the vitamin D supply is met partly by cutaneous vitamin D                                             DACH use a higher value (both +33%).
synthesis and partly by dietary intake. The cutaneous vitamin D synthesis                                             Older adults: EFSA’s AI is 25% lower than the RI/RDA values of HCNL,
depends on sunlight exposure of the skin and on skin type. In the EFSA                                                NCM, DACH and IOM. Note that for older adults, HCNL’s RDA and NCM’s
report and in most of the reports used for comparison, the reference                                                  RI are independent of cutaneous vitamin D synthesis, whereas the values
values for vitamin D intake refer to conditions of minimal cutaneous                                                  by EFSA, DACH and IOM refer to conditions of minimal cutaneous vitamin
vitamin D synthesis, because:                                                                                         D synthesis.
• cutaneous vitamin D synthesis depends on the latitude and can
      therefore better be estimated for the country or region where the                                               11.2 Explanation of differences between reports
      reference value is applied                                                                                      The WHO/FAO-values are based on the 1997 IOM reference values. As
• reference values are based mainly on studies carried out under                                                      IOM updated the reference values for vitamin D, WHO/FAO is left out of
      conditions of minimal cutaneous vitamin D.                                                                      consideration in the next paragraphs.
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All reports base their reference value on a biochemical parameter of                                             average vitamin D production in the skin of 7 μg/d over the course of the
status (serum 25-hydroxyvitamin D or 25(OH)D), but different cut-off                                             entire year.c Because there are no signs that all adults require vitamin D
values for 25(OH)D are used: EFSA, NCM, DACH and IOM use a cut-off                                               supplementation, HCNL set the AI at the value of 10 instead of 15 μg/
value of 50 nmol/L, whereas HCNL uses a cut-off value of 30 nmol/L.                                              day.34 Based on three publications by Cashman et al., almost everyone in
                                                                                                                 this group will have 25(OH)D levels >25 nmol/L with a vitamin D supply of
Furthermore, estimates of the vitamin D supply required to achieve                                               10 μg/day.34 A recent publication Cashman et al. confirms this estimate.52
25(OH)D levels of at least 50 nmol/L differ between the reports: according
to EFSA and IOM this cut-off level requires 15 μg/day, whereas NCM and                                           Sex differences
DACH estimate that this requires 20 μg/day. Estimates depend on the                                              None of the reports differentiate the AIs between men and women.
type of data used in the regression analysis, which may be either the
group/study averages, or data on individual subjects. The intake at which                                        Differences between older and younger adults
97.5% of the population achieves a serum 25(OH)D concentration above                                             EFSA does not differentiate the AI between younger and older adults,
50 nmol per litre is estimated to be 10-12 μg/day if group/study averages                                        whereas most of the reports used for comparison do. For older adults.
are used, but 20-25 μg/day if data on individual subjects are used.34,52                                         EFSA, HCNLd, NCM, DACH and IOM consistently aim at a serum 25(OH)
The Committee prefers regression analyses based on data of individual                                            D >50 nmol/L. For this age group, the evidence on the preventive effect of
subjects for setting the AI, because the AI aims to cover the needs of                                           vitamin D against fractures in older adults is also considered:
almost all individuals in the population.a                                                                       • HCNL, NCM, DACH and IOM consider the results from randomised
HCNL estimated that an intake of 11-15 μg/day was required to achieve a                                              controlled trials: the intake or supplemental levels used in these trials
serum 25(OH)D >30 nmol/L in almost all adults <70 years. However, the                                                and their effect on fracture risk.
estimated total vitamin D supply in Dutch adults with light skin types was
lower: 10 μg/d, based on a median intake of about 3 μg/day,b and an
                                                                                                                 c
                                                                                                                   This estimate was based on Dutch and British studies and refers to subjects with sufficient sunlight exposure of
                                                                                                                   the skin. Estimates by calendar month ranged between 0 μg/d (December/January) and 13 μg/d (June/July), but
a
  Estimates from regression analysis on group/study averages are too low, because between-person variation is      these estimates were based on indirect calculations and simple models, and therefore, they should be interpreted
  not taken into account. Estimates based on individual data do take between-person variation into account.        with caution.34
b
  The estimated median intake of Dutch adults of Dutch descent was about 3 μg/day. The estimated mean intake of  d
                                                                                                                   HCML considered that, based on data of individual subjects, 50% of the people aged >70 years achieve a 25(OH)
  Dutch adults of Turkish or Moroccan descent was about 2 μg/day.                                                  D >50 nmol/L with an intake of 10 μg/d; and 97.5% achieve 25(OH)D >50 nmol/L with intakes of 20-25 μg/d.
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• EFSA considers 25(OH)D levels associated with fracture risk, but            • For 4-69 year olds, HCNL uses a serum level of 25(OH)D >30 nmol/L,
   considers that the results from randomised controlled trials are not          which is the target value for young children based on the risk of rickets.
   useful as such for setting DRVs for vitamin D.                                HCNL did not consider the findings on intermediate measures of bone
In HCNL’s report on vitamin and mineral supplements,53 which served as a         health, such as bone density and calcium absorption (which could have
background report for the Dutch dietary guidelines 2015, HCNL concluded          led to a higher 25(OH)D target value), because HCNL considered that
that there was strong evidence from intervention studies that the use of         the meaning of these intermediate measures for bone health was
supplements with 10-20 μg/d vitamin D per day plus 0.5-1.2 g/d calcium           insufficiently clear.
reduces the risk of fractures by 10% and reduces the risk of hip fractures    • EFSA provides the following scientific basis for their use of 25(OH)D
by 15% in older adults and especially postmenopausal women.                      >50 nmol/L:
                                                                                 • “Some evidence” for a higher risk of increased loss of bone mass
11.3 Conclusion on the scientific basis of EFSA’s reference                         density / bone mass concentration with serum 25(OH)D <50 nmol/L.
      values                                                                        Note that HCNL considered that the meaning of these intermediate
                                                                                    measures for bone health was insufficiently clear.34
Reference values for older adults                                                • “Limited evidence” that osteomalacia was reported at 25(OH)D <20
The Committee has objections to the scientific basis of EFSA’s adequate             nmol/L and that risk appears to be small with serum 25(OH)D >50
intake for older adults: the Committee considers – unlike the EFSA Panel            nmol/L.
– that the reference values for adults aged >70 years can be based on the     • IOM notes that “calcium absorption is maximal at serum 25(OH)D
results from randomised controlled trials on the effect of using                 concentrations between 30 and 50 nmol/L with no consistent increase
supplements with vitamin D and calcium on the risk of fractures.                 in calcium absorption above approximately 50 nmol/L.” “For the
                                                                                 purposes of ensuring public health in the face of uncertainty and
Reference values for younger adults                                              providing a reference value for stakeholders, a prudent approach is to
EFSA, NCM, DACH and IOM use a cut-off value of 50 nmol/L, whereas                begin the consideration of the DRIs for these age groups with the level
HCNL uses a cut-off value of 30 nmol/L:                                          of 25OHD in serum that is consistent with coverage of the requirement
                                                                                 of nearly all adults in this age range, that is, 50 nmol/L.”
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<pre>chapter 11 | Vitamin D (ergocalciferol and cholecalciferol)              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 66 of 179
The Committee considers that the scientific evidence for the cut-off value
                                                                                    Background information – a summary of the information provided by the EFSA report –
of 50 nmol/L for 25(OH)D is not strong for adults <70 years; the use of this
                                                                                    on the function of the nutrient, and deficiency symptoms in adults
criterion appears to be a prudent approach. Furthermore, the Committee
                                                                                    In the body, vitamin D is converted to the main circulating form, calcidiol (25(OH)D), which can
considers that the cut-off value of 50 nmol/L would require a vitamin D             be transformed into the biologically active calcitriol (1,25(OH) 2D). The principal function of
supply of 20 μg/day, rather than EFSA’s estimate of 15 μg/day.34,52 In the          calcitriols is to maintain calcium and phosphorus homeostasis in the circulation, together with
                                                                                    parathyroid hormone and fibroblast growth factor. The main target tissues of calcitriols are the
Netherlands, all Dutch adults would need to take vitamin D supplements to           intestine, the kidneys and bone.
realise a supply of 20 μg/day. In 2012, HCNL considered that there were             The EFSA report does not provide information on the occurrence of vitamin D deficiency.
                                                                                    Symptoms in adults:
no signs that all Dutch adults would require vitamin D supplementation.34           •    Osteomalacia, caused by the impaired mineralisation of bone due to an inefficient absorption
The average supply of Dutch adults with light skin types who are                         of dietary calcium and phosphorus.
                                                                                    •    Clinical symptoms may include diffuse pain in muscles and bone, muscle pain and
sufficiently exposed to sunlight is 10 μg/day, which will result in 25(OH)D              weakness, poor physical performance, increased risk of falls/falling, and a higher risk of
levels >25 nmol/L in almost all individuals. The value of 25 nmol/L is                   bone fractures.
                                                                                    •    Prolonged vitamin D insufficiency may lead to low bone mineral density (BMD) and may
considered to be a threshold for vitamin D insufficiency52,54 although some              dispose older subjects, particularly post-menopausal women, to osteoporosis, a situation
organisations use a cut-off value of 30 nmol/L for this purpose.                         characterised by a reduction in bone mass, reduced bone quality and an increased risk of
                                                                                         bone fracture, predominantly in the forearm, vertebrae, and hip.
Therefore, the Committee has objections against the scientific basis of
EFSA’s reference values for vitamin D for adults aged <70 years.
Note that the EFSA report does not present research on the direct
relationship of intake levels and the occurrence, correction or prevention
of clinical deficiencies in younger adults.
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<pre>chapter 11 | Vitamin D (ergocalciferol and cholecalciferol)                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 67 of 179
11.4 Summary and conclusion                                                                         The Committee has objections against the scientific basis of EFSA’s
                                                                                                    reference values for vitamin D, and also against EFSA’s AI for adults.
Table 40. Summary of the evaluation of EFSA’s AI values for vitamin D
                                                                                                    In 2012, HCNL set reference values for vitamin D; the Committee has no
 Main findings, used for the conclusion
 Aspect                    Conclusion          Comment                                              objections against the scientific basis of these reference values. The
 EFSA’s AI compared to     Differences >10%    EFSA’s AI is 50% higher than HCNL’s AI for
 HCNL’s RDA 2003                               adults <70 years, but 33% lower than HCNL’s
                                                                                                    Committee recommends maintaining HCNL’s reference values and using
                                               RDA for adults >70 years.                            these values (Table 41) in the Netherlands.
 Scientific basis of       Objections          The scientific evidence for the cut-off value of 50
 EFSA’s AI                                     nmol/L for 25(OH)D is not strong. This cut-off
                                               value of 50 nmol/L would require a vitamin D         Table 41. AI, AR and PRI for vitamin D, recommended for the Netherlands
                                               supply of 20 μg/day, rather than EFSA’s estimate                                                          Men and women
                                               of 15 μg/day.                                                                                             18-69 years     >70 years
 Other findings                                                                                      Adequate intake (AI) under circumstances without    10 μg/day
 Aspect                    Conclusion          Comment                                               cutaneous vitamin D synthesis
 Differentiation between   Not applied by EFSA Consistent with DACH, but not with the other          Average requirement (AR)                                            10 μg/day
 younger and older adults                      reports used for comparison.                          Population reference intake (PRI)                                   20 μg/day
 Differentiation between   Not applied by EFSA Consistent with the reports used for comparison.
 men and women
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<pre>chapter 12 | Vitamin E (alpha-tocopherol)              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 68 of 179
12
vitamin E
(alpha-tocopherol)
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<pre>chapter 12 | Vitamin E (alpha-tocopherol)                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 69 of 179
                                                  Vitamin E                                                   12.1 Overview and comparison of values
                                                                                                              Table 42. Overview of the reference values for adults and the criteria on which these
           Should EFSA's reference values be rejected                                                         values are based
           based on a specific nutritional context in the                                YES
        Netherlands that differs from (the rest of) Europe?                                                     Report       PRI/RDA/AI/RI              AR             CV   Main criterion
                                                                                                                             (mg/d)                     (mg/d)         (%)
                                                                                                                             Type      ♂       ♀        ♂     ♀
                                                                                                                EFSA         AI        13      11       -     -        -    Intake observed in EU populations with no
                                  NO                                                                            201514       >10 yr                                         apparent vitamin E deficiency.
                                                                                                                NCM          RI        10      8        6     5        ♂33a RI eventually was based on 0.4-0.6 mg
                                                                                                                201437       >14 yr                                    ♀30a α-tocopherol equivalents (α-TE) per g
                                                                                                                = HCNL                                                      recommended intake of polyunsaturated fatty
                                                                                                                201433                                                      acids (PUFA); the origin of these values was
        Are there objections against EFSA’s scientific basis                                                                                                                not transparently described.
                          for this nutrient?
                                                                                                                                                                            Additionally, NCM considered a biochemical
                                                                                                                                                                            status parameter (plasma α-tocopherol), and
                                                                                                                                                                            the absence of signs of vitamin E deficiency at
                                                                                                                                                                            current intake levels.
                                              YES
                                                                                                                DACH         AI                         -     -        -    AI was determined from by PUFA intake,
                                                                                                                201538       19-24 yr  15      12                           assuming a basic daily requirement of 4 mg
                                                                                                                             25-50 yr  14      12                           TE and an additional requirement of 0.06, 0.4
                                                                                                                             51-64 yr  13      12                           and 0.6 g mg TE per gram of intake of fatty
                       Do (part of) EFSA's reference values differ 10% or                                                    >65 yr    12      11                           acid intake with respectively one, two or three
       NO                                                                                YES
                        more from the 2014 values for the Netherlands?
                                                                                                                                                                            double bonds. The origin of these values was
                                                                                         AIs
                                                                                                                                                                            not transparently described.
                                                                                                                IOM 20002 RDA          15      15       12    12       10   Function parameter: requirement = intake
                                                                                                                             >14 yr                                         sufficient for plasma alpha-tocopherol to limit
                                               NO                                                                                                                           peroxide-induced haemolysis to max 12%, i.e.
                                                                                                                                                                            12 μmol/L. This requires an intake of 12 mg/d.
                                                                                                                WHO/FAO AI             10      7.5      -     -        -    WHO/FAO considered the available data not
                                                                                                                200444       >10 yr                                         sufficient to formulate recommendations for
                                                                                                                                                                            vitamin E intake except for infants.
             No objections against the use of                   Major objection against the use of            a
                                                                                                                 CV calculated as 100% x [ ( PRI/RI/RDA – AR ) / 2 ] / AR.
       EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands
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<pre>chapter 12 | Vitamin E (alpha-tocopherol)                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 70 of 179
Table 42 shows that lowest RIs are from NCM and WHO/FAO (-25% and                                                   α-tocopherol intake and requirement could not be used on their own, nor
-27% relative to EFSA) and the highest from IOM (+25%). DACH’s value                                                in combination, to derive the requirement for adults.
is similar to EFSA’s (+6%).                                                                                         EFSA based the AI on vitamin E intakes observed in EU populations with
                                                                                                                    no apparent vitamin E deficiency. EFSA considered intakes of
α-Tocopherol versus α-tocopherol equivalents                                                                        α-tocopherol and/or α-tocopherol equivalents from eight dietary surveys in
The reference values used by EFSA, NCMa and IOM refer to α-tocopherol.                                              seven countries of the European Union (Finland, France, Ireland, Italy, the
The α-tocopherol equivalents (α-TE) used by DACH and WHO/FAO                                                        Netherlands, Sweden and the United Kingdom). The EFSA Panel
include α-, β-, γ- and δ-tocopherols and α-tocotrienols. The Committee                                              considered the approximate midpoints of the range of mean intakes for
agrees with the expression as α-tocopherol used by EFSA, NCM and IOM.                                               α-tocopherol and α- tocopherol equivalents (Table 43) and, after rounding,
                                                                                                                    set an AI for α-tocopherol at 13 mg/day for men and 11 mg/day for
12.2 Explanation of differences between reports                                                                     women. The EFSA Panel noted that these AIs are close to, or above, the
EFSA’s AIs are based on observed intakes, NCM’s AR and DACH’s AI on                                                 intakes that are suggested from available studies on markers of
the relationship between vitamin E requirement and PUFA intake, and                                                 α-tocopherol intake/status or on α-tocopherol kinetics and body pools.
IOM’s AR on a biochemical parameter of function. WHO/FAO considered
                                                                                                                    Table 43. Average intakes of α-tocopherol and/or α-tocopherol equivalents in EU
that the data were not sufficient to formulate recommendations for vitamin                                          countries
E intake for different age groups, except for infants, and therefore did not                                         Adults (age groups >18 yr)  Ranges of average intakes (midpoints of these ranges)
                                                                                                                                                 in EU countries (mg/day)
set a reference value for vitamin E for adults.                                                                                                  α-tocopherol                  α-tocopherol equivalents
                                                                                                                     Men                         8.2-16 (12.1)                 10.1-16.0 (13.1)
EFSA considered that available data on biochemical markers of
                                                                                                                     Women                       7.8-12.5 (10.2)               8.9-13.5 (11.2)
α-tocopherol intake, status and function, on α-tocopherol kinetics and
body pools, and on the relationship between PUFA intake and
                                                                                                                    IOM based the AR-value on a function parameter: the plasma
                                                                                                                    α-tocopherol concentration associated with in vitro hydrogen peroxide-
                                                                                                                    induced haemolysis <12%. IOM concludes: “Although the exact plasma
a
   In NNR 2012, vitamin E activity is confined to α-tocopherol. Vitamin E activity has previously been expressed as
  α-tocopherol equivalents (α-TE). Note that the tables in the NCM report mention α-TE instead of α-tocopherol as   α-tocopherol concentration that allows haemolysis to take place is
  the unit of expression.
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<pre>chapter 12 | Vitamin E (alpha-tocopherol)                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 71 of 179
unknown, it appeared to be prudent to estimate the lowest known plasma         EFSA did not use the ratio of α-tocopherol intake over PUFA intake
α-tocopherol concentration as that cut-off point where haemolysis would        (criterion used by NCM and DACH) as the criterion to set the AI, because
take place in 50 percent of the population. Thus, a plasma concentration       the required amount of α-tocopherol may differ according to the degree of
of 12 μmol/L was chosen as the concentration of plasma α-tocopherol            saturation of the various PUFAs. EFSA considers that there is little
associated with normal in vitro hydrogen peroxide-induced haemolysis. …        evidence to support the ratios of 0.4 mg (criterion NCM and used as
… The data of Horwitt (1960) support an EAR of 12 mg (27.9 μmol) of            supportive evidence by IOM) or 0.6 mg of α-tocopherol per gram of dietary
α-tocopherol. The data were derived from studies in men only, and no           PUFAs, and that there were uncertainties in the intake measurements on
similar data are available for women. However, there is no scientific basis    which both ratios were based. Still, EFSA does agree that PUFA intake is
for assuming different requirements for men and women, and although            probably associated with an adequate α-tocopherol intake.
body weights may be greater in men, women have larger fat masses as a
percent of body weight, and thus may have similar requirements.”               Differences between older and younger adults
EFSA did not use plasma/serum α-tocopherol concentration                       Note that DACH is the only organisation differentiating reference values
(IOM-criterion). EFSA did not consider this concentration to be a sensitive    between several age groups of adolescents/adults, which appears to
marker of dietary α-tocopherol intake, because an association between          result from differences in PUFA-intake. All other organisations set one
dietary α-tocopherol intake and plasma/serum α-tocopherol concentrations       value for adolescents and all adults (>10 or >14 or >15 years old).
has not consistently been observed and, when observed, the correlation
was weak. Furthermore, EFSA considered the evidence for the adequate           Sex differences
plasma value of 12 μmol/L insufficient. There is a lack of data on the         All organisations except IOM differentiate between women and men.
relationship between α-tocopherol concentrations in plasma/serum and
those in peripheral tissues. EFSA notes that plasma/serum α-tocopherol         12.3 Conclusion on the scientific basis of EFSA’s reference
<12 μmol/L may be indicative of α-tocopherol deficiency, but that there is a          values
lack of data to set a precise cut-off value above which α-tocopherol status    EFSA mentions that symptomatic α-tocopherol deficiency has not been
may be considered as adequate.                                                 reported in healthy individuals. Subjects consuming a diet with a very low
NCM and DACH based the AR on the PUFA-intake.                                  vitamin E content developed signs of deficiency after more than two years
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<pre>chapter 12 | Vitamin E (alpha-tocopherol)                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 72 of 179
on this diet (Table 44). The Committee has no objections against EFSA’s                                        12.4 Summary and conclusion
argumentation for using average intakes observed in European
                                                                                                               Table 45. Summary of the evaluation of EFSA’s AI values for vitamin E
populations as the basis for the AI, but notes that average intakes may                                         Main findings, used for the conclusion
                                                                                                                Aspect                  Conclusion           Comment
substantially exceed requirements.                                                                              EFSA’s AIs compared Higher                   EFSA’s AI is 30-40% higher than HCNL’s (=NCM’s) RI.
                                                                                                                to HCNL’s (=NCM’s) RI
Table 44. Vitamin E intake levels associated with the occurrence, correction or                                 Scientific basis of     No objections        EFSA based their AI on average intakes, and described
prevention of deficiencies, as described by EFSA                                                                EFSA’s AI                                    why they did not use the criteria used in the reports
                                                                                                                                                             used for comparison (NCM and DACH: PUFA-intake;
 Clinical manifestation                Associated           Subjects/Specific          EFSA’s reference                                                      IOM: limitation of peroxide-induced haemolysis). Note
 associated with deficiency            intake               group                                                                                            that WHO/FAO did not set reference values for adults
 After 28 months, in vitro             3 mg/d               19 men                     Horwitt et al. 1956,                                                  because of insufficient data.
 hydrogen peroxide-induced                                                             Horwitt 1960,            Other findings
 haemolysis increased from 0%                                                          Horwitt 1962,            Aspect                  Conclusion           Comment
 to 80%                                                                                Horwitt et al. 1963      Differentiation between Not applied by EFSA Consistent with most of the reports used for
                                                                                                                younger and older                            comparison. Only DACH differentiates between age
                                                                                                                adults                                       groups.
                                                                                                                Differentiation between Applied by EFSA      Consistent with the reports used for comparison.
    Background information – a summary of the information provided by the EFSA report –                         men and women
                                                                                                                EFSA’s unit of          α-tocopherol         Consistent with NCM and IOM, but DACH express their
    on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                                                expression                                   values in α-tocopherol equivalents.
    symptoms
    α-Tocopherol is a peroxyl radical scavenger and especially protects PUFAs within membrane                  EFSA’s AI for vitamin E is based on the approximate midpoint of observed
    phospholipids and plasma lipoproteins. By protecting PUFAs within membrane phospholipids,
    α-tocopherol preserves intracellular and cellular membrane integrity and stability, and plays an           average intakes in European countries which is assumed to be adequate
    important role in the stability of erythrocytes and in the conductivity in central and peripheral          because no signs of deficiency have been reported in healthy individuals.
    nerves.
    Symptomatic α-tocopherol deficiency in individuals without any disease and who consume diets               Vitamin E deficiency has not been reported in healthy subjects on normal
    ‘low’ in α-tocopherol has not been reported.                                                               diets, so that the adequate intake may substantially exceed requirements.
    Primary vitamin E deficiency, i.e. familial isolated α-tocopherol deficiency, results from a genetic
    defect in the α-TTP gene. Secondary vitamin E deficiency has been observed in specific patient             However, there is no evidence available to define a more evidence-based
    groups (abetalipoproteinaemia, cholestatic liver diseases, severe malnutrition, fat malabsorption,         AI. Therefore, the Committee has no objections against EFSA’s AI for adults
    and cystic fibrosis).
    Symptoms of vitamin E deficiency:                                                                          (Table 46).
    •   haemolytic anaemia
    •   neurological symptoms (ataxia, peripheral neuropathy, myopathy, pigmented retinopathy).                Table 46. AI for vitamin E (α-tocopherol), recommended for the Netherlands
                                                                                                                                                    Men >18 years                    Women >18 years
                                                                                                                 Adequate intake (AI)               13 mg/day                        11 mg/day
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 73 of 179
13
vitamin K1
(phylloquinone)
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 74 of 179
                                               Vitamin K1                                                     13.1 Overview and comparison of values
                                                                                                              Table 47. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected                                                           values are based
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?
                                                                                                                Report               Vitamin      AI                           Main criterion
                                                                                                                                     K1/K2        Age         μg/day
                                                                                                                EFSA 20176           K1           >18 yr      70 μg/d          The AI of 1 μg/kg/d was mainly based on the
                                                                                                                = HCNL 201433 a                                                depletion/repletion study in young men (72
                                                                                                                                                                               kg; SD 9) by Suttie et al. (1988), which
                                NO                                                                                                                                             showed that supplementation with 50 μg K1/
                                                                                                                                                                               day in addition to a restricted diet (median of
                                                                                                                                                                               about 32-40 μg K1/d) restored the
                                                                                                                                                                               Simplastin:Ecarin (S:E ratio, a measure of
      Are there objections against EFSA’s scientific basis                                                                                                                     functionally active prothrombin) and urinary
                        for this nutrient?                                                                                                                                     γ-carboxyglutamic acid (Gla) concentration
                                                                                                                                                                               to their baseline values.
                                                                                                                                                                               Considering the reference body weights, the
                                                                                                                                                                               daily phylloquinone intake would be 68.1 μg
                                             YES                                                                                                                               for men and 58.5 μg for women, rounded up
                                                                                                                                                                               to 70 μg/day for all adults.
                                                                                                                NCM 201437           K1 & K2      -                            NCM evaluated vitamin K, but established no
                                                                                                                                                                               recommended intake due to lack of
                                                                                                                                                                               evidence.
                     Do (part of) EFSA's reference values differ 10% or
      NO                                                                                YES
                      more from the 2014 values for the Netherlands?                                            DACH 201538          K1 & K2      15-50 yr    ♂ 70     ♀ 60 The AI of 1 μg/kg/d was based on the
                                                                                                                                                  >51 yr      ♂ 80     ♀ 65 coagulation role of vitamin K.
                                                                                                                IOM 200141 a         K1 & K2                  ♂ 120 ♀ 90 Median intake, supported by data on
                                                                                                                                                                               prevention of deficiency.
                                                                                                                WHO/FAO              K1 & K2                  ♂ 65     ♀ 55 The AI of 1 μg/kg/d was based on the
                                              NO
                                                                                                                200444                                                         coagulation role of vitamin K and average
                                                                                                                                                                               intakes.
                                                                                                              a
                                                                                                                 According to HCNL 2014,33 IOM’s reference values41 were used in the Netherlands until the publication of EFSA’s
                                                                                                                 AIs6 in 2017. Once available, EFSA’s reference values for vitamin K1 were used in the Netherlands. In this
           No objections against the use of                   Major objection against the use of                 chapter, HCNL 2014 refers to the Dutch reference values preceding the publication of this report, i.e. EFSA’s
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands            reference values.
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 75 of 179
Table 47 presents an overview of reference values and criteria. EFSA,         body weight per day, and agree that this estimate is based on limited
NCM, DACH and WHO/FAO agree on the adequate intake of 1 microgram             research.
of phylloquinone per kilogram body weight, so that differences between
the AIs in microgram per day between these reports result from                EFSA states that all possible approaches to set reference values for
differences in reference weights. IOM set substantially higher AI values      phylloquinone (vitamin K) have considerable uncertainties.
based on median intake.                                                       The EFSA Panel concludes that it is not possible to use the factorial
                                                                              approach to derive DRVs for vitamin K due to limitations of the data on
Phylloquinone (K1) and menaquinones (K2)                                      absorption and excretion of phylloquinone and menaquinones. However
The vitamin K reference intakes in the EFSA report refer to phylloquinone     EFSA’s attempt to use this approach results in an estimate that does not
(vitamin K1). Although the EFSA Panel considered vitamin K as                 conflict with the value of 1 μg/kg body weight per day. The EFSA Panel
phylloquinone and menaquinones, they concluded that the available             considers that a total body pool of phylloquinone of about 0.55 μg/kg body
evidence on intake, absorption, function and content in the body or organs    weight in healthy adults at steady state is associated with no signs of
of menaquinones was insufficient, and therefore, they set AIs for             vitamin K deficiency. Based on excretion rate estimates from a kinetic
phylloquinone only.                                                           study using isotope-labelled phylloquinone (Olson et al., 2002), EFSA
Values by NCM, DACH, IOM and WHO/FAO refer to phylloquinone and               assumes that the losses via faeces and urine are 0.34 μg/kg body weight
menaquinones, but the studies on which the reference value is based are       per day. EFSA notes that data on phylloquinone absorption in healthy
mainly on phylloquinone.                                                      adults are widely variable (range 3-80%), but that at an absorption
                                                                              efficiency of 35%, an intake of 1 μg/kg body weight per day would balance
13.2 Explanation of differences between reports                               the losses.
EFSA’s AI is based on a depletion-repletion study, NCM’s AI is based on       The EFSA Panel considers that none of the biomarkers is suitable by itself
the prevention of deficiency, DACH’s and WHO/FAO’s AI are based on            for assessing vitamin K adequacy and notes that the results on
biochemical parameter of function, and IOM’s AI on median intake. EFSA,       biomarkers suggest that vitamin K intakes sufficient for an adequate
DACH and WHO/FAO base their adequate intakes on the value of 1 μg/kg          prothrombine time (e.g. >10 μg phylloquinone/day) may not be enough for
                                                                              other functions controlled by vitamin K.
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 76 of 179
The EFSA Panel also reviewed data on vitamin K intakes in Europe. Mean                                             set DRVs (biomarker, factorial approach, intake data) have considerable
vitamin K intakes in adults (≥18 years) ranged between 72 and 196 μg/day,                                          uncertainties, and there is no scientific evidence to update the previous
but the intake estimates suffer from limitations and uncertainties of food                                         reference value. The EFSA Panel notes that there is no indication that 1
composition data with regard to both phylloquinone and menaquinones.                                               μg/kg body weight per day of phylloquinone would be associated with a
Two national surveys applied partially updated food composition data: the                                          risk of deficiency in the general population and is above the intake at
German National Nutrition Survey II estimated that median phylloquinone                                            which an increase in prothrombine time has been observed in healthy
intake was 76 μg/day for subjects aged 15-80 years, and the Dutch National                                         subjects.
Survey estimated that the median phylloquinone plus menaquinones intake                                            Based on the reference body weights used by EFSA, an intake of 1 μg/kg
in adults of was 100-117 μg/day.a However, the EFSA Panel notes that the                                           body weight per day corresponds to 68.1 μg/day in men and 58.5 μg/day
impact of the remaining uncertainty in the composition data on the results                                         in women. EFSA rounded these values up to establish the AI of 70 μg/day
was not entirely clear. The EFSA Panel concludes that an AI established                                            for all adults.
from these data cannot be sufficiently reliable.
SCF (1993) considered that an intake of phylloquinone of 1 μg/kg body                                              IOM based their AI on median intakes, taking into account that the
weight per day was adequate, mainly based on the depletion/repletion                                               resulting AIs are supported by data on the prevention of deficiency.
study in young men by Suttie et al. (1988), which showed that
supplementation with 50 μg phylloquinone/day in addition to a restricted                                           NCM gives no recommendation due to lack of sufficient evidence, but
diet (median of about 32-40 μg phylloquinone/day) restored the S:E ratio                                           does maintain the provisional recommended intake of 1 μg/kg body weight
(a measure of functionally active prothrombin) and urinary Gla                                                     per day in the 2004 NCM report, since no strong scientific evidence for
concentration to their baseline values.                                                                            change has emerged. Note that this value is not presented by NCM as a
The EFSA Panel concludes that the uncertainties pointed out by SCF                                                 recommended intake.
