<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>Metallic lead
Evaluation of the effects on reproduction, recommendation for classification
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<pre></pre>

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<pre>Gezondheidsraad                              Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris Sociale Zaken en Werkgelegenheid
Onderwerp           : Aanbieding advies ‘Metallic lead’
Uw kenmerk          : DGV/MBO/U-932542
Ons kenmerk         : U 98/AvdB/ra/543-M6
Bijlagen            :1
Datum               : 18 februari 2003
Mijnheer de staatssecretaris,
Bij brief van 3 december 1993, nr DGV/MBO/U-932542, verzocht de Staatssecretaris van
Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en Werkgelegenheid
om naast het afleiden van gezondheidskundige advieswaarden ook te adviseren over andere
onderwerpen ten behoeve van de bescherming van beroepsmatig aan stoffen blootgestelde
personen. In 1995 heeft de Staatssecretaris van Sociale Zaken en Werkgelegenheid besloten tot het
opstellen van een zogenaamde niet-limitatieve lijst van voor de voortplanting vergiftige stoffen.
Op deze lijst komen stoffen die volgens de richtlijnen van de Europese Unie ingedeeld moeten
worden in categorie 1, 2 en 3 wat betreft effecten op de voortplanting en stoffen die schadelijk
kunnen zijn voor het nageslacht via de borstvoeding. De Gezondheidsraad is verzocht om voor
stoffen een classificatie volgens de EU-criteria voor te stellen.
      In dit kader bied ik u hierbij een advies aan over metallisch lood. Dit advies is opgesteld door
de Commissie Reproductietoxische stoffen van de Gezondheidsraad en beoordeeld door de
Beraadsgroep Gezondheid en Omgeving.
Ik heb deze publicatie heden ter kennisname aan de Minister van Volksgezondheid, Welzijn en
Sport en aan de Minister van de Volkshuisvesting, Ruimtelijke Ordening en Milieu gestuurd.
Hoogachtend,
prof. dr JA Knottnerus
Bezoekadres                                                               Postadres
Parnassusplein 5                                                          Postbus 16052
2511 VX     Den Haag                                                      2500 BB    Den Haag
Telefoon (070) 340 7520                                                   Telefax (070) 340 75 23
E-mail:   A.vd.Burght@gr.nl                                               www.gr.nl
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<pre></pre>

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<pre>Metallic lead
Evaluation of the effects on reproduction, recommendation for classification
Committee for compounds toxic to reproduction
A Committee of the Health Council of the Netherlands
to:
the Minister and State Secretary of Social Affairs and Employment
No. 2003/03OSH, The Hague, February 18, 2003
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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...” (Section 21, Health Act).
     The Health Council receives most requests for advice from the Ministers of Health,
Welfare & Sport, Housing, Spatial Planning & the Environment, Social Affairs &
Employment, and Agriculture, Nature Preservation & Fisheries. 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.
Preferred citation:
Health Council of the Netherlands: Committee for Compounds toxic to reproduction.
Metallic lead; Evaluation of the effects on reproduction, recommendation for
classification. The Hague: Health Council of the Netherlands, 2003; publication no.
2003/03OSH.
all rights reserved
ISBN: 90-5549-468-2
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 13
1.3 Additional considerations 14
1.4 Labelling for lactation 15
1.5 Data 15
1.6 Presentation of conclusions 16
1.7 Final remark 16
2   Metalic lead 17
2.1 Introduction 17
2.2 Properties 18
2.3 Human studies 18
2.4 Animal studies 26
2.5 Conclusion 26
    Contents                       7
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<pre>  References 29
  Annexes 39
A The committee 41
B Comments on the public draft 43
C Directive (93/21/EEC) of the European Community 45
D Fertility and developmental toxicity studies 51
E Calculation safe levels of lead in (human) breast milk 73
F Abbreviations 75
8 Metallic lead
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<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt de
Gezondheidsraad de effecten op de reproductie van stoffen waaraan mensen tijdens de
beroepsuitoefening kunnen worden blootgesteld. De Commissie Reproductietoxische
stoffen, een commissie van de Raad, adviseert een classificatie van reproductietoxische
stoffen volgens Richtlijn 93/21/EEC van de Europese Unie. In het voorliggende rapport
heeft de commissie metallisch lood onder de loep genomen.
De commissie is van mening dat metallisch lood overeenkomstig de anorganische lood
verbindingen geclassificeerd moet worden (die reeds door de Europese Unie zijn
geëvalueerd).
    De aanbevelingen van de commissie zijn:
• Voor effecten op de fertiliteit adviseert de commissie metallisch lood te classificeren
    in categorie 3 (stoffen die in verband met hun mogelijke voor de fertiliteit
    schadelijke effecten reden geven tot bezorgdheid voor de mens) en met R62
    (mogelijk gevaarlijk voor de vruchtbaarheid) te kenmerken.
• Voor effecten op de ontwikkeling adviseert de commissie metallisch lood in
    categorie 1 (stoffen waarvan bekend is dat zij bij de mens ontwikkelingsstoornissen
    veroorzaken) te classificeren en men R61 (kan het ongeboren kind schaden) te
    kenmerken.
• Voor effecten tijdens lactatie adviseert de commissie om metallisch lood met R64
    (kan schadelijk zijn via de borstvoeding) te kenmerken.
Samenvatting                                                                              9
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<pre>10 Metallic lead</pre>

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<pre>Executive summary
On request of the Minister of Social Affairs and Employment, the Health Council of the
Netherlands evaluates the effects on the reproduction of substances at the workplace.
The Health Council's Committee for Compounds Toxic to Reproduction recommends to
classify compounds toxic to reproduction according to the Directive 93/21/EEC of the
European Union. In the present report the committee has reviewed metallic lead.
The committee is of the opinion that metallic lead should be classified consistent with
inorganic lead compounds (which have already been classified by the European Union).
    The committee's recommendations are
• For effects on fertility, the committee recommends to classify metallic lead in
    category 3 (substances which cause concern for human fertility) and to label with
    R62 (possible risk of impaired fertility).
• For developmental toxicity, the committee recommends to classify metallic lead in
    category 1 (substances known to cause developmental toxicity in humans) and to
    label with R61 (may cause harm to the unborn child)
• For effects during lactation, the committee recommends that metallic lead should be
    labelled with R64 (may cause harm to breastfed babies).
Executive summary                                                                       11
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<pre>Chapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to reproduction
        that came into force on 1 April 1995, the Minister of Social Affairs and Employment
        requested the Health Council of the Netherlands to classify compounds toxic to
        reproduction. The classification is performed by the Health Council's Committee for
        Compounds Toxic to Reproduction according to the guidelines of the European Union
        (Directive 93/21/EEC). The committee's advice on the classification will be applied by
        the Ministry of Social Affairs and Employment to extend the existing list of compounds
        classified as toxic to reproduction (class 1, 2 or 3) or labelled as ‘may cause harm to
        breastfed babies’ (R64).
1.2     Committee and procedure
        The present document contains the classification of metallic lead by the Health
        Council's Committee for Compounds Toxic to Reproduction. The members of the
        committee are listed in Annex A. The first draft of this report was prepared by dr ir
        MEM Kuilman and ir DH Waalkens-Berendsen at the Department of Target Organ
        Toxicology of TNO Nutrition and Food Research, Zeist, The Netherlands, by contract
        with the Ministry of Social Affairs and Employment. The classification is based on the
        evaluation of published human and animal studies concerning adverse effects with
        respect to fertility and development and lactation of the above mentioned compound.
        Scope                                                                                   13
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<pre>    Classification and labelling was performed according to the guidelines of the European
    Union listed in Annex C.
    Classification for fertility and development
    Category 1                    Substances known to impair fertility in humans (R60)
                                  Substances known to cause developmental toxicity in humans (R61)
    Category 2                    Substances which should be regarded as if they impair fertility in humans (R60)
                                  Substances which should be regarded as if they cause developmental toxicity in humans
                                  (R61)
    Category 3                    Substances which cause concern for human fertility (R62)
                                  Substances which cause concern for humans owing to possible developmental toxic effects
                                  (R63)
    No classification for effects on fertility or development
    Labelling for lactation:
                                  May cause harm to breastfed babies (R64)
                                  No labelling for lactation
    In 2002, the President of the Health Council released a draft of the report for public
    review. The individuals and organisations that commented on the draft report are listed
    in Annex B. The committee has taken these comments into account in deciding on the
    final version of the report.
1.3 Additional considerations
    The classification of compounds toxic to reproduction on the basis of the Directive 93/
    21/EEC is ultimately dependent on an integrated assessment of the nature of all parental
    and developmental effects observed, their specificity and adversity, and the dosages at
    which the various effects occur. The directive necessarily leaves room for interpretation,
    dependent on the specific data set under consideration. In the process of using the
    directive, the committee has agreed upon a number of additional considerations.
    • If there is sufficient evidence to establish a causal relationship between human
        exposure to the substance and impaired fertility or subsequent developmental toxic
        effects in the progeny, the compound will be classified in category 1, irrespective
        the general toxic effects (see Annex C, 4.2.3.1 category 1).
    • Adverse effects in a reproductive or developmental study, in the absence of data on
        parental toxicity, occurring at dose levels which cause severe toxicity in other
        studies, need not necessarily lead to a category 2 classification.
14  Metallic lead
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<pre>    •    If, after prenatal exposure, small reversible changes in foetal growth and in skeletal
         development (e.g. wavy ribs, short rib XIII, incomplete ossification) in offspring
         occur at a higher incidence than in the control group in the absence of maternal
         effects, the substance will be classified in category 3 for developmental toxicity. If
         these effects occur in the presence of maternal toxicity, they will be considered as a
         consequence of this and therefore the substance will not be classified for
         developmental toxicity (see Annex C, 4.2.3.3 developmental toxicity final
         paragraph).
    •    Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
    •    Effects on sex organs in a general toxicity study (e.g. in a subchronic or chronic
         toxicity study) may warrant classification for fertility.
    •    The committee not only uses guideline studies (studies performed according to
         OECD standard protocols*) for the classification of compounds, but non-guideline
         studies are taken into consideration as well.
1.4 Labelling for lactation
    The recommendation for labelling substances for effects during lactation is also based
    on Directive 93/21/EEC. The Directive defines that substances which are absorbed by
    women and may interfere with lactation or which may be present (including
    metabolites) in breastmilk in amounts sufficient to cause concern for the health of a
    breastfed child, should be labelled with R64. Unlike the classification of substances for
    fertility and developmental effects, which is based on a hazard identification only
    (largely independent of the dosage), the labelling for effects during lactation is based on
    a risk characterisation and therefore also includes consideration of the level of exposure
    of the breastfed child.
         Consequently, a substance should be labelled for effects during lactation when it is
    likely that the substance would be present in breast milk in potentially toxic levels. The
    committee considers a concentration of a compound as potentially toxic to the breastfed
    child when this concentration leads to exceedence of the exposure limit for the general
    population, eg the acceptable daily intake (ADI).
1.5 Data
    Literature searches were conducted in the on-line databases Toxline and Medline,
    starting from 1966 up to 2000. Literature was selected primarily on the basis of the text
*   Organisation for Economic Cooperation and Development
    Scope                                                                                       15
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<pre>    of the abstracts. Publications cited in the selected articles, but not selected during the
    primary search, were reviewed if considered appropriate. In addition, handbooks and a
    collection of most recent reviews were consulted as well as several websites regarding
    (publications on) toxicology and health. References are divided in literature cited and
    literature consulted but not cited.
         The committee chose to describe human studies in the text, starting with review
    articles and, in addition, the studies are summarised in Annex D. Of each study the
    quality of the study design (performed according to internationally acknowledged
    guidelines) and the quality of documentation are considered.
         Animal data are described in the text and summarised in Annex D.
1.6 Presentation of conclusions
    The classification is given with key effects, species and references specified. In case a
    substance is not classified as toxic to reproduction, one of two reasons is given:
    • Lack of appropriate data preclude assessment of the compound for reproductive
         toxicity.
    • Sufficient data show that no classification for toxic to reproduction is indicated.
1.7 Final remark
    The classification of compounds is based on hazard evaluation* only, which is one of a
    series of elements guiding the risk evaluation process. The committee emphasises that
    for derivation of health based occupational exposure limits these classifications should
    be placed in a wider context. For a comprehensive risk evaluation, hazard evaluation
    should be combined with dose-response assessment, human risk characterisation,
    human exposure assessment and recommendations of other organisations.
*   for definitions see Tox95
16  Metallic lead
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<pre>Chapter 2
        Metallic lead
2.1     Introduction
        The aim of this report is to classify metallic lead for its possible effects on reproduction.
        Lead occurs in different forms, which can be categorised in soluble and insoluble lead
        salts, ionic lead, metallic lead and organic lead compounds (e.g. tetra ethyllead).
        However, in papers regarding exposure to lead or toxic effects of lead, the different lead
        compounds are usually not specified. The analytical methods for determining the lead
        exposure do no specify the different lead species. In general, only a distinction is made
        between organic and inorganic lead compounds (IPC95). Inorganic lead comprises
        metallic lead, its salts and oxides/sulfides (ATS97). Because metallic lead partly
        decomposes in air in several lead compounds (eg leadoxide), the committee is of the
        opinion that exposure to pure metallic lead is unlikely. The committee assumes that
        exposure to metallic lead is always accompanied by exposure to other inorganic lead
        compounds.
             The group of lead compounds* has already been classified for effects on
        reproduction by the European Union. For effects on fertility, lead compounds have been
        classified in category 3 (substances which cause concern for human fertility) and
        labelled with R62 (possible risk of impaired fertility). Lead compounds have been
        classified for developmental toxicity in category 1 (Substances known to cause
*       The ministry of Social Affairs and Employment assumed that metallic lead was not included in the group of inorganic
        lead compounds which is classified by the EU for effects on reproduction
        Metallic lead                                                                                                       17
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<pre>    developmental toxicity in humans) and labelled with R61 (may cause harm to the
    unborn child). For effects during lactation lead compounds have not been labelled.
2.2 Properties
    Name              :    (metallic) lead
    CAS-no            :    7439-92-1
    Use               :    batteries, pigments, alloys
    Mol weight        :    207.19
    Chem formula      :    Pb
    Conversion factor :    1 ppm = 8.63 mg/m3 (101 kPa, 25ºC)
                           1 mg/m3 = 0.12 ppm
                           1% = 10000 ppm = 12000 mg/m3
2.3 Human studies
    Human studies are described in more detail in Tables 1, 2 and 3 (Annex D).