(1993) had not been resolved, that all possible approaches investigated to
                                                                                                                   Differences between older and younger adults
                                                                                                                   EFSA, NCM, IOM and WHO/FAO did not differentiate the AI between
a
  Note that new RIVM estimates of the habitual vitamin K-intakes in Dutch adults aged 18-50 years also include
  estimates specific for phylloquinone: the median of the habitual phylloquinone intakes was 88 μg/day for men     younger and older adults. EFSA notes that there was no evidence of
  and 77 μg/day for women.45
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 77 of 179
different vitamin K absorption and different losses according to age in       adults. However, if Dutch reference weights are applied, the AI still
adults. DACH did differentiate: as a precaution, DACH set a higher AIs for    appears to be 70 μg/day (Table 48).
adults >50 years than for adults <50 years, to take into account possible     Therefore, the Committee has no objection against the use of EFSA’s AI in
malabsorption and medication effects at a higher age.                         the Netherlands.
                                                                              Table 48. Effect of HCNL’s higher reference weights on the average requirements and
Sex differences                                                               population reference intake estimates using EFSA’s method
In contrast to the reports used for comparison, EFSA does not propose                                           Reference body       Intake estimate            Adequate intake after
                                                                                                                weight (kg)          requirement (μg/day)       rounding (μg/day)
different AI values for men and women. Based on the adequate intake per                                         ♂         ♀          ♂             ♀            Mean ♂ & ♀ Rounded
kilogram and the reference weights, the value for men was 10 μg per day        EFSA’s values, based on
                                                                               1 μg/kg/d, and EFSA’s            68.1      58.5       68            59           64           70
higher than for women, but EFSA rounded this up to 70 μg per day for all       reference weights
                                                                               Values based on 1 μg/kg/d,
adults, because of the large uncertainties.                                    but using HCNL’s reference 73.5            62.5       74            63           68           70
                                                                               weights35,36
13.3 Conclusion on the scientific basis of EFSA’s reference                       Background information – a summary of the information provided by the EFSA report –
      values                                                                      on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                  symptoms
Most reports agree that, based on limited data, 1 microgram per kilogram
                                                                                  Different vitamin K-dependent Gla-proteins display calcium-mediated actions. One group of
of body weight per day is considered adequate for the blood coagulation
                                                                                  vitamin K-dependent proteins comprises blood coagulation factors. Another group includes a
role of vitamin K (see paragraph 13.2). EFSA did not set separate values          protein involved in bone mineralisation and other proteins which may be involved in the control
                                                                                  of soft tissue calcification.
for men and women because of the large uncertainties. EFSA rounded the
                                                                                  EFSA does not provide information on the occurrence of clinical signs of vitamin K deficiency.
calculated values upwards (Table 48).                                             IOM 2001 provides the following information: “Spontaneous cases have been rare and have
                                                                                  usually been associated with various lipid malabsorption syndromes. There are numerous case
EFSA provides no information on vitamin K1 intake levels associated with
                                                                                  reports of bleeding episodes in antibiotic-treated patients, and these have often been ascribed to
the occurrence, correction or prevention of deficiencies.                         an acquired vitamin K deficiency resulting from a suppression of menaquinone-synthesizing
The Committee has no objection against the scientific basis of EFSA’s AI,         organisms. However, these reports are complicated by the possibility of general malnutrition in
                                                                                  this patient population and by the antiplatelet action of many of the same drugs.”
but notes that the reference body weights used by EFSA are relatively low         In adults, vitamin K deficiency is clinically characterised by:
for the Netherlands. On average, Dutch adults are taller than European            •    a bleeding tendency in relation to a low activity of the blood coagulation factors.
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<pre>chapter 13 | Vitamin K1 (phylloquinone)                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 78 of 179
13.4 Summary and conclusion                                                                     EFSA based the AI on an adequate intake of 1 μg/kg per day, but did not
                                                                                                set different values for men and women, because of the large
Table 49. Summary of the evaluation of EFSA’s AI values for vitamin K
 Main findings, used for the conclusion
                                                                                                uncertainties. The Committee notes that vitamin K is one of the few
 Aspect                         Conclusion          Comment                                     nutrients for which the method of establishing the reference value implies
 EFSA’s AI compared to HCNL’s Equal                 EFSA’s AI has been used in the
 (=EFSA’s) AI                                       Netherlands since 2017.                     a proportional effect of the reference weights on the reference values. The
 Scientific basis of EFSA’s AI  No objection        EFSA value of 1 μg/kg per day is used by
                                                                                                Committee considers that higher reference weights should be used for the
                                                    EFSA, DACH and WHO/FAO and
                                                    mentioned as a provisional recommended      Netherlands, because Dutch adults are relatively tall, but concludes that
                                                    intake by NCM. IOM based their AIs on
                                                    intake.                                     this does not result in a different AI (Table 48). The Committee has no
 Other findings
                                                                                                objection against the scientific basis of EFSA’s AI, or EFSA’s AI, and
 Aspect                         Conclusion          Comment
 Differentiation between        Not applied by EFSA Consistent with IOM and WHO/FAO, but        recommends using this value (Table 50) in the Netherlands.
 younger and older adults                           not with DACH.
 Differentiation between men    Not applied by EFSA Not consistent with DACH, IOM and WHO/      Table 50. AI for vitamin K1, recommended for the Netherlands
 and women                                          FAO.                                                                                 Men and women >18 years
 Unit in which the EFSA’s AI is μg vitamin K1       Not consistent with the reports used for     Adequate intake (AI)                    70 μg/day
 expressed                      (phyloquinone)      comparison, who express the AI in μg
                                                    vitamin K1+K2 (phylloquinone plus
                                                    menaquinones).
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<pre>chapter 14 | Biotin                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 79 of 179
14
biotin
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<pre>chapter 14 | Biotin                                                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 80 of 179
                                                        Biotin
                                                                                                                   14.1 Overview and comparison of values
                                                                                                                   Table 51. Overview of the reference values for adults and the criteria on which these
               Should EFSA's reference values be rejected
               based on a specific nutritional context in the
                                                                                                                   values are based
                                                                                             YES
            Netherlands that differs from (the rest of) Europe?
                                                                                                                    Report                AI (μg/d)  Main criterion
                                                                                                                    EFSA 2014   28
                                                                                                                                          40         Approximate midpoint of the observed mean/median intakes
                                                                                                                    = HCNL 201433
                                                                                                                    DACH 201538           30-60      Dietary intake surveys
                                     NO                                                                             IOM 1998 42
                                                                                                                                          30         Upward extrapolation of the AI for infants
                                                                                                                   Note that NCM and WHO/FAO did not establish reference values for
           Are there objections against EFSA’s scientific basis                                                    biotin.
                             for this nutrient?
                                                                                                                   Table 51 shows that EFSA’s AI is within the range set by DACH. The value
                                                                                                                   used by IOM is substantially lower.
                                                  YES
                                                                                                                   14.2 Explanation of differences between reports
                                                                                                                   Table 51 shows that EFSA’s and DACH’s AI’s are based on intake,
                          Do (part of) EFSA's reference values differ 10% or
           NO                                                                                YES
                           more from the 2014 values for the Netherlands?                                          whereas IOM’s AI is based on upward extrapolation of the AI for infants.
                                                                                                                   The EFSA Panel used the approximate midpoint of the observed mean/
                                                   NO
                                                                                                                   median intakes observed in European countries to set an AI for biotin at
                                                                                                                   40 μg/day for adults of all ages. The EFSA Panel notes that estimates of
                                                                                                                   the biotin content of foods vary widely, partly as a result of natural
                 No objections against the use of                  Major objection against the use of
           EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands
                                                                                                                   variation, and partly depending on the analytical method used, and that
                                                                                                                   this contributes to uncertainty regarding current intake estimates.
 Biotin has also been called – dependent on the country – vitamin B7, vitamin B8 or vitamin H, but biotin is the
 preferred name internationally.
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<pre>chapter 14 | Biotin                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 81 of 179
In adult men and women below about 65 years, mean/median intakes
                                                                                     Background information – a summary of the information provided by the EFSA report –
ranged from 26 to 50 μg/day, based on estimates from Germany, Ireland,
                                                                                     on the function of the nutrient, the occurrence of clinical deficiency and deficiency
Hungary, Austria and Latvia.                                                         symptoms
In older adult men and women, mean/median intakes ranged from 24 to                  Biotin is a co-factor for several enzymes which play critical roles in the synthesis of fatty acids,
43 μg/day, based on estimates from Germany, Ireland, Hungary and                     the catabolism of branched-chain amino acids and gluconeogenesis. Faecal excretion of biotin
                                                                                     has been observed to be three to six times higher than intakes, owing to the production of large
Austria.                                                                             amounts of biotin by the intestinal microbiota; however, the extent to which biotin is absorbed
                                                                                     from the large intestine and contributes to biotin requirements is uncertain.
                                                                                     Dietary biotin deficiency is rare. Cases of biotin deficiency have been observed in:
Differences between older and younger adults and sex differences                     •   patients receiving long-term total parenteral nutrition without biotin supplementation
The reports do not differentiate the AI between younger and older adults,            •   patients with biotinidase deficiency
                                                                                     •   people who had consumed large amounts of raw eggs (a protein in raw egg white, avidin,
nor between men and women.                                                               has a very high affinity for biotin and prevents its absorption in the small intestine).
                                                                                     Symptoms in adults:
                                                                                     •   fine scaly dermatitis
14.3 Conclusion on the scientific basis of EFSA’s reference                          •   hair loss
      values                                                                         •   conjunctivitis
                                                                                     •   ataxia.
EFSA based the AI on mean/median intakes in Europe (paragraph 14.2).
The Committee has no objection against the scientific basis of EFSA´s
reference value.
EFSA provides no information on biotin intake levels associated with the
occurrence, correction or prevention of deficiencies. There are no reports
on clinical signs of deficiency resulting from insufficient dietary intake of
biotine. Therefore, the adequate intake may substantially exceed
requirements.
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<pre>chapter 14 | Biotin                                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 82 of 179
14.4 Summary and conclusion                                                                      EFSA’s AI for biotin is based on the approximate midpoint of observed
                                                                                                 average intakes in European countries, which is assumed to be adequate
Table 52. Summary of the evaluation of EFSA’s AI values for biotin
 Main findings, used for the conclusion
                                                                                                 because no signs of deficiency have been reported in healthy individuals.
 Aspect                    Conclusion          Comment                                           As biotin deficiency has not been reported in healthy subjects on normal
 EFSA’s AIs compared       Equal               EFSA’s AI has been used in the Netherlands since
 to HCNL 2014’s                                2014.                                             diets, the adequate intake may substantially exceed requirements.
 (=EFSA’s) AI33
                                                                                                 However, there is no evidence available to define a more evidence-based
 Scientific basis of       No objection        EFSA and DACH based the AI on intake
 EFSA’s reference value                        estimates, whereas IOM extrapolated the value for AI. Therefore, the Committee has no objections against EFSA’s AI for
                                               infants. NCM and WHO/FAO did not establish
                                               reference values for biotin.                      adults (Table 53).
 Other findings
 Aspect                    Conclusion          Comment                                           Table 53. AI for biotin, recommended for the Netherlands
 Differentiation between   Not applied by EFSA Consistent with the reports used for comparison.                                             Men and women >18 years
 younger and older adults
                                                                                                  Adequate intake (AI)                      40 μg/day
 Differentiation between   Not applied by EFSA Consistent with the reports used for comparison.
 men and women
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<pre>chapter 15 | Choline                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 83 of 179
15
choline
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<pre>chapter 15 | Choline                                                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 84 of 179
                                                      Choline                                                      15.1 Overview and comparison of values
                                                                                                                   Table 54. Overview of the reference values for adults and the criteria on which these
              Should EFSA's reference values be rejected                                                           values are based
              based on a specific nutritional context in the                                YES
           Netherlands that differs from (the rest of) Europe?
                                                                                                                    Report    AI (mg/d)    Main criterion
                                                                                                                    EFSA      400          Mean choline intakes in 12 national surveys in 9 EU countries between
                                                                                                                    201612                 2000 and 2011 range from about 270 to 470 mg choline/day, with 370
                                                                                                                                           mg/d as the midpoint of the range. Populations were healthy but no
                                                                                                                                           information on choline status was available.
                                    NO                                                                                                     Supportive evidence: the amounts of choline needed to replete about
                                                                                                                                           70% of depleted subjects who showed signs of organ dysfunction in one
                                                                                                                                           depletion/repletion study (Fischer et al., 2007).
                                                                                                                    IOM       ♂550         One depletion/repletion study in 16 healthy male hospitalised volunteers
          Are there objections against EFSA’s scientific basis                                                      199842    ♀400         in which only one level of choline supplementation (500 mg choline/day)
                            for this nutrient?                                                                                             was examined and appeared to prevent alanine aminotransferase (ALT)
                                                                                                                                           abnormalities (Zeissel et al., 1991).
                                                                                                                   Note that NCM, DACH and WHO/FAO did not establish reference values
                                                 YES
                                                                                                                   for choline.
                                                                                                                   Table 54 shows that EFSA’s AI for women equals IOM’s value, whereas
          NO
                         Do (part of) EFSA's reference values differ 10% or
                                                                                            YES                    IOM’s AI for men is 38% higher than the value used by EFSA.
                           more from the 2014 values for the Netherlands?
                                                                                                                   15.2 Explanation of differences between reports
                                                  NO                                                               EFSA’s AI is based mainly on intake, IOM’s AI is based on a depletion/
                                                                                                                   repletion study. Both base the AI on limited data.
                No objections against the use of                  Major objection against the use of
          EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands          EFSA based the AI on the mean intake level in the EU with supportive
 Choline is the preferred name for a group substances in food, including free choline and esterified forms, mainly information from one depletion/repletion study.
 phosphatidylcholine (PC, lecithin), phosphocholine (PChol), glycerophosphocholine (GPC) and sphingomyelin
 (SPM). Other esterified forms occur in minor amounts in foods. PC accounts for approximately 95% of total
                                                                                                                   The mean choline intakes in twelve national surveys from nine EU
 choline found in animal tissues. Choline, PChol and GPC are water-soluble choline compounds, whereas PC and
                                                                                                                   countries (Finland, France, Germany, Ireland, Italy, Latvia, the
 SPM are lipid soluble.
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<pre>chapter 15 | Choline                                                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 85 of 179
Netherlands, Sweden and the United Kingdom) carried out between 2000                                                choline intake levels. In 25 depleted subjects, the amount of choline
and 2011 were estimated by using USA food composition data on the                                                   needed to replete them was available. About 70% needed up to about 400
choline content in foods (Vennemann et al. 2015).55 Mean intakes in adults                                          mg choline per 70 kilogram body weight for repletion. Some subjects
ranged between about 270 to 470 mg choline/day (midpoint 370 mg/day;                                                required more than IOM’s AIs for choline for repletion; some subjects
330-470 mg/day in men and 270-405 mg/day in women). EFSA mentions                                                   became deplete quickly, whereas others took almost 7 weeks on a
that these choline intake data were generally of the same magnitude as                                              low-choline diet to develop organ dysfunction. Fischer et al.56 concluded
the intakes in other published studies (from Belgium, USA, New Zealand                                              that “the requirement for choline in the diet is quite variable”.
and Taiwan).                                                                                                        For all adults, the EFSA Panel set an AI of 400 mg/day, based on the
The EFSA Panel notes that choline depletion/repletion studies indicate                                              midpoint of the range of observed mean intakes in healthy EU populations
large variability in dietary choline requirement. EFSA notes that only one                                          (about 370 mg/day), and in consideration of the results of the depletion/
depletion/repletion study56 is informative on the choline amount needed/                                            repletion study in which about 70% of the depleted subjects who had
sufficient to reverse signs of choline deficiency.a Fischer et al. (2007)56                                         developed signs of organ dysfunction were repleted with an intake of
defined choline deficiency by biochemical or clinical changesb between the                                          about 400 mg/70 kg body weight per day.
baseline diet (550 mg choline per 70 kg per day) and the low-choline diet
(<50 mg choline per 70 kg per day over <42 days). 57 subjects (men and                                              IOM based their AI on one depletion/repletion study in 16 healthy male
women) completed the study. Six subjects (all male) showed signs of                                                 (Zeissel et al., 1991).a A choline intake of 500 mg/day prevented ALT
choline deficiency after the baseline diet. After 42 days with <50 mg                                               abnormalities in these healthy men. IOM places the remark that “this
choline per 70 kg per day, 33 subjects had become depleted, but 18 had                                              estimate for an AI is uncertain because it is based on a single published
not. Fischer et al. determined the amount of choline needed to replete the                                          study; it may need revision when other data become available”. As only
depleted subjects, using a protocol of 10-day periods with increasing                                               one level of choline supplementation (500 mg choline/day) was examined,
                                                                                                                    EFSA rejected this study for the estimation of the choline amount needed/
a
  EFSA did not use 10 other depletion/repletion studies, including Zeisel et al. (1991) which was used by IOM, as
  these did not provide information on the amount needed/sufficient to reverse the signs of deficiency.
                                                                                                                    sufficient to reverse the signs of choline deficiency.
b
  Fischer et al. examined the following biochemical or clinical changes: a more than 5-fold increase in serum
  creatine phosphokinase activity indicating muscle dysfunction; a more than 1.5-fold increase in aspartate
  aminotransferase, alanine aminotransferase, γ-glutamyltransferase, or lactate dehydrogenase, indicating liver
  dysfunction; or a 28% increase in liver fat (hepatic steatosis).
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<pre>chapter 15 | Choline                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 86 of 179
Differences between older and younger adults                                      research group. The Committee has no objection against the scientific basis
Neither EFSA, nor IOM differentiated the AI between older and younger             of EFSA´s reference value.
adults.
                                                                                  Table 55. Choline intake levels associated with the occurrence, correction or
                                                                                  prevention of deficiencies, as described by EFSA
Sex differences                                                                    Clinical manifestation                 Associated            Subjects/Specific group        EFSA’s reference
                                                                                   associated with deficiency             intake
EFSA’s AI applies to men and women, whereas IOM set a higher AI for                Occurrence of biochemical              <50 mg / 70 kg/d      33 out of 57 men and           Fischer et al.
                                                                                   signs of muscle and liver              for up to 42 days     women                          (2007)
men than for women. Although premenopausal women may have a lower                  dysfunction (signs specified in        550 mg / 70 kg/d      6 out of 57 men and
requirement for dietary choline than postmenopausal women or men, and              paragraph 15.2)                                              women (these 6 were all
                                                                                                                                                men)
ranges of estimated mean total choline intake in Europe are slightly lower         Muscle and liver dysfunction           < 50 mg choline       Various groups in 11           EFSA report,
                                                                                                                                                depletion-repletion studies    Annex D
in women than men, the EFSA Panel considered it unnecessary to give                Increased risk of non-alcoholic        179 mg (the           Women with a BMI >25           Yu et al. (2014)
sex-specific AIs for adults.                                                       fatty liver disease                    lowest quintile)      kg/m2
15.3 Conclusion on the scientific basis of EFSA’s reference                            Background information – a summary of the information provided by the EFSA report –
                                                                                       on the function of the nutrient, the occurrence of clinical deficiency and deficiency
       values                                                                          symptoms
EFSA based their AI on the average intake observed in European countries,
                                                                                       Choline has a number of important functions: it is a precursor for the phospholipid
and on supportive information from a depletion/repletion study (paragraph              phosphatidylcholine; it is involved in the metabolism and transport of lipids and in the folate-
                                                                                       dependent onecarbon metabolism; and it is a precursor of acetylcholine and of betaine. EFSA
15.2). Choline deficiency has been reported in people on total parenteral
                                                                                       notes that genetic factors, sex, menopausal state and possibly the gastrointestinal microbiome
nutrition devoid of choline. Deficiency has been induced in several studies            may influence the choline requirement, which appears to be highly variable. Choline intake may
                                                                                       be essential for a large part of the population, but possibly not for all individuals.
at choline intakes of lower than 50 mg/day, but not in all subjects with this
                                                                                       The EFSA report does not provide information on the occurrence of choline deficiency, but IOM
intake level. Fischer et al. (2007) reported deficiency also in some subjects          reported that signs of choline deficiency were reported in some individuals on total parenteral
                                                                                       nutrition devoid of choline (but adequate for methionine and folate).
at a diet with a choline content of 550 mg per 70 kilogram body weight.
                                                                                       Symptoms:
(Table 55). These data indicate that most individuals require a sufficient             •    fatty liver (hepatic steatosis), which can result in non-alcoholic fatty liver disease
                                                                                       •    liver and muscle damage as indicated by an increase in creatine phosphokinase
intake of choline to maintain health, and that the amount of choline required
                                                                                            concentration in serum
may vary substantially, but the evidence appears to originate from one                 •    hepatic steatosis can progress to liver damage with release of liver enzymes into the blood.
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<pre>chapter 15 | Choline                                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 87 of 179
15.4 Summary and conclusion                                                                      The Committee has no objection against the scientific basis of EFSA´s
                                                                                                 reference value or EFSA’s AI for adults (Table 57). The Committee agrees
Table 56. Summary of the evaluation of EFSA’s AI values for choline
 Main findings, used for the conclusion
                                                                                                 with EFSA’s note that choline depletion/repletion studies indicate large
 Aspect                    Conclusion          Comment                                           variability in dietary choline requirement.
 EFSA’s AIs compared to    Not applicable      HCNL has not proposed a reference value for
 HCNL’s AI                                     choline intake as yet.
 Scientific basis of       No objection        EFSA is not consistent with IOM in using intake.  Table 57. AI for choline, recommended for the Netherlands
 EFSA’s AI                                     IOM’s AI and the supporting information used by
                                                                                                                                            Men and women >18 years
                                               EFSA are based on the relationship of intake with
                                                                                                  Adequate intake (AI)                      400 mg/day
                                               biochemical parameters of function.
 Other findings
 Aspect                    Conclusion          Comment
 Differentiation between   Not applied by EFSA Consistent with IOM.
 younger and older adults
 Differentiation between   Not applied by EFSA Not consistent with IOM.
 men and women
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<pre>chapter 16 | Calcium                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 88 of 179
16
calcium
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<pre>chapter 16 | Calcium                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 89 of 179
                                                       Calcium                                                  16.1 Overview and comparison of values
              Should EFSA's reference values be rejected                                                        Table 58. Overview of the reference values for adults and the criteria on which these
                                                                      ♀51-70
              based on a specific nutritional context in the                                  YES               values are based
           Netherlands that differs from (the rest of) Europe?        All >70 yr
                                                                                                                 Report   Age range  PRI/RDA/AI/RI      AR       CV      Main criterion
           All 19-24 yr & 25-50 yr
                                                                                                                                     Type     (mg/d)    (mg/d)   (%)
                        ♂ 51-70 yr
                                                                                                                 EFSA     18-24 yr  PRI       1,000     860      10%     AR derived as the intermediate
                                                                                                                 201519                                                  value between the AR for children
                                     NO
                                                                                                                                                                         aged 11-17 yr (AR 960 mg/d) and
                                                                                                                                                                         adults ≥25 years (AR 750 mg/d).
                                                                                                                          >25 yr    PRI       950       750              Balance data: 715 mg/d (without
                                                                                                                                                                         dermal loss) plus 40 mg/d for
          Are there objections against EFSA’s scientific basis                                                                                                           dermal losses. PRI is based on
                             for this nutrient?
                                                                                                                                                                         the upper limit of the 95%
              All 19-24 yr & 25-50 yr                                                                                                                                    prediction interval in the balance
              ♂ 51-70 yr                                                                                                                                                 data (904 mg/d) plus 40 mg/d for
                                                                                                                                                                         dermal losses.a
                                                 YES                                                             HCNL     19-49 yr  AI        1,000                      Factorial estimate (faecal loss:
                                                                                                                 200036                                                  110; urinary loss: 140; dermal
                                                                                                                 = HCNL                                                  loss: 30; retention 10 mg/d);
                                                                                                                 201433                                                  assuming 30-40% absorption,
          NO
                          Do (part of) EFSA's reference values differ 10% or
                                                                                              YES
                                                                                                                                                                         leading to a value of 730-970
                           more from the 2014 values for the Netherlands?                                                                                                mg/d. Balance data supported the
                                                                                         All >70 yr
                                                                                                                                                                         AI of 1,000 mg/d.
                                                                                         ♀51-70 yr
                                                                                                                          50-69 yr  AI        1,100                      The AI is in line with most
                                                                                                                                                                         observational data. Balance
                                                         All 19-24 yr & 25-50 yr                                                                                         studies indicate that an intake of
                                                  NO
                                                         ♂ 51-70 yr
                                                                                                                                                                         1.2 mg/d is adequate, but this is
                                                                                                                                                                         possibly too high. Intervention
                                                                                                                                                                         studies indicate that an intake of
                                                                                                                                                                         1.0-1.2 g/d is adequate.
                No objections against the use of                     Major objection against the use of                   >70 yr    AI        1,200                      Intervention studies and some
         EFSA's reference values in the Netherlands             EFSA's reference values in the Netherlands
                                                                                                                                                                         observational studies show that
                                                                                                                                                                         0.9-1.0 g/d is not sufficient for this
                                                                                                                                                                         age group.
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<pre>chapter 16 | Calcium                                                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 90 of 179
 Report   Age range  PRI/RDA/AI/RI  AR      CV     Main criterion                         Report       Age range        PRI/RDA/AI/RI               AR         CV         Main criterion
                     Type    (mg/d) (mg/d)  (%)                                                                         Type         (mg/d)         (mg/d)     (%)
 NCM      18-20 yr   RI      900                   Recommendation for adolescents         WHO/         ♂ 19-65 yr       RI          1,000           840        10%b       Null balance, assumed to be
 201437                                            was extended to 18-20 year olds        FAO          &                                                                  equivalent to AR.
                                                   as some bone mass is still             200444       ♀ preme-
                                                   accreted beyond 17 years of age.                    nopause
          >21 yr     RI      800    500     30%2   Based on 1 long term (7 months)                     ♂>65 yr &        RI           1,300          1,100      10%b       Strong evidence that Ca
                                                   balance study in which 23 of 26                     ♀postme-                                                           requirement rises during
                                                   men aged 20-79 yr adapted                           nopause                                                            menopause. Evidence about
                                                   gradually to maintain calcium                                                                                          ageing men is less convincing;
                                                   balance at an intake of 460 mg/d                                                                                       the extra allowance of 300 mg/d
                                                   (Malm, 1958). Supportive                                                                                               for men >65 yr is a precaution.
                                                   information from epidemiological     a
                                                                                           EFSA performed new analyses (Appendix F of EFSA-report). EFSA used the balance data from Hunt and
                                                   studies and clinical trials.            Johnson (2007), but added data from additional studies in which calcium supplements were given (which were
 DACH     >19 yr     RI      1,000  741     15%    Pooled analysis of calcium              not included by Hunt and Johnson, 2007), and excluded individual data from younger adults (18-24 years),
                                                                                           because of evidence that their calcium metabolism cannot be considered to be in a steady state.
 201538                                            balance studies (Hunt & Johnson
                                                                                        b
                                                                                           The coefficient of variation is not specified, but is calculated as 100% x [ ½ x (PRI/RI/RDA–AR)] / AR.
                                                   2007: 741 mg/d). There is no
                                                   clear evidence that intake >1,000
                                                   mg provides additional benefit
                                                                                        Table 58 shows that most reports (almost) agree on the value for adults
                                                   regarding the bone health of
                                                   adults >65 years old.                aged 18-50 years: HCNL’s AI, DACH’s RI, IOM’s RDA and WHO/FAO’s RI
 IOM      ♂ 19-70 yr RDA     1,000  800            Pooled analysis of calcium
 201139   &                                        balance studies (Hunt & Johnson      (all 1000 mg/d) equal EFSA’s PRI for adults aged 18 to 24 years, and are
          ♀ 19-50 yr                               2007). The estimate of 741 mg/d
                                                                                        5% higher than EFSA’s PRI for adults aged >25 yr. However NCM’s RI
                                                   was rounded to 800 mg/d to
                                                   account for uncertainty. RDA was     values are 10-20% lower than EFSA’s PRIs.
                                                   based on the upper limit of the
                                                   95% prediction confidence
                                                   interval (1,035 rounded to 1,000
                                                   mg/d).
                                                                                        For older adults, EFSA uses the same PRI (950 mg/d), whereas HCNL’s
          ♂ >70 yr   RDA     1,200  1,000   10%b   Intervention studies (meta-          AI, IOM’s RDA and WHO/FAO’s RI are 10-30% higher. However, NCM
          & ♀ >50 yr                               analysis Tang et al., 2007).
                                                   Supportive evidence from a           and DACH, like EFSA, do not differentiate the value between younger and
                                                   subgroup (60-79 yr) of the
                                                   Women’s Health Initiative trial      older adults.
                                                   (Jackson et al., 2006). Women
                                                   aged 50-69 yr: IOM decided to
                                                   provide public health protection in
                                                   the face of inconsistent data.
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<pre>chapter 16 | Calcium                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 91 of 179
16.2 Explanation of differences between reports                               Reference values for adults aged between 19/21/24 years and
                                                                              50/65/70 years
Reference values for the youngest adults (EFSA: 18-24 yr;                     All reference values for adults in this age group are based on either
NCM 18-20 yr)                                                                 balance data (EFSA, NCM, DACH, IOM and WHO/FAO) or a factorial
EFSA set higher reference values for men and women aged 18-24 years           approach (HCNL). Differences between reports are small for the PRI/RI/AI
than for older adults, because calcium continues to be deposited in bones     values, except for NCM who set a lower value based (mainly) on one
after they have ceased growing. EFSA did not base this AR and PRI on          Scandinavian balance study. EFSA, DACH, IOM and WHO/FAO used the
balance data, because the additional requirement for calcium in young         pooled analysis of the available balance studies from the USA; their PRI/
adults is unknown. Instead, EFSA derived the AR for 18-24 yr (860 mg/d)       RDA/RI-values differ little. HCNL used a factorial method resulting in an
as the intermediate value between the AR for children aged 11-17 yr (AR       AI-value almost equal to EFSA’s PRI.
960 mg/d) and adults ≥ 25 years (AR 750 mg/d). The PRI for 18-24 yr was
based on a CV of 10%, and rounded down to the nearest 50; EFSA notes          EFSA and IOM based the difference between their AR and PRI/
that the variation in requirements is unknown for this age group. As a        RDA-values on the observed variation. Calcium is one of the few nutrients
result, EFSA’s AR for adults aged 18-24 yr is substantially higher than       where data are available to account for the variation of requirements.
EFSA’s values for adults aged >25 yr (+15%), whereas the difference in
EFSA’s PRI-values is small (+5%).                                             Reference values for adults of 50/65/70 years and older
                                                                              Regarding older adults, the differences between the reports are more
NCM extended the recommendation for adolescents (RI 900 mg/d) to 18-20        substantial. The discrepancy is caused by a different judgement of the
year olds, as some bone mass is still accreted beyond 17 years of age.        evidence for the effect of a higher calcium intake on bone mass density
                                                                              and fracture risk in older adults.
The other reports do not set separate values for the youngest adults.         EFSA, NCM and DACH conclude that the evidence is inconclusive and
                                                                              therefore cannot be used for setting the reference values.
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<pre>chapter 16 | Calcium                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 92 of 179
HCNL, IOM and WHO/FAO based their higher reference values for adults            EFSA’s reference values for adults aged 24-49 years and men
older than 50, 65 or 70 years mainly on evidence from intervention studies      aged 24-69 years
indicating that supplementation with calcium and vitamin D (or                  All reports agree that the calcium intake of women aged 24-50 years and
supplementation with calcium alone) reduces fracture risk.                      men aged 24-70 years should be sufficient for the maintenance of the
                                                                                calcium content of the body, which is estimated by calcium balance data
Sex differences                                                                 or the factorial approach.
In two reports (IOM and WHO/FAO) the reference values for women                 The Committee has no objections against EFSA’s reference values for
increase from 50 years or after menopause, whereas the reference values         women aged 24-50 years and men aged 24-70 years.
for men increase at a higher age (from 70 and 65 years, respectively).