    Fertility
    Several studies regarding the effects of exposure to (unspecified) lead compounds on
    fertility in men were found.
    Lancranjan et al. (Lan75) studied the reproductive ability of men occupationally
    exposed to unspecified lead compounds in a battery plant. Exposed men were divided
    into 1) lead poisoned men, men showing 2) moderately increased, 3) slightly increased
    or 4) physiological absorption of lead. Mean BLLs (blood (total) lead levels) of the
    groups were 230, 410, 530 and 750 µg/l. All groups showed effects on spermatogenesis
    (hypospermia and asthenospermia) and the group with BLLs higher than 410µg/l
    showed teratospermia.
         Braunstein et al. (Bra78) found that the intercourse frequency and testosterone
    levels were significantly decreased in a small group of lead (unspecified) poisoned
    (BLL 387 µg/l) and (unspecified) lead exposed men (290 µg/l) working in a lead smelter
    compared to controls (161 µg/l). No significant differences occurred in sperm volume,
    motility and percentage of abnormal forms between the groups. Testicular biopsies of 2
    lead poisoned men showed both increased peritubular connective tissue, decreased
    spermatogenesis and the presence of lipofuscin bodies. Moreover, the excretion of LH
    (luteinizing hormones) differed in the poisoned men compared to the other groups.
    Poisoned men quit working and were treated with Ca EDTA 3 months before the onset
    of the study.
18  Metallic lead
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<pre>    Wildt et al. (Wil83) found no differences in sperm morphology, count, motility and
biochemistry of men with high (unspecified) lead exposure (mean BLL 450 µg/l)
compared to men with low exposure (220 µg/l) at a battery factory. However, the
chromatin of the spermatozoa of the men with high (unspecified) lead exposure had a
significantly lower stability than the chromatin of the lower exposed men and a
decreased function of the accessory genital gland was found more frequently among
higher exposed men.
    Cullen (Cul84) described 7 men with several occupations who were intoxicated with
(unspecified) lead compounds and underwent endocrine evaluation at the time of
diagnosis (maximum BLLs 660-1390 µg/l). Defects in thyroid function were present in
3 patients, whereas 6 patients had subnormal glucocorticoid production and plasma
cortisol responses. Although serum testosterone concentration was normal in 6 patients,
5 had defects in spermatogenesis, including 2 with oligospermia and 2 with
azoospermia. Repeated examinations after chelation therapy showed only partial
improvement.
    Chowdhury et al. (Cho86) showed a small group of men who worked at a printing
company with blood and semen (total) lead levels of 425 and 148 µg/l, respectively, to
have less motile sperm, lower sperm counts and a higher amount of sperm with tail
abnormalities than controls from the administrative staff (lead levels significantly lower,
but unknown). Seminal plasma acid phosphatase, succinic dehydrogenase and fructose
content were lower in exposed men, whereas sperm volume, pH, colour and viscosity
did not differ between exposed and controls.
    Wives of men working at a battery plant (mean BLL 640 µg/l) had a significantly
(p<0.01) higher rate of spontaneous abortions compared to the controls with 2-3 times
less lead (unspecified compounds) in their blood (AlH86).
    Govoni et al. (Gov87) showed that the prolactin levels in men who were working in
small pewter factories, were higher when blood lead (unspecified compounds) and ZPP
(zinc protoporphyrin) levels were higher than 400 µg/l or when ZPP is higher than 400
µg/l. However, all prolactin levels were within the normal range).
    Compared to cement workers, men working in a storage battery plant for 1 to 10
years showed significantly higher BLLs (610 versus 180 µg/l), semen lead (unspecified)
and zinc protoporphyrin IX levels (Ass87). No differences were found in mean
testosterone, prolactin, total neutral 17-ketosteroid, LH and FSH levels. However, the
frequency distribution of sperm count was significantly lowered in unspecified lead
exposed men.
    Fischer-Fischbein et al. (Fis87) described the case of a firearms instructor who had
not been able to conceive a child for 2 years. At the start of chelation therapy his BLL
was 880 µg/l which sank within 6 months to 300 µg/l. After 2.5 years of therapy, the
semen volume had decreased by a factor 2, whereas sperm density and total sperm count
Metallic lead                                                                               19
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<pre>   had increased about 16 and 9 times, respectively. The motility of the sperm had
   remained equal whereas normal morphological appearance and head defects had slightly
   improved. After 1 year of therapy a healthy child was conceived.
        Rodamilans et al. (Rod88) studied effects of exposure to (unspecified) lead
   compounds on several endocrine parameters of men working in a lead smelter for <1
   year, 1-5 years or >5 years. BLLs and zinc protoporphyrin IX were significantly
   increased in all exposed groups (BLL ca. 700 µg/l) compared to the controls (170 µg/l).
   Serum testosterone was significantly decreased after more than 5 years of exposure and
   the free testosterone index after more than 1 year of exposure compared to controls.
   Steroid binding globulin was increased after exposure for more than 1 year and LH at all
   exposure durations. FSH concentration did not change.
        Gustafson et al. (Gus89) studied hormone levels in men exposed to (unspecified)
   lead compounds in a secondary lead smelter (BLL 390 µg/l) and controls (50 µg/l). Only
   FSH levels were significantly decreased in the lead (unspecified) exposed men. When
   only workers aged younger than 40 years were taken into account (as correlations exist
   for several hormones and age), thyroxin levels were increased and FSH, LH and cortisol
   levels were decreased compared to controls.
        Coste et al. (Cos91) showed that BLLs higher than 600 µg/l (overall mean 463 µg/l)
   in men working at a battery factory, are not associated with fertility (defined as the
   number of live births to a couple in one year).
        Men exposed to (unspecified) lead compounds in three battery factories showed
   significantly higher blood lead (352 µg/l) and aminolevulinic acid dehydratase levels
   than controls (BLL 83 µg/l) (Ng91). Moreover, LH and FSH levels were significantly
   increased at the age of 40 years and younger, whereas testosterone was lower at the age
   of 40 years and older compared to controls. Prolactin levels did not differ. Both
   secondary hypogonadism and compensated primary hypogonadism were significantly
   elevated in the exposed group.
        Lindbohm et al. (Lin91) concluded from a case-control study using a set of Finnish
   registries in which the association between paternal exposure to (unspecified) lead
   compounds and spontaneous abortions was studied, that the data only demonstrated a
   significant relationship between spontaneous abortion and BLLs higher than 311 µg/l at
   time of spermatogenesis.
        Lerda et al. (Ler92) showed a significant decrease in sperm count, motility and
   death cells in men working at a battery factory with mean BLLs of 486-866 µg/l
   compared to controls working at the same factory (BLL 235 µg/l). In all exposed
   groups, the percentage of anomalies had increased significantly.
        Hu et al. (Hu92) also reported decreased number of sperm and increased the
   incidence of teratospermia as well as a decreased level of lactate dehydrogenase-x in
20 Metallic lead
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<pre>sperm of men exposed to (unspecified) lead compounds in a printing house or battery
factory (mean urine lead level 87.6 µg/l).
    Gennart et al. (Gen92a) did not find evidence for significant differences in a variety
of renal and endocrine blood parameters, total erythrocyte count and an autonomic
nervous system parameter between men employed in a lead (unspecified lead
compounds) acid battery factory for at least 1 year (mean BLL 510 µg/l) and
comparable controls (209 µg/l).
    Gennart et al. (Gen92b) studied the effects of exposure to (unspecified) lead
compounds on male reproductive function in a battery plant. While the fertility, the
probability of a live birth, of the lead-exposed workers (BLL 463 µg/l) was somewhat
greater than that of the unexposed (104 µg/l) before the onset of exposure, a significant
decrease in fertility was observed during the period of exposure to unspecified lead
compounds.
    Alexander et al. (Ale96) showed geometric mean sperm concentration and total
sperm count to be inversely related to BLL (BLL <150 µg/l, 150-240 µg/l, 250-390 µg/l
and >400 µg/l). Employees with BLLs higher than 400 µg/l had an increased risk of
having low sperm concentration and low total sperm count according to WHO norms.
Sperm concentration, total sperm count and total motile sperm count were inversely
related to long term lead exposure. No relations were found between (unspecified) lead
exposure and sperm motility and morphology and serum levels of reproductive
hormones.
    Lin et al. (Lin96) examined the relationship between exposure to (unspecified) lead
compounds and fertility (actual versus expected number of births) for exposed men
(BLLs 250-340 µg/l, 350-490 µg/l and >500 µg/l) with a group of bus drivers as a
control. The overall standard fertility ratio was significantly lower for the exposed men,
especially for men with heavy exposure (>500 µg/l and duration of exposure for 5 years)
and long exposure (more than 5 years). BLLs of bus drivers were not measured.
    Sallmén et al. (Sal00) studied the time to pregnancy of the wives of men
occupationally exposed to (unspecified) lead compounds. Exposure categories were
104-186 µg/l, 207-290 µg/l, 311-373 µg/l and >394 µg/l; only for the 3rd category a
significant relation was found between the adjusted fecundability density ratio for wives
of exposed men and controls (BLLs <104 µg/l).
    Sallmén et al. (1995) studied the fertility of women occupationally exposed to
(unspecified) lead compounds with BLLs in three categories: 100 µg/l, 100<BLL>190
µg/l and BLL 190 µg/l. No relationships were found between BLL and time to
pregnancy or decreased fecundability after adjustment for several confounders.
The committee emphasises that none of the above described fertility studies concerned
exposure to pure metallic lead.
Metallic lead                                                                              21
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<pre>   Development
   In a retrospective case control study, Sallmén et al. (Sal92) showed an increased odds
   ratio for congenital malformations after paternal exposure to (unspecified) lead
   compounds for 80 days prior to conception (BLLs controls <186 µg/l, exposed between
   207 µg/l and >394 µg/l). However, this increase was not significant. Moreover, all case
   children had a different type of malformation.
        Kristensen et al. (Kri93) studied the effects of paternal exposure to (unspecified)
   lead compounds in members of three printers' unions in Oslo. The (unspecified) lead
   exposure did not appear to have substantial impact on preterm birth, birth weight and
   gestational age. However, exposure to unspecified lead compounds was associated with
   an increased risk of death in the perinatal period (combining late abortions, stillbirths
   and early neonatal deaths). Birth defects were generally not associated with lead
   exposure, although a significantly increased risk of cleft lip and/or palate was observed
   among the male offspring of fathers belonging after exposure to lead or to lead and
   solvents together.
        Fahim et al. (Fah92) showed that preterm and term pregnancies with premature
   rupture of the membrane occured more in the area around a lead smelter than in an area
   without any mining activities. However, mean foetal and maternal BLL did not differ
   between the areas. For each area maternal and foetal BLLs for preterm and term with
   premature rupture were 2-4 times higher than for term pregnancies.
        Several papers compared women living around a lead smelter in Port Pirie
   (Australia) to women living in the surrounding agricultural area. The mean prenatal and
   perinatal BLLs in the Port Pirie women (106 µg/l) were significantly higher than in the
   agricultural women (76 µg/l) (Mc86). Although more Port Pirie women had a
   spontaneous abortion than non-Port Pirie women, these were not related to BLL. The
   relative risk for a pre-term delivery was significantly increased at BLLs of >140 µg/l.
   Stillbirths were negatively associated with individual maternal BLL. BLLs were not
   related to birth weight, crown heel length, head circumference, premature rupture of
   membranes, congenital anomalies or difficulties in conceiving.
        In the children born in the same Australian cohort, Wigg et al. (Wig88) studied
   neurological development at 24 months of age in relation to BLLs of the pregnant
   mother and of the child after birth. Bayley's Mental Development Index was only
   negatively correlated to the maternal BLL at 20 weeks of gestation, whereas Bayley's
   Psychomotor Development Index was not related to any BLL measured. At 4 years of
   age the children were assessed with the McCarthy Scales of Children's Abilities (Mc88).
   Although relations between antenatal BLLs and several parameters existed, they did not
   remain after adjustment for certain covariates.
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<pre>     A comparable cohort study was performed in Yugoslavia. BLLs were 160 and 52
µg/l for women living around the lead smelter and women from another town at the time
of study (Mur90). After adjustment for cofactors no differences were found regarding
town of residence and spontaneous abortion or stillbirths. In a different subgroup of this
cohort, no relation between birth weight or length of gestation and town of residence or
midpregnancy BLL (54 µg/l in the town versus 191 µg/l around the lead smelter) was
observed (Fac91). In addition, it was shown that preterm delivery did not increase with
BLL (neither with BLL at mid-pregnancy nor with cord or maternal BLL at delivery).
     Mean gestational age, birth weight, height and head circumference were also not
found to be related to BLLs of women working in a storage battery factory with
maximal mean BLLs of 203.8 µg/l in comparison to control women (max. mean BLL
72.5 µg/l) (Wan96).
     Finally, Rothenberg et al. (Rot92) described a case of a pregnant women whose
BLL was ca. 100 µg/l until week 36 of pregnancy and rose, after starting using a glazed
ceramic pitcher containing lead, to ca. 500 µg/l at delivery. The BLL of the baby
amounted to ca. 1000 µg/l at delivery and decreased to 175 µg/l at 3 years of age.
Psychometric and diagnostic testing yielded scores within normal limits out to 3 years.
However, hypertonia, irritability, abnormal cry and other neurological soft signs at 2, 15
and 30 days were found. EEG sleep patterns were fragmented at 20 days and 3 months
and abnormal respiratory patterns were noted to 6 months. Moreover, at every visit
hyperactivity and distractibility were noted until finishing of the follow up at three years
of age.
Again, the committee emphasises that none of the above described developmental
toxicity studies concerned exposure to pure metallic lead.
Lactation
Several studies are summarised regarding lead (unspecified compounds) levels in milk.
Two groups of studies are considered: exposure to chemically specified sources and
non-specified sources. The latter studies are further subdivided according to geographic
region because different lifestyle conditions may influence lead levels in breast milk.
     The FAO/WHO (FAO93) recommended a PWTI (provisional tolerable weekly
intake) for lead of 25 µg/kg body weight. From this, an acceptable lead level of 16 µg/l
in human breast milk can be calculated (see Annex D).
Metallic lead                                                                                23
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<pre>   Specified source
   Three reports regarding concentrations of (unspecified) lead compounds in breast milk
   of women exposed specifically to lead were available. In the first 2 months of lactation,
   Ryu et al. (Ryu78) measured up to 63 µg/l in breast milk of a woman who had worked
   for 3 years at a producer of batteries until 7 weeks before delivery. Namihira et al.
   (Nam93) found a maximum of 350 µg/l (mean 24.7 µg/l) in breast milk given within 2
   months after parturition by women living within 200 m of a lead smelter in Mexico City.
   Women around a lead smelter in Sweden gave, 6 weeks postpartum, milk with a mean of
   0.9 µg Pb/l (Pal95).
   Lead concentrations in breast milk of women not particularly exposed to lead also
   varied widely. The highest concentrations were reported by Noirfalise et al. (Noi67),
   who found up to 1500 µg/l in breast milk of women living in the province of Liège
   (Belgium). The mean lead content of the 76 samples amounted to 277 µg/l and 74
   samples contained between 0 and 900 µg Pb/l. The analytical method used by Noirfalise
   et al. (Noi67) (polarography), however, differs widely from the ones used in other
   studies (atomic absorption spectrometry and anodic stripping voltametry).
   Unspecified sources
   Europe
   Samples collected during four consecutive years in Germany (Niedersachsen) showed
   median breast milk lead (unspecified compounds) levels of <4, 43, 35 and 4 µg/l for
   1987, 1988, 1989 and 1990, respectively (End92). Significant differences in breast milk
   lead levels between rural and urban areas were found in Croatia (4.7 versus 10.6 µg/l)
   (Frk97) and Germany (9.2 versus 13.2 µg/l) (Ste85). However, in studies in Austria (Tir
   94) and Greece (Vav97) with mean breast milk lead levels of 3.4 µg/l (range 0-20.4 µg/
   l) and 90 µg/l (range 50-250 µg/l), these differences were not observed.
        Lead content (unspecified compounds) of milk collected at various time points
   during the day did not differ (Ste85) nor did the lead content of milk collected 3 or 6
   months post partum (mean 2 µg/l, range 0.5-9.0 µg/l) (Lar81). However, colostrum
   contained about 1.5-1.7 times more lead than mature milk (Ste85). Other European
   studies showed mean concentrations of lead in breast milk of 21 µg/l (Moo82), 4.1 µg/l
   (Kov84), 2.6 µg/l (Sch88), 16.8 µg/l (Par91) and 35.8 µg/l (Plo93) (overall range 0-70.3
   µg/l). Milk samples were taken between 2 days and 8 weeks post partum.
24 Metallic lead
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<pre>North-America
Mean lead (unspecified) content in breast milk obtained from North-American women
amounted to 20 µg/l (Lam73), 10.9 µg/l (Pin73), 26 µg/l (Dil74), 2.8 µg/l (Roc84), 17
µg/l (Rab 85) and 0.57 µg/l (Dab86) (overall range 0-72 µg/l). Samples were taken up to
16 months of lactation. Breast milk of mothers of full-term or premature infants did not
differ in lead content (0-4 µg/l) (Fri99).
Oceania
Two studies in the area of Oceania were performed. Casey et al. (Cas77) did not found
lead (unspecified) levels in milk above the detection limit (10 µg/l) in breast milk
collected on day 4-10 of lactation of women in New-Zealand. Gulson et al. (Gul89)
found a mean lead level as low as 0.73 µg/l (range 0.09-3.1 µg/l) in breast milk of
Australian immigrant women.
Asia
Women living in heavily polluted areas of Bangkok produced breast milk containing
84.6 µg Pb/l (range 13.6-222.23 µg/l) (Cha78). Breast milk of Malaysian (Ong85),
Phillippinian (Par91) and Indian (Tri99) women contained 47.7, 16.6 and 1.9 µg Pb/l
(overall range 0-105.7 µg/l), respectively. The lead (unspecified) level in breast milk of
rural and urban women in Malaysian differed significantly (21.1 versus 25.3 µg Pb/l)
(Hua83). Parr et al. (Par91) did not find any differences in lead content of breast milk of
women from different socio-economical classes in Malaysia.
Africa
Average concentrations of lead (unspecified) in breast milk of women in 20 urban and
rural areas in Egypt amounted to 9.0-101.4 µg/l (individual range 0-158 µg/l) with
highest concentration in urban areas (Sal96). Breast milk of women living in Nigeria
and Zaire contained 4.9 and 5.0 µg Pb/l (Par91). No differences were found in milk
samples obtained from women from different socio- economical classes.
South America
Only one report was available regarding lead (unspecified) levels in breast milk of
women living on the South American continent. Parr et al. (Par91) found a mean lead
level of 2.9 µg/l in breast milk of women from Guatemala. No differences were found in
breast milk lead levels of women from different socio economical classes.
Metallic lead                                                                               25
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<pre>2.4 Animal studies
    Quite a number of papers on the effects of lead exposure on reproduction are available.
    However, studies are performed with lead salts (predominantly lead acetate and lead
    nitrate) rather than with metallic lead. Moreover, in a number of papers, the exact entity
    of lead used for exposure is unclear.
    Fertility studies
    Animal studies regarding metallic lead exposure and fertility were not available.
    Developmental toxicity
    Sharma et al. (Sha76) dosed 12 Columbia-Rambouillet cross-bred ewes daily with 0.5 to
    16 mg/kg (unspecified) lead in the diet to maintain a BLL of approximately 400 µg/l.
    Three days after starting the experiment a Dorset ram was turned into the group every
    morning and evening. The rate of abortions in exposed and unexposed animals was 27
    and 0%, respectively. The rate of lambing in the exposed and unexposed sheep was 18
    and 100%, respectively. Three animals in the exposed group either did not conceive or
    their foetuses were resorbed; two others were nongravid. One sheep contained a
    mummified fetus in the uterus on postmortem examination. Aborted and born foetuses/
    lambs in the exposed group were all without apparent abnormalities.
    Lactation
    No publications were available.
2.5 Conclusion
    In general, metallic lead is considered to belong to the group of inorganic lead
    compounds. Fertility effects found after male exposure to lead (unspecified compounds)
    included decreased intercourse frequency (Bra78, Cul84), reduced likelihood to have
    any children (Lin96), increased rate of spontaneous abortions (AlH86), slightly
    increased time to pregnancy (Sal00) and effects on sperm/spermatogenesis (Lan75,
    Bra78, Wil83, Cho86, Ass87, Ler92, Hu92, Ale96). On the hormonal level, effects were
    observed on testosterone (Bra78, Rod88, Ng91), LH (Cul84, Rod88, Gus89, Ng91),
    FSH (Cul84, Ass87, Rod88, Gus89, Ng91), prolactin, thyroxin and cortisol (Cul84,
    Gov87, Gus89), however, these results were not always consistent. In the only human
26  Metallic lead
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<pre>study regarding reproduction and female exposure to lead no effects on fertility and time
to pregnancy were observed (Sal95).
     Animal data concerning exposure to pure metallic lead and effects on fertility were
not available.
     The committee concludes that several effects on fertility were described in humans
after exposure to (unspecified) lead compounds. However, these effects were not always
consistent. In addition, the European Union has already classified the inorganic lead
compounds in category 3. Because the committee assumes that exposure to metallic lead
always involves exposure to other inorganic lead compounds, the committee
recommends to classify metallic lead for effects on fertility in category 3 (substances
which cause concern for human fertility).
Kristensen et al. (Kri93) found a significantly increased risk for male offspring with
cleft lip and/or palate of fathers exposed to both lead and solvents. Lead exposure was
also associated with an increased risk of death in the perinatal period. McMichael et al.
(Mc86) found the relative risk for preterm delivery to be increased with maternal
BLLs>140 µg/l. Fahim et al. (Fah76) showed maternal and foetal BLLs to be 2-4 times
higher for preterm and term pregnancies with premature rupture compared to normal
term pregnancies. However, this was unrelated to the presence or absence of a lead
smelter in the area. Wigg et al. (Wig88) found Bayley's Mental Development Index at
24 months of age negatively correlated to maternal BLLs at 20 weeks of gestation.
     A child with very high BLLs, described in a case report, performed within normal
limits on the same psychometric tests. However, according to two behavioural scales,
the child was hyperactive and easily distracted.
     One animal study was available in which ewes received (unspecified) lead through
the diet, resulting in an increased abortion rate and a decreased lambing rate (Sha76).
     In conclusion, several effects on development were found in humans after exposure
to (unspecified) lead. Moreover, the European Union has classified the inorganic lead
compounds in category 1. Because the committee assumes that exposure to metallic lead
always involves exposure to other inorganic lead compounds, the committee
recommends to classify metallic lead for effects on development in category 1
(substances known to cause developmental toxicity in humans).
In several studies (Ryu78, Nam93, Pal95), mean (unspecified) lead levels in breast milk
were determined after exposure to specified (known) sources. These lead levels in breast
milk ranged up to 350 µg/l (Ryu78, Nam93, Pal95). These levels exceeded the
calculated acceptable level of 16 µg/l breast milk. Because the committee assumes that
exposure to metallic lead always involves exposure to other inorganic lead compounds,
Metallic lead                                                                             27
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<pre>   the committee recommends to label metallic lead for effects during lactation with R64
   (may cause harm to breastfed babies)*.
   Proposed classification for fertility
   Category 3
   Proposed classification for developmental toxicity
   Category 1
   Proposed labelling for effect during lactation
   R64
*  The committee is of the opinion that all inorganic lead compounds should be labelled with R64.
28 Metallic lead
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32    Metallic lead
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<pre>38 Metallic lead</pre>

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<pre>A The committee
B Comments on the public draft
C Directive (93/21/EEC) of the European Community
D Fertility and developmental toxicity studies
E Abbreviations
  Annexes
                                                  39
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<pre>Annex A
      The committee
      •  BJ Blaauboer, chairman
         Toxicologist, Institute for Risk Assessment Sciences, Utrecht
      •  AM Bongers, advisor
         Ministry of Social Affairs and Employment, Den Haag
      •  HFP Joosten
         Toxicologist, NV Organon, Department of Toxicology and Drug Disposition, Oss
      •  D Lindhout
         professor of Medical Genetics, paediatrician, UMC, Utrecht
      •  JHJ Copius Peereboom-Stegeman
         Toxicologist, Catholic University Nijmegen, Nijmegen
      •  AH Piersma
         Reproductive toxicologist, National Institute of Public Health and the Environment,
         Bilthoven
      •  N Roeleveld
         Epidemiologist, Catholic University Nijmegen, Nijmegen
      •  DH Waalkens-Berendsen
         Reproductive toxicologist, TNO Nutrition and Food Research, Zeist
      •  PJJM Weterings
         Toxicologist, Weterings Consultancy BV, Rosmalen
      •  ASAM van der Burght, scientific secretary
         Health Council of the Netherlands, Den Haag
      The committee                                                                          41
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<pre>   The first draft of the present document was prepared by MEM Kuilman and DH
   Waalkens-Berendsen, from the TNO Nutrition and Food Research in Zeist, by contract
   with the Ministry of Social Affairs and Employment.
   Secretarial assistance: A Aksel.
   Lay-out: M Javanmardi and J van Kan.
42 Metallic lead
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<pre>Annex B
      Comments on the public draft
      A draft of the present report was released in 2002 for public review. The following
      persons and organisations have commented on the draft review:
      • N van der Vliet, Uzimet BV, Rijswijk
      • V Digernes, Federation of Norwegian Process Industries, Norway
      Comments on the public draft                                                        43
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<pre>Annex C
      Directive (93/21/EEC) of the European
      Community
      4.2.3         Substances toxic to reproduction
      4.2.3.1       For the purposes of classification and labelling and having regard to the present state
                    of knowledge, such substances are divided into 3 categories:
      Category 1:
      Substances known to impair fertility in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance and
      impaired fertility.
      Substances known to cause developmental toxicity in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance and
      subsequent developmental toxic effects in the progeny.
      Directive (93/21/EEC) of the European Community                                                             45
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<pre>   Category 2:
   Substances which should be regarded as if they impair fertility in humans:
   There is sufficient evidence to provide a strong presumption that human exposure to the substance may
   result in impaired fertility on the basis of:
   •    Clear evidence in animal studies of impaired fertility in the absence of toxic effects, or, evidence of
        impaired fertility occurring at around the same dose levels as other toxic effects but which is not a sec-
        ondary non-specific consequence of the other toxic effects.
   •    Other relevant information.
   Substances which should be regarded as if they cause developmental toxicity to humans:
   There is sufficient evidence to provide a strong presumption that human exposure to the substance may
   result in developmental toxicity, generally on the basis of:
   •    Clear results in appropriate animal studies where effects have been observed in the absence of signs of
        marked maternal toxicity, or at around the same dose levels as other toxic effects but which are not a
        secondary non-specific consequence of the other toxic effects.
   •    Other relevant information.
   Category 3:
   Substances which cause concern for human fertility:
   Generally on the basis of:
   •    Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
        impaired fertility in the absence of toxic effects, or evidence of impaired fertility occurring at around
        the same dose levels as other toxic effects, but which is not a secondary non-specific consequence of
        the other toxic effects, but where the evidence is insufficient to place the substance in Category 2.
   •    Other relevant information.
   Substances which cause concern for humans owing to possible developmental toxic effects:
   Generally on the basis of:
   •    Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
        developmental toxicity in the absence of signs of marked maternal toxicity, or at around the same dose
        levels as other toxic effects but which are not a secondary non-specific consequence of the other toxic
        effects, but where the evidence is insufficient to place the substance in Category 2.
   •    Other relevant information.
46 Metallic lead
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<pre>4.2.3.2       The following symbols and specific risk phrases apply:
Category 1:
For substances that impair fertility in humans:
T; R60: May impair fertility
For substances that cause developmental toxicity:
T; R61: May cause harm to the unborn child
Category 2:
For substances that should be regarded as if they impair fertility in humans:
T; R60: May impair fertility
For substances that should be regarded as if they cause developmental toxicity in humans:
T; R61: May cause harm to the unborn child.
Category 3:
For substances which cause concern for human fertility:
Xn; R62: Possible risk of impaired fertility
For substances which cause concern for humans owing to possible developmental toxic effects:
Xn; R63: Possible risk of harm to the unborn child.