None of the other reports differentiate between men and women. EFSA’s           EFSA’s reference values for women aged >50 years and men
AR and PRI were mainly based on the publication by Hunt et al. (2007);          aged >70 years
Hunt et al. reported that the relation between calcium output and intake,       Since 2012, HCNL advises all Dutch persons aged 70 and over to take a
expressed as mg/d, was not sex dependent (p=.5).                                daily supplement of 20 micrograms of vitamin D, and recommends all
                                                                                women aged between 50 and 70 years to take a daily supplement of 10
16.3 Conclusion on the scientific basis of EFSA’s reference                     micrograms of vitamin D. This recommendation to use vitamin D
      values                                                                    supplements has consequences for the calcium requirement of older adults
                                                                                in the Netherlands: in order for the extra vitamin D to be effective, a
EFSA’s reference values for the youngest adults (18-24 yr)                      sufficient calcium intake is required. Although the protective effects of the
EFSA assumes that the youngest adults (18-24 years) require more                use of vitamin D supplements on bone health has primarily been reported in
calcium than older adults, because of the continuation of calcium               combination with the use of calcium supplements, HCNL concluded that
deposition in bones during the first years after growth has stopped (EFSA       there are indications that additional vitamin D without supplemental calcium
refers to Teegarden et al., 1995; Ohlsson et al., 2011; Darelid et al., 2012).  also has protective effects on fracture risk if dietary calcium intake is 1,100
The Committee has no objections against EFSA’s reference values for             mg/d in women aged 50-69 years, and 1,200 mg/d in adults >70 years.34
adults aged 18-24 years.
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<pre>chapter 16 | Calcium                                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 93 of 179
The scientific basis of HCNL’s recommendation for the combination of                                           The Dutch dietary guidelines 2015 conclude: “Because normal calcium
vitamin D supplements with an increased calcium intake in older adults, has                                    intake is quite high in the Netherlands, there is generally no need for vitamin
been confirmed in the Dutch dietary guidelines 2015. HCNL concluded in                                         D supplementation to be combined with calcium supplementation. However,
the background report on vitamin and mineral supplements53 that there was                                      people in high-risk groups who don’t eat dairy products or eat them in
strong evidence from intervention studies that the use of supplements with                                     unusually small quantities should combine vitamin D supplementation with
0.5-1.2 g/d calcium plus 10-20 μg/d vitamin D per day reduces the risk of                                      calcium supplementation.” The Committee notes that adverse effects of
fractures by 10% and reduces the risk of hip fractures by 15% in older                                         higher calcium intakes have only been associated with calcium
adults and especially postmenopausal women. For calcium                                                        supplements, not with higher dietary calcium intakes.
supplementation alone – without the use of a vitamin D supplement – the                                        The Committee considers that EFSA’s AR and PRI for adults aged >25
evidence was limited. HCNL furthermore concluded that the use of calcium                                       years are not sufficient for women aged 50-69 years and adults aged >70
supplements increases the risk of coronary heart disease (strong evidence).                                    years in the Netherlands.
                                                                                                               16.4 Summary and conclusion
   Background information – a summary of the information provided by the EFSA report – on
                                                                                                               Table 59. Summary of the evaluation of EFSA’s AR values for calcium
   the function of the nutrient, the occurrence of clinical deficiency and deficiency symptoms
   in adults                                                                                                    Main findings, used for the conclusion
                                                                                                                Aspect                    Conclusion   Comment
   Calcium is an integral component of the skeleton; approximately 99% of total body calcium is                 EFSA’s PRI compared to Equal / Lower   18-24 yr: EFSA’s PRI equals HCNL’s AI;
   found in bones and teeth, where it is mainly present as calcium hydroxyapatite. It has a structural          HCNL’s AI                              25-49 yr: EFSA’s PRI is ~5% lower than HCNL’s AI;
   role, and is needed for tissue rigidity, strength and elasticity.                                                                                   50-69 yr: EFSA’s PRI is ~15% lower than HCNL’s AI;
   The remaining 1% of calcium found in the body acts as an essential intracellular messenger in                                                       >70 yr: EFSA’s PRI is ~20% lower than HCNL’s AI.
   cells and tissues. It has a critical role in many physiological functions involved in the regulation of      Scientific basis of       No objection EFSA used balance data which, for younger adults, is
                                                                                                                EFSA’s AR and PRI for                  consistent with NCM, DACH, IOM and WHO/FAO.
   metabolic processes, including vascular contraction and vasodilation, muscle contraction, enzyme
                                                                                                                women aged 18-50                       HCNL used a factorial method.
   activation, neural transmission, membrane transport, glandular secretion and hormone function.
                                                                                                                years, and for men aged
   A low intake of calcium often co-exists with vitamin D deficiency. Older adults with osteomalacia            18-70 years.
   will have a reduced bone mass which leads to impaired bone strength. EFSA notes that genetic
   and environmental factors play a role in the prevention of osteopenia, osteoporosis and bone
   fracture.
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<pre>chapter 16 | Calcium                                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 94 of 179
 Main findings, used for the conclusion
 Aspect                    Conclusion          Comment
                                                                                                       For women aged 50-69 years and for adults (men and women) aged >70
 Scientific basis of       Objections based    HCNL recommends that these groups use vitamin D
 EFSA’s AR and PRI for     on a different      supplements and, in order for the extra vitamin D to    years, the Committee does have objections against EFSA’s reference
 women aged >50 years      nutritional context be effective, calcium intake should be higher than
 and for men aged >70      in the Netherlands  EFSA’s PRI. Note dat EFSA considers the evidence        values, based on a different nutritional context in the Netherlands: HCNL
 years.                                        for the preventive effect against fractures in
                                               intervention studies insufficient.
                                                                                                       recommends that all Dutch women aged >50 years and all men aged >70
 Other findings                                                                                        years, use vitamin D supplements. As a consequence, EFSA’s PRI for
 Aspect                    Conclusion          Comment
 Differentiation between   Not applied by      Consistent with NCM and DACH, but not with HCNL,
                                                                                                       calcium appears to be too low for these groups. The Committee
 younger and older adults EFSA                 IOM and WHO/FAO.                                        recommends maintaining the current Dutch AIs for calcium (Table 60).
 Differentiation between   Not applied by      Consistent with the reports used for comparison.
                                                                                                       Table 60. AR and PRI for calcium, recommended for the Netherlands
 men and women             EFSA
                                                                                                                                          18-24      25-49    50-69 years            >70 years
For adults aged 18-24 years, for women aged 25-50 years, and for men                                                                      years      years
                                                                                                                                          ♂&♀        ♂&♀      ♂           ♀          ♂&♀
aged 25-70 years, the Committee has no objections against the scientific                                Average requirement (AR)          860 mg/d   750 mg/d 750 mg/d    -          -
                                                                                                        Population reference intake (PRI) 1,000 mg/d 950 mg/d 950 mg/d    -          -
basis of EFSA’s reference values, or EFSA’s PRIs and ARs and
                                                                                                        Adequate intake (AI)              -          -        -           1,100 mg/d 1,200 mg/d
recommends accepting these values in the Netherlands (Table 60).
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<pre>chapter 17 | Chromium (III)                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 95 of 179
17
chromium (III)
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<pre>chapter 17 | Chromium (III)                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 96 of 179
17.1 Overview and comparison of values                                                          EFSA furthermore notes that no symptoms have been reported in
                                                                                                apparently healthy subjects that can be related to low chromium intake
Table 61. Overview of the reference values for adults and the criteria on which these
values are based                                                                                (Stearns, 2007).
 Report     Age range    AI             Main criterion                                          EFSA describes (based on case reports) that 5 patients on total parenteral
                         Type    (μg/d)
 DACH       ≥19 yr       AI      30-100 Estimated need for physiological functions by WHO
                                                                                                nutrition (TPN) for at least several months (up to 13 years), developed
 201338                                 in 1996 (20 μg/d), with safety margin for body          symptoms which improved after chromium supplementation.a These
                                        reserves and presumed underestimation. In the
                                        absence of satisfactory data, an AI range was           symptoms included impaired glucose tolerance, weight loss, ataxia,
                                        derived.
 IOM 200141 19-50 yr     AI      35 (♂) Estimated intake:
                                                                                                neuropathy, hyperaesthesia in hands and feet, postural tremor, unsteady
                                        Chromium content of a mixed diet was estimated to       gait and muscle weakness. EFSA notes that, in threeb cases, the
                                 25 (♀) be 3.2 μg/MJ (range 2-5.7 μg/MJ), based on chemical
                                        analysis of 22 adult diets designed by nutritionists    chromium concentration in the TPN solution was reported. EFSA
                                        (Anderson et al. 1992). The AI for men and women
                                        aged 19-50 yr was calculated assuming energy            estimated that the supply via TPN in these three cases (5-10 μg/d) is
                                        intake to be 11.7 and 7.8 MJ/d, respectively.
                                                                                                equivalent to an oral intake of 100-200 μg/day.c EFSA notes that the
            ≥51 yr       AI      30 (♂) Estimated intake:
                                        The AI for men and women aged >51 yr was                estimated median intakes in European countries are lower: 55-85 μg/day.d
                                 20 (♀) calculated using the estimated dietary content of 3.2
                                        μg/MJ, and assuming energy intake to be 8.8 and 6.3     EFSA concludes that, on the basis of these case reports, it is unclear
                                        MJ/d, respectively.
                                                                                                whether deficiency of chromium could be considered the only cause of
Note that EFSA,27 NCM,37 and WHO/FAO44 did not establish reference                              glucose intolerance in these patients, whether deficiency of chromium has
values for trivalent chromium. HCNL33 does not include reference values
for chromium.
                                                                                                a
                                                                                                  EFSA refers to the following publications: Jeejeebhoy et al. (1977); Freund et al. (1979); Brown et al. (1986);
                                                                                                  Verhage et al. (1996); Tsuda et al. (1998). EFSA describes one additional publication on five acute-care patients
17.2 Explanation of differences between reports                                                   with inconclusive results: Wongseelashote et al. (2004).
                                                                                                b
                                                                                                  EFSA notes that the chromium supply via the TPN solutions was reported in three publications: Jeejeebhoy et al.
EFSA notes that attempts to create chromium deficiency in animal models                           (1977); Brown et al. (1986); Verhage et al. (1996).
                                                                                                c
                                                                                                  EFSA calculated the equivalent oral intake assuming an absorption efficiency of 5%, which is the upper end of the
have not produced consistent results, and that there is no evidence of the                        range observed for supplemental chromium. Use of a lower absorption efficiency would result in an even higher
                                                                                                  value for the oral intake equivalent.
essentiality of chromium (III) in animal nutrition.                                             d
                                                                                                  EFSA reported that chronic dietary chromium intake data were available from 17 European countries. Median
                                                                                                  dietary chromium intakes in European adults were estimated to be 57.3-83.8 μg/day (medians of lower and upper
                                                                                                  bounds).57
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<pre>chapter 17 | Chromium (III)                                         An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 97 of 179
occurred in these patients and whether chromium deficiency occurs in        17.3 Conclusion on the scientific basis of EFSA’s reference
healthy populations.                                                              values
                                                                            EFSA concludes that data from reported improvements associated with
DACH used the estimation in a 1996 WHO report as the basis for its          chromium supplementation in patients do not provide sufficient information
reference value, although WHO/FAO did not set a reference intake for        to identify a dietary requirement for humans. The Committee has no
chromium in 2004.                                                           objections against EFSA’s evaluation.
IOM (2001) based its reference value on the mean chromium content of        17.4 Summary and conclusion
22 adult diets designed by nutritionists and assumptions on energy intake.  EFSA did not derive reference values for chromium, because it is not clear
                                                                            whether chromium is an essential trace element for healthy subjects.
Differences between older and younger adults and sex differences
IOM differentiates between older and younger adults and between men         The Committee agrees with EFSA’s conclusion that it is not clear whether
and women, based on assumed energy intake. DACH did not differentiate       chromium is an essential trace element and with EFSA’s decision to not
between groups of adults.                                                   set reference values for chromium.
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<pre>chapter 18 | Copper                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 98 of 179
18
copper
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<pre>chapter 18 | Copper                                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 99 of 179
                                                   Copper                                                  18.1 Overview and comparison of values
                                                                                                           Table 62. Overview of the reference values for adults and the criteria on which these
      Should EFSA's reference values be rejected                                                           values are based
      based on a specific nutritional context in the                                 YES
    Netherlands that differs from (the rest of) Europe?
                                                                                                            Report        PRI/RDA/AI/RI      AR       CV     Main criterion
                                                                                                                          (mg/d)             (mg/d)   (%)
                                                                                                                          Type ♂         ♀   ♂    ♀
                                                                                                            EFSA 2015  17
                                                                                                                          AI     1.6     1.3 -    -   -      Observed intakes in EU for men,
                                                                                                                                                             combined with results of balance studies.
                             NO
                                                                                                            NCM 201437    RI     0.9     0.9 0.7  0.7 15     NCM mentions the IOM criteria and
                                                                                                            = HCNL                                           additional criteria, and adopts the IOM
                                                                                                            201433                                           values.
                                                                                                            DACH 201538   AI     1.0-1.5     -    -   -      Estimated value is based on three
   Are there objections against EFSA’s scientific basis                                                                                                      references without further specifications
                     for this nutrient?                                                                                                                      (the balance study estimate of 1.25 mg/d
                                                                                                                                                             by Klevay et al., 1980; a WHO estimate of
                                                                                                                                                             1.1 μg/kg body weight dated 1996 [WHO
                                                                                                                                                             did not set reference values for copper in
                                          YES                                                                                                                2004]; and the Scientific Committee on
                                                                                                                                                             Food 1993 estimate of 1.1 mg/d).
                                                                                                            IOM 200141    RDA    0.9     0.9 0.7  0.7 15     IOM used a combination of two types of
                                                                                                                                                             data:
                  Do (part of) EFSA's reference values differ 10% or                                                                                         Status and function parameters: plasma
   NO                                                                                YES
                   more from the 2014 values for the Netherlands?                                                                                            and platelet copper concentration, serum
                                                                                      AI s                                                                   caeruloplasmin concentration, and
                                                                                                                                                             erythrocyte SOD activity in controlled
                                                                                                                                                             depletion-repletion studies.
                                                                                                                                                             Factorial method.
                                           NO
                                                                                                           Note that WHO/FAO 200444 did not specify reference values for copper.
        No objections against the use of                   Major objection against the use of
   EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands         Table 62 shows that the RDA/AIs in the reports used for comparison are
                                                                                                           lower than EFSA’s AIs. The differences relative to EFSA’s AIs are -38%
                                                                                                           (NCM and IOM) and -14% (DACH).
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<pre>chapter 18 | Copper                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 100 of 179
18.2 Explanation of differences between reports                                which of the intake estimates (i.e. the EFSA intake estimate or the
In 2014, HCNL advised using the NCM-value in the Netherlands. NCM              published one) would be closer to the actual copper intake.
adopted their values from IOM. The AI used by DACH is not further              For men, EFSA also took balance data into account. The EFSA Panel
discussed in this paragraph because of insufficient information on the         describes that positive copper balance were reported at intakes of
derivation of this value. Therefore, the Committee only explains the           2.49 mg/day (Turnlund et al., 1998) and 7.8 mg/day (Harvey et al., 2003),
differences between EFSA and IOM in this paragraph.                            that negative balances were reported at intakes from 0.38 to 0.7 mg/day
                                                                               (Turnlund et al., 1998; Harvey et al., 2003), and that zero balance was
EFSA’s AI is based on intakes, IOM’s AR is based on biochemical                reported at an intake of approximately 1.6 mg/day (Harvey et al., 2003;
parameters of status and function and on a factorial method.                   Turnlund et al., 2005). The EFSA Panel mentions two significant limitations
                                                                               to the balance studies. Firstly, underestimation of requirements appears
EFSA’s AIs are mainly based on intakes, but for men balance data were          likely, because of underestimation of copper losses: sweat and dermal
also taken into account (balance data were not available for women).           losses often are not considered and were estimated to be 0.3 mg/d, on
The intake data used by EFSA are from dietary surveys carried out in nine      average. Secondly, in some studies, the period during which dietary intake
EU countries: Finland, France, Germany, Ireland, Italy, Latvia, the            is maintained at a fixed level before balance measurement is relatively
Netherlands, Sweden and the UK. Average copper intakes ranged                  short and may be too short for homeostatic adaptation to occur. EFSA
between 1.15 and 2.07 mg/day in adults. EFSA notes some discrepancy            concludes that balance studies cannot be used as the sole criterion for
(up to around 25%) between EFSA’s estimates and the published intake           setting copper DRVs, but may be used together with other data.
estimates from the same survey and same age ranges, resulting from             EFSA rejects the biomarkers used by IOM. EFSA considers that these
several sources of uncertainties: inaccuracies in mapping food                 biomarkers poorly respond to copper intakes, and have limited value as
consumption data according to food classifications, inaccuracies in            biomarkers of copper status in individuals. EFSA notes that the limitation
nutrient content estimates available from the food composition tables, the     as a status parameter is especially related to copper overload: low
use of “borrowed” copper values from other countries in the food               concentrations may indicate copper depletion. EFSA describes that, at
composition database, and replacing missing copper values by values of         copper intakes >0.7 mg/d, no effect of copper intake on caeruloplasmin
similar foods or food groups. EFSA notes that it is not possible to conclude   concentration was reported. Thus EFSA’s objections against these
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<pre>chapter 18 | Copper                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 101 of 179
biomarkers are related to copper intake levels equal to, or higher than,          By application of a linear model to the data of these two studies in men,
IOM’s EAR.                                                                        the copper requirement to maintain copper status in half of a group was
                                                                                  estimated to be 0.55 mg/day.
IOM’s EARs and RDAs                                                               One study in women:
IOM rejected the use of balance data for setting copper reference values          • Milne & Nielsen, 1996: in 13 women, serum copper and ceruloplasmin
(which were used by EFSA), because zero balance can be achieved over                 concentrations did not decline significantly at intakes of 0.57 mg/day,
a broad range of dietary copper intakes and because balance studies are              but platelet copper concentration declined significantly in eight out of
prone to numerous errors, and are seldom long enough to obtain valid                 ten women, and increased with copper supplementation.
results.                                                                          This study in women suggests that 0.6 mg/day may be a marginal intake
Note that IOM used the biomarkers in the lower range of copper intakes,           in over half of the population. Therefore, IOM added another increment to
where these levels are responsive to copper intake. IOM’s derivation of           cover half of the population: IOM’s EAR is 0.7 mg/day.
the EAR of 0.7 mg/day is based on two studies in men (which taken                 IOM used a factorial method as supporting information, resulting in the
together involved 22 men) and one study in 13 women.                              estimation that an intake of 0.51 mg/day would replace the obligatory
The two studies in men:                                                           copper losses via faeces, urine, sweat and other routes.
• Turnlund et al., 1997: in 11 men serum copper and ceruloplasmin
   concentrations decreased over 42 days at an intake of 0.4 mg copper            Differences between older and younger adults
   per day, and increased with copper repletion. IOM notes that the serum         All reports set one value for the age group >18 years.
   levels did not fall to the deficient range in this study, but were expected
   to have fallen to the deficient range, had the deficient diet been fed for     Sex differences
   a period longer than 42 days.                                                  EFSA set a higher value for men than for women, whereas all reports
• Turnlund et al. 1990: serum copper and ceruloplasmin concentrations             used for comparison set one value without differentiation for sex.
   did not decline significantly in 11 men at intakes of 0.79 mg/day.
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<pre>chapter 18 | Copper                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 102 of 179
18.3 Conclusion on the scientific basis of EFSA’s reference                   4-24 yr). Two patients had neutropenia, one had macrocytic,
      values                                                                  normochromic anemia, and some had bone abnormalities including
In paragraph 18.2, the Committee described the inconsistency between          reduced bone density. Copper supplementation normalised neutrophil
EFSA and IOM in the type of data that can be used for setting the             counts and improved bone abnormalities. IOM notes that, based on
reference values.                                                             extrapolation of the copper intake levels in these patients to adults, copper
• Both organisations note that balance data have significant limitation.      deficiency might be expected to develop in adults at copper intakes equal
   Still, EFSA used the intake level associated with zero balance (1.6 mg/    to, or lower than, about 0.4 and 0.3 mg/d in adult men and women,
   day) as supportive information. IOM rejected balance data, because         respectively.
   zero balance can be achieved over a broad range of dietary copper          EFSA presented some information on copper intake levels associated with
   intakes. The Committee notes that the balance data described by EFSA       the occurrence of deficiency, but one of these publications did not provide
   refer to copper intake levels that were either lower (<0.7 mg/day) or      electrocardiogram information and, in the other, the occurrence of
   higher (>1.6 mg/day) than IOM’s EAR (0.9 mg/day). EFSA does not            deficiency signs was associated with high zinc levels (Table 63).
   present balance estimates for intakes larger than 0.7 mg/day and
                                                                              Table 63. Copper intake levels associated with the occurrence, correction or
   smaller than 1.6 mg/day.                                                   prevention of deficiencies, as described by EFSA
• EFSA rejects the biomarkers used by IOM: EFSA considers that                 Clinical manifestation associated with deficiency Associated Subjects/          EFSA’s
                                                                                                                                   intake       Specific group reference
   plasma and serum copper concentrations are of limited value as              3 out of the 13 women: significant increase in the  0.57 mg/d    13 postmeno-   Milne and
   biomarkers of copper status, especially in relation to copper overload,     number of premature ventricular discharges after    for 105      pausal women   Nielsen, 1996
                                                                               21, 63 and 91 days (no electrocardiogram            days
   although low concentrations may indicate copper depletion. However,         information provided by Milne & Nielson).
                                                                               3 out of the 12 women: exhibited abnormal           1 mg/d for   12 postmeno-   Milne et al.,
   IOM uses these biomarkers as indicators of a marginal status, and           electrocardiographic recording (premature           90 days      pausal women   2001
   EFSA’s objections against these biomarkers do not apply at these            ventricular discharge).
                                                                               2 women still exhibited an increased number of      +3 mg/d,
   levels. Therefore, IOM’s EAR can be considered relevant for the             abnormal premature ventricular discharges after     duration not
                                                                               using a supplement with 3 mg/d. They were           specified
   prevention of deficiency.                                                   excluded from the final paper, because they both
                                                                               had very high zinc levels from the cement they were
IOM notes that signs of clinical deficiency have been reported in six
                                                                               using for their dentures.
severely handicapped patients on prolonged enteral nutrition (age range
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<pre>chapter 18 | Copper                                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 103 of 179
The Committee concludes that EFSA did not provide evidence that intakes                                18.4 Summary and conclusion
as high as EFSA’s AIs are required for the prevention of deficiency
                                                                                                       Table 64. Summary of the evaluation of EFSA’s AI values for copper
symptoms.                                                                                               Main findings, used for the conclusion
                                                                                                        Aspect                    Conclusion Comment
IOM’s EAR of 0.7 mg/day corresponds with the intake level reported to be
                                                                                                        EFSA’s AIs compared to Higher         EFSA’s AI for men and women is about 80% and 45% higher
associated with prevention of a marginal copper status, and provides a                                  HCNL’s (=NCM’s) RI                    than the current RI used in the Netherlands (NCM’s RI).
                                                                                                        Scientific basis of       Objections  EFSA is not consistent with IOM.
margin above the intake level of 0.3-0.4 mg/day which is expected to be                                 EFSA’s AIs                            EFSA based the AIs on intake data, and for men, additionally
                                                                                                                                              on balance data. EFSA did not provide evidence that intakes
associated with the occurrence of copper deficiency. Therefore, IOM’s                                                                         as high as EFSA’s AIs are required for the prevention of
EAR appears to have sufficient relevance for the prevention of deficiency.                                                                    deficiency symptoms.
                                                                                                                                              IOM’s EAR is based on status & function parameters at low
IOM takes into account an assumed coefficient of variation of                                                                                 copper intake levels, with a factorial estimate as supportive
                                                                                                                                              information. The Committee considers that this value has
requirements of 15%, resulting in an RDA of 0.9 mg/day.                                                                                       sufficient clinical relevance.
                                                                                                        Other findings
                                                                                                        Aspect                    Conclusion Comment
   Background information – a summary of the information provided by the EFSA report –                  Differentiation between   Not applied Consistent with the reports used for comparison.
   on the function of the nutrient, the occurrence of clinical deficiency and deficiency                younger and older adults by EFSA
   symptoms in adults                                                                                   Differentiation between   Applied by  Not consistent with the reports used for comparison.
                                                                                                        men and women             EFSA
   Copper serves as an electron donor and acceptor in a similar chemical reaction to that for iron.
   In humans, cupro-enzymes are involved in many functions, including neurotransmitter synthesis,      The Committee has objections against EFSA’s AI for adults. EFSA did not
   deamination, iron metabolism, superoxide dismutation, energy metabolism, dopamine to
                                                                                                       provide evidence that the substantial increase from the current Dutch RDA
   noradrenaline conversion, collagen and elastin cross-linking, and melanin synthesis.
   EFSA mentions that clinical symptoms of copper deficiency are not common in humans and              to EFSA’s AIs is required for the prevention of deficiency symptoms or is
   generally are seen as a consequence of mutations in the genes involved in copper metabolism
                                                                                                       beneficial for health. The Committee recommends maintaining HCNL’s
   (Menkes disease).
   Symptoms of copper deficiency may include:                                                          reference values (which are the values used by IOM and NCM; Table 65),
   •   normocytic and hypochromic anaemia, that is not responsive to iron supplementation
                                                                                                       because this AR appears to have sufficient relevance for the prevention of
   •   neurological findings, most commonly due to neuromyelopathy (human swayback)
   •   increased risk of aneurysm as a consequence of impaired collagen and elastin synthesis          deficiency.
   •   skin and hair hypopigmentation
   •   leukopenia, neutropenia, hypercholesterolaemia,                                                 Table 65. AR and PRI for copper, recommended for the Netherlands
   •   myelodysplasia
                                                                                                                                                         Men and women >18 years
   •   alterations in immune function.
                                                                                                        Average requirement (AR)                         0.7 mg/day
                                                                                                        Population reference intake (PRI)                0.9 mg/day
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<pre>chapter 19 | Fluoride                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 104 of 179
19
fluoride
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<pre>chapter 19 | Fluoride                                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 105 of 179
                                                   Fluoride                                                 19.1 Overview and comparison of values
                                                                                                            Table 66. Overview of the reference values for adults and the criteria on which these
              Should EFSA's reference values be rejected                                                    values are based
              based on a specific nutritional context in the                                 YES
            Netherlands that differs from (the rest of) Europe?                                              Report         AI (mg/d)  Main criterion
                                                                                                                            ♂     ♀
                                                                                                             EFSA 201331    3.4   2.9  Data on the dose-response relationship between caries incidence and
                                                                                                             = HCNL 201433             consumption of drinking water with different fluoride concentrations
                                                                                                                                       which were confirmed by more recent data on total fluoride intake
                                     NO
                                                                                                                                       from a study in the US. The AI of 0.05 mg per kg body weight per day
                                                                                                                                       is used both for children and adults. EFSA calculated values for men
                                                                                                                                       and women based on reference weights of 68.1 and 58.5 kg.
                                                                                                             DACH 201538    3.8   3.1  Based on IOM value of 0.05 mg per kg body weight per day as the
           Are there objections against EFSA’s scientific basis                                                                        adequate intake for caries prevention.
                             for this nutrient?
                                                                                                             IOM 199743     4     3    In areas with water fluoridation, the estimated intakes in children were
                                                                                                                                       close to 0.05 mg fluoride per kg body weight per day. Average dietary
                                                                                                                                       fluoride intakes of adults ranged from 0.02-0.05 mg per kg body
                                                                                                                                       weight per day. The value of 0.05 mg fluoride per kg body weight per
                                                  YES                                                                                  day was chosen as the AI for all ages above six months, based on the
                                                                                                                                       extensively documented relationship between caries prevalence and
                                                                                                                                       fluoride concentration of water. IOM calculated values for men and
                                                                                                                                       women based on reference weights of 76 and 61 kg (3.8 and 3.1
                          Do (part of) EFSA's reference values differ 10% or                                                           mg/d) and rounded these values to achieve the AIs of 4 and 3 mg/d.
           NO                                                                                YES
                           more from the 2014 values for the Netherlands?
                                                                                                            Note that NCM37 and WHO/FAO44 did not specify reference values for
                                                   NO                                                       fluoride.
                                                                                                            Table 66 shows that the differences in AIs for fluoride are limited: DACH’s
                No objections against the use of                   Major objection against the use of
          EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands  AIs are 11% higher (men) and 7% higher (women) than EFSA’s AIs; IOM’s
                                                                                                            AIs are 18% higher (men) and 3% higher (women) than EFSA’s AIs.
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<pre>chapter 19 | Fluoride                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 106 of 179
19.2 Explanation of differences between reports                                 children in the US and Canada that were published from 1943 to 1988.
The NCM report does contain an evaluation of fluoride. NCM concludes            EFSA adds that the efficacy of water fluoridation in preventing caries has
that fluoride has a well-documented role in the prevention and treatment        been confirmed in a number of predominantly observational studies, either
of dental caries, but that the mechanism is attributed to local effects on the  cross-sectional or prospective and retrospective cohort studies, referring
tooth enamel surface rather than systemic effects. NCM considers that           to a systematic review of studies in children and a meta-analysis of
fluoride is not essential for humans.                                           studies in adults.
                                                                                However, EFSA notes: (1) that very few of the many reviewed studies
The AIs by EFSA, DACH and IOM are based on the prevention of dental             provide information on the total dietary fluoride intake, (2) that the
caries.                                                                         outcome measure for caries may have been affected by additional uses of
EFSA, DACH and IOM all use 0.05 mg per kg body weight per day as the            non-dietary fluoride via supplements or fluoride-containing dental hygiene
adequate intake for caries prevention, largely using the same scientific        products, (3) that there are methodological difficulties in the measurement
basis. The differences in AIs result from different reference weights used      of the fluoride content of food and beverages, (4) that these contents
and rounding:                                                                   appear to vary widely, and (5) that the majority of studies have not
• reference weights for men were 68.1 kg (EFSA) and 76 kg (DACH and             systematically addressed other factors which influence caries
   IOM);                                                                        development (e.g. diet, dental hygiene, environment, and genetic
• reference weights for women were 58.5 kg (EFSA) and 61 kg (DACH               disposition).
   and IOM);                                                                    EFSA considers that reliable and representative data on the total fluoride
• the difference between DACH and IOM is the result of the fact that IOM        intake of the European population are not available; the available data are
   did, whereas DACH did not round the value.                                   variable and generally at or below 0.05 mg/kg body weight per day.
                                                                                EFSA considers that the AI for children of 0.05 mg/kg body weight per day
EFSA notes that both the concentration of 1 mg fluoride/L in drinking water     can also be applied to adults, including pregnant and lactating women.
and the fluoride intake of 0.05 mg/kg body weight per day appear to be
“optimal” in reducing caries prevalence and keeping dental fluorosis
prevalence and severity in the population low, based on 7 studies in
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<pre>chapter 19 | Fluoride                                                                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 107 of 179
Differences between older and younger adults                                                              different nutritional situation in the Netherlands compared to the situation
None of the reports differentiate the AIs between older and younger                                       on which EFSA based their AIs.
adults.
                                                                                                          19.4 Summary and conclusion
Sex differences
                                                                                                          Table 67. Summary of the evaluation of EFSA’s AI values for fluoride
All reports differentiate the AIs between men and women.                                                   Main findings, used for the conclusion
                                                                                                           Aspect                     Conclusion          Comment
                                                                                                           EFSA’s AIs compared to     Not applicable      In the Netherlands, the preventive effect of
19.3 Conclusion on the scientific basis of EFSA’s reference                                                the Dutch approach                             fluoride against caries is achieved via the use of
                                                                                                                                                          fluoride-containing dental hygiene products and
       values                                                                                                                                             not via fluoride intake.
EFSA concluded that fluoride is not an essential nutrient, but still based                                 Scientific basis of EFSA’s Objections          EFSA assumes that fluoride intake is required for
                                                                                                           reference value                                caries prevention, which is consistent with DACH
the AI for fluoride on the preventive effect against caries.                                                                                              and IOM. In the Netherlands, intake is not
                                                                                                                                                          considered necessary; fluoride-containing dental
                                                                                                                                                          hygiene products are used for caries prevention.
   Background information – a summary of the information provided by the EFSA report –                     Other findings
   on the function of the nutrient, the occurrence of clinical deficiency and deficiency                   Aspect                     Conclusion          Comment
   symptoms                                                                                                Differentiation between    Not applied by EFSA Consistent with DACH and IOM.