4.2.3.3        Comments regarding the categorisation of substances toxic to reproduction
Reproductive toxicity includes impairment of male and female reproductive functions or capacity and the
induction of non-inheritable harmful effects on the progeny. This may be classified under two main
headings of 1) Effects on male or female fertility, 2) Developmental toxicity.
1    Effects on male or female fertility, includes adverse effects on libido, sexual behaviour, any aspect of
     spermatogenesis or oogenesis, or on hormonal activity or physiological response which would interfere
Directive (93/21/EEC) of the European Community                                                               47
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<pre>          with the capacity to fertilise, fertilisation itself or the development of the fertilised ovum up to and
          including implantation.
   2      Developmental toxicity, is taken in its widest sense to include any effect interfering with normal devel-
          opment, both before and after birth. It includes effects induced or manifested prenatally as well as those
          manifested postnatally. This includes embrytoxic/fetotoxic effects such as reduced body weight,
          growth and developmental retardation, organ toxicity, death, abortion, structural defects (teratogenic
          effects), functional defects, peripostnatal defects, and impaired postnatalmental or physical develop-
          ment up to and including normal pubertal development.
   Classification of chemicals as toxic to reproduction is intended to be used for chemicals which have an
   intrinsic or specific property to produce such toxic effects. Chemicals should not be classified as toxic to
   reproduction where such effects are solely produced as a non-specific secondary consequence of other toxic
   effects. Chemicals of most concern are those which are toxic to reproduction at exposure levels which do
   not produce other signs of toxicity.
   The placing of a compound in Category 1 for effects on Fertility and/or Developmental Toxicity is done on
   the basis of epidemiological data. Placing into Categories 2 or 3 is done primarily on the basis of animal
   data. Data from in vitro studies, or studies on avian eggs, are regarded as 'supportive evidence' and would
   only exceptionally lead to classification in the absence of in vivo data.
   In common with most other types of toxic effect, substances demonstrating reproductive toxicity will be
   expected to have a threshold below which adverse effects would not be demonstrated. Even when clear
   effects have been demonstrated in animal studies the relevance for humans may be doubtful because of the
   doses administrated, for example, where effects have been demonstrated only at high doses, or where
   marked toxicokinetic differences exist, or the route of administration is inappropriate. For these or similar
   reasons it may be that classification in Category 3, or even no classification, will be warranted.
   Annex V of the Directive specifies a limit test in the case of substances of low toxicity. If a dose level of at
   least 1000 mg/kg orally produces no evidence of effects toxic to reproduction, studies at other dose levels
   may not be considered necessary. If data are available from studies carried out with doses higher than the
   above limit dose, this data must be evaluated together with other relevant data. Under normal circumstances
   it is considered that effects seen only at doses in excess of the limit dose would not necessarily lead to
   classification as Toxic to Reproduction.
48 Metallic lead
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<pre>Effects on fertility
For the classification of a substance into Category 2 for impaired fertility, there should normally be clear
evidence in one animal species, with supporting evidence on mechanism of action or site of action, or
chemical relationship to other known antifertility agents or other information from humans which would
lead to the conclusion that effects would be likely to be seen in humans. Where there are studies in only one
species without other relevant supporting evidence then classification in Category 3 may be appropriate.
Since impaired fertility may occur as a non-specific accompaniment to severe generalised toxicity or where
there is severe inanition, classification into Category 2 should only be made where there is evidence that
there is some degree of specificity of toxicity for the reproductive system. If it was demonstrated that
impaired fertility in animal studies was due to failure to mate, then for classification into Category 2, it
would normally be necessary to have evidence on the mechanism of action in order to interpret whether any
adverse effect such as alteration in pattern of hormonal release would be likely to occur in humans.
Developmental toxicity
For classification into Category 2 there should be clear evidence of adverse effects in well conducted studies
in one or more species. Since adverse effects in pregnancy or postnatally may result as a secondary
consequence of maternal toxicity, reduced food or water intake, maternal stress, lack of maternal care,
specific dietary deficiencies, poor animal husbandry, intercurrent infections, and so on, it is important that
the effects observed should occur in well conducted studies and at dose levels which are not associated with
marked maternal toxicity. The route of exposue is also important. In particular, the injection of irritant
material intraperitoneally may result in local damage to the uterus and its contents, and the results of such
studies must be interpreted with caution and on their own would not normally lead to classification.
Classification into Category 3 is based on similar criteria as for Category 2 but may be used where the
experimental design has deficiencies which make the conclusions less convincing, or where the possibility
that the effects may have been due to non-specific influences such as generalised toxicity cannot be
excluded.
In general, classification in category 3 or no category would be assigned on an ad hoc basis where the only
effects recorded are small changes in the incidences of spontaneous defects, small changes in the
proportions of common variants such as are observed in skeletal examinations, or small differences in
postnatal developmental assessments.
Directive (93/21/EEC) of the European Community                                                                49
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<pre>   Effects during Lactation
   Substances which are classified as toxic to reproduction and which also cause concern due to their effects on
   lactation should in addition be labelled with R64 (see criteria in section 3.2.8).
   For the purpose of classification, toxic effects on offspring resulting only from exposure via the breast milk,
   or toxic effects resulting from direct exposure of children will not be regarded as 'Toxic to Reproduction',
   unless such effects result in impaired development of the offspring.
   Substances which are not classified as toxic to reproduction but which cause concern due to toxicity when
   transferred to the baby during the period of lactation should be labelled with R64 (see criteria in section
   3.2.8). This R-phrase may also be appropriate for substances which affect the quantity or quality of the milk.
   R64 would normally be assigned on the basis of:
   a    toxicokinetic studies that would indicate the likelihood that the substance would be present in poten-
        tially toxic levels in breast milk, and/or
   b    on the basis of results of one or two generation studies in animals which in- dicate the presence of
        adverse effects on the offspring due to transfer in the milk, and/or
   c    on the basis of evidence in humans indicating a risk to babies during the lactational period.
        Substances which are known to accumulate in the body and which subsequently may be released into
        milk during lactation may be labelled with R33 and R64.
50 Metallic lead
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<pre>Annex        D
             Fertility and developmental toxicity
             studies
Table 1.1 Human studies on effects of Pb on fertility
authors     subjects     exposure             design              effect/observations                 remarks
occupationally exposed men
Lancran-    exposed      men working at a     physical and toxi-  in all four exposed groups a sig-   classification was based on
jan et al.  men (n=16-   storage battery      cological examina-  nificant increase in alterations in clinical (group 1) and toxico-
(1975)      29) and a    plant which were     tion (Pb levels in  spermatogenesis (hypospermia        logical criteria: BLLs were
            control      1) Pb poisoned or    blood and urine,    and asthenospermia) was             750, 530, 410 and 230 µg/l,
            group        showed               analysis of copro-  observed; in the three highest      urine Pb levels 390, 250, 100
            (n=50)       2) moderately        porphyrine and d-   exposed groups teratospermia        and 92 µg/l, coproporphyrine
                         increased,           ALA levels and      was found no relation was found     levels 0.39, 0.30, 0.08 and
                         3) slightly          total neutral 17-Ks between total neutral 17-Ks elimi-  0.04 mg/l and δ-ALA levels
                         increased or 4)      elimination);       nation and the level of Pb absorp-  56.5, 22.4, 7.7 and 4.4 mg/l
                         physiological        semen analysis of   tion (groups 1-4)                   for group 1, 2, 3 and 4,
                         absorption           semen collected                                         respectively mean age of men
                                              after 3 days of                                         was 38 years alcohol con-
                                              abstinence                                              sumption was in all groups
                                                                                                      equally distributed 44% of
                                                                                                      the investigated men smoked
                                                                                                      BLLs in controls were
                                                                                                      unknown
             Fertility and developmental toxicity studies                                                                          51
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<pre>Braunstein Pb poisoned  Poisoned men had     testicular biopsies frequency of intercourse had sig-    poisoned men suffered from
et al.     men (n=6),   a 2-11 year (mean    were taken of two   nificantly decreased in both Pb      peripheral neuropathy, satu-
(1978)     Pb exposed   6 year) history of   out of 6 poisoned   exposed groups compared to con-      rine gout and encephalopathy
           men (n=4)    chronic exposure     men in all groups   trols. BLL at time of testing was    and/or recurrent abdominal
           and controls at a secondary Pb    FSH, LH, TST,       387 and 290 µg/l in the poisoned     colicky pains controls were
           (n=9)        smelter.             estradiol and pro-  and exposed group compared to        of similar socioeconomic
                        Exposed men          lactin were mea-    161 µg/l in the controls. After      background as the exposed
                        worked at the        sured and semen     administration of EDTA only the      groups mean age did not dif-
                        same smelter for     samples were        urine Pb level in the Pb poisoned    fer between groups (30-39
                        1-23 years (mean     taken these param-  group was significantly higher       years) all poisoned men had
                        8.1 years), but had  eters were also     than the controls (999.3 vs. 224.6   been treated with Ca EDTA
                        no clinical signs of determined after    µg/24°). No significant differ-      before the analyses were per-
                        poisoning, 3 of      administration of   ences occurred in sperm volume,      formed poisoned men were
                        them had noted       clomiphene or       motility and % abnormal forms        removed from this work for
                        some decrease in     human chorionic     between the groups. The biopsies     at least 3 months and had
                        libido and fre-      gonadotropin or     were similar and showed an           received one or more courses
                        quency of inter-     gonadotropin        increase in peritubular connec-      of chelation therapy
                        course.              releasing hormone   tive tissue, a decrease in sper-
                        Controls had no                          matogenesis and the presence of
                        present or past his-                     lipofuscin bodies (degrading lyso-
                        tory of excessive                        somes) in the Sertoli cells. Differ-
                        environmental Pb                         ences in basal hormone levels
                        exposure                                 were apparent for TST for both
                                                                 Pb exposed groups (lower TST
                                                                 levels in treated groups). Follow-
                                                                 ing administration of human
                                                                 chorionic gonadotropin, incre-
                                                                 ment of TST was significantly
                                                                 increased in the Pb poisoned men,
                                                                 following administration of clo-
                                                                 miphene the increment of estra-
                                                                 diol in both Pb exposed groups
                                                                 was significantly decreased, in
                                                                 poisoned men increment of LH
                                                                 was also decreased; in poisoned
                                                                 men the peak response of LH had
                                                                 decreased after administration of
                                                                 gonadotropin releasing hormone
52          Metallic lead
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<pre>Table 1.2 Human studies on effects of Pb on fertility
authos    subjects   exposure    design                effects/observations                                                      rem.