                                                                                                           younger and older adults
   No signs of fluoride deficiency have been identified in humans. One cohort study on infants from        Differentiation between    Applied by EFSA     Consistent with DACH and IOM.
   an area with a low fluoride content of drinking water described a higher rate of length and body        men and women
   weight gain with a fluoride supplement (0.25 mg/day from birth) than without; EFSA considers
   that this observation does not provide sufficient evidence to prove a causal relationship between
   fluoride intake and growth.                                                                            The Committee rejects EFSA’s AIs for fluoride, because of a different
   A lack of fluoride intake during development will not alter tooth development but may result in
                                                                                                          nutritional situation in the Netherlands compared to the situation on which
   increased susceptibility of enamel to acid attacks after eruption. However, caries is not a fluoride
   deficiency disease and EFSA concludes that fluoride is not an essential nutrient.                      EFSA based their AIs. In the Netherlands, fluoride-containing dental
                                                                                                          hygiene products are used for caries prevention; contrary to EFSA,
In the Netherlands, the preventive effect of fluoride against caries is                                   fluoride intake is not considered necessary for caries prevention.
achieved via the use of fluoride-containing dental hygiene products and
not via fluoride intake. EFSA’s AIs for fluoride are rejected, based on a
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<pre>chapter 20 | Iodine                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 108 of 179
20
iodine
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<pre>chapter 20 | Iodine                                                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 109 of 179
                                                    Iodine                                                    20.1 Overview and comparison of values
                                                                                                              Table 68. Overview of the PRI/RDA/RI/AI values for adults and the criteria on which
         Should EFSA's reference values be rejected                                                           these values are based
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?                                                      Report       PRI/RDA/        AR         CV      Main criterion
                                                                                                                             AI/RI (μg/d) (μg/d)        (%)
                                                                                                                EFSA         AI      150                        AI is based on urinary iodine concentration >100 μg/L
                                                                                                                201425
                                                                                                                NCM          RI      150     100        25%a    AR is based on:
                                NO
                                                                                                                201437                                          • intake at which thyroid iodine concentration reaches a
                                                                                                                = HCNL                                            plateau
                                                                                                                201433                                          • daily iodine turnover in subjects with normal thyroid
                                                                                                                                                                  function.
      Are there objections against EFSA’s scientific basis                                                      DACH         AI      150                        Based on urinary iodine concentration >100 μg/L and
                        for this nutrient?                                                                      2015 38
                                                                                                                                                                taking into account that iodine supply is sufficient in
                                                                                                                Switzerland                                     Switzerland as a result of the Swiss iodised salt
                                                                                                                                                                programme.
                                                                                                                DACH         AI      200                        Based on urinary iodine concentration >100 μg/L and
                                             YES                                                                201538                                          taking into account that iodine supply is insufficient in
                                                                                                                Germany,                                        Germany and Austria.
                                                                                                                Austria
                                                                                                                IOM 200141 RDA 150b          95b        20%c    AR is based on:
                     Do (part of) EFSA's reference values differ 10% or                                                                                         • the average thyroid iodine accumulation and turnover.
      NO                                                                                YES
                      more from the 2014 values for the Netherlands?                                                                                            With as supporting data:
                                                  AI                                                                                                            • obligatory iodine excretion is lower than AR
                                                                                                                                                                • the approximate intake at which iodine balance was
                                                                                                                                                                  achieved in men; however, in women, iodine balance
                                              NO
                                                                                                                                                                  was estimated to be reached at a considerably higher
                                                                                                                                                                  intake.
                                                                                                                                                                (Note: IOM uses the EFSA key reference as supporting
                                                                                                                                                                data for the RDA in children aged 9-13 years.)
                                                                                                                WHO/FAO      RI      150                        RI:
           No objections against the use of                   Major objection against the use of                200444                                          • corresponds to the daily urinary iodine excretion and
     EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands
                                                                                                                                                                  to the food iodine content in non-endemic areas
                                                                                                                                                                • necessary to maintain plasma iodine >0.10 μg/dl
                                                                                                                                                                • necessary to maintain thyroid iodine stores >10 mg
                                                                                                                                                                • corresponds to urinary iodine concentration >100 μg/L.
                                                                                                              a
                                                                                                                 NCM CV calculated from AR and RDA: 100% x [ (150-100) / 2 ] / 100 = 25%.
                                                                                                              b
                                                                                                                 IOM rounded the RDA to the nearest 50 μg/d and the EAR to the nearest 5 μg/d.
                                                                                                              c
                                                                                                                 The CV presented in the IOM report is 20%, however, the CV calculated from AR and RDA is 29%.
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<pre>chapter 20 | Iodine                                                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 110 of 179
Table 68 presents an overview of reference values and criteria. EFSA,                                          Arroyave, 1970). The EFSA Panel notes that other approaches, such as
NCM, DACH (value for Switzerland), IOM and WHO/FAO agree on an                                                 the approach based on thyroid hormone production and the factorial
RDA/RI of 150 μg iodine per day. The DACH value for Germany and                                                approach, support the AI of 150 µg/day.
Austria is 33% higher.                                                                                         EFSA did not consider the results of balance studies because these are
                                                                                                               highly variable and balances may be null at very different levels of intakes.
20.2 Explanation of differences between reports
                                                                                                               NCM maintained their 2004 recommendations for adults and children,
EFSA’s AI for adult men and women (150 µg/day) is based on two                                                 based on the iodine requirement to prevent goitre and maintain normal
estimates:                                                                                                     thyroid function, because there was no new data supporting changes.
1. A urinary iodine concentration >100 μg/L was associated with the                                            NCM 2004 considered the iodine requirement to prevent goitre (increased
    lowest prevalence of goitre in a study of 7,599 European children aged                                     thyroid gland size) to be 50-75 µg/d or approximately 1 µg/kg bodyweight
    6-15 years (DeLange et al., 1997).a Similar suitable data for other age                                    per day, based on the 1989 Recommended dietary allowances for the
    groups were not available. Therefore, this threshold was also applied                                      USA and the 1992 Nutrient and energy intakes for the European
    for adults, infants and young children.                                                                    Community. NCM estimates the average requirement to be 100 µg/d,
2. EFSA assumed the average daily urinary volume to be 1.5 L, based on                                         based on the 2001 IOM report. The recommended intake of 150 µg/d for
    scientific opinion on the dietary reference values for water.58                                            adults includes a safety margin for any goitrogenic substances in foods.
Furthermore, the EFSA Panel considered that a urinary iodine excretion of
100 μg/day, estimated from late morning spot urine samples (which is                                           DACH based their reference values on a urinary iodine concentration
supposed to be equivalent to an iodine intake of 110 μg/day) had been                                          >100 μg/L, and used data on iodine turnover and iodine supply as
associated with a goitre prevalence of up to 10% in Central America in the                                     additional evidence. This would result in an AI of 150 μg/day. DACH
1960s, indicating that an iodine intake of 110 μg/day may be lower than                                        considered that iodine supply is sufficient in Switzerland as a result of the
the iodine requirements in up to 10% of the population (Ascoli and                                             Swiss iodised salt programme, and that an AI of 150 μg/day was sufficient
                                                                                                               for Switzerland. Because of an insufficient iodine supply in certain age
a
  This study (DeLange et al., 1997) was carried out in the Netherlands. Belgium, Luxemburg, France, Germany,   groups and regions of Germany and Austria and considering that the
  Austria, Italy, Poland, the Czech and Slovak Republics, Hungary and Romania.
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<pre>chapter 20 | Iodine                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 111 of 179
amount of goitrogenic substances in foods increases, DACH maintained          to the iodine intake in non-endemic areas. It also provides the iodine
their higher AI (200 μg/day) for Germany and Austria.                         intake necessary to maintain the plasma iodine concentration above the
                                                                              critical limit of 0.1 μg/dL, which is the average level likely to be associated
IOM refers to three studies on the thyroid iodine accumulation and            with the onset of goitre. Moreover, this level of iodine intake is required to
turnover in 18, 274 and 4 adults, which consistently support the EAR of 95    maintain the thyroid iodine stores above the critical threshold of 10 mg,
μg/day. IOM notes that these data provide no evidence to suggest that the     below which an insufficient level of iodination of thyroglobulin leads to
average iodine requirement is altered with aging, or that differences exist   disorders in thyroid hormone synthesis.
based on gender in adults.
IOM notes the methodological limitations of balance studies, but still        Differences between older and younger adults and sex differences
mentions two balance studies as supporting evidence. In one balance           The reports consistently do not differentiate the AIs between older and
study in 13 subjects, an intake of 100 μg/day resulted on average in a        younger adults, or between men and women.
slightly positive balance. In a study in 4 non-pregnant (and 5 pregnant)
women, balance was estimated to occur at 160 μg/day, which was used           20.3 Conclusion on the scientific basis of EFSA’s reference
as supporting evidence for making no distinction between the EAR for                 values
men and women based on body weight.                                           The Committee has no objections against the scientific basis of EFSA’s AI.
Based on the study on thyroid iodine accumulation and turnover in 18          The value of 150 μg/day is supported by the results of other approaches
adults, a CV of 40% was calculated, but IOM assumed that half of this         to estimate the iodine requirements. Furthermore, the EFSA Panel
variation was due to the complexity of the experimental design and the        considered that an iodine intake of 110 μg/day may be lower than the
calculations used to estimate turnover. IOM used a CV of 20% to calculate     iodine requirements in up to 10% of the population (based on the Central
the RDA and rounded the resulting value to the nearest 50 μg.                 American study by Ascoli and Arroyave, 1970, mentioned in paragraph
                                                                              20.2). The AI of 150 μg/day appears to be appropriate for the prevention
WHO/FAO based their reference values on a urinary iodine concentration        of iodine deficiency.
>100 μg/L, corresponding to an iodine intake of 150 µg/day, and on three
additional types of evidence. The intake level of 150 μg/day corresponds
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<pre>chapter 20 | Iodine                                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 112 of 179
                                                                                                          IOM based the EAR on the average iodine accumulation by the thyroid
  Background information – a summary of the information provided by the EFSA report –
                                                                                                          obtained from the two studies of Fisher and Oddie (1969a, 1969b). The
  on the function of the nutrient, the occurrence of clinical deficiency and deficiency
  symptoms                                                                                                EFSA Panel notes that the average urinary iodine excretion in these
  Iodine is a mandatory structural and functional element of thyroid hormones. The function of the        studies was about 410 and 280 μg/day, respectively, which is substantially
  thyroid hormones T3 and T4 encompasses the regulation of mitochondrial energy metabolism                higher than found in European studies. Because both medium-term and
  as well as cellular oxidation, thermoregulation, intermediate metabolism, carbohydrate, lipid and
  protein metabolism and nitrogen retention. They are particularly necessary during early growth,         short-term iodine accumulation in the thyroid is down-regulated with
  development and maturation of most organs. The target organs are, in particular, the developing         increasing intake and reaches a plateau for intakes above 80-100 μg/day,
  brain, affecting the development of hearing and vision, muscles, the heart, the pituitary gland,
  the kidney, the reproductive system, and the bones.                                                     the EFSA Panel concludes that the values of 96.5 and 91.2 μg/day for
  According to their thyroid function, individuals are classified as euthyroid (i.e. having normal        mean iodine accumulation cannot be used for deriving an average
  thyroid function), hypothyroid or hyperthyroid. Various mechanisms can lead to thyroid disorders,
  and hypo- and hyperthyroid status can be observed in cases of both insufficient and excessive           requirement for the European context. The Committee agrees with EFSA’s
  iodine intakes.                                                                                         line of reasoning for not establishing an AR and PRI, but an AI.
  In 2003, 16% of the European population had goitre. In 2011, it was estimated that 44% of the
  population in Europe, i.e. 393 million inhabitants, had insufficient iodine intakes as evidenced by
  a urinary iodine concentration <100 µg/L.                                                               The Health Council has previously recommended to reduce the salt
  Chronic iodine deficiency may lead to:
  •   compensatory thyroid hypertrophy/hyperplasia with goitre. Goitre increases the risk of              consumption in the Netherlands.62 As iodine-fortified salt is the main
      thyroid cancer; a large goitre may cause obstruction of the trachea and the oesophagus.             source of iodine for the Dutch population, a lower salt intake could lead to
      Note that goitre may also result from chronic excessive iodine supply
  •   hypothyroidism (myxoedema), observed with severe iodine deficiency, also results from               a greater risk of iodine deficiency and goitre. Therefore, careful monitoring
      hormone deficiency and is associated with reduced metabolic rate, cold intolerance, weight          of the iodine intake of the Dutch population based on 24-hour urinary
      gain, puffy face, oedema, hoarse voice and mental sluggishness
  •   cretinism, i.e. a condition of severely stunted growth and retarded physical and mental             iodine excretion values is crucial. For this application, carried out by the
      development.                                                                                        Dutch RIVM Institute, the Committee recommends to continue using the
                                                                                                          AR (100 μg/day) and RI (150 μg/day) from the NCM report, because these
                                                                                                          values enable a more detailed evaluation of the changes in iodine supply
                                                                                                          than the use of an AI value.
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<pre>chapter 20 | Iodine                                                                            An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 113 of 179
20.4 Summary and conclusion                                                                             The Committee has no objections against the scientific basis of EFSA’s AI,
                                                                                                        or EFSA’s AI-value. EFSA’s AI equals NCM’s RI, which has been used in
Table 69. Summary of the evaluation of EFSA’s AI values for iodine
 Main findings, used for the conclusion
                                                                                                        the Netherlands since 2014. The Committee recommends using this value
 Aspect                          Conclusion    Comment                                                  (Table 70) in the Netherlands.
 EFSA’s AIs compared to          Equal         EFSA’s AI is equal to HCNL 2014’s (=NCM’s) RI
 HCNL’s (=NCM’s) RI                            which is currently used in the Netherlands.              Table 70. AI and PRI for iodine, recommended for use in the Netherlands
 Scientific basis of EFSA’s AI   No objections The AI appears to be directly related to the
                                               prevention of iodine deficiency, as supported by the                                              Men and women >18 years
                                               several criteria for setting this reference value.        Adequate intake (AI)                    150 μg/day
 Other findings
 Aspect                          Conclusion    Comment
 Differentiation between         No            Consistent with the reports used for comparison.
 younger and older adults in the
 EFSA report
 Differentiation between men     No            Consistent with the reports used for comparison.
 and women in the EFSA report
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<pre>chapter 21 | Iron                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 114 of 179
21
iron
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<pre>chapter 21 | Iron                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 115 of 179
                                                      Iron                                                    21.1 Overview and comparison of values
                                                                                                              Table 71. Overview of the reference values for adults and the criteria on which these
           Should EFSA's reference values be rejected                                                         values are based.a
           based on a specific nutritional context in the                                 YES
         Netherlands that differs from (the rest of) Europe?                                                    Report            PRI/RDA/AI/RI (mg/day)                     AR (mg/day)                     Main criterion
                                                                                                                                  Type ♂          ♀                ♀         ♂     ♀             ♀
                                                                                                                                                  post-            pre-            post-         pre-
                                                                                                                                                  meno-            meno-           meno-         meno-
                                                                                                                                                  pause            pause           pause         pause
                                  NO
                                                                                                                EFSA 201518       PRI     11      as ♂             16        6     as ♂          7           Factorial method
                                                                                                                NCM 2014 = RI37
                                                                                                                                          9       9 (or 8 )
                                                                                                                                                         b
                                                                                                                                                                   15        7     6             9 (or 10 )
                                                                                                                                                                                                         c
                                                                                                                                                                                                             Factorial method
                                                                                                                HCNL 201433
                                                                                                                DACH 201538       AI      10      as ♂             15                                        Factorial method
        Are there objections against EFSA’s scientific basis                                                    IOM 2001    41
                                                                                                                                  RDA     8       as ♂             18        6     as ♂          8           Factorial method
                          for this nutrient?
                                                                                                                WHO/FAO           RNI     9.1                      19.6      for 15% bioavailability  d
                                                                                                                                                                                                             Factorial method
                                                                                                                200444                    11.4                     24.5      for 12% bioavailability
                                                                                                                                          13.7                     29.4      for 10% bioavailability
                                                                                                                                          27.4                     58.8      for 5% bioavailability
                                               YES                                                            a
                                                                                                                 No CVs presented, because the PRI/RDA are based on the 90th, 95th or 97.5th percentile of losses.
                                                                                                              b
                                                                                                                 NCM’s RI-value for postmenopausal women is unclear: NCM specifies values of 8 and 9 mg/d
                                                                                                                 (see paragraph 20.2).
                                                                                                              c
                                                                                                                 NCM’s AR-value for premenopausal women is not clear: NCM specifies values of 9 and 10 mg/d
                                                                                                                 (see paragraph 20.2).
                       Do (part of) EFSA's reference values differ 10% or
       NO                                                                                 YES                 d
                                                                                                                 WHO/FAO present RNI values for four levels of bioavailability in the range from 5% to 15%. For the comparison
                        more from the 2014 values for the Netherlands?
                                                                                                                 of reports, WHO/FAO’s RI at a bioavailability of 15% was used, because the other reports used bioavailability
                                                                       PRI ♂ & PRI ♀postmenopauze                values in the range of 15% to 18%.
                                                                         AR ♂ & AR ♀premenopauze
                                                       PRI ♀premenopauze
                                                NO
                                                       AR ♀postmenopauze
                                                                                                              Table 71 presents an overview of reference values and criteria. Table 72
                                                                                                              presents the underlying information used.
             No objections against the use of                   Major objection against the use of
       EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands       For men, the RDA/AI/RIs by NCM (=HCNL), DACH, IOM and WHO/FAO
                                                                                                              are -18%, -9%, -27% and -19% relative to EFSA’s PRI.
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Table 72. Estimated daily iron losses and absorption percentages used to set the AR                                 21.2 Explanation of differences between reports
and PRI/RDA/RI/AI values for adults                                                                                 EFSA and all the reports used for comparison base their reference values
  Report        Estimated daily iron losses (mg/d)                                                    Absorption    on a factorial method in which the required dietary intake is estimated
                ♂                                    ♀ premenopause (♀ postmenopause)                 (%)
                P50a      P90      P95     P97.5     P50a        P90        P95           P97.5                     from the estimated iron losses from the body and the assumed efficiency
  EFSA          0.95      1.48     1.61    1.72      1.34        2.44       2.80          3.13        ♂16%          of iron absorption. The underlying thinking behind this method is that the
  201518                                   used                             used for                  ♀18%
                                           for                              PRI ♀                                   daily losses should be replenished by dietary intake. The estimated iron
                                           PRI ♂
  NCM           1.05               1.37              1.35        2.22       2.77                      15%c
                                                                                                                    losses comprise the losses via faeces, urine, sweat and skin, and for
  201437 =                         used              (0.87)      used for (1.13)b                                   premenopausal women also via menses.
  HCNL                             for                           RI ♀ pre-
  201433                           RI ♂                          meno-                                              Iron is one of the few nutrients for which data are available not only on the
                                                                 pause
  DACH          Not specified                                                                         10-15%        average losses, but also on the variability of iron losses between
  201538
                                                                                                                    individuals. Instead of calculating the PRI/RDA/RI’s from the AR and an
  IOM           1.08               1.45    1.53      1.4         2.35       2.67          3.15        18%
  200141                                   used                                           used                      assumed coefficient of variation of the requirements, the PRI/RDA/RI’s are
                                           for                                            for
                                           PRI ♂                                          PRI ♀                     based on the 90th, 95th, or 97.5th percentile of the distribution of iron
  WHO/FAO                          1.37d                                    2.94d                     15%           losses.
  200444                           used                                     used for
                                   for                                      RNI ♀                                   All reports differentiate between premenopausal and postmenopausal
                                   RNI ♂
a
   The P50 was used to set the AR-value.                                                                            women, because menses contributes substantially to the daily iron losses.
b
   NCM values as specified in Table 34.2 of the NCM report.
c
   NCM specify explicitly that for premenopausal women they used an absorption percentage of 15%. However,          In most reports, the values for adult men are also used for
   the absorption percentage(s) used for men and postmenopausal women is not specified by NCM.
d
   WHO/FAO’s estimated daily iron loss at a bioavailability of 15% were deduced for this table by multiplying
                                                                                                                    postmenopausal women.
   the RNI by 0.15.
For premenopausal women, NCM and DACH use 6% lower RDA/AI/RIs                                                       Despite the relatively large knowledge on iron requirements, including the
than EFSA’s PRI, whereas IOM’s and WHO/FAO’s values are 12% and                                                     variation between subjects, the reference values vary between the
27% higher than EFSA’s PRI.                                                                                         reports. The use of different references or datasets may result in different
For postmenopausal women, NCM, DACH and IOM have RDA/AI/RIs                                                         estimates of (1) iron losses and (2) absorption efficiencies. The PRI/RDA/
which are between 9% and 27% lower than EFSA’s PRIs.                                                                RI-values are additionally influenced by differences in the chosen (3)
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<pre>chapter 21 | Iron                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 117 of 179
percentile of the distribution of iron loss. These three types of differences     choice regarding the percentile within the distribution of iron losses: EFSA
either add up to larger differences, or (partly) counterbalance each other,       used the 97.5th percentile, whereas NCM and WHO/FAO used the 95th
which is elucidated on the next pages.                                            percentile.
                                                                                  IOM and EFSA both used the 97.5th percentile of iron losses, but EFSA’s
DACH uses the factorial method, but did not specify the components of             estimate is higher than IOM’s estimate. In addition, EFSA uses a lower
their calculation; therefore this report is not included in the evaluation by     absorption percentage than IOM (16% versus 18%). The differences in
the Committee.                                                                    the two underlying estimates work in the same direction: IOM’s RDA is
                                                                                  substantially lower than EFSA’s PRI.
Explanation of the differences between the reference values for                   The Committee notes that EFSA’s values for men imply that the variation
men                                                                               of the requirements for iron is relatively large (CV ~40%).a
ARs                                                                               Explanation of the differences between the reference values for
NCM’s AR is 17% higher than EFSA’s AR for men, because the differences            premenopausal women
in two underlying estimates work in the same direction: NCM’s estimate of
the median iron losses is higher than EFSA’s estimate, and NCM uses a             ARs
slightly lower absorption percentage than EFSA (15% versus 16%).                  NCM’s AR for premenopausal women is not clear: NCM specifies values
EFSA and IOM set the same AR for men, because the differences in two              of 9 and 10 mg/d.b Both NCM-values are substantially higher than EFSA’s
underlying estimates work in opposite directions: EFSA’s lower estimate of        AR (7 mg/d). The difference is caused solely by NCM’s use of a
the median losses is compensated by EFSA’s use of a lower absorption
percentage than IOM (16% versus 18%).                                             a
                                                                                    The coefficient of variation (CV) of iron requirements can then be deduced from EFSA’s and IOM’s values, as
                                                                                    both organisations based the PRI/RDA on the 97.5th percentile of iron losses. Assuming a ‘normal’ distribution, the
                                                                                    PRI, calculated as AR + [ (2xCV/100) x AR ], covers 97.5% of the individual requirements in the population.
                                                                                    Therefore: CV can be calculated if the PRI is based on the 97.5th percentile of losses as:
PRI/RIs                                                                             100% * ½ * (PRI - AR) / AR. For men, the estimated CVs are ~40% (EFSA) and ~20% (IOM).
                                                                                    NCM mentions the AR of 9 mg/d for premenopausal women in the text (page 555 of the NCM report) and in Table
For men, EFSA’s PRI is higher than the values in the other reports. The
                                                                                  b
                                                                                    34.2 (page 556) of the NCM report; this value is consistent with the underlying values presented in this table.
differences between NCM and WHO/FAO is mainly explained by the                      However, NCM’s AR-value for premenopausal women in the summarising Table 1.8 (page 40 of the NCM report)
                                                                                    and in the table at the beginning of their chapter on iron (page 543 of the NCM report) is 10 mg/d.
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<pre>chapter 21 | Iron                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 118 of 179
substantially lower absorption percentage than EFSA (15% versus 18%);         The 27% higher value of WHO/FAO relative to EFSA is the result of two
NCM and EFSA use the same value for the median iron losses in                 differences working in the same direction: the higher estimate for the 95th
premenopausal women.                                                          percentile of losses by WHO/FAO compared to EFSA, and the
IOM’s AR is 16% higher than EFSA’s AR for premenopausal women,                substantially lower absorption percentage used by WHO/FAO relative to
solely because of IOM’s higher estimate of the median iron losses             EFSA (15% versus 18%).
compared to EFSA’s estimate. IOM and EFSA use the same value for the
iron absorption percentage in women (18%).                                    Explanation of the differences between the reference values for
                                                                              postmenopausal women
PRI/RIs
For premenopausal women, NCM uses a lower RI than EFSA’s PRI,                 ARs
whereas IOM and WHO/FAO use higher levels.                                    For postmenopausal women, EFSA, NCM and IOM set the same AR (6
The 6% lower value of NCM relative to EFSA is the result of three             mg/d). EFSA and IOM use their values for men and for postmenopausal
differences working in opposite directions: the choice regarding the          women.
percentile of losses used (EFSA: 95th percentile; NCM: 90th percentile),
and NCM’s lower estimate of the 90th percentile of losses compared to         PRI/RIs
EFSA, both work in the direction of a lower NCM value. This is partly         For postmenopausal women, as for men, EFSA’s PRI is higher than the
compensated by the use of a substantially lower absorption percentage by      values in all reports used for comparison. NCM’s value for
NCM compared to EFSA (15% versus 18%), which works in the direction           postmenopausal women is unclear: NCM specifies values of 8 and 9
of a higher NCM value. The resulting difference between NCM’s RI and          mg/d.a The other reports apply the values for men also to postmenopausal
EFSA’s PRI is small.                                                          women.
The 12% higher value of IOM relative to EFSA is solely the result of the
choice regarding the percentile of losses used (EFSA: 95th percentile;
IOM: 97.5th percentile).                                                        NCM mentions the RI of 9 mg/d for postmenopausal women in the summarising Table 1.3 (page 31 of the NCM
                                                                              a
                                                                                report) and in the table at the beginning of their chapter on iron (page 543). However, in the right column of Table
                                                                                34.2 (page 556) and the text (page 558) of the NCM report, NCM mentions the value of 8 mg/d for
                                                                                postmenopausal women.
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<pre>chapter 21 | Iron                                                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 119 of 179
21.3 Conclusion on the scientific basis of EFSA’s reference                                                               percentile (EFSA, WHO/FAO). The Committee had no objections
         values                                                                                                           against EFSA´s choice for the 95th percentile of iron losses.
The Committee has no reason to object against EFSA’s estimates of iron                                                 Therefore, the Committee considers that it had no objections against the
losses, or against EFSA’s assumption regarding the absorption efficiency;                                              scientific basis of EFSA’s reference values.
these estimates appear to have sufficient scientific basis.a The Committee
also agrees with EFSA´s choices regarding the percentile of the
                                                                                                                          Background information – a summary of the information provided by the EFSA report –
distribution of iron losses on which the PRIs are based:                                                                  on the function of the nutrient, the occurrence of clinical deficiency and deficiency
                                                                                                                          symptoms
• For men and postmenopausal women, there is no reason to assume
    that the distribution of iron requirements would deviate from a “normal”                                              Iron is necessary for most, if not all, pathways for energy and substrate metabolism. Globin-
                                                                                                                          haems are transporters of oxygen, carbon dioxide, carbon monoxide and nitric oxide, stores of
    (Gaussian) distribution.b Therefore, EFSA’s choice to base the PRI for                                                oxygen and scavengers of free radicals. The cytochrome P-450 oxidase system embraces over
    men on the 97.5th percentile of iron losses seems appropriate.                                                        11,000 diverse activities including the metabolism of endogenous substrates such as organic
                                                                                                                          acids, fatty acids, prostaglandins, steroids and sterols including cholesterol and vitamins A, D
• For premenopausal women the distribution of the iron losses is not                                                      and K. The citric acid cycle and respiratory chain involves six different haem proteins and six
    ‘normal’, but skewed as a result of the high iron losses via menses in a                                              iron-sulphur clusters.
                                                                                                                          Iron deficiency anaemia (a microcytic anaemia with haemoglobin concentrations below normal)
    proportion of these women. IOM still bases the RDA for this group on                                                  is the most common nutritional deficiency disorder, being found in all countries of the world.
    the 97.5th percentile of iron losses. The skewed part of the distribution                                             Women with high menstrual losses are at risk of developing iron deficiency.
                                                                                                                          Other symptoms which are not specific to iron deficiency are: spoon-shaped nails, soft nails,
    is only relevant for the subgroup of women with high iron losses via                                                  glossitis, cheilitis (dermatitis at the corner of the mouth), mood changes, muscle weakness and
    menses and, therefore, other reports base the PRI/RDA/RI for                                                          impaired immunity.
                                                                                                                          Iron deficiency is a risk factor for increased blood concentrations of cadmium.
    premenopausal women on the 90th percentile (NCM) or the 95th
a
  EFSA used the dataset by Hunt et al., 200959, see Appendix H in EFSA report. EFSA´s estimated iron losses of
  premenopausal women were based on data of 19 menstruating women plus one woman aged 30 years with
  unknown menstrual status. EFSA´s estimated iron losses of men were based on data of 29 men. EFSA assumes             There is international agreement on the use of the factorial method to
  that the estimates for men also apply to postmenopausal women.
b
  For nutrients with a ‘normal’ or ‘Gaussian’ distribution of the requirements of individuals, the PRI/RDA/RI value is
                                                                                                                       calculate the reference values for iron. The underlying thinking, that the
  – by definition – calculated as the AR plus twice the standard deviation of requirements, which implies that these
  PRI/RDA/RI-values equal the 97.5th percentile of the requirement distribution. Therefore, it seems appropriate
                                                                                                                       daily losses should be replenished, can be considered relevant for the
  that PRIs for groups with a ‘normal’ distribution of requirements (men and postmenopausal women) are based on
  the 97.5th percentile of iron losses.
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<pre>chapter 21 | Iron                                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 120 of 179
prevention of deficiency. The Committee has no objections against the                          The Committee has no objections against the scientific basis of EFSA’s
scientific basis of EFSA’s reference values for iron (paragraph 21.2).                         reference values, and recommends accepting EFSA’s PRIs and ARs in
                                                                                               the Netherlands (Table 74). The Committee notes that the iron
Note that the EFSA report does not provide information on intake levels                        requirements of women with high blood losses during menses may not be
associated with the occurrence or correction of deficiencies.                                  covered by the PRI for premenopausal women.
21.4 Summary and conclusion                                                                    Table 74. AR and PRI for iron, recommended for the Netherlands
                                                                                                                                  Men            Women
Table 73. Summary of the evaluation of EFSA’s AI values for iron                                                                                 premenopausal postmenopausal
 Main findings, used for the conclusion                                                         Average requirement (AR)          6              7             6
 Aspect                     Conclusion      Comment                                             Population reference intake (PRI) 11             16            11
 EFSA’s ARs compared to     Lower           EFSA’s AR is lower than HCNL’s (=NCM’s) ARs
 HCNL’s (=NCM’s) ARs                        for men and premenopausal women, but their AR
                                            for postmenopausal women is equal.
 EFSA’s PRIs compared to    Higher          EFSA’s PRIs are higher than HCNL’s (=NCM’s)
 HCNL’s (=NCM’s) RIs                        RIs for all three groups (men, premenopausal
                                            and postmenopausal women).
 Scientific basis of EFSA’s No objections   All reports use the same methods, although the
 ARs                                        resulting values vary substantially.
 Other findings
 Aspect                     Conclusion      Comment
 Differentiation between    Applied by EFSA All reports differentiate between pre- and
 younger and older adults                   postmenopausal women, but not between
                                            younger and older men.
 Differentiation between    Applied by EFSA All reports differentiate between men and
 men and women                              pre-menopausal women; most do not differentiate
                                            between men and postmenopausal women.