Wildt et  Group A:   all men     31 men in group A     no difference was noted between the exposed and non-exposed men           men were matched
al.       men        worked in   were matched with     regarding sperm morphology, count, motility and biochemistry. Of          for age and ethnic
(1983)    exposed    a battery   31 men in group B.    group A, 28% had a low semen volume compared to 4% in group B.            and social factors
          to Pb      factory in  Semen samples were    43.5% of group A and 12.5% of group B showed a decreased function         group A: BLL > 0.5
          (n=31)     Sweden      obtained after 5 days of the accesssory genital glands and the statistical analysis showed a    mg/l once in 6
          and                    of abstinence in Sep- significant difference only for zinc spermatozoa from exposed men         months prior to the
          Group B:               tember and April and  had a significantly lower resistance against SDS treatment (chromatin     study (mean 450
          men not                quality was assessed  stability) than those from the control group                              µg/l);
          exposed                                                                                                                group B: BLL
          to Pb                                                                                                                  occasionally >0.3
          (n=31)                                                                                                                 mg/l and ZPP lev-
                                                                                                                                 els <0.3 mg/l (mean
                                                                                                                                 220 µg/l)
                                                                                                                                 September was 3
                                                                                                                                 months after the
                                                                                                                                 period with lowest
                                                                                                                                 exposure in the
                                                                                                                                 year and April 3
                                                                                                                                 months after the
                                                                                                                                 period with highest
                                                                                                                                 exposure in the
                                                                                                                                 year
Cullen et men diag-  men were    follow-up study       case 1 (11 y exp) was impotent and had chronic diffuse dermatitis and     cases
al.       nosed for  shake out   patient were exam-    small testes with a BLL 550 µg/l and a free erythrocyte protoporphyrin    men lived in Con-
(1984)    Pb intoxi- man (1),    ined and patients 1,  of 533 units; sperm was not found in the ejaculate and LH and FSH         necticut and were
          cation     furnace     3, 4, 5 and 7 were    levels were elevated;                                                     between 22 and 43
          (n=7)      man (2),    treated with Ca       case 2 (15 y exp) suffered from persistent back pain with BLL of 660      years of age (mean
                     storage     EDTA until BLL        µg/l and a free erythrocyte protoporphyrin of 345 units; sperm count      35 year) normal
                     battery     were <300 µg/l        was 18x106/ml with 40% motile sperm;                                      free erythrocyte
                     worker (3,                        case 3 (6 mo exp) was impotent and had developed colic with a BLL         protoporphyrin
                     7), chemi-                        of 830 µg/l and ZPP of 285 units; sperm count was 12x106/ml with          <40; normal ZPP
                     cal opera-                        11% motile sperm;                                                         <28 units; normal
                     tor (4) or                        case 4 (2 mo exp) suffered from headaches, abdominal pain and pares-      sperm count >20
                     painter (5,                       thesias in his left arm with BLL 980 µg/l and ZPP 132 units; gonadal      106/ml and %
                     6), expo-                         function was within the normal range;                                     motile >50%
                     sure                              case 5 (5 y exp) had decreased libido, insomnia, arhtralgia and depres-
                     ranged                            sion with BLL of 700 µg/l and ZPP 222 units; sperm was 25% motile;
                     from 5                            case 6 (5 wk exp) developed colic with a BLL of 900 µg/l and ZPP of
                     weeks to                          135 units (vasectomized);
                     15 years                          case 7 (7 y exp) had developed diffuse arthralgias, intermittent abdom-
                                                       inal pains and irritability with a BLL 390 µg/l; slightly small testes of
                                                       normal texture with no sperm in ejaculate and elevated FSH;
                                                       cases 1, 2 and 7 had defects in thyroid function and except 6, all men
                                                       had subnormal glucocorticoid production after treatment. case 1 had
                                                       slightly improved thyroid and adrenal corticoid function, case 3 had
                                                       slightly improved adrenal corticoid function and sperm count rise, case
                                                       4 had sperm count drop (due to re-exposure after treatment), case 5 had
                                                       sperm count rise and case 7 had slightly improved adrenal corticoid
                                                       function
              Fertility and developmental toxicity studies                                                                                          53
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<pre>Table 1.3 Human studies on effects of Pb on fertility
authors    subjects exposure        design           effect/observations                              remarks
Chowdh exposed      exposed men     semen sam-       average Pb level in blood and semen of the       mean age was 30 years and mean
ury et al. men      were work-      ples were        exposed was 425 and 148 µg/l, respectively,      weight was 55 kg, controls were
(1986)     (n=10)   ing at a news-  colleted and     and significantly higher than in the controls    from the same age and body
           and a    paper printing  physical         average sperm counts were significantly          weight group no figures were
           control  press and       characteris-     lower and sperm was less motile, seminal         given in the article, just descrip-
           group    were exposed    tics of the      plasma acid phosphatase, succinic dehydro-       tions of the effects Pb levels of the
           (n=10)   8 h/day for 10  semen were       genase and fructose content was decreased        controls were not given
                    years, con-     recorded         and tail abnormalities of sperm were of
                    trols were                       marked predominance compared to the con-
                    from the                         trols; volume, pH, colour and viscosity of the
                    administra-                      semen were unaffected compared to the con-
                    tive staff of                    trols
                    the same
                    press
Al-        healthy  exposed men     question-        the rate of spontaneous abortion (mean num-      controls were matched for sex,
Hakkak     exposed  were work-      naire sheets     ber of abortions per family) was significantly   age, work, years of service, social
et al.     men      ing at a stor-  on preg-         higher in the workers' family (1.04) com-        status and education BLLs were
(1986)     (n=22)   age battery     nancy out-       pared to that in the controls (0.30) (p<0.01)    not measured, but in a paper
           and a    plant, con-     come were                                                         regarding the same plant, dust
           control  trols were      distributed                                                       samples contained 9725 µg/g and
           group    employees of                                                                      BLLs of exposed and unexposed
           (n=22)   the Scientific                                                                    men amounted to 380-960 µg/l
                    Research                                                                          (mean 640 µg/l) and 60-300 µg/l
                    Council                                                                           (mean 240 µg/l), respectively
Govoni     Pb       all men         men were         BLLs were 282, 603, 331 and 491 µg/l for         men were divided into 4 groups:
et al.     exposed  worked in       randomly         group A, B, C and D, respectively ZPP levels     A BLL and ZPP <400 µg/l (n=22)
(1987)     men      small pewter    selected from    were 244, 1310, 770 and 340 µg/l for group       B BLL and ZPP > 400 µg/l (n=33)
           (n=76)   factories       those regu-      A, B, C and D, respectively                      C BLL <, ZPP >400 µg/l (n=13)
                                    larly con-       prolactin levels were 34.4, 50.6, 53.4 and       D BLL >, ZPP <400 µg/l (n=8)
                                    trolled by the   33.1 µg/l for group A, B, C and D, respec-
                                    NHS blood        tively (all prolactin levels are within the nor-
                                    was taken        mal range) ZPP and prolactin levels were
                                    and analysed     significantly increased in group B and C
                                    for BLL, pro-    compared to group A
                                    lactin and
                                    ZPP men
                                    were divided
                                    into 4 groups
54            Metallic lead
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<pre>Table 1.4 Human studies on effects of Pb on fertility
authors subjects exposure       design                effects/observations                                       remarks
Assen-   exposed  exposed       monitoring of         blood Pb (610 vs.180 µg/l), urinary Pb (79 vs.18 µg/l),    mean age of both
nato et  men      men worked    exposure, ques-       semen Pb (79 vs. 22 µg/l) and ZPP levels (2.1 vs. 0.24     groups was 40-41
al.      (n=18)   at a storage  tionnaire, physical   mg/l) were significantly higher in battery workers than in year no differences
(1987)   and a    battery plant examination,          cement workers; mean TST, prolactin, total neutral 17-     between groups in
         control  (exposure     semen donation        ks, LH and FSH levels were not significantly different     wine and coffee con-
         group    0.054-0.584   after 3-5 days of     the cumulative frequency distribution of battery worker    sumption and smok-
         (n=18)   mg Pb/m3)     abstinence, collec-   sperm counts was significantly shifted when compared to    ing habits
                  during 1-10   tion of blood,        cement workers (38% lower median sperm count (45 vs.
                  years con-    urine and semen       73x106 cells/cc))
                  trol group    for analyses of Pb,
                  were          ZPP, TST, prolac-
                  cement        tin, total neutral
                  workers not   17-ks, LH and
                  particularly  FSH
                  exposed to
                  Pb
Fis-     reduced  occupa-       man was physi-        blood Pb level was 880 µg/l and blood ZPP level 3.6 mg/    case
cher-    fertile  tional expo-  cally examined,       l, after chelating therapy for 6 months blood Pb level had man was 41 years of
Fisch-   man      sure as       blood Pb and ZPP      sank to ca. 300 µg/l and blood ZPP level to 0.3 mg/l,      age, having one child
bein et  (n=1)    firearms      levels were deter-    both only slightly sank further during the course of the   from a previous mar-
al.               instructor    mined as well as      therapy 2.5 years after starting therapy semen volume      riage and trying to
(1987)            and during    semen quality; the    had decreased from 1.3 to 0.7 ml, sperm density had        have another child
                  cleaning      man was hospital-     increased from 9.6 to 158x106/ml and total sperm count     since 2 years
                  and mainte-   ized for chelation    had increased from 12.5 to 110x106/ ejaculate; motility    man did not smoke
                  nance of the  therapy               had remained equal (50-60%) and the intensity of motil-    and drank alcohol
                  range                               ity had changed from poor to good; normal morphologi-      infrequently results of
                                                      cal appearance of sperm cells had increased from 40 to     a physical examina-
                                                      61% and head defects had decreased from 30 to 22%          tion were normal
                                                      after 1 year of therapy a healthy child was conceived
Rodami   exposed  men worked    blood and serum       BLL increased significantly from 170 µg/l in control       none of the men had
las et   (n=23)   in a Pb       were collected at 8   men to ca. 700 µg/l in all exposed groups; ZPP had sig-    clinical symptoms of
al.      and      smelting      am and analysed       nificantly increased in all exposed groups (2.5 vs. 0.19   Pb exposure
(1988)   non-     works dur-    for BLL, serum        mg/l); there were no differences between exposed groups    1) mean age 30 y (21-
         exposed  ing           TST level, red        for BLL and ZPP serum TST was only significantly           44, n=5)
         (n=20)   1) < 1 year   blood cell, ZPP,      lower in the longest exposed group (18.6 vs. 22.9 nmol/l)  2) mean age 33 y (21-
         men      2) 1-5 years  SBG level and         SBG had significantly increased in the two longest         46, n=8)
                  3) >5 years   serum LH and          exposed groups to the same extend compared to the con-     3) mean age 34 y (25-
                                FSH levels            trol group (34 vs. 25 nmol/l) the free TST index was       52, n=10)
                                                      decreased in the two longest exposed groups (71 and        control men between
                                                      55% vs. 93%) LH concentration was significantly            20-60 years of age
                                                      increased in all exposed groups to the same extend (10
                                                      vs. 6 U/l) FSH concentration did not change significantly
                                                      (5 U/l)
              Fertility and developmental toxicity studies                                                                            55
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<pre>Table 1.5 Human studies on effects of Pb on fertility
authors   subjects      exposure       design          effects/observations                          remarks
Gustafso healthy men    exposed men    matched study   BLLs differed significantly between           average age was 36 and 36.8
n et al. exposed        worked at a    BLL was deter-  exposed men and controls (390 vs. 50 µg/      years for exposed and control
(1989) (n=25) and       secondary Pb   mined as well   l)                                            men
          non-exposed   smelter con-   as LH, FSH,     FSH level was significantly decreased in      none of the subjects had any
          to Pb (n=25)  trols were     total TST and   exposed men compared to controls (3.6 vs.     known alcohol or drug prob-
                        engineering    PRL in plasma   4.5 U/l) when persons who had taken sele-     lems
                        industry       and cortisol,   nium pills* were excluded from the study,     general health was assessed by
                        workers and    TSH, T3, thy-   the lower FSH in exposed workers was          liver function and serum urate
                        post-office    roxine and free more pronounced, whereas a higher thy-        level
                        employees      TST in serum    roxine level became significant. as correla-  men were matched for age and
                                                       tions existed for age and TST, age and        shiftsall values were within the
                                                       FSH and age and TSH, a subgroup of            normal range
                                                       workers <40 years of age was selected:
                                                       significant differences existed for thyrox-   *Pb might influence selenium
                                                       ine (exposed vs. control, 88 vs 73 nmol/l),   metabolism
                                                       FSH (2.9 vs. 4.1 U/l), LH (7.6 vs. 8.9 U/l)
                                                       and cortisol (295 vs. 382 nmol/l)
Coste et fertile men    men working    person-year-    Pb exposure did not appear to be associ-      men were aged 20-60 (mean
al.       exposed       at a battery   analysis taking ated with infertility, in contrast to age >40 36.5) and had worked at least 1
(1991) (n=229) and      factory        confounders     years, French origin, primary school edu-     year in the factory; average fol-
          non-exposed   divided in 4   into account;   cation level and having a child or children   low-up was 4.1 years and 63%
          (n=125) to    groups:        infertility was                                               of the subjects was observed
          Pb (exposed   1) workpost    defined by the                                                for the entire duration of the
          886 person-   non-exposed    non-occur-                                                    study confounders taken into
          years, non-   2) workpost    rence of live                                                 account were age, ethnic ori-
          exposed 598   with BLL       birth during                                                  gin, education level, socio-eco-
          person-       <400 µg/l      one observed                                                  nomic status, no. of previous
          years)        3) workpost    year                                                          live births, alcohol consump-
                        with 400 µg/l                                                                tion, smoking, exposure to
                        BLL 600 µg/l                                                                 heat, working hours and sulfu-
                        4) workpost                                                                  ric acid exposure
                        with BLL
                        >600 µg/l
Lind-     men occupa-   men were       case-referent   Pb exposure in cases and referents did not    * model was adjusted for pater-
bohm et   tionally      occupation-    study question- differ significantly: ca. 25% of the men      nal exposure to Cd and Hg,
al.       exposed to    ally exposed   naire on job    had BLL <207 µg/l and ca. 2.5% >394 µg/       maternal exposure to organic
(1991)    Pb and their  to Pb and      and pregnan-    l BLLs were not found to be related signif-   solvents, Hg and alcohol, par-
          pregnant      worked in      cies, data were icantly to the incidence of spontaneous       ity, contraception, previous
          wives having  numerous       obtained from   abortion in general                           spontaneous abortion and the
          had a sponta- fields of      medical regis-  when only BLLs measured during or close       index of missing information
          neous abor-   industry       ters and the    to the time of spermatogenesis were taken
          tion (n=213)                 Institute of    into account, an increased risk on sponta-
          or had given                 Occupational    neous abortion was detected for BLL >311
          normal birth                 Health          µg/l (OR 3.8, 95% CI 1.2-12)*
          (n=300)                      BLLs were as
                                       much as possi-
                                       ble obtained
                                       from the sper-
                                       mato-
                                       genesis period
56            Metallic lead
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<pre>Table 1.6 Human studies on effects of Pb on fertility
authors   subjects      exposure        design        effects/observations                                  remarks
Ng et al. men           exposed men     BLL and       average BLLs amounted to 352 and 83 µg/l for          none of the subjects had
(1991)    exposed       worked in       ALAD in       exposed and control men (p=0.0001)                    a history of liver, renal
          (n=122) and   three Pb bat-   erythrocytes  ALAD was 0.45 µM/h/ml RBC in exposed men and          or other recent or
          non-          tery factories  analysis was  1.25 µM/h/ml RBC in controls (p<0.0001); LH and       chronic diseases or ill-
          exposed       (mean 18 mg     carried out   FSH were significanlty increased in exposed men       nesses no significant
          (n=49) to     Pb/m3)          every 6       compared to controls (LH 4.59 vs. 3.24 IU/l and       differences in age,
          Pb            controls were   months start- FSH 2.52 vs. 1.92 IU/l);TST and PRL did not differ    smoking and drinking
                        hospital engi-  ing January   significantly (TST ca. 7 ng/ml, PRL ca. 194 mIU/l);   habits existed between
                        neering and     1982 (mean    when the groups were divided in men younger than      the two groups mean
                        maintenance     6.2 times)    40 years and 40 years and older, TST was signifi-     age was 34.4 and 32.6
                        workers or      TST, LH,      cantly lower in the exposed group aged 40 years and   years in non-exposed
                        technicians     FSH and       above than in controls (p<0.01) and LH and FSH        and exposed groups;
                                        PRL levels    were significantly higher in exposed men younger      mean years of exposure
                                        were deter-   than 40 years compared to controls (p<0.01); PRL      was 6.0
                                        mined         did not show any age-specific differences reduced
                                                      TST and normal LH levels (sec. hypogonadism)
                                                      were noted in 13.9% of the exposed subjects and
                                                      4.1% of the non-exposed subjects (p=0.05); raised
                                                      LH values with normal TST levels (compensated
                                                      prim. hypogonadism) were found in 23.8% of the
                                                      exposed and 6.1% of the non-exposed subjects
                                                      (p<0.05)
Lerda     healthy fer-  men working     blood and     mean δ-ALA levels in blood were 14.2, 19.4, 24.6      average exposure time
(1992)    tile men      at a battery    sperm sam-    and 39.3 U/l for A, B, C and controls, respec-        11.7 years mean age 36
          exposed       factory         ples were     tivelysperm count (A vs. control, 69.2 vs.            years (exposed) and 35
          (n=38) and    grouped         collected     101.5x106/ml), motility (49.0 vs. 70.4%) and death    years (controls)
          non-          according to    after 4 days  (68.1 vs. 82.9%) had significantly decreased in all
          exposed       Pb blood        of absti-     exposed groups compared to controls; the percent-
          (n=30) to     level           nencelevels   age of anomalies had increased significantly (72.5
          Pb            A) 866 µg/l     of Pb and d-  vs. 33.4%) in all groups
                        B) 659 µg/l     ALA in
                        C) 486 µg/l     blood were
                        control 235     analysed as
                        µg/l            well as sev-
                                        eral sperm
                                        parameters
Hu et al. men           exposed men     question-     mean Pb urine level differed significantly between    age, living conditions,
(1992)    exposed       worked at       naire; analy- exposed (87.6 µg/l) and controls (4.2 µg/l) sperm of  smoking and drinking
          (n=24) and    small print-    sis of urine  exposed men contained significanlty less cells/ml     habits and exposure to
          non-          ing house or    Pb level and  (56.9 vs. 76.7x108/ml) and significantly more ter-    other toxicants harmful
          exposed       battery fac-    several       atospermic cells (21.0 vs. 12.3%); sperm motility did to the reproductive sys-
          (n=24) to     tory (concen-   semen         not differ significantly between groups; a decreased  tem did not differ sig-
          Pb            tration of Pb   parameters    level of lactate dehydrogenase-x was found in sperm   nificantly between the
                        exceeded                      of the exposed group                                  groups
                        0.03 mg/m3
                        all year long),
                        controls were
                        building
                        workers
             Fertility and developmental toxicity studies                                                                           57
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<pre>Table 1.7 Human studies on effects of Pb on fertility
authors    subjects     exposure         design           effects/observations                                remarks
Gennart    men          exposed men      questionnaire, no effect of Pb could be evidenced on the renal       no statistically signifi-
et al.     exposed      were             determination and endocrine parameters, total erythrocyte count      cant difference in age,
(1992a)    (n=98) and   employed in a    of several       or autonomic nervous system                         weight, height, smok-
           non-         Pb acid bat-     parameters in                                                        ing and drinking habits
           exposed      tery factory     blood and                                                            and urinary cadmium
           (n=85) to    and were         urine, and car-                                                      levels were observed
           Pb           moderately       diac parasym-                                                        between controls and
                        exposed          pathic function                                                      exposed menblood
                        according to                                                                          parameters measured
                        their BLL                                                                             were ZPP, creatinine,
                        (mean 510 µg/                                                                         β2-microglobulin, tri-
                        l, range 400-                                                                         iodothyronine, thyrox-
                        750 µg/l) for                                                                         ine, triiodothyroine
                        at least 1 year,                                                                      resin uptake, TSH,
                        controls                                                                              FSH, LH urine parame-
                        worked in fac-                                                                        ters measured were
                        tories in the                                                                         ALA, creatinine, ret-
                        area and had a                                                                        inol-binding protein,
                        mean BLL of                                                                           albumin, β2-microglo-
                        209 µg/l                                                                              bulin, N-acetyl- b-D-
                        (range 44-390                                                                         glucosaminidas; para-
                        µg/l)                                                                                 sympathic function
                                                                                                              was assessed by mea-
                                                                                                              suring interval varia-
                                                                                                              tion between the
                                                                                                              consecutive R waves
                                                                                                              on the electrocardio-
                                                                                                              gram
Lerda      healthy fer- men working      blood and        mean d-ALA levels in blood were 14.2, 19.4, 24.6    average exposure time
(1992)     tile men     at a battery     sperm samples    and 39.3 U/l for A, B, C and controls, respectively 11.7 years mean age 36
           exposed      factory          were collected   sperm count (A vs. control, 69.2 vs. 101.5x106/     years (exposed) and 35
           (n=38) and   grouped          after 4 days of  ml), motility (49.0 vs. 70.4%) and death (68.1 vs.  years (controls)
           non-         according to     abstinencelev-   82.9%) had significantly decreased in all exposed
           exposed      Pb blood level   els of Pb and d- groups compared to controls; the percentage of
           (n=30) to    A) 866 µg/l      ALA in blood     anomalies had increased significantly (72.5 vs.