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<pre>chapter 22 | Magnesium                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 121 of 179
22
magnesium
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<pre>chapter 22 | Magnesium                                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 122 of 179
                                               Magnesium                                                      22.1 Overview and comparison of values
                                                                                                              Table 75. Overview of the PRI/RDA/RI/AI values for adults and the criteria on which
        Should EFSA's reference values be rejected                                                            these values are based
        based on a specific nutritional context in the                                 YES
      Netherlands that differs from (the rest of) Europe?                                                      Report       AI/RI/RDA (mg/d)            AR (mg/d)    Main criterion
                                                                                                                            Type   Age       ♂   ♀      ♂     ♀
                                                                                                               EFSA 201520  AI               350 300                 Mean intakes in Europe combined
                                                                                                                                                                     with the results of balance studies.
                                                                                                               NCM 201437   RI               350 280                 There has been no substantial
                               NO
                                                                                                               = HCNL                                                new data since NCM 2004
                                                                                                               201433                                                indicating that these values should
                                                                                                                                                                     be changed.
                                                                                                               DACH 201538  AI     19-24 yr  400 310                 Balance studies.
     Are there objections against EFSA’s scientific basis                                                                          >25 yr    350 300
                       for this nutrient?                                                                      IOM 199743   RDA    19-30 yr  400 310    330   255    Balance studies.
                                                                                                                                   31-70 yr  420 320    350   265    Note that balance data were
                                                                                                                                                                     scarce for women (1 study in
                                                                                                                                                                     women aged 31-50 years, no
                                            YES                                                                                                                      study in women aged 51-70
                                                                                                                                                                     years).
                                                                                                                                   >70 yr    420 320    350   265    Balance data are not available and
                                                                                                                                                                     estimates from other methods are
                    Do (part of) EFSA's reference values differ 10% or                                                                                               uncertain.
     NO                                                                                YES
                     more from the 2014 values for the Netherlands?                                            WHO/FAO      RI     19-65 yr  260 220                 RIs are based on energy intake.
                                                                                                               2004                >65 yr    224 190                 WHO/FAO notes that their RIs
                                                                                                                                                                     must be regarded as provisional,
                                                                                                                                                                     because of the scarcity of studies.
                                             NO     AIs
                                                                                                              Table 75 presents an overview of reference values and criteria.
                                                                                                              NCM’s RI for men is equal to EFSA’s AI for men. NCM’s AI for women is
          No objections against the use of                   Major objection against the use of
     EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands          6% lower than EFSA’s value.
                                                                                                              DACH’s AI are higher than EFSA’s value, especially for younger men
                                                                                                              (men 19-24 years +14% relative to EFSA’s AI). DACH’s value for younger
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<pre>chapter 22 | Magnesium                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 123 of 179
women differs little from EFSA’s value (+3%). DACH’s AIs for men and            EFSA mentions that a pooled analysis of well-controlled balance studies
women aged >25 years equal EFSA’s AIs.                                          (Hunt & Johnson, 2006)a was published after the IOM report; this study
IOM’s RDAs are higher than EFSA’s AIs, especially in men (♂ 19-30               suggested that zero magnesium balance may occur at an intake as low as
years: +14, ♂ >31 years: +20% relative to EFSA). IOM’s RDAs are slightly        165 mg/d and that homeostatic control appears to be strong over a large
higher in women (♀ 19-30 years: +3; ♀ >31 years: +6% relative to EFSA).         range of intakes (84-598 mg/d). EFSA does not use these new balance
                                                                                data as the primary criterion for setting the AI, because results of some
22.2 Explanation of differences between reports                                 large-scale and long-term prospective observational studies point to a
The AIs by EFSA is based on intakes. DACH and IOM base their AIs on             relationship between a higher magnesium intake and a lower risk of
balance data.                                                                   diabetes mellitus type 2. EFSA does not base the AI on these findings
                                                                                from prospective observational studies, because the interpretation is
EFSA decided, considering all evidence available, to base the AIs on            complicated by the correlation between the intake levels of magnesium,
observed intakes in eight European countries (Finland, France, Ireland,         fibre and potassium.b,c
Italy, Latvia, the Netherlands, Sweden, the United Kingdom). The EFSA
Panel set AIs according to sex, because differences in magnesium intakes        DACH based their RIs for younger (19-24 years) and older (>25 years)
between men and women were rather large.                                        adults on balance studies. DACH refers to the IOM report, and also to two
• For men, average intakes ranged between 264 and 439 mg/day
   (midpoint 352 mg/day; median 341 mg/day), and EFSA proposed an AI              This pooled analysis (Hunt & Johnson, 2006) compiled the results of 27 balance studies conducted between 1976
                                                                                a
                                                                                  and 2000 in a metabolic unit under well-controlled conditions; the minimum length of the dietary periods was 18
   of 350 mg/day.                                                                 days. After excluding subjects with insufficient or excessive intakes of possibly interacting nutrients (calcium,
                                                                                  copper, iron, phosphorus or zinc), the dataset comprised 150 healthy women (mean age 51 years) and 93 healthy
• For women, average intakes ranged between 232 and 357 mg/day                    men (mean age 28 years).
                                                                                b
                                                                                  EFSA mentions that some large-scale and long-term prospective observational studies indicate that higher
   (midpoint 295 mg/day; median 298 mg/day), and EFSA proposed an AI              magnesium intake (ranges of median intakes were 244-773 mg/day in the highest quintiles, and 115-270 mg/d in
                                                                                  the lowest quintiles) were associated with a lower risk of diabetes mellitus type 2. However, this association was
   of 300 mg/day.                                                                 not found in a meta-analysis on results adjusted for dietary fibre intake (i.e. when results which were not adjusted
                                                                                  for dietary fibre intake were excluded). Therefore, the EFSA Panel did not use this data on the association
The EFSA Panel noted that the role of magnesium in bone structure and             between magnesium intake and diabetes mellitus type 2 for setting reference values for magnesium.
                                                                                  EFSA Panel also reported on meta-analyses of prospective cohort studies showing a significant inverse
physiology is well established, but that there are insufficient quantitative
                                                                                c
                                                                                  association between a higher magnesium intake and a lower risk of stroke. EFSA did not take this finding into
data to use this relationship for setting AIs for magnesium. Furthermore,         account, because foods rich in magnesium are also rich in other dietary substances such as dietary fibre and
                                                                                  potassium, so that the effect of magnesium per se cannot be unravelled.
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original research publications mentioned by IOM (Lakshmanan et al.,             Sex differences
1984; Wisker et al., 1991) and three publications not mentioned by IOM          All reports differentiate between men and women.
(Gullestad et al., 1994; Jones et al., 1967; Marxhall et al., 1976). DACH
does not provide more information on the background of their RIs.               22.3 Conclusion on the scientific basis of EFSA’s reference
                                                                                          values
IOM also based their ARs and RDAs for younger (19-30 years) and older           EFSA uses the average magnesium intake as the criterion for setting the
(>31 years) adults on nine balance studies. IOM included balance studies        AI, because balance studies may underestimate the AI, considering
with an adaptation period of at least 12 days, and studies determining the      research associating higher magnesium intake with lower risks of specific
balance while the subjects consumed self-selected diets. The values for         chronic diseases (paragraph 22.2). The Committee has no objection
adult women relied heavily on the findings from one study in 18 women           against this scientific basis EFSA’s AIs, but notes that intake data provide
(and 16 men) consuming self-selected diets in a free-living environment         little evidence on requirements.
(Lakshmanan et al., 1984).
                                                                                     Background information – a summary of the information provided by the EFSA report –
                                                                                     on the function of the nutrient, the occurrence of clinical deficiency and deficiency
WHO/FAO notes that the scarcity of studies from which to derive                      symptoms
estimates of dietary allowances for magnesium has been emphasised by
                                                                                     Magnesium is a cofactor of more than 300 enzymatic reactions. It is essential in the intermediary
virtually all the agencies faced with this task.                                     metabolism for the synthesis of carbohydrates, lipids, nucleic acids and proteins, as well as for
                                                                                     specific actions in various organs such as the neuromuscular or cardiovascular system.
                                                                                     Magnesium can interfere with calcium at the membrane level or bind to membrane phospholipids,
Differences between older and younger adults                                         thus modulating membrane permeability and electrical characteristics. Magnesium has an impact
                                                                                     on bone health through its role in the structure of hydroxyapatite crystals in bone.
EFSA and NCM do not differentiate between older and younger adults.
                                                                                     Magnesium deficiency can have many different causes, including renal and gastrointestinal
DACH uses slightly higher values for the youngest adults (19-24 years                dysfunctions. Owing to the widespread involvement of magnesium in numerous physiological
                                                                                     functions and the metabolic interactions between magnesium and other minerals, it is difficult to
versus >25 years), whereas IOM uses slightly lower values for the
                                                                                     relate magnesium deficiency to specific symptoms such as neuromuscular irritability, muscle
youngest adults (19-30 years versus >31 years).                                      tremors and cramps, fasciculation, wasting and weakness, restless leg syndrome, fibromyalgia,
                                                                                     i.e. conditions where the use of magnesium supplementation has led to inconsistent results.
                                                                                     Magnesium deficiency can cause hypocalcaemia and hypokalaemia, leading to neurological or
                                                                                     cardiac symptoms when it is associated with marked hypomagnesaemia (< 0.5 mmol/L).
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<pre>chapter 22 | Magnesium                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 125 of 179
22.4 Summary and conclusion                                                                    The Committee has no objections against the scientific basis of EFSA’s
                                                                                               AIs, or EFSA’s AI-values and recommends using these values (Table 77)
Table 76. Summary of the evaluation of EFSA’s AI values for magnesium
 Main findings, used for the conclusion
                                                                                               in the Netherlands.
 Aspect                    Conclusion     Comment
 EFSA’s AIs compared to    (Almost) equal For men, EFSA’s AI is equal to NCM’s AI. For
                                                                                               Table 77. AR and PRI for magnesium, recommended for use in the Netherlands
 HCNL’s (NCM’s) RI                        women, EFSA’s AI is 7% higher than NCM’s AI.                                      Men >18 years         Women >18 years
 Scientific basis for      No objections  EFSA uses the average magnesium intake as the         Adequate intake (AI)        350                   300
 EFSA’s AIs                               criterion to set the AI. Intake data provide little
                                          evidence on requirements.
 Other findings
 Aspect                    Conclusion     Comment
 Differentiation between   No             Consistent with the reports used for comparison,
 younger and older adults                 DACH and IOM differentiate the value for the
 in the EFSA report                       youngest adults (up to 24 or 30 years) from older
                                          adults, but not in a consistent way.
 Differentiation between   Yes            Consistent with the reports used for comparison.
 men and women in the
 EFSA report
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<pre>chapter 23 | Manganese                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 126 of 179
23
manganese
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<pre>chapter 23 | Manganese                                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 127 of 179
                                                  Manganese                                                  23.1 Overview and comparison of values
                                                                                                             Table 78. Overview of the reference values for adults and the criteria on which these
            Should EFSA's reference values be rejected                                                       values are based
            based on a specific nutritional context in the                                 YES
          Netherlands that differs from (the rest of) Europe?                                                 Report          AI               Main criterion
                                                                                                                              (mg/d)
                                                                                                              EFSA 201330 =   3.0              Mean intakes in Europe combined with the consideration that
                                                                                                              HCNL 201433                      null or positive balances have consistently been observed
                                                                                                                                               with intakes >2.5 mg/day.
                                   NO
                                                                                                              DACH 201538     2-5              Intake level associated with neither deficiency nor toxicity.
                                                                                                              IOM 200141
                                                                                                                              ♂2.3; ♀1.8       Median intakes in the USA.
                                                                                                             Note that NCM and WHO/FAO did not establish reference values for
         Are there objections against EFSA’s scientific basis
                           for this nutrient?                                                                manganese.
                                                                                                             Table 78 shows that EFSA’s AI is within the range used by DACH. IOM’s
                                                                                                             AIs are lower than EFSA’s value (-23% for men and -40% for women).
                                                YES
                                                                                                             23.2 Explanation of differences between reports
                        Do (part of) EFSA's reference values differ 10% or
         NO
                         more from the 2014 values for the Netherlands?
                                                                                           YES               EFSA and IOM base their AIs on intakes, but EFSA also considers the
                                                                                                             results from balance studies. The differences between these reports
                                                                                                             reflect the difference in intake levels between European countries and the
                                                NO                                                           United States.
                                                                                                             EFSA considers that national dietary surveys from Austria, France,
              No objections against the use of                   Major objection against the use of
         EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands     Germany, Hungary, Ireland, and the UK reported mean daily intake
                                                                                                             estimates for manganese ranging from 2.5 to 6.6 mg in men and from 2.0
                                                                                                             to 5.5 mg in women, with most values around 3 mg/day.
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<pre>chapter 23 | Manganese                                                   An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 128 of 179
EFSA considers that several balance studies demonstrated that the                 North American population, IOM considered that a recommended dietary
body adapts quickly to changes in manganese intake, that balance may              allowance (RDA) based on balance data would be most likely to
be maintained at intakes below 2.5 mg/day, and that null or positive              overestimate the requirement for most North American individuals.
balances have consistently been observed with manganese intakes above
2.5 mg/day. EFSA notes that manganese balance may be influenced by                Differences between older and younger adults
the overall diet, variations in individual rates of absorption or excretion,      None of the reports differentiate between older and younger adults.
differences in body contents and adaptation to varying dietary levels.
EFSA proposed an AI of 3 mg/day for adults, because observed mean                 Sex differences
intakes of adults in the EU are typically around 3 mg/day, and, in addition,      EFSA and DACH do not differentiate between men and women, whereas
null or positive balances have consistently been observed with intakes of         IOM does, based on median intakes.
manganese above 2.5 mg/day.
IOM used manganese intake estimates from the US total dietary survey              23.3 Conclusion on the scientific basis of EFSA’s reference
1991-1997. The median dietary manganese intake was 2.1-2.3 mg/day for                   values
men and 1.6-1.8 mg/day for women. IOM considered that dietary intake              EFSA based their AI on average intakes in European populations, and
assessment methods tend to underestimate the actual daily intake of               used results from balance studies as supportive information (see
foods and, therefore, considered the highest intake value reported for the        paragraph 23.2). A specific manganese deficiency syndrome has not been
four adult age groups (19-30 years, 31-50 years, 51-70 years, 71 years            described in humans, but deficiency signs have been induced after 39
and over) to set the AI for each sex. The AI was set as 2.3 mg/day for men        days on a very low manganese diet (Table 79).
and 1.8 mg/day for women.                                                         The Committee has no objections against the scientific basis of EFSA’s AI,
IOM did not use balance data to set an EAR, because a wide range of               but notes that mean intakes may substantially exceed requirements, as
manganese intakes can result in manganese balance. In addition,                   deficiencies have not been reported in healthy subjects on normal diets.
because overt symptoms of manganese deficiency are not apparent in the
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<pre>chapter 23 | Manganese                                                                         An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 129 of 179
                                                                                                        23.4 Summary and conclusion
    Background information – a summary of the information provided by the EFSA report –
    on the function of the nutrient, the occurrence of clinical deficiency and deficiency               Table 80. Summary of the evaluation of EFSA’s AI values for manganese
    symptoms
                                                                                                         Main findings, used for the conclusion
                                                                                                         Aspect                         Conclusion              Comment
    Manganese is a component of metalloenzymes such as superoxide dismutase, arginase and
                                                                                                         EFSA’s AIs compared to         Equal                   EFSA’s AI is already used in the
    pyruvate carboxylase, and is involved in amino acid, lipid and carbohydrate metabolism.
                                                                                                         HCNL’s (EFSA’s) AI                                     Netherlands.
    Evidence of manganese deficiency in humans is poor. A specific deficiency syndrome has not
                                                                                                         Scientific basis of EFSA’s AIs No objections           EFSA bases the AI on intake data,
    been described in humans. A depletion-repletion study indicated that fleeting dermatitis and
                                                                                                                                                                consistent with IOM. EFSA uses balance
    miliaria crystallina are deficiency signs (Table 83).                                                                                                       data as supportive information, unlike IOM.
                                                                                                         Other findings
                                                                                                         Aspect                         Conclusion              Comment
                                                                                                         Differentiation between        Not applied by EFSA     Consistent with the reports used for
                                                                                                         younger and older adults                               comparison.
Table 79. Manganese intake levels associated with the occurrence, correction or
                                                                                                         Differentiation between men    Not applied by EFSA     Not consistent with the IOM report.
prevention of deficiencies, as described by EFSA                                                         and women
 Clinical manifestation associated           Associated intake      Subjects /         EFSA’s
 with deficiency                                                    Specific group     reference        EFSA’s AI for manganese is based on mean intakes and supportive
 Fleeting dermatitis, miliaria crystallina   0.11 mg manganese      7 men              Friedman et al.,
                                                                                                        information from balance studies. Mean intakes are assumed to be
 occurred in 5 out of the 7 men (and         per day for 39 days    (depletion-        1987
 disappeared after repletion began)          (depletion phase)      repletion study)                    adequate because no signs of deficiency are reported in healthy subjects
                                                                                                        on normal diets. The average intakes may exceed requirements. Because
                                                                                                        there is no evidence available to define a more evidence-based AI, the
                                                                                                        Committee has no objections against the scientific basis of EFSA’s AI for
                                                                                                        adults, or the AI-value (Table 81).
                                                                                                        Table 81. AI for manganese, recommended for the Netherlands
                                                                                                                                                         Men and women >18 years
                                                                                                         Adequate intake (AI)                            3.0 mg/day
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<pre>chapter 24 | Molybdenum                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 130 of 179
24
molybdenum
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<pre>chapter 24 | Molybdenum                                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 131 of 179
                                                 Molybdenum                                                   24.1 Overview and comparison of values
                                                                                                              Table 82. Overview of the reference values for adults and the criteria on which these
            Should EFSA's reference values be rejected                                                        values are based
            based on a specific nutritional context in the                                 YES
          Netherlands that differs from (the rest of) Europe?                                                  Report          AI/RDA         EAR     CV     Main criterion
                                                                                                                               Type   (μg/d)  (μg/d)  %
                                                                                                               EFSA 201332     AI     65                     The lower end of mean intakes in European
                                                                                                               = HCNL 201433                                 countries, supported by data of one balance
                                                                                                                                                             study (see IOM).
                                   NO
                                                                                                               DACH 201538     AI     50-100                 Molybdenum intakes with a mixed diet.
                                                                                                               IOM 2001 41
                                                                                                                               RDA    45      34      15%    Balance study in 4 young males and an
                                                                                                                                                             assumed bioavailability of 75%.
         Are there objections against EFSA’s scientific basis
                           for this nutrient?                                                                 Note that NCM and WHO/FAO did not establish reference values for
                                                                                                              molybdenum.
                                                                                                              Table 82 shows that EFSA’s AI is within the range used by DACH.
                                                YES
                                                                                                              IOM’s AI is 30% lower than EFSA’s value.
         NO
                        Do (part of) EFSA's reference values differ 10% or
                         more from the 2014 values for the Netherlands?
                                                                                           YES                24.2 Explanation of differences between reports
                                                                                                              EFSA and DACH based their AIs on intakes. IOM’s AR is based on a
                                                                                                              small balance study. The difference between EFSA and IOM is the result
                                                 NO                                                           of the criterion used.
                                                                                                              EFSA’s AI was based on the lower end of the mean intakes in European
                                                                                                              countries: 74 μg/day in men and 58 μg/day in women estimated with the
              No objections against the use of                   Major objection against the use of
        EFSA's reference values in the Netherlands            EFSA's reference values in the Netherlands      duplicate diet method. Based on these values, EFSA proposed an AI of 65
                                                                                                              μg/day for all adults.
                                                                                                              EFSA used the results from a small balance study with long duration as
                                                                                                              supportive evidence (this is the balance study on which IOM based their
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<pre>chapter 24 | Molybdenum                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 132 of 179
EAR). In 4 adult men, balance was reported to be near zero from day 49           102 days (Table 83); it is possible that molybdenum balance can be
until day 102 of the depletion period at molybdenum intakes of 22 μg/day         achieved at even lower intakes.
(Table 83).
                                                                                     Background information – a summary of the information provided by the EFSA report –
                                                                                     on the function of the nutrient, the occurrence of clinical deficiency and deficiency
The AR by IOM was based on the balance data in 4 young males                         symptoms
described above. Because of the small number of subjects in this study,
                                                                                     In humans, molybdenum-containing enzymes (molybdoenzymes: sulphite oxidase, xanthine
the value is uncertain for the group studied (young males) and the                   oxidoreductase, aldehyde oxidase and mitochondrial amidoxime reducing component) are
                                                                                     linked with a pterin (molybdopterin) as cofactor. These enzymes are involved in the catabolism
applicability to other groups (older men, younger and older women) is
                                                                                     of sulphur-containing amino acids and heterocyclic compounds, including purines, pyrimidines,
unknown.                                                                             pteridins and pyridines, and in the metabolism of aromatic aldehydes.
                                                                                     Clinical signs of molybdenum deficiency in otherwise healthy humans have not been observed.
                                                                                     A syndrome suggestive of dietary molybdenum deficiency was reported in one 24-year-old male
Differences between older and younger adults and between men and                     patient with Crohn’s disease and short bowel syndrome, who had used total parenteral nutrition
                                                                                     for 12 months. Deficiency of all molybdoenzymes occurs in people with molybdenum cofactor
women
                                                                                     deficiency, a rare autosomal recessive syndrome with a defective hepatic synthesis of
None of the reports differentiate between older and younger adults, or               molybdenum cofactor. This genetic defect, for which three subtypes are known according to the
                                                                                     gene affected, has been found in a variety of ethnic groups and all over the world. It is
between men and women.
                                                                                     associated with feeding difficulties and seizures starting shortly after birth, neurological and
                                                                                     developmental abnormalities, mental retardation, encephalopathy, ectopy of the lens and usually
                                                                                     death at an early age.
24.3 Conclusion on the scientific basis of EFSA’s reference
       values
EFSA uses the average intake observed in populations with no apparent
                                                                                 Table 83. Molybdenum intake levels associated with the occurrence, correction or
deficiency as the criterion for setting the AI, with a small balance study of    prevention of deficiencies, as described by EFSA
long duration as supportive evidence.                                             Clinical manifestation                Associated         Subjects/Specific           EFSA’s reference
                                                                                  associated with deficiency            intake             group
EFSA noted that, in the balance study in four men mentioned in paragraph
                                                                                  Absence of biochemical changes        22 μg/day for      4 adult males               Turnlund et al.
24.2, biochemical changes or clinical symptoms suggestive of                      or symptoms suggestive of             102 days                                       (1995a)
                                                                                  molybdenum deficiency
molybdenum deficiency were not observed after consuming 22 μg/day for
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<pre>chapter 24 | Molybdenum                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 133 of 179
The Committee has no objections against the scientific basis of EFSA’s AI,                      EFSA’s AI for molybdenum is based on the lowest estimates of mean
but notes that mean intakes may substantially exceed requirements, as                           intakes and on supportive information from a small balance study. Mean
deficiencies have not been reported in healthy subjects on normal diets.                        intakes are assumed to be adequate because no signs of deficiency are
                                                                                                reported in healthy subjects on normal diets. The mean intakes may
24.4 Summary and conclusion                                                                     substantially exceed requirements. However, there is no evidence
                                                                                                available to define a more evidence-based AI.
Table 84. Summary of the evaluation of EFSA’s AI values for molybdenum
 Main findings, used for the conclusion
                                                                                                The Committee has no objections against the scientific basis of EFSA’s AI
 Aspect                         Conclusion          Comment                                     for adults, or the AI-value (Table 85).
 EFSA’s AIs compared to         Equal               EFSA’s AI is already used in the
 HCNL’s (EFSA’s) AI                                 Netherlands.                                Table 85. AI for molybdenum, recommended for the Netherlands
 Scientific basis of EFSA’s AIs No objections       EFSA bases the AI on intake data,
                                                    consistent with DACH. EFSA uses a small                                             Men and women >18 years
                                                    balance study of long duration as            Adequate intake (AI)                   65 μg/day
                                                    supportive evidence. IOM based their EAR
                                                    on this balance study.
 Other findings
 Aspect                         Conclusion          Comment
 Differentiation between        Not applied by EFSA Consistent with the reports used for
 younger and older adults                           comparison.
 Differentiation between men    Not applied by EFSA Consistent with the reports used for
 and women                                          comparison.
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<pre>chapter 25 | Phosphorus                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 134 of 179
25
phosphorus
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<pre>chapter 25 | Phosphorus                                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 135 of 179
                                              Phosphorus                                                     25.1 Overview and comparison of values
                                                                                                             Table 86. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected                                                          values are based
         based on a specific nutritional context in the                                 YES
       Netherlands that differs from (the rest of) Europe?                                                     Report                 PRI/RDA/AI/RI       AR          CV       Main criterion
                                                                                                                                      Type      (mg/d)    (mg/d)      (%)
                                                                                                               EFSA 201513            AI        550                            Molar Ca:P intake ratio of 1.4:1 in combination
                                                                                                                                                                               with the PRI for calcium.
                                                                                                               NCM 201437             RI        600       450         17%a     Intake of 400 mg/d maintains a plasma
                                NO
                                                                                                               = HCNL 201433                                                   concentration of 0.8 mmol/L No substantial new
                                                                                                                                                                               data indicating that the RI should be changed.
                                                                                                                                                                               Therefore the NCM (2004) RI is maintained.
                                                                                                               DACH 201538            RI        700       580         10%      Refers to IOM (1997).
      Are there objections against EFSA’s scientific basis                                                     IOM 199743             RDA       700       580         10%      Absorbed P needed to achieve serum Pi > 0.87
                        for this nutrient?
                                                                                                                                                                               mmol/L.
                                                                                                                                                                               P-absorption efficiency = 62.5%.
                                                                                                             a
                                                                                                                If the coefficient of variation was not specified in the report, it was calculated as
                                                                                                                100% x [ (PRI/RI/RDA – AR) / 2 ] / AR
                                             YES
                                                                                                             Note that WHO/FAO did not evaluate phosphorus.
      NO
                     Do (part of) EFSA's reference values differ 10% or
                                                                                        YES                  Table 86 shows that the NCM RI is 9% higher than EFSA’s AI, whereas
                      more from the 2014 values for the Netherlands?
                                                   AI                                                        the RDAs by IOM and DACH are 27% higher than EFSA’s AI.
                                              NO                                                             25.2 Explanation of differences between reports
                                                                                                             EFSA bases the AI on the intake of calcium assuming that phosphorus
                                                                                                             intake should be sufficient in relation to calcium intake. NCM, DACH and
           No objections against the use of                   Major objection against the use of
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands        IOM base their AIs on a biochemical parameter of status.
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<pre>chapter 25 | Phosphorus                                                                                       An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 136 of 179
EFSA bases the adequate intake of phosphorus on the molar ratio of                                                       notes that the ratio fails to take into account the differing absorption
calcium to phosphorus (Ca:P) in the body,a combined with the PRI for                                                     efficiencies for dietary calcium and phosphorus. Moreover, IOM considers
calcium.                                                                                                                 that the ratio has little meaning or value, because of the relative surplus of
EFSA assumes that the Ca:P molar ratio in the diet should be in line with                                                phosphorus in the diet.d IOM considers that it would be inappropriate to
the ratio in the whole body. EFSA does not take into account that the                                                    conclude, simply on the basis of a departure from some theoretical Ca:P
estimated average absorption is higher for phosphorus (55%-80%)                                                          ratio, either that calcium intake should be elevated or, phosphorus intake
compared to calcium (<25%19), considering that data on phosphorus                                                        reduced. IOM notes that, in balance studies in human adults, Ca:P molar
absorption are limited and vary substantially.                                                                           ratios ranging from 0.08:1 to 2.40:1 (a 30-fold range) had no effect on
EFSA estimates that the Ca:P molar ratio in the body ranges from 1.4:1 to                                                either calcium balance or calcium absorption.
1.9:1, based on data on whole-body Ca and P contents in Caucasian
adults and on data on the Ca:P ratio in bones of healthy adults that are                                                 NCM and IOM based the AR on the intake needed to achieve a serum
adjusted for the proportion of phosphorus found outside bone. As                                                         inorganic phosphorus concentrations (serum Pi) at the lower end of the
phosphorus intakes are high in Western countries, EFSA bases the AI for                                                  normal range in adults.
phosphorus on the lower end of this range: a molar Ca:P ratio of 1.4:1,                                                  • NCM’s AR (450 mg/d) is based on the intake (400 mg/d) required to
corresponding to a weight ratio 1.81:1.b EFSA then calculates the AI for                                                     achieve a serum Pi of 0.8 mmol/L.
phosphorus using the PRI for calcium.c                                                                                   • IOM’s AR (580 mg/d) is based on the intake (580 mg/d) required to
IOM rejected the use of the Ca:P ratio of the diet as the basis for setting                                                  achieve a serum Pi. of 0.87 mmol/L. IOM notes that the value of serum
reference values, considering that this ratio has some utility under                                                         Pi selected has a large impact on the intake estimate because, above
conditions of rapid growth, but no demonstrable relevance in adults. IOM                                                     the ‘renal threshold’, increases in intake result in a very gradual
                                                                                                                             increase in serum Pi.e
a
  EFSA mentions that some observational studies in adults suggest that the Ca:P ratio in the diet may have a greater
  influence on bone health than the absolute intake of phosphorus, although other studies present conflicting
  evidence. EFSA furthermore refers to the review by Calvo and Tucker (2013 ) showing that in several animal models      d
                                                                                                                           This also applies to the habitual phosphorus intakes in Dutch adults aged 18-50 years. Estimates show that 95%
  the combination of a high phosphorus intake with a low calcium intake is bad for bone health. The Committee notes        of these men and women have intakes >1,200 and >900 mg phosphorus per day, respectively. Average intakes
  that this has more relevance for an upper level for phosphorus intake than for the adequate intake.                      were 1,800 mg/day in men and 1.400 mg/day in women. The top 5% of these groups had intakes >2,500 mg/day
b
  The use of the upper end of the range would have resulted in a substantially lower AI for phosphorus.                    (men) and >1,900 mg/day (women).45
c
  The differentiation for calcium between adults aged 18-24 and >25 years (PRIs of 1000 and 950 mg calcium per           e
                                                                                                                            Note that at different places in the IOM report, 0.8-0.9 mmol/L and 0.87 mmol/L are mentioned to be the lower
  day, respectively) is not applied to the AI for phosphorus which, for all adults aged 18 years or older, is set at 550   end of the normal adult range: the value of 0.87 mmol/L is the 2.5th percentile in adults (page 149 of the IOM
  mg per day.                                                                                                              report). Later in the report, IOM mentions that there is a grey zone between the empirical normal range and
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<pre>chapter 25 | Phosphorus                                                                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 137 of 179
EFSA rejected the use of serum Pi to derive the AI for phosphorus,
                                                                                                                      Background information – a summary of the information provided by the EFSA report –
considering that serum Pi is not a reliable biomarker of P intake and
                                                                                                                      on the function of the nutrient, the occurrence of clinical deficiency and deficiency
status: fasting serum Pi shows only minimal modifications, even in the                                                symptoms
presence of wide variations in intake,a serum Pi inadequately reflects body                                           Phosphorus is involved in many physiological processes, such as in the cell’s energy cycle, in
stores, and serum Pi is influenced by many factors other than phosphorus                                              regulation of the body’s acid–base balance, as a component of the cell structure, in cell
                                                                                                                      regulation and signalling, and in the mineralisation of bones and teeth. About 85% of the body’s
intake (age, sex, lactation, diurnal and seasonal variations, vitamin D                                               phosphorus is in bones and teeth, 14% is in soft tissues, including muscle, liver, heart and
status, apart from pathological conditions such as malabsorption                                                      kidney, and only 1% is present in extracellular fluids. Phosphorus homeostasis is intricately
                                                                                                                      linked to that of calcium because of the actions of calcium-regulating hormones, such as
syndromes and insulin-dependent diabetes mellitus).                                                                   parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D (1,25(OH)2D), at the level of the
                                                                                                                      bone, the gut and the kidneys.