           Pb           B) 659 µg/l      were analysed    33.4%) in all groups
                        C) 486 µg/l      as well as sev-
                        control 235      eral sperm
                        µg/l             parameters
58            Metallic lead
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<pre>Table 1.8 Human studies on effects of Pb on fertility
authors    subjects   exposure      design          effects/observations                          remarks
Alex-      men        men work-     cross sec-      mean blood Pb concentration was 224 µg/l      mean age of men 38.2-41.8 years
ander et (n=12-46) ing at a Pb      tional study    (range 50-580 µg/l) geometric mean sperm      mean years of service 15.7-19.8
al. (1996)            smelter       blood and       concentration and total sperm count were
                      were          semen sam-      inversely related to BLL; workers with BLL    *alcohol consumption, presence of
                      divided into  ples were       >400 µg/l had an increased risk of having a   other metals in blood, period of
                      4 groups:     collected       below WHO normal sperm concentration          abstinence, history of reproduction
                      1) BLL        after 48h of    and total sperm count also after controlling  difficulties, use of hot tubs and sau-
                      <150 µg/l     abstinence      for several effects* independent of current   nas and history of reproductive tract
                      2) BLL        and analy-      Pb exposure, sperm concentration, total       infection
                      150-240 µg/   sed for Pb      sperm count and total motile sperm count
                      l             level; semen    were inversely related to measures of long
                      3) BLL        was analy-      term Pb exposure no association was found
                      250-390 µg/   sed for TST,    between Pb exposure and measures of
                      l             FSH and LH      sperm motility and morphology or serum
                      4) BLL 400    level           concentrations of reproductive hormones
                      µg/l
Lin et al. Pb         exposed       retrospec-      50.4% of the cases reported had low, 39.1%    men were matched to age and resi-
(1996)     exposed    men were      tive cohort     medium and 10.4% high BLLs                    dence BLLs of bus drivers were not
           (n=4256)   reported to   study           Pb exposed workers had fewer births than      measured no differences exist
           and non-   the New       Pb exposure     expected (overall SFR 0.88, 95% CI 0.81-      between groups for distribution of
           exposed    York State    was divided     0.95) mean group BLLs were not associated     race, wife's age, parity of history of
           men        Heavy Met-    into high       with fertility, but workers with heavy expo-  abortion men were registered when
           (n=5148)   als Regis-    (500 µg/l),     sure (>500 µg/l and duration of exposure >5   BLL 400 µg/l (1981-1986) or when
                      try; controls medium          years) were significantly less likely to have BLL 250 µg/l (1986-1992) SFR =
                      were bus      (350-490 µg/    any children compared to the control group    standard fertility ratio confounders
                      drivers       l) and low      (ratio 0.4 95% CI 0.2-0.7) as well as any     were education, race and residence
                      licenced in   (250-340 µg/    worker with exposure time > 5 years (ratio
                      the State of  l) BLLs birth   0.3, 95% CI 0.2-0.5) (after adjustment for
                      New York      certificates    confounders: ratio 0.38, 95% CI 0.23-0.61)
                                    were con-
                                    sulted
             Fertility and developmental toxicity studies                                                                              59
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<pre>Table 1.9 Human studies on effects of Pb on fertility
authors    subjects    exposure       design               effects/observations                  remarks
Occupationally exposed women
Sallmén    wives of    exposed men    retrospective study  24.5% of the men in the study had     paternal exposure was assessed when
et al.     husband     were           Pb exposure was      BLL >207 µg/l and 4.6% had BLL        possible about 80 days before the
(2000)     occupa-     reported to    assessed from        >394 µg/l                             attempt at pregnancy began
           tionally    the Finnish    blood Pb measure-    the fecundability density ratios,
           exposed     Institute of   ments and ques-      adjusted for potential confounders*,  *age of wife, unplanned pregnancy,
           to Pb       Occupa-        tionnaires           were 0.92 (95% CI 0.73-1.16), 0.89    maternal and paternal life style, use of
           (n=502)     tional Health  completed by the     (0.66-1.20), 0.58 (0.33-0.96) and     contraception, menstruational fac-
                                      men. data on         0.83 (0.50-1.32) for blood Pb cate-   tors, age at menarche, previous preg-
                                      wives was            gories 104-186 µg/l, 207-290 µg/l,    nancies, year of pregnancy, frequency
                                      obtained from the    311-373 µg/l and >394 µg/l**          of intercourse, pregnancy outcome,
                                      central population                                         maternal exposure to organic sol-
                                      register, TTP was                                          vents or Pb, paternal exposure to
                                      calculated based                                           organic solvents or other metals
                                      on data obtained                                           ** discontinuous categories arise
                                      from the women                                             from the translation of µmol/l in the
                                      themself                                                   paper to µg/l in this report
Sallmén    women       women had      based on biologi-    there were no systematic differences exposure categories were: not
et al.     occupa-     been occupa-   cally monitoring,    in the distribution of time to preg-  exposed, BLL 100 µg/l,
(1995)     tionally    tionally       work description     nancy between exposed and non-        100<BLL>190 µg/l, BLL 190 µg/l
           exposed     exposed to     and a self-report of exposed women exposure to Pb was
           to Pb       Pb and had     exposure, women      not significantly associated with
           (n=65)      been moni-     were divided in      decreased fecundability (measured
           and non-    tored at the   four exposure        as the incidence density ratio which
           exposed     Institute of   groups; time-to-     estimates an average ratio of inci-
           women       Occupa-        pregnancy was        dence densities of pregnancies for
           (n=56)      tional Health  related to exposure  exposed women compared with the
                       (Finland);     with the discrete    unexposed through menstrual cycle
                       women from     proportional haz-    classes) after adjustment for expo-
                       the two high-  ards regression      sure to carcinogens, age, parity, use
                       est catego-                         of alcohol, use of coffee, older age
                       ries worked                         at menarche, vaginitis and fre-
                       in the graphic                      quency of intercourse
                       industry,
                       chemical
                       industry and
                       metal indus-
                       try
ALA= -aminolevulinic acid; ALAD = aminolevulnic acid dehydratase; BLL= blood Pb level; FSH= follicle-stimulating hormone;
ks= ketosteroid; LH=luteinizing hormone; PRL = prolactin; SHBG = sex hormone binding globulin; SBG = serum steroid binding
globulin; T3 = triiodothyronine; TSH=thyroid-stimulating hormone; TST = testosterone; TTP = time to pregnancy; ZPP = zinc proto-
porphyrin IX
60            Metallic lead
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<pre>Table 2.1 Human studies on effects of Pb on development
authors   subjects        exposure     design                    effects/observation                            remarks
Exposed men
Sallmén   children with   men had      retrospective case con-   80.7% of the controls had a BLL <186 µg/l      BLLs used were
et al.    (n=27) or       been occu-   trol study ata on expo-   and 19.3% had a BLL between 207-290            obtained within 36
(1992)    without         pationally   sure (1973-1983)          µg/l; for the cases 63% and 18.5% were in      months of the sper-
          (n=57) con-     exposed to   women and pregnancies     these first two groups, whereas 14.8% and      matogenesis period
          genital mal-    Pb and had   and pregnancy outcomes    3.7% had BLL between 311-373 µg/l and          prior to conception (80
          formations of   been moni-   were collected all 18-40  >394 µg/l, respectively* the distribution of   d) occupations were
          Pb exposed      tored at the year women with a mal-    exposed cases by the type of malformation      repair of automobiles,
          and non-        Institute of formed child were         was heterogeneous and all the five case        electrical, painting and
          exposed men     Occupa-      defined as cases and      children of the men in the two highest Pb      welding work and other
                          tional       matched with 3 times as   exposure categories had a different type of    iron and metal work
                          Health       much age controls cases   malformation the OR of congenital malfor-      *categories given in the
                          (Finland)    and controls were         mations for paternal Pb exposure was           paper are 0-0.9 µmol/l,
                                       divided in 4 groups       increased (OR 2.4, 95% CI 0.9-6.5) though      1.0-1.4 µmol/l, 1.5-1.8
                                       based on estimated        not reaching statistical significance          µmol/l and 1.9 µmol/l
                                       BLLs during 80 d period
                                       before conception
Kris-     men exposed     Pb           men were categorised as   deaths occurring during the perinatal
tensen et to Pb only      exposed      to their exposure to Pb   period (including late abortions, stillbirths,
al.       (n=1205) and    men were     and solvents, non-        early neonatal deaths) were significantly
(1993)    all children    involved in  exposed employees         increased for children of the Pb exposed
          born to print-  several      served as controls; all   men (adjusted OR 2.4, 95% CI 1.2-4.9)
          ers (n=6251)    printing     births that occurred in   (early) preterm birth, length of gestational
                          tasks        Oslo during the same      age, small for gestational age and low birth
                          (composi-    period served as an       weight were not related to Pb exposure the
                          tors, litho- external reference        standardized morbidity ratio for boys with
                          graphers,    records from the printers fathers exposed to Pb or exposed to Pb and
                          bookbind-    union and birth registra- solvents (no distinction was made) was
                          ers)         tion were linked          significantly increased for cleft lip (SMR
                                                                 4.1, 95% CI 1.8-8.1)
              Fertility and developmental toxicity studies                                                                             61
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<pre>Table 2.2 Human studies on effects of Pb on development
authors    subjects exposure       design           effects/observation                              remarks
Exposed women
Fahim et pregnant   women liv-     Pb analyses in   In the area around the smelter 70.0% of the      women were between 20 and 25
al.        women    ing in the     maternal and     women were term, 17.0% were term with            years of age and living in the
(1976) around       neighbour-     cord blood, pla- PRM and 13.0% were preterm, in the control       subsequent areas for at least 10
           delivery hood of a Pb   centa and mem-   area these percentages were 96.4, 0.4 and 3%     years definitions:
           (n=249-  smelter        brane,           fetal and maternal BLLs did not differ signifi-  premature: neonate born before
           253)     (Rolla, Mis-   recording of     cantly between the areas, however for both       37 weeks of gestation and
                    souri) were    placenta weight  areas BLLs were significantly higher in term     weighing less than 2500 g
                    compared to    and length and   with PRM and preterm pregnancies compared        premature rupture of the mem-
                    women liv-     diameter of      to term pregnancies (maternal BLL 256-301        brane (PRM): spontaneous rup-
                    ing in an      umbilical cord,  µg/l vs. 131-143 µg/l and fetal BLL 96-175       ture of the membrane before the
                    area without   morphological    µg/l vs. 43-46 µg/l)                             onset of labour and when labour
                    any Pb min-    and histological no differences were observed for ceruloplas-     does not begin within 12 hours
                    ing activi-    examination of   min levels in both maternal and fetal blood
                    ties           placenta, ques-  except for premature pregnancies: fetal ceru-    *figures are obtained from a
                    (Colombia,     tionnaire        loplasmin levels were significantly decreased    graph in the paper
                    Missouri)      regarding preg-  for both the exposed and control group (98-
                                   nancy and new-   105 mg/l vs. 175 mg/l)
                                   born             Pb levels in placenta and cord did not differ
                                                    significantly (placenta 60-90 µg/kg, cord 90-
                                                    120 µg/l)
                                                    Pb levels in the membrane increased in both
                                                    exposure groups significantly in preterm and
                                                    term with PRM compared to term deliveries
                                                    (ca. 250-400 µg/kg vs. 50-100 µg/kg)*
                                                    no pathological findings in the cell structure
                                                    were observed in histological sections taken
                                                    from placenta, cord or membrane
McMich pregnant     women lived    during 3 years   The mean prenatally and perinatally BLLs         Port Pirie cohort study age dis-
ael et al. mothers  in the city of women were       were in PP women significantly higher than in    tribution over Port Pirie (PP)
(1986) and their    Port Pirie     enrolled for     NP women, except between weeks 21-29 of          and non-Port Pieri (NP) women
           newborn  (78%), a Pb    prospective      gestation (106 µg/l vs. 76 µg/l) in NP women     were similar among PP women,
           babies   smelter com-   study BLLs       1 woman had a spontaneous abortion, whereas      85% had lived there for at least
           (n=774-  munity, or in  were deter-      in PP women 22; these were not related to        3 years, while 79% and 70%
           831)     the sur-       mined at 14-20   BLL the relative risk for a pre-term delivery    had lived there for at least 5 and
                    rounding       weeks' gesta-    increased with maternal BLL and was signifi-     10 years, respectively pre-term
                    agricultural   tion, around 32  cantly increased when BLL >140 µg/l (RR          delivery: birth before the 37th
                    area (22%)     weeks' gesta-    4.4, 95% CI 1.2-16.8) and highest with BLL at    week, including stillbirths