                                                                                                                      Phosphorus deficiency presents as hypophosphataemia, i.e. serum phosphorus concentrations
Differences between older and younger adults and between men and                                                      below 0.80 mmol/L in adults. This occurs only rarely because of inadequate dietary phosphorus
women                                                                                                                 intake, and is almost always due to metabolic disorders. The incidence of hypophosphataemia is
                                                                                                                      high in certain subgroups of patients, such as those with sepsis, chronic alcoholism, major
None of the reports differentiate between older and younger adults, or                                                trauma or chronic obstructive pulmonary disease, and may also develop in kidney patients.
between men and women.                                                                                                Hypophosphataemia may also occur during the management of diabetic ketoacidosis. Mild
                                                                                                                      hypophosphataemia can also occur as a common, generally asymptomatic, consequence of
                                                                                                                      hyperparathyroidism.
25.3 Conclusion on the scientific basis of EFSA’s reference                                                           Clinical symptoms of hypophosphataemia usually occur when serum phosphorus concentrations
                                                                                                                      fall below 0.3 mmol/L, particularly when this is associated with total body phosphorus depletion.
         values                                                                                                       The nature and severity of the clinical symptoms depend on the extent of the phosphorus
The type of data used as a basis for the reference value of phosphorus is                                             depletion and are highly variable, depending on the underlying cause and the individual patient’s
                                                                                                                      status. At a whole organism level, the effects of hypophosphataemia include anorexia, anaemia,
problematic: IOM rejects the use of the Ca:P ratio (which is the basis for                                            muscle weakness, bone pain, rickets and osteomalacia, increased susceptibility to infection,
EFSA’s AI); but EFSA rejects the use of serum Pi (which is the basis of                                               paraesthesia, ataxia, confusion and even death.
IOM’s and NCM’s AR).
                                                                                                                   Phosphorus deficiency is rare in healthy persons on normal diets.
  values associated with evident deficiency disease: the lower end of the established normal range for serum Pi is EFSA provides no information on phosphorus intake levels associated
  0.8 to 0.9 mmol/L, whereas clear evidence of bony or soft tissue dysfunction is not common until serum Pi levels
  drop below 0.3 to 0.5 mmol/L (page 159 of the IOM report).                                                       with the occurrence, correction or prevention of deficiencies.
a
  EFSA notes that, after the ingestion of a meal, serum Pi increases for a short period and then decreases again
  and remains within a relatively narrow range as a result of homeostatic mechanisms.
                                                                                                                   Almost all Dutch adults have intakes (far) above EFSA’s AI.
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<pre>chapter 25 | Phosphorus                                                                An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 138 of 179
EFSA’s AI differs little from the current RDA which has been used in the                        The Committee concludes that there is no consensus on the best outcome
Netherlands since 2014 (NCM’s RI). Therefore, switching to EFSA’s AI will                       parameter to evaluate the phosphor intake and set reference values. As
have no implications, and the Committee has no objections against the                           EFSA’s AI differs little from the current RDA which has been used in the
use of EFSA’s values in the Netherlands.                                                        Netherlands since 2014 (NCM’s RI), switching to EFSA’s AI will have no
                                                                                                implications. The Committee has no objections against the use of EFSA’s
25.4 Summary and conclusion                                                                     values in the Netherlands and recommends using these values (Table 88).
Table 87. Summary of the evaluation of EFSA’s AI values for phosphorus                          Table 88. AR and PRI for phosphorus, recommended for the Netherlands
 Main findings, used for the conclusion                                                                                                  Men and women >18 years
 Aspect                       Conclusion          Comment                                        Adequate intake (AI)                    550 mg/day
 EFSA’s AIs compared to       <10% lower          EFSA’s AI is 8% lower HCNL’s (=NCM’s) RI.
 HCNL’s (NCM’s) RI
 Scientific basis of EFSA’s   Problematic         EFSA is not consistent with the reports used
 AIs                                              for comparison. IOM and NCM use serum
                                                  inorganic phosphorus concentration.
 Other findings
 Aspect                       Conclusion          Comment
 Differentiation between      Not applied by EFSA Consistent with the reports used for
 younger and older adults                         comparison.
 Differentiation between men  Not applied by EFSA Consistent with the reports used for
 and women                                        comparison.
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<pre>chapter 26 | Potassium                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 139 of 179
26
potassium
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<pre>chapter 26 | Potassium                                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 140 of 179
                                                 Potassium                                                    26.1 Overview and comparison of values
                                                                                                              Table 89. Overview of the reference values for adults and the criteria on which these
          Should EFSA's reference values be rejected                                                          values are based
          based on a specific nutritional context in the                                 YES
        Netherlands that differs from (the rest of) Europe?                                                    Report     PRI/RDA/AI/RI   Main criterion
                                                                                                                          Type  (g/d)
                                                                                                               EFSA       AI    3.5       • K-intake >3.5 g/d is beneficial for blood pressure.
                                                                                                               201611                     • K-intake <3.5 g/d is associated with a higher risk of stroke.
                                                                                                               NCM 201437 RI    ♂ 3.5     A diet rich in potassium alone, or in combination with calcium and
                                 NO
                                                                                                               = HCNL           ♀ 3.1     magnesium, might have a favourable effect on blood pressure and
                                                                                                               201433                     might reduce the risk of stroke and other cardiovascular endpoints.
                                                                                                                                          The reference values in NNR 2012 are kept unchanged compared to
                                                                                                                                          NNR 2004 because there are no new data to justify any major
       Are there objections against EFSA’s scientific basis                                                                               changes.
                         for this nutrient?
                                                                                                               DACH       RI    2         K-intake needed for the maintenance of electrolyte homeostasis. The
                                                                                                               201538,60                  DACH report does not specify the origin of the value of 2 g/d.
                                                                                                               IOM 200540 AI    4.7       The AI for potassium is based on:
                                                                                                                                          • blunting the severe salt sensitivity prevalent in African-American
                                              YES                                                                                           men
                                                                                                                                          • decreasing the risk of kidney stones (a 3-year double-blind
                                                                                                                                            randomised controlled trial)
                                                                                                                                          • lowering of blood pressure in nonhypertensive individuals
       NO
                      Do (part of) EFSA's reference values differ 10% or                                                                  • decreasing bone loss
                                                                                         YES
                       more from the 2014 values for the Netherlands?                                                                     The beneficial effects of potassium in these studies appears to be
                                                                                        AI ♀                                              mainly from the forms of potassium that are found naturally in foods
                                                                                                                                          such as fruits and vegetables.
                                               NO     AI ♂                                                    Note that WHO/FAO did not establish reference values for potassium.
                                                                                                              Table 89 shows that NCM’s RI for men, which is the current Dutch
                                                                                                              reference value for men, equals EFSA’s AI. EFSA uses the same value for
            No objections against the use of                   Major objection against the use of
       EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands        men and women, whereas NCM uses an 11% lower value for women. The
                                                                                                              value used by DACH is 43% lower than EFSA’s value. The IOM value is
                                                                                                              34% higher than EFSA’s value.
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<pre>chapter 26 | Potassium                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 141 of 179
26.2 Explanation of differences between reports                                 DACH’s lower reference intake is based on the maintenance of electrolyte
EFSA, NCM and IOM base their AIs on the relationship with disease risk.         balance. The DACH report does not further elaborate on the origin of the
DACH’s RI is based on a factorial method.                                       value of 2000 mg/d.
EFSA concludes that there is evidence that a potassium intake of 3,500
mg/day has a beneficial effect on blood pressure in adults. EFSA                Differences between older and younger adults
furthermore considers that there is consistent evidence that potassium          None of the reports differentiate between older and younger adults.
intakes below 3,500 mg/day are associated with a higher risk of stroke.
EFSA derives an AI because the available data do not allow the                  Sex differences
determination of the AR and distribution of individual requirements. The        EFSA, DACH and IOM do not differentiate between men and women, but
AI-value is 3.5 gram per day.                                                   NCM has set a lower RI for women than for men.
NCM uses a line of reasoning which is similar to EFSA’s.
                                                                                26.3 Conclusion on the scientific basis of EFSA’s reference
IOM’s AI for potassium is based on blunting the severe salt sensitivity in            values
nonhypertensive African-American men (achieved at an intake of 4.7 g/day        The Committee agrees with the scientific basis of EFSA’s AI (blood
in a salt loading study with a total duration of 14 days) and on the            pressure and stroke risk), which is consistent with the conclusions on
association of intakes of 4.0-4.7 gram potassium per day with a lower risk of   potassium in HCNL’s report Dutch dietary guidelines 2015.61
kidney stones in three prospective cohort studies (relative to intakes of 2.0,  EFSA does not explain why they did not make a difference between the AI
<2.9 and 3.8 g/d). Blood pressure studies in nonhypertensive individuals are    for men and women, and the NCM do not explain why they did. The
supportive of this level of intake as a means to lower blood pressure.          Committee considers that most randomised controlled trials and cohort
Epidemiological studies suggest that higher levels of potassium intake from     studies reported conclusions only on mixed populations of men and
foods are associated with decreased bone losses. IOM notes that the             women, and not on men and women separately. In their meta-analysis,
beneficial effects of potassium in these studies appear to be mainly from the   Aburto et al. (2013) concluded that, because of this, they could not
forms of potassium that are found naturally in foods such as fruits and         evaluate differences by sex.62 D’Elia et al. (2011) did explore the influence
vegetables.                                                                     of sex in their meta-analysis, based on the few studies that presented
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<pre>chapter 26 | Potassium                                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 142 of 179
results for men and women separately; they concluded that sex appeared                                        26.4 Summary and conclusion
to be no significant source of heterogeneity.63 Therefore, the Committee
                                                                                                              Table 90. Summary of the evaluation of EFSA’s AI values for potassium
agrees with EFSA’s use of the same AI for men and women.                                                       Main findings, used for the conclusion
                                                                                                               Aspect                     Conclusion          Comment
                                                                                                               EFSA’s AIs compared to     Equal for men,      EFSA’s AI is equal to HCNL’s (=NCM’s) RI for
                                                                                                               HCNL’s (NCM’s) RI          higher for women    men, and 11% higher than HCNL’s (=NCM’s) RI
   Background information – a summary of the information provided by the EFSA report –
                                                                                                                                                              for women.
   on the function of the nutrient, the occurrence of clinical deficiency and deficiency                       Scientific basis of EFSA’s No objections       Consistent with NCM and HCNL; and partly
   symptoms                                                                                                    AIs                                            consistent with IOM. DACH is not consistent with
                                                                                                                                                              the other reports.
   Potassium is the predominant osmotically active element inside cells. It plays a major role in the          Other findings
   distribution of water inside and outside cells, assists in the regulation of the acid-base balance,         Aspect                     Conclusion          Comment
   and contributes to establishing a membrane potential which supports electrical activity in nerve            Differentiation between    Not applied by EFSA Consistent with the reports used for comparison.
   fibres and muscle cells. Potassium has a role in cell metabolism, participating in energy                   younger and older adults
   transduction, hormone secretion, and the regulation of protein and glycogen synthesis.                      Differentiation between    Not applied by EFSA Consistent with IOM and DACH, but not with
   Potassium deficiency, presenting as hypokalaemia, is defined as a serum potassium                           men and women                                  NCM. NCM set a lower value for women than for
   concentration lower than 3.5 mmol/L. In general, deficiency may be caused by increased                                                                     men, but did not explain why.
   potassium losses via diarrhoea, vomiting, burns or excessive renal losses (owing, for example,
                                                                                                              The Committee agrees with the scientific basis of EFSA’s AI and with
   to renal tubular acidosis, high secretion of mineralocorticoids, some diuretics) leading to low
   total body potassium. Hypokalaemia can also occur when total body potassium is normal in                   EFSA’s AI for all adults and recommends using this value in the
   case of an intracellular shift of potassium. The most important causes of an intracellular shift
                                                                                                              Netherlands (Table 91).
   include alkalosis, insulin excess, catecholamine excess and the genetic disease called familial
   periodic paralysis.
                                                                                                              Table 91. AI for potassium, recommended for the Netherlands
   Hypokalaemia resulting from insufficient dietary intake is rare and may be associated with
   severe hypocaloric diets or occur as the result of an increased requirement needed for the                                                      Men and women >18 years
   synthesis of new tissue (e.g. muscle) during recovery from malnutrition.                                    Adequate intake (mg/d)              3.5 g/d
   Hypokalaemia is generally associated with increased morbidity and mortality, especially from
   cardiac arrhythmias or sudden cardiac death. When serum potassium concentration is
   <3 mmol/L, the prevalence of malignant ventricular arrhythmia has been observed to increase
   twofold in patients on diuretic treatment. The risk of atrial fibrillation is higher in hypokalaemic
   subjects compared to the general population. Other adverse consequences of hypokalaemia
   include polyuria, muscle weakness, decreased peristalsis possibly leading to intestinal ileus,
   mental depression and respiratory paralysis in severe cases.
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<pre>chapter 27 | Selenium                                  An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 143 of 179
27
selenium
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<pre>chapter 27 | Selenium                                                                               An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 144 of 179
                                                Selenium                                                     27.1 Overview and comparison of values
                                                                                                             Table 92. Overview of the reference values for adults and the criteria on which these
         Should EFSA's reference values be rejected
         based on a specific nutritional context in the
                                                                                                             values are based
                                                                                        YES
       Netherlands that differs from (the rest of) Europe?
                                                                                                               Report            PRI/RDA/AI/       AR       CV    Main criterium
                                                                                                                                 RI (μg/d)         (μg/d)   (%)
                                                                                                                                 Type    ♂, ♀      ♂, ♀     ♂, ♀
                                                                                                               EFSA 201422       AI      70                       Function parameter: the selenium intake level
                                NO                                                                                                                                required for plasma SEPP1 to reach a plateau
                                                                                                                                                                  value.
                                                                                                               NCM 201437        RI      60, 50    35, 30  36, 33 Function parameter: optimal plasma SEPP1.
                                                                                                               = HCNL 201433
                                                                                                               DACH 201538,64    AI      70, 60                   Function parameter: the selenium intake level
      Are there objections against EFSA’s scientific basis
                        for this nutrient?                                                                                                                        required for plasma SePP 1 concentration to
                                                                                                                                                                  reach a plateau value.
                                                                                                                                                                  AI-values are based on 1 μg/kg/d, with body
                                                                                                                                                                  weights. ♂ 70.7 kg, ♀ 60.0 kg.
                                             YES                                                               IOM 20002         RDA     55        45      10     Function parameter: maximising plasma GPx
                                                                                                                                                                  activity. No difference between values for men
                                                                                                                                                                  and women, because of greater susceptibility of
                                                                                                                                                                  women to develop Keshan disease.
                                                                                                               WHO/FAO                                            Function parameter: maximising plasma GPx
                     Do (part of) EFSA's reference values differ 10% or
      NO                                                                                YES                    200444                                             activity.
                      more from the 2014 values for the Netherlands?
                                                                                        AIs                    19-65 yr          RI      34, 26    27, 20  12.5   ♂ AR 0.42 μg/kg/d; body weight 65 kg.
                                                                                                                                                                  ♀ AR 0.37 μg/kg/d; body weight 55 kg.
                                                                                                               >66 yr            RI      33, 25    27, 20  12.5   ♂ AR 0.41 μg/kg/d; body weight 64 kg.
                                                                                                                                                                  ♀ AR 0.37 μg/kg/d; body weight 54 kg.
                                             NO                                                              a
                                                                                                                Note that DACH mentions SePP instead of SEPP1.
                                                                                                             Table 92 shows that EFSA’s AI is higher than the RI/AI/RDA in other
           No objections against the use of                   Major objection against the use of
      EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands        reports (NCM -21%, DACH -7%, IOM -21% and WHO/FAO -57% relative
                                                                                                             to EFSA).
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<pre>chapter 27 | Selenium                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 145 of 179
27.2 Explanation of differences between reports                                                                    considered that SEPP1 is the most informative biomarker of selenium
Most reports base their reference values on biochemical parameters of                                              function on the basis of its role in selenium transport and metabolism and
function: either SEPP1 (EFSA, NCM and DACHa) or GPx activity (IOM                                                  its response to different forms of ingested selenium. EFSA assumed that
and WHO/FAO).                                                                                                      this levelling off is indicative of an adequate supply of selenium to all
                                                                                                                   tissues, and therefore, of the fulfilment of selenium requirement. However,
EFSA, NCM and DACH use the same function parameter: the selenium                                                   the EFSA Panel notes that evidence on associations between plasma
intake level required for plasma SEPP1 to reach a plateau value.                                                   SEPP1 concentration and health outcomes is insufficient; this is part of
                                                                                                                   the research recommendations expressed by the EFSA Panel in the
EFSA refers to three studies: a Chinese study (Xia et al., 2010) and a                                             Opinion.
study from New Zealand (Duffield et al., 1999), including both men and                                             EFSA derived an AI instead of an AR and PRI, because of uncertainties in
women, and a study from Finland, including only men (Persson-Moschos                                               estimates of background dietary selenium intake, the extrapolation of
et al., 1998). The EFSA Panel noted that there were uncertainties related                                          results from Chinese individuals to the European population, and the
to the intake estimates, the extrapolation of results from Chinese                                                 extrapolation of findings on L-selenomethionine to dietary selenium.
individuals to the European population, and the extrapolation of findings
regarding supplemental L-selenomethionine to dietary selenium. The                                                 NCM and DACH refer to only one of the three studies used by EFSA: the
Finnish study indicated a higher adequate selenium intake compared to                                              Chinese study (Xia et al., 2010). DACH’s AI is higher than the RI by NCM,
the studies from China and New Zealand, explaining why EFSA’s PRI is                                               because DACH rounded the adequate selenium intake per kg body weight
higher than the RI by NCM.                                                                                         per day upwards.
EFSA noted that measures of glutathione peroxidases (GPxs) activity can
be used as a biomarker of selenium function, but that the activity of GPxs                                         IOM and WHO/FAO based the AR for selenium on the intake required for
reaches a steady state with levels of selenium intake that are lower than                                          maximal plasma GPx activity. The values are based on the results of two
those required for the levelling off of SEPP1 (Xia et al., 2010).a EFSA                                            intervention studies that were done in different countries but had similar
                                                                                                                   designs. The Chinese study (Yang et al., 1987) suggests that a plateau of
a
  Xia et al. (2010) reports that optimisation of SEPP1 required a higher intake of selenium than maximising plasma plasma GPx activity was reached with a selenium intake of 41 μg/d (this
  GPx activity. The Committee notes, however, that Duffield et al. (1999) reported the opposite.
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<pre>chapter 27 | Selenium                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 146 of 179
was the lowest intake at which the activity of plasma GPx activity reached                                           Differences between older and younger adults
a plateau after 4 months). With a weight adjustment for North American                                               EFSA, NCM, DACH and IOM do not differentiate between older and
males, the selenium intake was 52 μg/d. The New Zealand study (Duffield                                              younger adults. WHO/FAO’s RI-values for adults >66 years are almost the
et al., 1999) can be interpreted to suggest an EAR in the vicinity of 38                                             same as for adults 18-65 years.
μg/d (this was the intake necessary to reach two-thirds of maximum
GSHPx activity). IOM choose to use the average of those estimates, 45                                                Sex differences
μg/d, as the EAR.                                                                                                    EFSA and IOM did not differentiate between men and women, whereas
IOM did not use SEPP for establishing the reference values, because an                                               NCM, DACH and WHO/FAO did.
assay for SEPP was not widely available at that time and the data for                                                One publication used by EFSA indicating that a habitual dietary selenium
selenoprotein P were insufficient to estimate a dietary requirement.                                                 intake of 50-60 μg/day is not sufficient for SEPP1 concentration to level off,
EFSA considered that measures of glutathione peroxidases (GPxs)                                                      referred to a study in men only (Persson-Moschos et al., 1998). Both other
activity can be used as a biomarker of selenium status, but noted the                                                studies used by EFSA included women and indicated that 50-60 μg/day
following limitations: (1) GPxs activity reaches a steady state with levels of                                       may be sufficient (Xia et al., 2010; Duffield et al., 1999). EFSA, NCM and
selenium intake that are lower than those required for the levelling off of                                          DACH mention an estimated requirement per kilogram body weight based
SEPP1,a (2) plasma GPx3 activity probably reflects selenium status in the                                            on one study (Xia et al., 2010), however, this estimate appears to be
kidney rather than in the whole body, (3) the relationship of intake with                                            calculated by dividing the estimated requirement of 49 μg/day by the
GPxs activity is affected by the chemical nature of the selenium, the                                                average body weight of 58 kg over all 95 subjects (43 men and 52 women).
baseline selenium status and the presence of certain diseases or                                                     The two publications that included both men and women do not present
polymorphisms, and (4) different expression units for GPxs activity limit                                            results in μg/day or in μg/kg/day for men and women separately.
comparisons between studies.                                                                                         It therefore appears to be appropriate to set an AI without making a sex
                                                                                                                     difference.
a
  The Committee already noted on the previous page that, on this issue, Xia et al. (2010) and Duffield et al. (1999)
  reported the opposite.
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<pre>chapter 27 | Selenium                                                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 147 of 179
27.3 Conclusion on the scientific basis of EFSA’s reference
                                                                                                                       Background information – a summary of the information provided by the EFSA report –
          values                                                                                                       on the function of the nutrient, the occurrence of clinical deficiency and deficiency
EFSA considers that there is insufficient evidence on associations                                                     symptoms
between plasma SEPP1 concentration and health outcomes. EFSA                                                           A total of 25 selenoproteins have been identified in humans. These have a variety of functions,
describes that the association between SEPP1 concentration and health                                                  including antioxidant effects, T-cell immunity, thyroid hormone metabolism, selenium
                                                                                                                       homeostasis and transport, and skeletal and cardiac muscle metabolism. Selenoprotein P
outcomes has been investigated in only two nested case–control studies                                                 (SEPP1) plays a central role in selenium supply to tissues and participates in the regulation of
(Persson-Moschos et al., 2000; Epplein et al., 2014); both suggested an                                                selenium metabolism in the organism.
                                                                                                                       Selenium deficiency affects the expression and function of selenoproteins. Clinical
inverse association between plasma SEPP1 concentration and overall                                                     manifestations of selenium deficiency are poorly defined. Symptoms observed in patients
cancer risk, and in particular, risk of cancer of the digestive and respiratory                                        receiving selenium-free total parenteral nutrition (TPN) include skeletal myopathy and muscle
                                                                                                                       weakness. Several cases of cardiomyopathy were reported, although selenium deficiency
tract. The EFSA Panel considered that these and other findings on                                                      appeared to be only one of the aetiological factors in these subjects. Pseudoalbinism and red
selenium and chronic diseases cannot be used to derive DRVs, but that                                                  blood cell macrocytosis were also observed in children receiving selenium-free TPN.
                                                                                                                       There are concerns that combined low intake of iodine and selenium contributes to the risk of
they are compatible with the DRVs derived based on the levelling off of                                                myxoedematous cretinism, described in the endemic goitre area of central Africa.
plasma SEPP1.a Note that selenium deficiency (Keshan disease) is                                                       Selenium deficiency is also involved in the degeneration of organs and tissues leading to the
                                                                                                                       manifestation of Keshan and Kashin-Beck diseases.
reported at intakes <15 μg/day (Table 93).                                                                             Keshan disease is an endemic cardiomyopathy occurring mainly in children and young women.
                                                                                                                       It is apparent in population groups in China with particularly low selenium intake (around 15 μg/
Table 93. Selenium intake levels associated with the occurrence, correction or                                         day). Keshan disease is not yet fully understood, but there is some evidence for a dual aetiology,
prevention of deficiencies, as described by EFSA                                                                       including both selenium deficiency and infection with an enterovirus.
                                                                                                                       Kashin-Beck disease is a chronic degenerative osteochondropathy occurring in pre-adolescence
  Clinical                  Associated       Subjects/Specific group                        EFSA’s reference
  manifestation             intake                                                                                     or adolescence in selenium-deficient areas. It is endemic in some areas in China, but also in
  associated with                                                                                                      Mongolia, Siberia and North Korea. The aetiology of the disease is largely unknown. Possible
  deficiency                                                                                                           risk factors seem to include mycotoxins in food, humic and fulvic acids in drinking water and
  Keshan disease            around 15        Chinese subjects with low selenium             Ge and Yang, 1993;         selenium and iodine deficiency.
                            μg/day           intake from an area with endemic               NNR; SCF
                                             Keshan disease
  Absence of Keshan         >17 μg/day       Population groups in China                     Yang et al., 1987
  disease                                                                                                           The Committee has no objections against the scientific basis of EFSA’s AI.
                                                                                                                    The Committee agrees with EFSA that there is insufficient evidence on
a
   After the publication of EFSA’s report, findings of the European Prospective Investigation into Cancer (EPIC)    associations between the levelling off of plasma SEPP1 concentration and
   described an association between higher plasma SEPP and a lower cancer risk.65,66
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<pre>chapter 27 | Selenium                                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 148 of 179
health outcomes, although limited results from observational studies                                The Committee has no objections against the scientific basis of EFSA’s AI,
indicate that the concentration of plasma SEPP1 may be inversely                                    or EFSA’s AI-value, and recommends using EFSA’s AI in the Netherlands
associated with cancer risk. The Committee notes that other reports                                 (Table 95). The Committee notes that the evidence on which EFSA based
established lower AI-values based on the levelling off of plasma SEPP1                              their relatively high AI-value, is limited.
concentration. The Committee has no major objections against EFSA’s AI,
                                                                                                    Table 95. AI for selenium, recommended for the Netherlands
but notes that the evidence that EFSA’s relatively high AI for selenium will                                                                  Men and women >18 years
result in health gain compared to the lower values in some other reports,                            Adequate intake (AI)                     70 μg/day
is limited.
27.4 Summary and conclusion
Table 94. Summary of the evaluation of EFSA’s AI values for selenium
 Main findings, used for the conclusion
 Aspect                    Conclusion     Comment
 EFSA’s AIs compared to    Higher         EFSA’s AI is 17% higher than HCNL’s (=NCM’s) RI for
 HCNL’s (=NCM’s) RI                       men and 40% higher than HCNL’s (=NCM’s) RI for men.
 Scientific basis of       No objections  EFSA, NCM and DACH use SEPP1, whereas IOM and
 EFSA’s AIs                               WHO/FAO use maximal plasma GPx activity.
 Other findings
 Aspect                    Conclusion     Comment
 Differentiation between   Not applied by Consistent with the reports used for comparison.
 younger and older adults EFSA
 Differentiation between   Not applied by EFSA and IOM do not differentiate between men and
 men and women             EFSA           women, whereas NCM, DACH and WHO/FAO do.
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28
zinc
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                                                       Zinc                                                    28.1 Overview and comparison of values
                                                                                                               Table 96. Overview of the reference values for adults and the criteria on which these
             Should EFSA's reference values be rejected                                                        values are based.
             based on a specific nutritional context in the                                  YES
          Netherlands that differs from (the rest of) Europe?                                                   Report        PRI/RDA/RI       AR         CV Main criterion          Physio-   Absorp-
                                                                                                                              (mg/d)           (mg/d)     (%)                        logical   tion
                                                                                                                                                                                     require-  (%)
                                                                                                                                                                                     ment
                                                                                                                                                                                     (mg/d)
                                   NO
                                                                                                                              Type ♂      ♀    ♂     ♀                               ♂     ♀
                                                                                                                EFSA 2014 21
                                                                                                                                                              Factorial approach     3.2   2.9 Using
                                                                                                                Phytate                                       using regression                 regres-
                                                                                                                intake:                                       analysis on data of              sion
         Are there objections against EFSA’s scientific basis                                                   300 mg/day    PRI    9.4  7.5  7.5   6.2  a
                                                                                                                                                              individuals to                   analysis
                           for this nutrient?                                                                   600 mg/day    PRI    11.7 9.3  9.3   7.6      estimate:
                                                                                                                900 mg/day    PRI    14.0 11.0 11.0  8.9      1) physiological
                                                                                                                1,200 mg/day  PRI    16.3 12.7 12.7  10.2     requirement for
                                                                                                                                                              absorbed Zn;
                                                YES                                                                                                           2) zinc intake
                                                                                                                                                              needed to meet this
                                                                                                                                                              physiological
                                                                                                                                                              requirement,
                        Do (part of) EFSA's reference values differ 10% or                                                                                    estimated for 4
         NO                                                                                  YES
                         more from the 2014 values for the Netherlands?                                                                                       phytate intake levels.
                                                                                      ARs and PRIs                                                            PRI is based on the
                                                                                                                                                              97.5th percentile of
                                                                                                                                                              reference weight.
                                                        At the lowest                                                   (Averages: b 12.9 10.1 10.1 8.2)
                                                 NO
                                                        phytate intake
                                                                                                                NCM 201437    RI     9    7    6.4   5.7  15  Factorial method.      2.27 2.0  40%
                                                                                                                = HCNL                                        Estimates for
                                                                                                                201433                                        endogenous Zn
                                                                                                                                                              losses (sweat, urine,
              No objections against the use of                      Major objection against the use of                                                        sperm, menses,)
         EFSA's reference values in the Netherlands           EFSA's reference values in the Netherlands                                                      adopted from IOM:
                                                                                                                                                              ♂ 1.27 mg/d;
                                                                                                                                                              ♀ 1.0 mg/d, but
                                                                                                                                                              intestinal losses
                                                                                                                                                              estimated to be 1.4
                                                                                                                                                              mg/d (♂ & ♀).
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  Report           PRI/RDA/RI            AR              CV Main criterion               Physio-       Absorp-
                   (mg/d)                (mg/d)          (%)                             logical       tion
                                                                                         require-      (%)         substantially lower (NCM -30%; DACH -26%; IOM -17%; WHO/FAO
                                                                                         ment
                                                                                                                   -48%). Values by IOM and values for males by DACH are within the range
                                                                                         (mg/d)
                   Type ♂         ♀      ♂      ♀                                        ♂      ♀                  presented by EFSA, whereas values by NCM and WHO/FAO and the
  DACH 2015     38
                   RI     10.0 7.0       7.5    5.5      15     Factorial method.        2.2    1.6    30%
                                                                                                                   values for females by DACH are lower than this range.
  IOM 2001   41
                   RDA    11     8       9.4    6.8      10     Factorial method.        3.84 3.3      Using
                                                                Physiological                          regres-
                                                                requirement for                        sion
                                                                absorbed zinc is the                   analysis    28.2 Explanation of differences between reports
                                                                point at which
                                                                                                                   All reports use factorial methods based on estimates of physiological
                                                                absorbed Zn equals
                                                                the endogenous                                     requirements (the requirements for absorbed zinc) and absorption (the
                                                                losses (sweat, urine,
                                                                sperm, menses:                                     zinc intake needed to meet this physiological requirement). EFSA
                                                                ♂ 1.27 mg/d;
                                                                ♀ 1.00 mg/d). The
                                                                                                                   performed regression analyses on data at the level of the individual and
                                                                EAR is estimated by                                based the PRI on the 97.5th percentile of reference weight. IOM performed
                                                                regression analysis
                                                                on group mean                                      regression analyses which were similar in nature, but IOM used group
                                                                values.
  WHO/FAO                                                       Physiological            1.4    1.0
                                                                                                                   mean values. Other reports based their estimates on the factorial method,
  200444                                                        requirement for                                    using average values.
  Bioavailability:                                              absorbed zinc was
  High             RI     4.2 3.0        2.8    2.0      25     defined as losses                      High
  Moderate         RI     7.0 4.9        4.7    3.2      25     during the early                       Moderate
  Low              RI     14.0 9.8       9.4    6.5      25     phase of Zn                            Low         Differentiation based on phytate intakea
                                                                depletion before
                                                                                                                   EFSA does not set one, but four PRIs/ARs for zinc per sex, because of
                                                                reductions in
                                                                excretion take place.                              the large variation in requirement related to different phytate intakes.
             (Averages:b 8.4     5.9)
a
   EFSA estimated PRI directly based on the 97.5th percentile of reference body weights (thus did not estimate PRI When phytate intake is high, the requirement is estimated to be about
   as AR + 2xCV).
b
   These averages were not presented in the report, but calculated by the Committee for the comparison with other  70% higher than when phytate intake is low.
   reports.
                                                                                                                   EFSA reports that the range of dietary phytate intake in the few European
                                                                                                                   countries for which English-language data are available varies widely.
Table 96 shows that, in comparison to the average of PRI-values for four
levels of phytates intake presented by EFSA, the RIs in other reports are                                          a
                                                                                                                     Phytate can also decrease the absorption of other minerals, such as iron and calcium.
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EFSA notes that ranges of phytate intakes by adults have been estimated        content of minerals and phytate, solubility of phytates and concentration of
for a mixed diet (300 to 800 mg/day), mixed diets with a high proportion of    enhancers or inhibitors.67,a The Committee notes that phytate intake
unrefined cereal grain products and legumes (700 to 1,400 mg/day), and         cannot be estimated in the Netherlands yet, because phytate is not
vegetarian diets (1,600 to 2,500 mg/day). The wide variation in phytate        included in the Dutch food composition table.
intake can partially be explained by differences in dietary patterns within    Furthermore, EFSA estimates the PRIs for adults as the zinc requirement of
and between countries, and partially by methodological problems                individuals with a body weight at the 97.5th percentile for reference body
associated with phytate intake assessment.                                     weights for men and women, i.e. 79.4 kg for men and 68.1 kg for women.
NCM and DACH acknowledge the differences in bioavailability, but set           EFSA considers that body weight is a strong determinant of the requirement
their reference values based on an average bioavailability value.              for zinc, and therefore, this approach would have less uncertainty than the
WHO sets reference values for three levels of bioavailability (high,           mathematical application of a CV of between 10 and 20%. The Committee
moderate and low).                                                             notes that the concept of a percentile of reference body weights is unclear
                                                                               and not further explained by EFSA; body weights in the adult populations
Differences between older and younger adults                                   differ much more than indicated by this 97.5th percentile.
None of the reports differentiate the ARs and PRI/RI/RDAs between              The Committee considers that the average of EFSA’s values is high
younger and older adults                                                       relative to the reports used for comparison, including the NCM values
                                                                               which are now used in the Netherlands, which is undesirable because of
Sex differences                                                                the narrow margin between the PRI and the upper level (25 g/day).
All reports differentiate the ARs and PRI/RI/RDAs between men and women.       EFSA provides no information on zinc intake levels associated with the
                                                                               occurrence, correction or prevention of deficiencies. Based on these three
28.3 Conclusion on the scientific basis of EFSA’s reference                    arguments, the Committee has objections against the scientific basis of
       values                                                                  EFSA’s reference values.
The Committee considers that EFSA may over-emphasise the role of
phytate intake in zinc absorption, because the inhibitory effect of phytate    a
                                                                                 Schlemmer et al. (2009) conclude that prediction of the bioavailability of minerals from diets just based on the
on mineral bioavailability is dependent of many factors, such as pH,             phytate content in foods is not reliable, as all other factors involved in the phytic acid–mineral interaction have to
                                                                                 be taken into consideration.
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                                                                                                           28.4 Summary and conclusion
  Background information – a summary of the information provided by the EFSA report –
  on the function of the nutrient, the occurrence of clinical deficiency and deficiency
  symptoms
                                                                                                           Table 97. Summary of the evaluation of EFSA’s AR and PRI values for zinc
                                                                                                            Main findings, used for the conclusion
  Zinc has a wide array of vital physiological functions and is ubiquitous within every cell in the         Aspect                    Conclusion Comment
  body. Three general functional classes (structural, regulatory, and catalytic) define zinc’s role in      EFSA’s ARs compared       Higher      EFSA’s ARs are 15-100% higher than HCNL’s (NCM’s) ARs
  biology. There is protection against deficiency by homeostatic mechanisms at both a whole body            to HCNL’s (=NCM’s) AR                 for men and 10-80% higher than HCNL’s (NCM’s) ARs for
  and a tissue level.                                                                                                                             women, dependent on the phytate level considered.
  It is the abundance that is thought to be the reason why it has proved so challenging to link zinc        EFSA’s PRIs compared      Higher      EFSA’s PRIs are 5-80% higher than HCNL’s (NCM’s) RIs for
  deficiency with specific symptoms (infants with acrodermatitis enteropathica are the exception:           to HCNL’s (=NCM’s) RIs                men and women, dependent on the phytate level
  for this group, specific symptoms of severe zinc deficiency have been observed).                                                                considered.
                                                                                                            Scientific basis of       Objections  The Committee considers that EFSA may over-emphasise
  Clinical features of zinc deficiency are non-specific. Mild to moderate dietary zinc depletion is a
                                                                                                            EFSA’s ARs                            the role of phytate intake in zinc absorption. The Committee
  cause of several non-specific features including growth retardation, depressed immune function
                                                                                                                                                  considers that EFSA’s use of the 97.5th percentile of
  with susceptibility to infections, delayed wound healing, loss of appetite and loss of cognitive                                                reference body weights for setting the PRIs, is unclear and
  function. Severe restriction of dietary zinc is a cause of other clinical features including skin                                               not explained by EFSA.
  rashes.                                                                                                   Other findings
  Acute acquired zinc deficiency states have been extensively documented, primarily in patients             Aspect                    Conclusion Comment
  dependent on intravenous nutrition lacking zinc. From the IOM report it can be added that                 Differentiation between   Not applied Consistent with the reports used for comparison.
  individuals with malabsorption syndromes including sprue, Crohn’s disease, and short bowel                younger and older adults by EFSA
  syndrome are at risk of zinc deficiency due to malabsorption of zinc and increased urinary zinc           Differentiation between   Applied by  Consistent with the reports used for comparison.
  losses.                                                                                                   men and women             EFSA
                                                                                                           The Committee recommends maintaining HCNL’s (NCM’s) ARs and RDAs
                                                                                                           (Table 98).
                                                                                                           Table 98. AR and PRI for zinc, recommended for the Netherlands
                                                                                                                                                       Men >18 years                  Women >18 years
                                                                                                            Average requirement (AR)                   6.4 mg/d                       5.7 mg/d
                                                                                                            Population reference intake (PRI)          9 mg/d                         7 mg/d
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29
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29.1 The 2018 reference values for the Netherlands                               • For calcium, the Committee adopts EFSA’s reference values for
As described in the introduction to this background document (paragraph             calcium for adults aged between 18 and 50 years, and for men aged 51
1.1), the point of departure of this evaluation of the Dutch reference values       to 70 years. However, for women aged 51 to 70 year and for adults
was to adopt EFSA’s dietary reference values for use in the Netherlands,            older than 70 years, the Committee maintains the reference values
unless there were major objections against these values. The Committee              which have been used since 2000. In the Netherlands, it is
considered three key questions: (1) Should EFSA’s reference values be               recommended that these groups of older adults use vitamin D
rejected based on a specific nutritional context in the Netherlands that            supplements. A calcium intake higher than EFSA’s PRI is required for
differs from (the rest of) Europe? (2) Do (some of) EFSA’s reference                these vitamin D supplements to be effective in reducing the risk of bone
values differ 10% or more from the 2014 values for the Netherlands? (3)             fractures.
Are there objections against the scientific basis for EFSA’s reference           • For vitamin A, the Committee does adopt EFSA’s method for estimating
value(s) for this nutrient?                                                         the average requirement, but uses the higher Dutch reference weights
                                                                                    instead of EFSA’s reference weights. Therefore, the reference values
For most nutrients, the evaluations in this report resulted in the                  proposed for vitamin A also differ from EFSA’s values. Furthermore, the
recommendation to adopt EFSA’s reference values for use in the                      Committee does not support EFSA’s choice regarding the conversion
Netherlands (Table 99, for more information see Annex C).                           factors for carotenes (EFSA expresses the reference values as retinol
• The Committee adopts EFSA’s reference values for 16 micronutrients:               equivalents), but recommends expressing the reference values as
    thiamin, riboflavin, niacin, pantothenic acid, vitamin E, vitamin K1,           retinol activity equivalents instead.
    biotin, choline, iodine, iron, magnesium, manganese, molybdenum,
    phosphorus, potassium and selenium.                                          The Committee does not adopt EFSA’s values for 8 nutrients:
• Regarding trivalent chromium, the Committee adopts EFSA’s                      • For 7 micronutrients, the Committee maintains the reference values
    conclusion to set no reference value.                                           that have been used in the Netherlands since 2014: vitamin B6, folate,
                                                                                    vitamin B12, vitamin C, vitamin D, copper, and zinc, based on
For two nutrients, the conclusions by EFSA were accepted partially.                 objections against the scientific basis of EFSA’s reference values.
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• For fluoride, the Committee also does not accept EFSA’s reference                             fluoride-containing dental-hygiene products (in adults: toothpaste).
    value. Based on a nutritional context in the Netherlands that differs                       Therefore, the Committee does not consider it appropriate to apply a
    from (the rest of) Europe: in the Netherlands, fluoride intake is not                       dietary reference intake in the Netherlands.
    considered necessary for caries prevention because of the use of
Table 99. Overview of the old and new reference values for the Netherlandsa
 Nutrient                                  The 2018 Dutch reference values                          2018 versus 2014 Dutch values The 2014 Dutch reference values
                                           Reference value                          Origin                                        Reference value                 Origin
 Vitamin A as retinol activity equivalents AR♂                      615 μg RAE/d    This report     Changed                       AR♂               600 μg RAE/d  NCM 2014
 (RAEs)                                    AR♀                      525                                                           AR♀               500
                                           PRI♂                     800                                                           PRI♂              900
                                           PRI♀                     680                                                           PRI♀              700
 Thiamin                                   AR                       0.072 mg/MJ     EFSA 2016       Changed                       AR                0.8 mg/d      HCNL 2000
                                           PRI                      0.1                                                           PRI               1.1
 Riboflavin                                AR                       1.3 mg/d        EFSA 2017       Changed                       AR♂               1.1 mg/d      HCNL 2000
                                           PRI                      1.6                                                           AR♀               0.8
                                                                                                                                  PRI♂              1.5
                                                                                                                                  PRI♀              1.1
 Niacin                                    AR                       1.3 mg/MJ       EFSA 2014       Changed                       AR♂               12 mg/d       HCNL 2000
                                           PRI                      1.6                                                           AR♀               9
                                                                                                                                  PRI♂              17
                                                                                                                                  PRI♀              13
 Pantothenic acid                          AI                       5 mg/d          EFSA 2014       Unchanged                     AI                5 mg/d        HCNL 2000
 Vitamin B6                                19-50 years:                                                                           19-50 years:
                                           AR                       1.1 mg/d        HCNL 2003       Unchanged                     AR                1.1 mg/d      HCNL 2003
                                           PRI                      1.5                                                           PRI               1.5
                                           >50 years:                                                                             >50 years:
                                           AR♂                      1.3 mg/d        HCNL 2003       Unchanged                     AR♂               1.3 mg/d      HCNL 2003
                                           AR♀                      1.1                                                           AR♀               1.1
                                           PRI♂                     1.8                                                           PRI♂              1.8
                                           PRI♀                     1.5                                                           PRI♀              1.5
 Folateb                                   AR                       200 μg/d        HCNL 2003       Unchanged                     AR                200 μg/d      HCNL 2003
                                           PRI                      300                                                           PRI               300
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 Nutrient                           The 2018 Dutch reference values                       2018 versus 2014 Dutch values The 2014 Dutch reference values
                                    Reference value                           Origin                                    Reference value                 Origin
 Vitamin B12 c
                                    AR                       2.0 μg/d         HCNL 2003   Unchanged                     AR                 2.0 μg/d     HCNL 2003
                                    PRI                      2.8                                                        PRI                2.8
 Vitamin C                          AR♂                      60 mg/d          NCM 2014    Unchanged                     AR♂                60 mg/d      NCM 2014
                                    AR♀                      50                                                         AR♀                50
                                    PRI                      75 (♂&♀)                                                   PRI                75 (♂&♀)
 Vitamin Dd                         18-69 years: e                                                                      18-69 years:
                                    AI                       10 μg/d          HCNL 2012   Unchanged                     AI                 10 μg/d      HCNL 2012
                                    >70 years:f                                                                         >70 years:
                                    AR                       10 μg/d          HCNL 2012   Unchanged                     AR                 10 μg/d      HCNL 2012
                                    PRI                      20                                                         PRI                20
 Vitamin E as α-tocopherol          AI♂                      13 mg/d          EFSA 2015   Changed                       AR♂                6 mg/d       NCM 2014
                                    AI♀                      11                                                         AR♀                5
                                                                                                                        PRI♂               10
                                                                                                                        PRI♀               8
 Vitamin K1 (phylloquinone)         AI                       70 μg/d          EFSA 2017   Unchanged                     AI                 70 μg/d      EFSA 2017
 Biotin                             AI                       40 μg/d          EFSA 2014   Unchanged                     AI                 40 μg/d      EFSA 2014
 Choline                            AI                       400 mg/d         EFSA 2016   Changed                       No reference value
 Calcium                            18-24 years:                                                                        19-49 years (♂&♀):
                                    AR                       860 mg/d         EFSA 2015   Changed                       AI                 1,000 mg/d   HCNL 2000
                                    PRI                      1,000
                                    25-49 years (♂&♀) and men 50-69 years:
                                    AR                       750 mg/d         EFSA 2015   Changed
                                    PRI                      950
                                    Women 50-69 years:                                                                  50-69 years (♂&♀):
                                    AI                       1,100 mg/d       HCNL 2000   Unchanged                     AI                 1,100 mg/d   HCNL 2000
                                    >70 years (♂&♀):                                                                    >70 years (♂&♀) :
                                    AI                       1,200 mg/d       HCNL 2000   Unchanged                     AI                 1,200 mg/d   HCNL 2000
 Chromium III                       No reference value                        EFSA 2014   Unchanged                     No reference value
 Copper                             AR                       0.7 mg/d         NCM 2014    Unchanged                     AR                 0.7 mg/d     NCM 2014
                                    PRI                      0.9                                                        PRI                0.9
 Fluoride                           No reference value                        This report Changed                       AI♂                3.4 mg/d     EFSA 2013
                                                                                                                        AI♀                2.9
 Iodine                             AI                       150 μg/d         EFSA 2014   Changed                       PRI                150 μg/d     NCM 2014
                                                                                                                        AR                 100
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  Nutrient                                              The 2018 Dutch reference values                                             2018 versus 2014 Dutch values The 2014 Dutch reference values
                                                        Reference value                                          Origin                                                      Reference value                              Origin
  Iron                                                  Men                                                                                                                  Men
                                                        AR                           6 mg/d                     EFSA 2015           Changed                                  AR                    7 mg/d                 NCM 2014
                                                        PRI                          11                                                                                      PRI                   9
                                                        Women premenopause                                                                                                   Women premenopause
                                                        AR                           7 mg/d                     EFSA 2015           Changed                                  AR                    9 (10?g) mg/d          NCM 2014
                                                        PRI                          16                                                                                      PRI                   15
                                                        Women postmenopause                                                                                                  Women postmenopause
                                                        AR                           6 mg/d                     EFSA 2015           Unchanged                                AR                    6 mg/d                 NCM 2014
                                                        PRI                          11                                             Changed                                  PRI                   9 (8?a)
  Magnesium                                             AI♂                          350 mg/d                   EFSA 2015           Changed                                  AI♂                   350 mg/d               NCM 2014
                                                        AI♀                          300                                                                                     AI♀                   280
  Manganese                                             AI                           3.0 mg/d                   EFSA 2013           Unchanged                                AI                    3.0 mg/d               EFSA 2013
  Molybdenum                                            AI                           65 μg/d                    EFSA 2013           Unchanged                                AI                    65 μg/d                EFSA 2013
  Phosphorus                                            AI                           550 mg/d                   EFSA 2015           Changed                                  AR                    450 mg/d               NCM 2014
                                                                                                                                                                             PRI                   600
  Potassium                                             AI                           3.5 g/d                    EFSA 2016           Changed                                  AI♂                   3.5 g/d                NCM 2014
                                                                                                                                                                             AI♀                   3.1
  Selenium                                              AI                           70 μg/d                    EFSA 2014           Changed                                  AR♂                   35 μg/d                NCM 2014
                                                                                                                                                                             AR♀                   30
                                                                                                                                                                             PRI♂                  60
                                                                                                                                                                             PRI♀                  50
  Zinc                                                  AR♂                          6.4 mg/d                   NCM 2014            Unchanged                                AR♂                   6.4 mg/d               NCM 2014
                                                        AR♀                          5.7                                                                                     AR♀                   5.7
                                                        PRI♂                         9                                                                                       PRI♂                  9
                                                        PRI♀                         7                                                                                       PRI♀                  7
a
    All abbreviations in the table are explained in the glossary (Annex B).
b
    Note that women who wish to conceive are advised to use a supplement containing 400 μg/d of folic acid, starting at least four weeks prior to conception until the eighth week of pregnancy, in addition to these reference values.
c
    In the Netherland, it is recommended that adults on a vegan diet use supplemental vitamin B12 to achieve an adequate supply of this vitamin.53
d
    In most people, vitamin D supply is met partly by cutaneous vitamin D synthesis and partly by dietary intake. The reference values for vitamin D intake refer to conditions of minimal cutaneous vitamin D synthesis.34
e
    In the Netherlands, it is recommended that adults with dark skin or who do not spend enough time outdoors, women who wear a veil, and all women aged 50-70 years use a daily supplement with 10 μg vitamin D to ensure an
    adequate vitamin D supply.34
f
    In the Netherlands, it is recommended that adults over 70 years use a daily supplement with 20 μg vitamin D to ensure an adequate vitamin D supply.34
g
    For iron, NCM’s AR for premenopausal women and NCM’s RI for postmenopausal women are not clear. This is described in footnotes in paragraph 21.2, where the differences between the ARs for premenopausal women and the PRIs
    for postmenopausal women are explained.
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29.2 Scientific basis for the 2018 Dutch reference values                          Table 100. Scientific basis of the 2018 Dutch reference values for specific nutrientsa
                                                                                     Nutrient            Biomarker                 Factorial method          Intervention        Intake data
The scientific basis for the different reference values varies (Table 100).                                                        or balance data           studies
For some nutrients, the reference values are based on the intake required                                Status      Function      Stores      Losses        (clinical effect)   Midpoint    Lower end
                                                                                     Thiamin            +            +             -           -             -                   -           -
to achieve a certain cut-off value for a biomarker of status or function.            Riboflavin         +            +             -           -             -                   -           -
Other reference values are based on a factorial method in which the                  Niacin             +            -             -           -             -                   -           -
                                                                                     Vitamin B6         +            -             -           -             -                   -           -
estimated averages for specific underlying aspects (‘factors’) are                   Folate             +            -             -           -             -                   -           -
                                                                                     Vitamin C          +            -             -           -             -                   -           -
combined to calculate the reference value; the estimates for the factors
                                                                                     Vitamin D,         +            -             -           -             -                   -           -
generally originate from different studies. A third approach is the balance          younger adults
                                                                                     Vitamin K1         -            +             -           -             -                   -           -
method, which follows a similar line of reasoning as the factorial method;
                                                                                     Copper             +            +             -           -             -                   -           -
these studies often use isotopes and produce estimates at the level of the           Iodine             +            -             -           -             -                   -           -
                                                                                     Selenium           +            -             -           -             -                   -           -
individual. As a fourth approach, reference values can be based on the               Vitamin A          -            -             +           -             -                   -           -
clinical effects of different intake levels in intervention studies. For some        Vitamin B12        -            -             +           -             -                   -           -
                                                                                     Calcium,           -            -             -           +             -                   -           -
nutrients none of these four methods are available or can be used to                 younger adults
                                                                                     Iron               -            -             -           +             -                   -           -
establish the reference value. In such cases, the reference values are
                                                                                     Zinc               -            -             -           +             -                   -           -
based on intake data alone, often based on intake levels of healthy                  Vitamin D,         -            -             -           -             + fracture risk     -           -
                                                                                     older adults
individuals on normal diets with no signs of deficiency.                             Calcium, older -                -             -           -             + fracture risk     -           -
                                                                                     adults
                                                                                     Potassium          -            -             -           -             + blood             -           -
Biomarkers of status or function                                                                                                                             pressure, stroke
                                                                                     Pantothenic        -            -             -           -             -                   +           -
The type of data that is predominantly used as the basis for the reference           acid
values, especially for vitamins, are biomarkers of status or function, or both.      Vitamin E          -            -             -           -             -                   +           -
                                                                                     Biotin             -            -             -           -             -                   +           -
Reference values for 11 micronutrients are based on this type of data.               Choline            -            -             -           -             (+ depletion &      +           -
                                                                                                                                                             repletion)
                                                                                     Magnesium          -            -             -           -             -                   +           -
                                                                                     Manganese          -            -             -           (+)           -                   +           -
                                                                                     Molybdenum         -            -             -           (+)           -                   -           +
                                                                                   a
                                                                                       The primary criteria are indicated in bold, supportive criteria in italics and between brackets.
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<pre>chapter 29 | Summary                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 160 of 179
A factorial method or balance data                                               population reference intakes (PRIs) and adequate intakes (AIs) can be
The reference values for 5 nutrients are based on a factorial method or          applied. There are differences in application possibilities between nutrients
balance data. The method appears to aim at a different goal when it is           for which an AR and PRI is established, compared to those with an AI. This
applied to vitamins compared to when it is applied to minerals. For the two      information is not repeated here, but Table 101 summarises which type of
vitamins for which this method was used, the method assesses the intake          reference value is available in the 2018 Dutch reference values, and whether
needed to maintain body stores associated with prevention of deficiency.         this implies a change compared to the 2014 guidelines.
For the three minerals, the method assesses the intake needed to replace
                                                                                 Table 101. Type of reference value in 2018 and 2014
daily losses of the nutrient from the body.                                                                       2014 Dutch reference value type
                                                                                                                  AR & PRI                             AI
                                                                                                                  vitamin A
Intervention studies relating intake to clinical effects                                                          thiamin
                                                                                                                  riboflavin
The reference values for three micronutrients are based on intervention
                                                                                                                  niacin
studies relating intake to clinical effects.                                                                      vitamin B6
                                                                                                        AR &      folate                               calcium ♂& ♀ 18-49 yr and ♂ 50-69 yr
                                                                                                        PRI       vitamin B12
                                                                                                                  vitamin C
Intake data                                                                                                       vitamin D ♂& ♀ >70 years
The reference values for most of the remaining nutrients are based on              2018 Dutch                     copper
                                                                                   reference value                iron
intake data, which is the case for 4 vitamins and 3 minerals. For two              type                           zinc
                                                                                                                                                       pantothenic acid
minerals, EFSA used intake data in combination with the available                                                                                      vitamin D ♂& ♀ 18-69 yr
                                                                                                                                                       vitamin K1
information from balance studies.
                                                                                                                  vitamin E                            biotin
                                                                                                        AIa       iodine                               calcium ♀ 50-69 yr and ♂& ♀ >70 yr
                                                                                                                  phosphorus                           magnesium
29.3 The type of reference value                                                                                  selenium                             manganese
                                                                                                                                                       molybdenum
This report is the background document for the advisory report on the 2018                                                                             potassium
micronutrient dietary reference values for Dutch adults.4 In the advisory         a
                                                                                    The 2018 Dutch reference value for choline is an AI as well, but choline was not part of the 2014 Dutch reference
                                                                                    values.
report, the Committee summarises how the average requirements (ARs),
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<pre>chapter 29 | Summary                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 161 of 179
Average requirements (ARs) and population reference intakes (PRIs)                29.4 Differentiation between subgroups of adults
In the 2018 Dutch reference values, ARs and PRIs are available for 8              The evaluations per nutrient in Chapters 2-28 of this background report
vitamins (vitamin A, thiamin, riboflavin, niacin, vitamin B6, folate, vitamin     include a description of whether or not reference values differ between
B12, vitamin C) and, for the subgroup of older adults (>70 years), also for       subgroups of adults: (men versus women; younger versus older age
vitamin D.                                                                        groups), and information on the argumentation for these choices, if
This type of reference values (ARs and PRIs) is available for 3 minerals          available from the reports. The Committee concludes that a scientific
(copper, iron, zinc) and, for the subgroup of younger adults and middle-          basis for either differentiating between subgroups or not, is not available
aged men, also for calcium.                                                       for many nutrients, but is available more frequently for the differentiation
This implies a change from AI values to AR and PRI values for calcium only.       between men and women, than for the differentiation between age
                                                                                  groups.
Adequate intakes (AIs)
The 2018 Dutch reference values, comprise AIs for 5 vitamins                      Differentiation of the reference values between men and women
(pantothenic acid, vitamin E, vitamin K1, biotin, choline) and, for the           The 2018 reference values differ between men and women for 8 nutrients:
subgroup of younger adults (18-69 years), also for vitamin D.                     vitamin A, vitamin B6 for adults aged >50 years, vitamin C, vitamin E,
This type of reference values (AIs) are available for 7 minerals (iodine,         calcium for adults aged 50-69 years, iron for younger adults, magnesium
magnesium, manganese, molybdenum, phosphorus, potassium,                          and zinc. The arguments for differentiating between men and women are
selenium) and, for the subgroup of older adults and middle-aged women,            listed in Table 102.
also for calcium.                                                                 The reference values for thiamin and niacin are expressed in grams per
This implies a change from AR and PRI values to AI values for vitamin E,          megajoule, without differentiation between men and women. However, this
iodine, phosphorus and selenium.                                                  implies that the values in milligrams per day – on average – are higher for
                                                                                  men than for women, based on the differences in energy intake.
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<pre>chapter 29 | Summary                                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 162 of 179
Table 102. Differentiation of reference values between adult men and women                                pantothenic acid, vitamin B12, vitamin K1, biotin, choline, manganese,
  Nutrient           Argument for differentiation between men and women                         Origin
                                                                                                          molybdenum, phosphorus and selenium.
  Vitamin A          Requirements are assumed to be proportional with the reference body        EFSA &
                     weight, which is higher in men than in women.                              IOM       The Committee notes that the reference values for five of these are based
  Vitamin B68        In the age group >50 yr, the reference values for men are higher than for  HCNL
                     women, based on the available evidence on each group.                                on intake data, which seems to be inconsistent with magnesium and
  Vitamin C          The AR is higher for men than for women, because in men the adequate       NCM       vitamin E (Table 100). However, the intake data for pantothenic acid,
                     biomarker level (plasma ascorbate >32 μmol/L) requires a higher vitamin C
                     intake than in women. The PRI is equal for men and women, because of                 biotin, choline, manganese and molybdenum have larger uncertainties
                     the higher PRI for iron in premenopausal women (vitamin C improves iron
                     absorption).                                                                         than those for magnesium and vitamin E. Pantothenic acid, biotin, choline,
  Vitamin E          Vitamin E intake is higher in men than in women.                           EFSA      manganese and molybdenum are not included in the Dutch Food
  Calciuma           In this age group 51-70 yr, it is recommended that women (but not men)     HCNL
                     use supplemental vitamin D, and in order for this vitamin D supplement to            Composition Database, contrary to vitamin E and magnesium. Iodine
                     be effective, their calcium requirement is higher than in men of this age
                     group.                                                                               intake is preferably estimated from the urinary excretion over a 24-hour
  Irona              Estimated iron losses are higher in premenopausal women than in men        EFSA      period, and therefore the availability of valid intake data is limited
                     (whereas iron losses in postmenopausal women are assumed to be equal
                     to those in men).                                                                    compared to other nutrients. The larger uncertainties explain why a
  Magnesium          Magnesium intake is higher in men than in women.                           EFSA
  Zinc               Estimated zinc losses are higher in men than in women.                     NCM
                                                                                                          different choice is made for these five nutrients.
    Differentiation between the reference values for men and women only in subgroups of adults.           The reference values for vitamin K1 and phosphorus also have substantial
a
For most nutrients, the 2018 reference values are equal for men and                                       uncertainty. Note that the vitamin K1 requirement is assumed to be
women. In eight nutrients this has a scientific basis: the available                                      proportional to body weight, but still, EFSA does not differentiate between
estimates for men (almost) equal the available estimates for women, or                                    men and women because of these uncertainties. For iodine and selenium,
the male versus female sex did not significantly contribute to the variation                              there are no data or insufficient data for men and women separately.
in requirements between individuals. This applies to riboflavin, vitamin B6
(younger adults), folate, vitamin B12, vitamin D, calcium, iodine, copper                                 Differentiation of the reference values between adult age groups
and potassium, and to vitamin B6 (age groups 18-50 years), and calcium                                    For four nutrients, the reference values differ between age groups: vitamin
(age groups 18-49 and >70 years).                                                                         B6, vitamin D, calcium and iron. The arguments for differentiating between
However, for nine nutrients, no scientific evidence is presented for                                      age groups, are listed in Table 103.
applying the same reference value to men and women. This applies to
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<pre>chapter 29 | Summary                                                     An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 163 of 179
The reference values for thiamin and niacin are expressed in grams per            Table 103. Differentiation of reference values between age groups
                                                                                   Nutrient    Argument for differentiation between men and women                            Origin
megajoule, without differentiation between age groups. However, this implies
                                                                                   Vitamin B6  The available research indicates that the requirement is higher for older     HCNL
that the values in milligrams per day – on average – are higher for younger                    versus younger men.
                                                                                   Vitamin D   Evidence from randomised controlled trials in older adults indicated that the HCNL
adults than for older adults, based on the differences in energy intake.                       use of supplements with 10 to 20 μg/d of vitamin D in combination with
                                                                                               calcium may reduce the risk of bone fractures.
For riboflavin, vitamin B6 (women) and folate, the report from which the 2018
                                                                                   Calcium     In the Netherlands, it is recommended that older women (>50 years) and        HCNL
Dutch reference value is adopted, explicitly notes that there are no                           older men (>70 years) use vitamin D supplements. A higher calcium intake
                                                                                               is required in order for the extra vitamin D to be effective in reducing the
indications that the requirements are influenced by age. (Note that the                        risk of fractures.
reference values refer to the healthy population, so that, e.g. for vitamin B12,   Iron        Iron losses are higher in premenopausal women than in postmenopausal          EFSA
                                                                                               women because of menses.
they do not apply to older people with vitamin B12 absorption problems).
For 16 nutrients, the requirement of older versus younger adults is not
addressed in the report from which the 2018 Dutch reference value is
adopted. This applies to: vitamin A, pantothenic acid, vitamin C, vitamin E,
biotin, choline, copper, iodine, iron (men), magnesium, manganese,
molybdenum, phosphorus, potassium, selenium, and zinc.
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<pre>References                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 164 of 179
references
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<pre>References                                                           An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 165 of 179
1
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                                                                                 European Food Safety Authority. Scientific opinion on dietary reference
   8(3): 1458.                                                                   values for choline. EFSA journal 2016; 14(8): 4484.
2
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   and carotenoids. 2000.                                                     14
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3
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4
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   Netherlands, 2018; publication no. 2018/19.                                16
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5
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6
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   values for vitamin K. EFSA journal 2017; 15(5): 4780.                      18
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7
   European Food Safety Authority. Scientific opinion on dietary reference       values for iron. EFSA journal 2015; 13(10): 4254.
   values for riboflavin. EFSA journal 2017; 15(8): 4919.                     19
                                                                                 European Food Safety Authority. Scientific opinion on dietary reference
8
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   values for vitamin D. EFSA journal 2016; 14(10): 4547.                     20
                                                                                 European Food Safety Authority. Scientific opinion on dietary reference
9
   European Food Safety Authority. Scientific opinion on dietary reference       values for magnesium. EFSA Journal 2015; 13(7): 4186.
   values for thiamin. EFSA journal 2016; 14(12): 4653.                       21
                                                                                 European Food Safety Authority. Scientific opinion on dietary reference
10
   European Food Safety Authority. Scientific opinion on dietary reference       values for zinc. EFSA journal 2014; 12(10): 3844.
   values for vitamin B6. EFSA journal 2016; 14(6): 4485.                     22
                                                                                 European Food Safety Authority. Scientific opinion on dietary reference
11
   European Food Safety Authority. Scientific opinion on dietary reference       values for selenium. EFSA journal 2014; 12(10): 3846.
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24
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25
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26
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27
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30
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   https://www gezondheidsraad nl/nl/nieuws/tijdelijke-voedingsnormen.          boron, chromium, copper, iodine, iron, manganese, molybdenum,
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<pre>Annexes                                               Titel advies | page 169 of 179
annexes
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<pre>Annexes                                                                                             An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 170 of 179
A          types of reference values and                                                                     • Both PRIs and AIs describe the levels of intake which are sufficient for
           their definitions                                                                                    almost all the individuals in the population group considered.