                                   tion and at      delivery although more still births occurred in
                                   delivery         the PP women (17.5/1000 vs. 5.8/1000 live
                                   (mother and      births), still births were negatively associated
                                   umbilical cord), with individual maternal BLL
                                   31% enrolled     BLLs were not significantly related to birth
                                   much earlier     weight, crown heel length, head circumfer-
                                   and also then a  ence, premature rupture of membranes, con-
                                   blood samples    genital anomalies or difficulties in conceiving
                                   was taken data
                                   on pregnancy
                                   outcome and
                                   socio-eco-
                                   nomic status
                                   was obtained
62            Metallic lead
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<pre>Table 2.3 Human studies on effects of Pb on development
authors subjects     exposure       design                    effects/observation                         remarks
Wigg et pregnant     all children   BLLs were determined at   mean BLL of umbilical blood amounted Port Pirie cohort study
al.      mothers     were born in   enrollment of the mothers to 83 µg/l
(1988) and their     the city of    (at 14-20 weeks of gesta- the mean MDI was 109.2 and the mean
         newborn     Port Pirie, a  tion), early in the third PDI 105.3
         babies      Pb smelter     trimester, at delivery,   MDI was significantly negatively corre-
         (n=497-     community,     from cord, and at postna- lated with BLL after 20 weeks of gesta-
         523)        or in the sur- tal age 6, 15 and 24      tion but not at delivery nor with cord
                     rounding       months of age and anu-    BLL, PDI was not related with any of the
                     agricultural   ally thereafter, at 24    BLLs measured prenatally or around
                     area           months of age the devel-  birth
                                    opmental status of each
                                    child was assessed with
                                    the Bayley scales
McMic    pregnant    all children   see previous study chil-  mean maternal BLL varied from 91 µg/l       Port Pirie cohort study
hael et  mothers     were born in   dren were assessed with   at 16 weeks of gestation to 95 µg/l at      covariates included sex,
al.      and their   the city of    the McCarthy Scales of    delivery, mean BLL in the cord was 83       residence, HOME score
(1988)   newborn     Port Pirie, a  Children's Abilities at 4 µg/l                                        and aspects regarding par-
         babies      Pb smelter     years of age              mean scores for verbal, perceptual per-     ents and delivery
         (n=537-     community,                               formance, quantitative, GCI , memory
         463)        or in the sur-                           and motor were 53.5, 56.9, 50.5, 107.1,
                     rounding                                 48.2 and 53.8 on a 100 (GCI) or 50 (all
                     agricultural                             others) scale
                     area                                     antenatal (average) BLL was signifi-
                                                              cantly negatively correlated with GCI
                                                              and memory scale, whereas BLL at
                                                              delivery was significantly negatively
                                                              related to GCI, perceptual-performance
                                                              and memory scale, cord BLL was not
                                                              related to any of the scales; after partial
                                                              regression analyses incorporating covari-
                                                              ates no associations remained
             Fertility and developmental toxicity studies                                                                          63
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<pre>Table 2.4 Human studies on effects of Pb on development
authors   subjects   exposure       design        effects/observation                              remarks
Murphy    pregnant   women          BLLs were     current BLLs were 160 and 52 µg/l for women      Kosovo study women were
et al.    women      lived in       determined    from T. Mitrovica and Pristina, respectively     selected who had at least one pre-
(1990)    (n=304-    Titova         and preg-     erythrocyte protoporphyrin was higher in         vious pregnancy and had not
          335)       Mitrovica in   nancy out-    exposed women than in controls (0.71 vs. 0.5     moved since their first pregnancy
                     the neigh-     come (first   µmol/l) haemoglobin was similar for both         mean maternal and paternal age
                     bourhood of    pregnancy)    groups (123-125 g/l) as well as serum ferritin   was 21.7-22.1 and 25.6-26.0
                     a Pb           recorded      (10.8-12.5 µg/l) adjustment for maternal age at  years for both regions, respec-
                     smelter,                     first pregnancy, current smoking, ethnic group,  tively mean maternal and paternal
                     refinery and                 and maternal education, resulted in a small dif- education was 8.7 and 11.2-11.3
                     battery                      ference in the odds ratio regarding town of res- for both regions, respectively in
                     plant con-                   idence and spontaneous abortion (OR 1.1          T. Mitrovica 28.8% of the hus-
                     trols were                   (95% CI 0.9-1.4) or stillbirths (OR 1.0 (95%     bands were employed in Pb
                     from Pris-                   CI 0.6-1.5)                                      industry whereas in Pristina none
                     tina both                                                                     of them was occupationally
                     towns are in                                                                  involved with Pb mean number of
                     Yugoslavia                                                                    previous pregnancies, percentage
                                                                                                   current smokers and alcohol users
                                                                                                   and ethnic groups were equally
                                                                                                   distributed among both regions
Factor-   pregnant   women          women were    BLLs at mid-pregnancy, delivery and in           Kosovo study
Litvak et women      lived in       enrolled at   umbilical cord were 191, 234 and 222 µg/l for
al.       exposed    Titova         mid-preg-     T. Mitrovica and 54, 68 and 56 µg/l for Pris-
(1991)    (n=401)    Mitrovica in   nancy and     tina birth weight did not vary significantly
          and non-   the neigh-     BLL were      between both towns or mid-pregnancy BLLs
          exposed    bourhood of    determined;   (TM 3308 g vs. P 3361 g) nor did length of
          (n=506)    a Pb           at delivery   gestation (TM 274 days vs. P 275 days) pre-
          to Pb and  smelter,       birth weight  term delivery occurred in 16.8% of births in
          their new- refinery and   and length of TM and 11.4% in P (unadjusted OR, using
          born       battery        gestation     town as exposure variable = 1.6, 95% CI 1.3-
          babies     plant con-     were recorded 1.9), however, when exposure was defined by
                     trols were     as well as    BLL the odds of preterm delivery did not
                     from Pris-     BLL in cord   increase with BLL (neither mid-pregnancy nor
                     tina both      blood         cord or maternal BLL at delivery)
                     towns are in
                     Yugoslavia
64           Metallic lead
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<pre>Table 2.5 Human studies on effects of Pb on development
authors subjects          exposure        design           effects/observation                                        remarks
Roth-     pregnant        family lived    follow-up for    during pregnancy maternal BLL was ca. 100 µg/l until      case
enberg    women and       in Mexico       3 years          week 36, at delivery the BLL had risen to ca. 500 µg/l    at week 36 a glazed ceramic pitcher
et al.    her infant      City            BLLs of          cord BLL amounted to ca. 700 µg/l, babies BLLs            was brought into the family
(1992)    (n=1)                           mother and       amounted to ca. 1000, 400, 350, 425, 325, 350 and         woman complained of lumbar pain
                                          child were       175 µg/l at 1.5, 6, 12, 15, 18, 24, 30 and 36 months of   radiating to the abdomen, paresthesia
                                          determined       age, respectively NBAS and G/R showed hypertonia,         in the lower extremities, nausea, occa-
                                          child was reg-   irritability, abnormal cry and other neurological soft    sional vomiting and hypertension
                                          ularly assessed  signs at 2, 15 and 30 days; brainstem auditory evoked     child was nursed continuously until
                                          for neurologic   responses and clinical EEG were essentially normal at     the age of 27 months psychometric
                                          and general      20 days, 3, 6 and 12 months; EEG sleep pattern was        testing included Bayley scales, Ter-
                                          development      fragmented at 20 days and 3 months and abnormal res-      man Merril and McCarthy scales diag-
                                                           piratory patterns were noted at 6 months; psychomet-      nostic testing included Fagan test of
                                                           ric and diagnostic testing yielded scores within normal   infant intelligence
                                                           limits up to 3 years; at every examination, testing pro-
                                                           tocols noted some combination of restlessness, agita-
                                                           tion, distractibility, high energy level, lack of
                                                           persistence, short attention span and poor fine motor
                                                           control
Wan et pregnant           women           blood and        BLLs in the first trimester, at delivery and in the cord  women had an average age of 25.5 y
al.       mothers         worked in a     urine was col-   amounted to 178.8, 203.8 and 185.6 µg/l for the           (23-34) and a mean exposure time of
(1996) exposed            storage bat-    lected at the    exposed group and 54.1, 72.5 and 71.3 µg/l for the        3.5 years (0.6-6) pregnancies were
          (n=45) and      tery, the con-  beginning of     controls, respectively ZPP levels were 841.5, 936.2       diagnosed as normal and women had
          non exposed     centration of   pregnancy and    and 692.4 µg/l for the exposed group and 319.8, 436.2     no chronic illnesses control women
          (n=56) to Pb    air Pb in their then every       and 491.1 µg/l for the controls, respectively values for  were selected with similar age distri-
          and their       work room       three months     BLL and ZPP were significantly different between the      bution
          newborn         ranged          till delivery    exposed and control women mean gestational age in
          infants         between 0.05-   and analysed     the exposed group was 274.6 days and birth weight,
                          0.5 mg/m3       for Pb and       height and head circumference were 3352 g, 49.5 cm
                          depending on    ZPP (blood)      and 33.7 for the male babies and 3315 g, 49.7 cm and
                          operational     and ALA and      33.6 cm for the female babies, no significant differ-
                          site controls   creatinine       ences existed between the control and the exposed
                          worked in a     (urine) birth    groups in the exposed group there were 2 still births
                          electronics     characteristics  and 4 pre-term births, whereas in the control group
                          assembly        were recorded    there were 3 pre-term births and no stillbirths
                          plant
δALA= δ-aminolevulinic acid; BLL = blood Pb level; CI = confidence interval; G/R = Graham/Rosenblith Behavioural Examination of the Neonate
included General Maturation scale, Neurological Soft Sign Score and Muscle Tonus; HIAA = 5-hydroxy indoleacetic acid; HOME = Home Observa-
tion for Measurement of the Environment; MDI = mental development index (Bayley); NBAS = the Brazelton Neonatal Behavioural Assessment
Scale; PDI = psychomotor development index (Bayley); ZPP = zinc protoporphyrin IX.
Mental Development Index is an age-corrected scale that assesses infants "sensory-perceptual acuities, discriminations, and the ability to respond to
these; the early acquisition of 'object constancy', memory, learning, and problem solving ability: vocalizations and the beginnings of verbal communi-
cation; and early evidence of the ability to form generalizations and classifications, which is the basis of abstract thinking".
The McCarthy Scales of Children's Abilities can be subdivided in verbal, perceptual-performance and quantitative scales contributing to the general
cognitive index and, partially overlapping the first three, in a memory and motor scale.
The items recorded for the G/R Soft Signs Scale included ratings of slight or moderate jitteriness, decreased strength of cry, high pitched cry, slight or
definite indication of hypersensitivity to touch, to sound or to light, sharp state swings, and setting sun sign (one instance).
                 Fertility and developmental toxicity studies                                                                                             65
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<pre>Table 3.1 Human studies on effects of Pb on lactation
authors   subjects   exposure         design        effects/observation                            remarks
Ryu et    lactating  woman had        determina-    during exposure maternal blood Pb concen-      case
al.       woman      worked 3         tion of Pb    tration ranged from 0.43-0.57 mg/l which       woman was 25 years old first
(1978)               years (until 7   content in    decreased to 0.33 mg/l at delivery (mean       born daughter to the women and
                     weeks before     milk and      Iowa women 0.1 mg/l (range 0.02 to 0.29));     weight 2982 g, physical and neu-
                     delivery) by a   blood of      during lactation Pb levels were higher with a  rologic examinations did not
                     producer of      mother and    peak after 6 months (0.63 mg/l) Pb concen-     reveal any abnormality
                     electrical stor- child from 8  tration in cord blood amounted to 0.33 mg/l
                     age batteries    weeks         and in blood taken from the child aged 12 h,
                     and had been     before parti- 6 days and 9 months 0.7, 0.51 and 0.2 mg/l,
                     exposed dur-     tion until    respectively.
                     ing this occu-   day 245 of    milk Pb concentrations were in the first three
                     pation to        lactation     weeks of lactation 19-63 µg/l and the follow-
                     considerable                   ing month 36-62 µg/l, where after it
                     amounts of Pb                  decreased.; mean value 3rd month of lacta-
                     dust                           tion 24 µg/l, and month 4-7 of lactation 4-14
                                                    µg/l.