                                                                                                             A PRI is established only if an AR is available. The PRI is calculated as
                                                                                                             the AR plus twice the assessed or assumed standard deviation of the
  EFSA defines the reference values as follows :       1
                                                                                                             requirements of individuals. When an AR cannot be established, the PRI
  •    Average Requirement (AR):                                                                             cannot be calculated, and an AI is established instead. The AI is the intake
       the level of (nutrient) intake that is adequate for half of the people in a population group,
       given a normal distribution of requirement.
                                                                                                             level associated with adequate (markers of) health in (almost) all
  •    Population Reference Intakes (PRI):                                                                   individuals.
       the level of (nutrient) intake that is adequate for virtually all people in a population group.
  •    Adequate Intake (AI):
                                                                                                             Note that the reports use different names for these three types of
       the value estimated when a Population Reference Intake cannot be established because an               reference values, see Table 104. The Committee adopted EFSA’s
       average requirement cannot be determined. An Adequate Intake is the average observed
       daily level of intake by a population group (or groups) of apparently healthy people that is
                                                                                                             terminology.
       assumed to be adequate.                                                                               • ULs describe the highest intake levels which are considered to be safe;
  Note that the tolerable upper intake levels are not evaluated in this background document, but
  will be described and evaluated in a separate report. EFSA defined the tolerable upper intake
                                                                                                                at intakes higher than the UL, the risk of undesirable effects of
  level as follows3:                                                                                            overconsumption increases. The ULs are not evaluated in this report.
  •    Tolerable upper intake level (UL)
       The maximum level of total chronic daily intake of a nutrient (from all sources) judged to be
       unlikely to pose a risk of adverse health effects to humans.                                          Figure 1 illustrates these reference values. It shows that AR- and
                                                                                                             PRI-values both correspond to a specific point in the distribution of
This background document evaluates the average requirements (ARs),                                           individual requirements: they are considered to represent the intake level
population reference intakes (PRIs), and adequate intakes (AIs) for                                          sufficient for 50% and 97.5% of the population group, respectively. If an AI
micronutrients for adults.                                                                                   is established, there is some uncertainty – by definition – regarding the
• The AR describes the level of intake which is required by half of the                                      place of this intake level on the distribution of individual requirements. This
  subjects in the population group.                                                                          also applies to the UL.
The AR is the average value of the assessed requirements of individuals.
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                                                       Population                                                                           Table 104. Terms used for the reference values in the six (sets of) reports
                                           Average     reference
                                         requirement     intake                                                                             European Food           Dietary          Average          Population                Adequate
                   100%                                                                                100%
                                                                                                                                            Safety Authority        Reference Values Requirement (AR) Reference Intake          Intake (AI)
                                                                                                                                            (EFSA)                                                    (PRI)
Risk that intake is too low                                                                                  Risk that intake is too high
                                                                                                                                            Health Council of the Dietary Reference       Estimated Average   Recommended       Adequate Intake
                                                            Adequate                      Tolerable                                         Netherlands (HCNL) Intakes                    Requirement         Daily Allowance   (AI)
                              50%                            intake                      upper level   50%                                                        (in Dutch:              (EAR)               (RDA)
                                                                                                                                                                  voedingsnormen)         (in Dutch:          (in Dutch:        (In Dutch:
                                                                                                                                                                                          gemiddelde          aanbevolen        adequate
                                                                                                                                                                                          behoefte)           hoeveelheid)      inname)
                                                                                                                                            Nordic Council of       Dietary Reference     Average             Recommended       Recommended
                                                                       Nutrient intake
                                                                                                                                            Ministers (NCM)         Values                Requirement (AR)    Intake (RI)       Intake (RI)
                                                                                                                                            Germany, Austria        Reference values      Average             Recommended       Estimated value
                                                                                                                                            and Switzerland         for nutrient intake   Requirement         Intake            for nutrient
                                                                                                                                            (DACH)                                                                              intake
Figure 1. Types of dietary reference values in relation to the intake of the nutrient
                                                                                                                                            Institute of Medicine   Dietary Reference     Estimated Average Recommended         Adequate Intake
(x-axis) and the risk that intake is to low or too high (left and right y-axis, respectively)                                               (IOM)                   Intakes               Requirement       Daily Allowance     (AI)
                                                                                                                                                                                          (EAR)             (RDA)
                                                                                                                                            World Health            -                     Estimated Average Recommended         Recommended
                                                                                                                                            Organization (WHO)                            Requirement       Nutrient Intake     Nutrient Intake
                                                                                                                                            / Food and Agri-                              (EAR)             (RNI)               (RNI)
                                                                                                                                            cultural Organization
                                                                                                                                            (FAO)
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<pre>Annexes                                                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 172 of 179
B         list of abbreviations
Abbreviation    Meaning                                        Short explanation (of relevance), mainly based on the EFSA reports on dietary reference values
AI              Adequate Intake                                The AI is the level of (nutrient) intake that is adequate for virtually all in an apparently healthy people in a population group; the AI is
                                                               established when the AR (and thus the PRI/RDA) cannot be determined.
ALT             Alanine aminotransferase                       ALT is an enzyme found mostly in liver and kidney cells. ALT is released into the blood when the liver is damaged.
AR              Average Requirement                            The AI is the level of (nutrient) intake that is adequate for half of the people in an apparently healthy population group, given a normal
                                                               distribution of requirement.
BMR             Basal Metabolic Rate                           BMR is the energy expenditure in a both physically and psychologically undisturbed state (but not asleep), post-absorptive, in a thermally
                                                               neutral environment.
CV              Coefficient of Variation                       In this report, CV is generally used as the coefficient of variation of the nutrient requirement, expressed as a percentage. If the nutrient
                                                               requirement is normally distributed, the PRI/RDA/RI is calculated as (1 + [2xCV/100]) times the average requirement.
DACH            Deutschland (Germany), Austria, and            DACH (or D-A-CH) are the German-speaking countries which establish dietary reference values together.
                Confoederatio Helvetica (Switzerland)
DRV / DRI       Dietary Reference Value                        A DRV / DRI is a quantitative reference value (such as AR, PRI, AI, UL) for nutrient intakes for healthy individuals and populations which
                / Dietary Reference Intake                     may be used for assessment and planning of diets.
EAR             Estimated Average Requirement                  The EAR is IOM’s and HCNL’s reference value equivalent to EFSA’s AR.
EGRAC           Erythrocyte Glutathione Reductase Activation   EGRAC is the ratio of the activity of Erythrocyte Glutathione Reductase, measured in-vitro with, and without, addition of the cofactor flavin
                Coefficient                                    adenine dinucleotide (FAD).
EFSA            European Food Safety Authority                 EFSA is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging
                                                               risks associated with the food chain, including the establishment of dietary reference values.
ETKA            Erythrocyte TransKetolase Activity             ETKA is a functional marker of thiamin status. It represents the basal value of the enzyme erythrocyte transketolase, without stimulation by
                                                               thiamin diphosphate (TDP).
αETK            Erythrocyte TransKetolase Activity Coefficient αETK is a functional marker of thiamin status. It represents the degree to which ETKA rises in response to addition of thiamin diphosphate
                                                               (TDP). αETK can discriminate low ETKA due to thiamin deficiency from low ETKA due to a lack of the apoenzyme. A value of αETK < 1.15
                                                               is generally considered to reflect an adequate thiamin status.
GPx             Glutathione Peroxidase                         GPx activity is a biomarker of selenium function.
HCNL            Health Council of the Netherlands              HCNL is an independent Dutch scientific advisory body with the task of advising the government and parliament about matters in the areas
                                                               of public health and medical research, including dietary reference intakes.
HoloTC          Holotranscobalamin                             Serum holoTC is the physiologically active form of cobalamin that delivers the vitamin to cells. It is considered an earlier biomarker for
                                                               changes in cobalamin status than serum cobalamin concentration. EFSA notes that lower limits of reference intervals for serum holoTC
                                                               range between 11 and 48 pmol/L in adults, depending on the reference population used.
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Abbreviation     Meaning                                       Short explanation (of relevance), mainly based on the EFSA reports on dietary reference values
IOM              Institute of Medicine                         IOM is the institute which established the DRIs for the USA and Canada. IOM is the former name of the Health and Medical Devision
                                                               programme of the National Academy of Medicine (NAM). The NAM is the American nonprofit, non-governmental organisation, which
                                                               provides national advice on issues relating to biomedical science, medicine, and health, and serves as an adviser to the nation to improve
                                                               health. The NAM is a part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Sciences
                                                               (NAS), National Academy of Engineering (NAE), and the National Research Council (NRC).
MCV              Mean Corpuscular Volume of erythrocytes       MCV is a measure of the average volume of a red blood cell, attained by multiplying a volume of blood by the proportion of blood that is
                                                               cellular (the hematocrit), and dividing that product by the number of erythrocytes (red blood cells) in that volume.
NCM              Nordic Council of Ministers                   NCM is a geo-political inter-parliamentary forum for co-operation between the Nordic countries Denmark, Finland, Iceland, Norway and
                                                               Sweden as well as the autonomous areas of the Faroe Islands, Greenland and the Åland Islands. NCM develops the Nordic Nutrition
                                                               Recommendations (NNR).
NMN              N-methylnicotinamide                          The excretion of niacin metabolites is mainly as NMN and 2-Pyr. NMN is formed by methylation of niacin in the liver.
NE               Niacin Equivalent                             1 mg NE = 1 mg niacin (nicotinic acid and nicotinamide) = 60 mg tryptophan.
25(OH)D          25-hydroxyvitamin D                           Serum 25(OH)D concentration is used as a biomarker of vitamin D status in adult and children populations. It reflects the amount of vitamin
                                                               D attained from both cutaneous synthesis and dietary sources.
Pi               Inorganic phosphorus                          Serum inorganic phosphorus is the most commonly used indicator of phosphorus status.
P50, P97.5       50th and 97.5th percentiles of a distribution A percentile (or a centile) is a measure used in statistics indicating the value below which a given percentage of observations in a group of
                                                               observations fall. The dietary reference values AR and PRI/RDA are set respectively at the P50 and P97.5 of the distribution of
                                                               requirements.
PAL              Physical Activity Level                       The PAL is a person’s energy expenditure over a 24-hour period, divided by his or her basal metabolic rate (BMR).
PLP              Pyridoxal 5’-Phosphate                        PLP is one of the six substances with vitamin B6 activity present in food. PLP and pyridoxamine 5’-phosphate (PMP) are metabolically
                                                               active (the other four substances with vitamin B6 activity are converted in the body into PLP or PMP). Plasma PLP is considered to be the
                                                               most suitable biomarker for deriving reference values for vitamin B6, because it reflects the tissue stores (biomarker of status) and has a
                                                               defined cut-off value for an adequate vitamin B6 status.
PRI              Population Reference Intake                   The PRI is EFSA’s reference value for the level of (nutrient) intake that is adequate for virtually all apparently healthy people in a population
                                                               group, on condition that this value is established based on the average requirement (AR).
PUFA             Poly-Unsaturated Fatty Acids                  PUFA are fatty acids with at least two double bonds in their chemical structure.
2-Pyr            N-methyl-2-pyridone-5-carboxamide             The excretion of niacin metabolites is mainly as NMN and 2-Pyr. 2-Pyr is formed by oxidation of NMN.
                                                               (2-Pyr) and N-methyl-4-pyridone-carboxamide (4-Pyr).
RE / RAE         Retinol Equivalent                            The biological value of substances with vitamin A activity is expressed RE or RAE. The conversion factors for the conversion of carotenes
                 / Retinol Activity Equivalent                 to vitamin A (retinol) differ between RE and RAE. EFSA uses RE, with 1 μg RE equalling 1 μg of retinol, 6 μg of β-carotene and 12 μg of
                                                               other provitamin A carotenoids. IOM, NCM and DACH use RAE, with 1 μg RAE equalling 1 μg of retinol, 12 μg of β-carotene and 24 μg of
                                                               other provitamin A carotenoids.
RDA              Recommended Daily Allowance                   The RDA is IOM’s and HCNL’s reference value equivalent to EFSA’s PRI.
RI               Recommended Intake                            The RI is NCM’s, DACH’s and WHO/FAO’s reference value equivalent to EFSA’s PRI.
RIVM             Rijksinstituut voor Volksgezondheid en Milieu RIVM is the Dutch National Institute for Public Health and the Environment.
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<pre>Annexes                                                                      An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 174 of 179
Abbreviation    Meaning                              Short explanation (of relevance), mainly based on the EFSA reports on dietary reference values
SEPP1           Selenoprotein P                      SEPP1 is considered the most informative biomarker of selenium function on the basis of its role in selenium transport and metabolism and
                                                     its response to different forms of selenium intake. Intervention studies using different levels of selenium intake showed that plasma SEPP1
                                                     concentration levels off in response to increasing doses of selenium. The levelling off of plasma SEPP1 was considered to be indicative of
                                                     an adequate supply of selenium to all tissues and to reflect saturation of the functional selenium body pool, ensuring that selenium
                                                     requirement is met.
tHcy            Total homocysteine                   Plasma tHcy is a marker of cobalamin status. Plasma tHcy is not a specific marker, because it is also affected by other dietary factors (e.g.
                                                     selected B vitamins, choline and betaine), as well as renal insufficiency and some lifestyle factors.
SOD             SuperOxide Dismutase                 Erythrocyte SOD activity is used by IOM as a biomarker of copper status. EFSA considers that erythrocyte SOD is not a suitable biomarker
                                                     of copper status.
α-TE            alpha-Tocopherol Equivalent          α-TE is a generic term for compounds with vitamin E activity: α-, β-, γ- and δ-tocopherols and α-, β-, γ- and δ-tocotrienols.
UL              tolerable Upper intake Level         The UL is the maximum level of total chronic daily intake of a nutrient (from all sources) judged to be unlikely to pose a risk of adverse
                                                     health effects to humans.
WHO/FAO         World Health Organisation / Food and WHO and FAO are specialised agencies of the United Nations. WHO is specialised in international public health; FAO in food and
                Agriculture Organisation             agriculture.
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<pre>Annexes                                                                                                 An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 175 of 179
C overview of the 2018 and 2014 reference values for the Netherlandsa
  Nutrient          The 2018 Dutch reference values                                                                   2018 versus The 2014 Dutch reference values
                    Reference values                   Origin         Type of data on which the values are based      2014        Reference values         Origin    Type of data on which the values are
                                                                                                                                                                     based
 Vitamin A          AR♂             615 μg RAE/d       This report    EFSA’s factorial method estima-ting the intake  Changed     AR♂        600 μg RAE/d  NCM 2014  Factorial approach as IOM 1998
                    AR♀             525                               needed to maintain body stores associated with              AR♀        500
                    PRI♂            800                               absence of deficiency, but using HCNL’s                     PRI♂       900
                    PRI♀            680                               reference weights                                           PRI♀       700
 Thiamin            AR              0.072 mg/MJ        EFSA 2016      Biomarkers of status (urinary excretion) and    Changed     AR         0.8 mg/d      HCNL 2000 Biomarkers of status (urinary excretion)
                    PRI             0.1                               function (αETK, ETKA)                                       PRI        1.1                     and function (αETK, ETKA)
 Riboflavin         AR              1.3 mg/d           EFSA 2017      Biomarkers of status (intake at which urinary   Changed     AR♂        1.1 mg/d      HCNL 2000 Biomarkers of status (intake at which
                    PRI             1.6                               excretion sharply increases) and function                   AR♀        0.8                     urinary excretion sharply increases) and
                                                                      (EGRAC)                                                     PRI♂       1.5                     function (EGRAC)
                                                                                                                                  PRI♀       1.1
 Niacin             AR              1.3 mg/MJ          EFSA 2014      Biomarkers of status (urinary excretion of      Changed     AR♂        12 mg/d       HCNL 2000 Biomarkers of status (urinary excretion of
                    PRI             1.6                               metabolite)                                                 AR♀        9                       metabolite)
                                                                                                                                  PRI♂       17
                                                                                                                                  PRI♀       13
 Pantothenic        AI              5 mg/d             EFSA 2014      Midpoint of observed median / mean intakes in   Unchanged   AI         5 mg/d        HCNL 2000 Habitual population intakes
 acid                                                                 Europe
 Vitamin B6         19-50 years:                                                                                                  19-50 years:
                    AR              1.1 mg/d           HCNL 2003      Biomarker of status (plasma PLP)                Unchanged   AR         1.1 mg/d      HCNL 2003 Biomarker of status (plasma PLP)
                    PRI             1.5                                                                                           PRI        1.5
                    >50 years:                                                                                                    >50 years:
                    AR♂             1.3 mg/d           HCNL 2003                                                      Unchanged   AR♂        1.3 mg/d      HCNL 2003
                    AR♀             1.1                                                                                           AR♀        1.1
                    PRI♂            1.8                                                                                           PRI♂       1.8
                    PRI♀            1.5                                                                                           PRI♀       1.5
 Folatea            AR              200 μg/d           HCNL 2003      Biomarkers of status (serum folate, erythrocyte Unchanged   AR         200 μg/d      HCNL 2003 Biomarkers of status (serum folate,
                    PRI             300                               folate, plasma homocysteine)                                PRI        300                     erythrocyte folate, plasma homocysteine)
 Vitamin B12b       AR              2.0 μg/d           HCNL 2003      Factorial method estimating intake needed to    Unchanged   AR         2.0 μg/d      HCNL 2003 Factorial method estimating intake
                    PRI             2.8                               maintain the smallest body stores associated                PRI        2.8                     needed to maintain the smallest body
                                                                      with absence / prevention of deficiency                                                        stores associated with absence /
                                                                                                                                                                     prevention of deficiency
  Vitamin C         AR♂             60 mg/d            NCM 2014       Biomarkers of status (plasma ascorbate)         Unchanged   AR♂        60 mg/d       NCM 2014  Biomarkers of status (plasma ascorbate)
                    AR♀             50                                                                                            AR♀        50
                    PRI             75 (♂&♀)                                                                                      PRI        75 (♂&♀)
a
   All abbreviations in the table are explained in the glossary (Annex B).
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<pre>Annexes                                                                              An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 176 of 179
Nutrient      The 2018 Dutch reference values                                                      2018 versus The 2014 Dutch reference values
              Reference values          Origin    Type of data on which the values are based       2014        Reference values         Origin    Type of data on which the values are
                                                                                                                                                  based
Vitamin Dc    18-69 years:                                                                                     18-69 years:
              AI          10 μg/d       HCNL 2012 Biomarker of status (25(OH)D)                    Unchanged   AI         10 μg/d       HCNL 2012 Biomarker of status (25(OH)D)
              >70 years:                          randomised controlled trials on the effect of                >70 years:                         randomised controlled trials on the effect
              AR          10 μg/d       HCNL 2012 using supplements with vitamin D and calcium     Unchanged   AR         10 μg/d       HCNL 2012 of using supplements with vitamin D and
              PRI         20                      on fracture risk                                             PRI        20                      calcium on fracture risk
Vitamin E as  AI♂         13 mg/d       EFSA 2015 Midpoint of range of mean intakes in Europe      Changed     AR♂        6 mg/d        NCM 2014  RI of polyunsaturated fatty acids (PUFA),
α-tocopherol  AI♀         11                                                                                   AR♀        5                       assuming that the average requirement is
                                                                                                               PRI♂       10                      1 mg vitamin E per gram PUFA
                                                                                                               PRI♀       8
Vitamin K1    AI          70 μg/d       EFSA 2017 Biomarkers of function (simplastin:ecarin ratio; Unchanged   AI         70 μg/d       EFSA 2017 Biomarkers of function (simplastin:ecarin
                                                  urinary Gla concentration)                                                                      ratio; urinary Gla concentration)
Biotin        AI          40 μg/d       EFSA 2014 Midpoint of range of mean intakes in Europe      Unchanged   AI         40 μg/d       EFSA 2014 Midpoint of range of mean intakes in
                                                                                                                                                  Europe
Choline       AI          400 mg/d      EFSA 2016 Midpoint of mean choline intakes in Europe,      Changed     No reference value                 Choline was not mentioned in HCNL 2014
                                                  rounded upwards, with supportive evidence from
                                                  a depletion-repletion study
Calcium       18-24 years:                                                                                     18-50 years:                       Factorial method based on the
              AR          860 mg/d      EFSA 2015 Intermediate between value 11-17 and >25         Changed     AI         1,000 mg/d    HCNL 2000 replacement of daily calcium losses and
              PRI         1,000                   years                                                                                           balance data
              25-50 years (♂&♀) and
              Men 51-70 years:
              AR          750 mg/d      EFSA 2015 Balance data based on the replacement of daily   Changed
              PRI         950                     calcium losses
              Women 51-70 years:                  Randomised controlled trials on the effect of                51-70 years (♂&♀) :                Randomised controlled trials on the effect
              AI          1,100 mg/d    HCNL 2000 using supplements with vitamin D and calcium     Unchanged   AI         1,100         HCNL 2000 of using supplements with calcium and
              >70 years (♂&♀):                    on fracture risk, considering that HCNL advises              >70 years (♂&♀) :                  vitamin D on fracture risk for older adults
              AI          1,200 mg/d    HCNL 2000 these groups to take a vitamin D supplement      Unchanged   AI         1,200         HCNL 2000
Chromium III                                      HCNL adopted EFSA’s conclusion in 2014 (no                                                      HCNL adopted EFSA’s conclusion in
                                                  reference values)                                                                               2014 (no reference values)
Copper        AR          0.7 mg/d      NCM 2014  Biomarkers of status (plasma & platelet copper Unchanged     AR         0.7 mg/d      NCM 2014  Biomarkers of status (plasma & platelet
              PRI         0.9                     concentration, serum caeruloplasmin concentra-               PRI        0.9                     copper concentration, serum
                                                  tion), biomarkers of function (erythrocyte SOD                                                  caeruloplasmin concentra-tion),
                                                  activity) and a factorial method                                                                biomarkers of function (erythrocyte SOD
                                                                                                                                                  activity) and a factorial method
Fluoride                                          No reference value                               Changed     AI♂        3.4 mg/d      EFSA 2013 Relationship between caries incidence
                                                                                                               AI♀        2.9                     and fluoride intake from drinking water
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<pre>Annexes                                                                                                    An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 177 of 179
  Nutrient            The 2018 Dutch reference values                                                                         2018 versus       The 2014 Dutch reference values
                      Reference values                Origin         Type of data on which the values are based               2014              Reference values                 Origin          Type of data on which the values are
                                                                                                                                                                                                 based
  Iodine              AI            150 μg/d          EFSA 2014      Biomarker of status (urinary iodine                      Changed           PRI          150 μg/d            NCM 2014        Biomarker of status (thyroid iodine
                                                                     concentration)                                                             AR           100                                 concentration), and the intake required to
                                                                                                                                                                                                 prevent goitre and maintain a normal
                                                                                                                                                                                                 thyroid function
  Iron                Men                                                                                                                       Men
                      AR            6 mg/d            EFSA 2015      Factorial method based on the replacement of             Changed           AR           7 mg/d              NCM 2014        Factorial method based on the
                      PRI           11                                                                                                          PRI          9                                   replacement of daily iron losses
                      Women premenopause                                                                                                         Women premenopause
                      AR            7 mg/d            EFSA 2015                                                               Changed           AR           9 (10?) mg/dd       NCM 2014
                      PRI           16                                                                                                          PRI          15
                      Women postmenopause                                                                                                        Women postmenopause
                      AR            6 mg/d            EFSA 2015                                                               Unchanged         AR           6 mg/dd             NCM 2014
                      PRI           11                                                                                        Changed           PRI          9 (8?)
  Magnesium           AI♂           350 mg/d          EFSA 2015      Mean intakes in Europe combined with the                 Changed           AI♂          350 mg/d            NCM 2014        There are no substantial new data since
                      AI♀           300                              results of balance studies                                                 AI♀          280                                 NCM 2004 indicating that these values
                                                                                                                                                                                                 should be changed
  Manganese           AI            3.0 mg/d          EFSA 2013      Mean intakes in Europe combined with findings            Unchanged         AI           3.0 mg/d            EFSA 2013       Mean intakes in Europe combined with
                                                                     in balance studies                                                                                                          findings in balance studies
  Molybdenum          AI            65 μg/d           EFSA 2013      Mean intakes in Europe combined with findings            Unchanged         AI           65 μg/d             EFSA 2013       Mean intakes in Europe combined with
                                                                     in balance studies                                                                                                          findings in balance studies
  Phosphorus          AI            550 mg/d          EFSA 2015      Recommended calcium intake, assuming that                Changed           AR           450 mg/d            NCM 2014        Biomarker of status (plasma
                                                                     the adequate intake is 1 mol phosphorus per 1.4                            PRI          600                                 concentration)
                                                                     mol calcium
  Potassium           AI            3.5 g/d           EFSA 2016      Effects on blood pressure and stroke risk                Changed           AI♂          3.5 g/d             NCM 2014        Effects on blood pressure and stroke risk
                                                                                                                                                AI♀          3.1
  Selenium            AI            70 μg/d           EFSA 2014      Biomarker of status (plasma SEPP1)                       Changed           AR♂          35 μg/d             NCM 2014        Biomarker of status (plasma SEPP1)
                                                                                                                                                AR♀          30
                                                                                                                                                PRI♂         60
                                                                                                                                                PRI♀         50
  Zinc                AR♂           6.4 mg/d          NCM 2014       Factorial method based on the replacement of             Unchanged         AR♂          6.4 mg/d            NCM 2014        Factorial method based on the
                      AR♀           5.7                              daily zinc losses                                                          AR♀          5.7                                 replacement of daily zinc losses
                      PRI♂          9                                                                                                           PRI♂         9
                      PRI♀          7                                                                                                           PRI♀         7
a
    Note that women who wish to conceive are advised to use a supplement containing 400 μg/d of folic acid, starting at least four weeks prior to conception until the eighth week of pregnancy, in addition to these reference values.
b
    In the Netherlands, it is recommended that adults on a vegan diet use supplemental vitamin B12 to achieve an adequate supply of this vitamin.53
c
    In most people, the vitamin D supply is met partly by cutaneous vitamin D synthesis and partly by dietary intake. The reference values for vitamin D intake refer to conditions of minimal cutaneous vitamin D synthesis. In the
    Netherlands, it is recommended that adults with dark skin or who do not spend enough time outdoors, women who wear a veil, and all women aged 50-70 years use a daily supplement with 10 μg vitamin D to ensure an adequate
    vitamin D supply. In the Netherlands, it is recommended that adults over 70 years use a daily supplement with 20 μg vitamin D to ensure an adequate vitamin D supply.34
d
    For iron, NCM’s AR for premenopausal women and NCM’s RI for postmenopausal women are not clear. This is described in footnotes in paragraph 21.2, where the differences between the ARs for premenopausal women and the PRIs
    for postmenopausal women are explained.
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<pre>Annexes                                                                                        An evaluation of the EFSA’s dietary reference values (DRVs), Part 1 | page 178 of 179
Committee and working group                                                                             Scientific secretaries:
                                                                                                        •  Dr. K.G. van der Mark-Reeuwijk, Health Council of the Netherlands, The Hague
Committee on Nutrition:                                                                                 •  Drs. E.J. Schoten, Health Council of the Netherlands, The Hague
•  Prof. J. Brug, Professor of Health Behaviour and Health Education, University of Amsterdam,          •  Dr. ir. C.J.K. Spaaij, Health Council of the Netherlands, The Hague
   Chairman (until August 31th, 2018)                                                                   •  Dr. ir. R.M. Weggemans, Health Council of the Netherlands, The Hague
•  Prof. S.J.L. Bakker, Professor of Internal Medicine, University Medical Center Groningen
•  Dr. J.W.J. Beulens, Epidemiologist, VU University Medical Center Amsterdam
                                                                                                        Working group on Dietary reference values:
•  Prof. E.E. Blaak, Professor of the Physiology of Fat Metabolism, Maastricht University
                                                                                                        •  Prof. J. Brug, Professor of Health Behaviour and Health Education, University of Amsterdam,
•  Prof. J.M. Geleijnse, Professor of Nutrition and Cardiovascular Diseases, Wageningen University
                                                                                                           Chairman (until August 31th, 2018)
   (until December 31th, 2017)
                                                                                                        •  Prof. S.J.L. Bakker, Professor of Internal Medicine, University Medical Center Groningen
•  Prof. J.B. van Goudoever, Professor of Paediatrics, VU University Medical Center Amsterdam
                                                                                                        •  Dr. H. van den Berg, Biochemist-nutritionist, retired, Zeist
   and Academic Medical Center, Amsterdam
                                                                                                        •  Dr. J.W.J. Beulens, Epidemiologist, VU University Medical Center Amsterdam
•  Prof. A.W. Hoes, Professor of Clinical Epidemiology and General Practice, University Medical
                                                                                                        •  Prof. E. Blaak, Professor of the Physiology of Fat Metabolism, Maastricht University
   Center Utrecht
                                                                                                        •  Prof. J.M. Geleijnse, Professor of Nutrition and Cardiovascular Diseases, Wageningen
•  Prof. M.T.E. Hopman, Professor of Integrative Physiology, Radboud University Medical Center,
                                                                                                           University (until December 31th, 2017)
   Nijmegen
                                                                                                        •  Prof. J.B. van Goudoever, Professor of Paediatrics, VU University Medical Center Amsterdam
•  Dr. J.A. Iestra, Nutritionist, University Medical Center Utrecht
                                                                                                           and Academic Medical Center, Amsterdam
•  Prof. S. Kremers, Professor Prevention of Obesity, Maastricht University Medical Center+
                                                                                                        •  Dr. J.A. Iestra, Nutritionist, University Medical Center Utrecht
•  Prof. R.P. Mensink, Professor of Molecular Nutrition, Maastricht University
                                                                                                        •  Prof. R.P. Mensink, Professor of Molecular Nutrition, Maastricht University
•  Prof. H. Pijl, Professor of Diabetology, Leiden University Medical Center (until December 31th,
                                                                                                        •  Prof. M. Visser, Professor of Healthy Aging, VU University Amsterdam and VU University
   2016)
                                                                                                           Medical Center, Amsterdam
•  Prof. dr. J.A. Romijn, Professor of Internal Medicine, Academic Medical Center, Amsterdam
•  Prof. dr. C.D.A. Stehouwer, Professor of Internal Medicine, Maastricht University Medical Center+
                                                                                                        Observer:
•  Prof. M. Visser, Professor of Healthy Aging, VU University Amsterdam
                                                                                                        •  Dr. C.T.M. van Rossum, National Institute for Public Health and the Environment, Bilthoven
•  Prof. M.H. Zwietering, Professor of Food Microbiology, Wageningen University and Research
   Centre
                                                                                                        Scientific Secretaries:
•  Dr. H. van den Berg, Biochemist-nutritionist, retired, Zeist, Structurally consulted expert
                                                                                                        •  Dr. C.J.K. Spaaij, Health Council of the Netherlands, The Hague
                                                                                                        •  Dr. S.V. Vink, Health Council of the Netherlands, The Hague
Observer:
•  Dr. C.T.M. van Rossum, National Institute for Public Health and the Environment (RIVM), Bilthoven
•  B.H. Smale, Ministry of Health, Welfare and Sport, The Hague
          Health Council of the Netherlands | No. 2018/19A
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body. Its remit is “to advise the government and
Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
The Health Council receives most requests for advice from the Ministers of Health, Welfare and Sport, Infrastructure and Water Management, Social
Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
order to ask attention for developments or trends that are thought to be relevant to government policy.
Most Health Council reports are prepared by multidisciplinary Committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity.
The reports are available to the public.
This publiation can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. An evaluation of the EFSA’s dietary reference values
(DRVs), Part 1. Dietary reference values for vitamins and minerals for adults. Background
document to Voedingsnormen voor vitamines en mineralen voor volwassenen. The Hague:
Health Council of the Netherlands, 2018; publication no. 2018/19A.
All rights reserved
          Health Council of the Netherlands | No. 2018/19A
</pre>

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