Nami-     healthy    living <200 m    Pb determi-   mean blood Pb level was 0.46 mg/l (range       women were 15-39 years of age
hira et   lactating  around a Pb      nation in     0.15-0.99 mg/l) geometric mean milk level      and belonged to low socioeco-
al.       women      smelter in 3     blood and     was 24.7 µg/l (range 9.2- 350 µg/l); 54% of    nomic class 51% of women had
(1993)    aged 15-39 areas of Mex-    milk col-     samples was below detection level high cor-    lived >10 years in this area 74%
          (n=35)     ico City >1      lected over a relation blood-milk Pb level (r=0.88) no cor-  of the women had never smoked
                     year             2 months      relations between parity, months of lactation, and the rest smoked <5 cigarettes/
                                      time          no. of children, years of residence and breast w 57% of the women had not
                                                    milk levels                                    nursed before mean duration of
                                                                                                   nursing 5.85 mo (range 1-27 mo)
Palm-     healthy    women lived      Pb analysis   mean Pb concentration in blood from            the mean age of both groups of
inger     pregnant   in Rönnskär or   in maternal   exposed mothers was 38.7 µg/l differed sig-    women was 29 years
Hallén    women      Holmsund in      blood at      nificantly from the control group, 32.3 µg/l   13 and 17 women in the exposed
et al.    (n=39)     the neighbour-   delivery and  at delivery (range 18-70 µg/l) 6w postpartum   area and control group, respec-
(1995)               hood of          6 weeks       Pb concentration in the blood of exposed       tively, were primaparous
                     Rönnskär is a    postpartum    mothers had reduced to 31.7 µg/l, whereas      8 and 4 children in the exposed
                     copper and Pb    and in milk   the concentration in the control group         and control group, respectively,
                     smelter situ-    6 weeks       remained stable Pb concentration in milk 6w    received infant formula in addi-
                     ated             postpartum    postpartum differed significantly between      tion to breast-feeding 6 weeks
                                                    the exposed and control group, 0,9 µg/l ver-   postpartum
                                                    sus 0.5 µg/l (range 0.1-2.2 µg/l)              16/35 and 37/39 samples of milk
                                                    6w after delivery no correlation between Pb    in exposed and control women
                                                    levels in blood and milk was observed, Pb      respectively, were below the
                                                    levels in blood at delivery and in milk 6w     defined detection limit (1 µg/l)
                                                    postpartum were correlated as well as living
                                                    area and milk Pb concentration
66            Metallic lead
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<pre>Table 3.2 Human studies on effects of Pb on lactation
authors     subjects   exposure               design             effects/observation                                 remarks
Noirfalise  lactating  no particular expo- Pb analyses in        milk contained on average 277 µg Pb/l (range        women did not suffer from saturn-
et al.      women      sure, women lived in breast milk          0-900 µg/l) two samples contained ca. 1200          ism analytical method applied was
(1967)      (n=76)     the province of                           and 1500 µg/l                                       a polarographic method
                       Liège
Lamm et     lactating  no particular expo-    determination of milk Pb concentrations amounted to 20 µg/l
al. (1973)  women      sure                   Pb content in      (range 0-70 µg/l)
            (n=7)      women lived in         milk
                       USA
Pinkerton   healthy    no particular expo-    determination of Pb concentration in human and bovine milk             women were 21-37 years of age
et al.      lactating  sure                   Pb content in      ranged 6.0-20 µg/l (median 10.9 µg/l) and 9-        women already had 1-6 children
(1973)      women      women lived in Cin-    milk samples       154 µg/l (median 42.0 µg/l), respectively           and nursed the present infant 2-46
            aged 21-   cinnati, Ohio          collected                                                              weeks at sampling time
            37 years                          between weeks                                                          8 women smoked
            (n=14)                            2 and 46 post-
                                              partum
Dillon et   lactating  no particular expo- determination of mean milk Pb concentration was 26 µg/l (range women were white, urban, middle-
al. (1974)  women      sure women lived       Pb content in      6-58 µg/l)                                          class donors, aged 23-28
            (n=29)     throughout the USA milk samples
Casey       lactating  no particular expo- pooled milk           milk Pb content <10 µg/l
(1977)      women      sure women lived in sample taken 4-
            (n=25)     New Zealand            10 days after
                                              start of lactation
Chatranon   lactating  no particular expo-    Pb analyses in     mean milk Pb level was 84.6 µg/l (range 13.6-
et al.      women      sure, women lived in   breast milk col-   222.2 µg/l) no differences were observed
(1978)      (n=164)    heavily polluted       lected from 1      between Pb levels in milks collected in differ-
                       areas of Bangkok       day to more than   ent periods post partum
                                              9 months post
                                              partum
Larsson et  healthy    no particular expo-    measurement of     mean Pb content in milk 2 µg/l (fresh weight)
al. (1981)  lactating  sure                   Pb in breast       (range 0.5-9.0 µg/l) no differences in milk Pb
            women      women lived in         milk 3 (18) and    content existed between the groups the calcu-
            (n=41)     Uppsala (S)            6 (23) months      lated median weekly intake was 1.9 and 1.2 µg/
                                              post partum        kg bw for 3 and 6-month-old infants, respec-
                                                                 tively
Moore et    healthy    no particular expo-    determination of   geometric means for maternal and infant blood       none of the women (aged 17-37)
al. (1982)  lactating  sure                   Pb in milk and     were 0.16 and 0.13 mg Pb/l, respectively,           had any known history of previous
            women      women lived in         blood samples      which were highly correlated                        industrial Pb exposure
            (n=93)     Glasgow                PN 6 w             median value for breast milk Pb concentration       all children showed normal mental
                                                                 was 21 µg/l, which was correlated with mater-       and physical development
                                                                 nal blood Pb concentration
Huat et al. lactating three rural and three determination of     mean milk Pb concentration significantly dif-       the estimated intake was for urban
(1983)      women      urban 3 areas in       Pb in milk at      fered between urban (25.3 µg/l) and rural (21.1     areas 15.5, 18.1 and 25.2 µg/day
            (n=89-91) Malaysia                various times of   µg/l) areas                                         and for rural areas 12.9, 15.1 and
                                              lactation (<1-     no specific pattern in Pb levels at different peri- 21.0 µg/day for infants at birth, and
                                              >12 months)        ods of lactation both among the urban and rural     at the age of 6 and 12 months,
                                                                 samples was observed                                respectively
              Fertility and developmental toxicity studies                                                                                               67
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<pre>Table 3.3 Human studies on effects of Pb on lactation
authors subjects    exposure      design              effects/observation                         remarks
Kovar    healthy    no particu-   measurement of      9 breast milk samples contained 4.1 µg Pb/  mean age of women 29.2 medi-
et al.   pregnant   lar expo-     Pb in blood of      l on average (range 0-8.9 µg/l), 19 samples cally uncomplicated pregnancies
(1984)   women      sure          mother at delivery  contained amounts below the detection       birth weight mean 3470 g
         (n=28) and women         and PN day 5, in    limit (1 µg/l)                              all but one women took iron sup-
         their      lived in      blood of child      maternal blood contained 99.5 and 101.5     plements during pregnancy and 9
         infants    London        (cord) at delivery  µg Pb/l at delivery and 5 days post partum, took also multivitamins
                                  and in milk PN      respectively and cord blood 87.0 µg Pb/l at 6 women smoked during preg-
                                  day 5               delivery                                    nancy and 2 until pregnancy was
                                                                                                  diagnosed
Rock-    lactating  no particu-   measurement of      milk and blood contained 2.8 µg Pb/l and women were 22-47 years of age
way et   women in   lar expo-     Pb concentration    119 µg Pb /l; hair contained 2002 µg Pb/kg
al.      rural and  sure          in milk, hair and   no correlations were observed between the
(1984)   urban      women         blood 1-16 months   three parameters or between content in
         areas (in  originated    after partition     milk, month of lactation, concentration in
         total 39   from rural                        other tissues and environmental concentra-
         women)     and urban                         tion
                    areas                             no differences between locations
                    around
                    Tucson,
                    Arizona
Ong et   pregnant/  no particu-   Pb analysis in      on average maternal BLL was 151.3 µg/l
al.      lactating  lar expo-     maternal and cord   (range 75.6-238.3), cord BLL was 114 µg/l
(1985)   women      sure,         blood collected at  (range 49.7-254.9) and breast milk con-
         and their  women         delivery and in     tained 47.66 µg Pb/l (range 24.86-105.7
         babies     lived in      milk collected PN   µg/l)
         (n=114)    Malaysia      day 3-5; 9 women    BLL in maternal and cord blood were
                                  continued to col-   strongly relatedPb concentrations in breast
                                  lect milk at PN     milk did not vary significantly from three
                                  days 3, 7, 10, 14,  days to over a month postpartum
                                  20 and 30
Rabino   lactating  no particu-   Pb analysis in milk breast milk contained on average 17 µg      children were selected out of
witz et  women      lar expo-     collected 1 and 6   Pb/l (range 0-72 µg/l)                      11837 consecutive births and were
al.      and their  sure;         months post par-    no differences were found in Pb level of    drawn equally from the highest,
(1985)   new borns  families      tum, in cord blood  breast milk collected 1 or 6 months post    lowest and centermost deciles of
         (n=249)    lived within  and in capillary    partum                                      blood Pb
                    Greater       blood at 6 months   cord blood Pb (mean 0.072 mg/l, range 0-    children were free of serious med-
                    Boston        of age              0.25) correlates poorly with breast milk Pb ical conditions
                                                      (mean 0.062 mg/l, range 0-0.49 mg/l)        in general, the mothers were white
                                                      blood Pb at 6 months of age correlate very  (87%) and well educated (mean
                                                      well with dietary Pb intake among children  maternal schooling = 14.5 years),
                                                      who were nursed                             their mean age was 30 years
68            Metallic lead
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<pre>Table 3.4 human studies on effects of Pb on lactation
authors     subjects    exposure       design           effects/observation                                       remarks
Sternowsky lactating    no particular  measurement      colostrum and mature milk contained 15.5 and 9.1 µg/l     non-smoking females one rural
and Wesso- women        exposure       of Pb in milk 0- and 12.5 and 8.0 µg/l in urban and rural areas, respec-   women excreted very high lev-
lowski      (n=10)      women origi-   90 days post-    tively                                                    els of Pb into milk (cause
(1985)                  nate from      partum           from day 15 on mean concentrations were 13.2 and 9.1      unknown) and was excluded
                        rural (Soltau)                  µg/l, differing significantly from day 45 on (Hamburg     from study
                        and urban                       increasing, Soltau decreasing) no differences in milk Pb
                        areas (Ham-                     content during day
                        burg, D)                        women >30 years excreted significantly more Pb into
                                                        milk till day 5 than women <30 years
                                                        calculated daily intake (840 ml milk, bw 5.5 kg)
                                                        amounted to 0.9-1.3 and 1.5-2.3 µg/kg/day for rural and
                                                        city infants, respectively
Dabeka et   volunteers no particular   determination    geometric mean milk level amounted to 0.57 µg/l (range
al. (1986)  across      exposure       of Pb content    <0.05- 15.8 µg/l)
            Canada                     in milk sam-     levels were highly correlated with age of house and traf-
            (n=210)                    ples             fic exposure (p<0.012)
Schramel et pregnant    no particular  measurement      maternal blood and cord blood contained 39 and 30 µg/l,
al. (1988)  women       exposure       of Pb in mater-  respectively
            (n=33) and  women lived    nal blood just   placenta contained 18.7 µg/kg (fresh weight)
            their new-  in Munich      before delivery, milk contained 2.6 µg/l
            born        (D)            in cord blood    correlations exist between placenta and maternal blood
            babies                     after birth, in  (r=0.69), placenta and cord blood (r=0.67) and maternal
                                       placenta and in  and cord blood (r=0.90)
                                       milk
Parr et al. lactating   no particular  Pb determina-    median milk Pb levels were 2.9, 14.9, 4.9, 16.6, 16.8 and
(1991)      women       exposure       tion in milk     5.0 µg/l in Guatemala, Hungary, Nigeria, Philippines,
            (n=2-74)    women          collected at     Sweden and Zaire, respectively
                        belonged to    noon 2 months    no significant differences existed between the different
                        A (well-to-    after start of   socioeconomic classes
                        do), B (urban  lactation
                        poor) or C
                        (living in
                        rural environ-
                        ment) groups
                        in Guate-
                        mala, Hun-
                        gary, Nigeria,
                        Philippines,
                        Zaire (only A
                        and C) and
                        Sweden (one
                        group)
              Fertility and developmental toxicity studies                                                                                    69
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<pre>Table 3.5 Human studies on effects of Pb on lactation
authors        subjects    exposure       design          effects/observation                             remarks
Ende and       lactating   no particular Pb-determina-    1987: milk Pb level <4-81 µg/l (median <4
Hille (1992) women         exposure       tion in milk    µg/l)
               (n=102-     women lived                    1988: milk Pb level <2-124 µg/l (median 43
               238) over   in Niedersa-                   µg/l)
               the years   chsen, Ger-                    1989: milk Pb level <10-94 µg/l (median 35
               1987-1990   many                           µg/l)
                                                          1990: milk Pb level <3-50 µg/l (median 4 µg/
                                                          l)
Plöckinger women           no particular  measurement     maternal and cord blood contained 37.0 and      deliveries without problems at full term
et al. (1993) just after   exposure       of Pb in mater- 26.3 µg/l, respectively                         mean age of mothers 23.7 years
               delivery    women lived    nal and cord    urine of mother and child contained 0.05 and    30 mother with first-child 10 women
               (n=51)      in Vienna      blood immedi-   0.29 µg/l, respectively                         smoked cigarettes pregnancy
                           (A)            ately after     milk contained 35.8 µg/l (range 19-70.3 µg/l)   40.4 w birth weight 3354 g
                                          delivery, in    a correlation was found between the Pb con-
                                          urine of mother centration in mother and child blood (r=0.66)
                                          and child on
                                          PN day 2, in
                                          milk from PN
                                          day 2 to PN
                                          day 4
Tiran et al.   lactating   no particular Pb analyses in   the median milk Pb concentration was 3.4 µg/ mean age of women 29 years
(1994)         women       exposure,      milk            l (range 0-20.4 µg/l) there was no difference
               (n=32)      women lived                    in Pb concentration between milk from urban
                           in Graz, capi-                 mothers and from mothers from the country-
                           tal of Styria                  side
                           and the coun-
                           tryside of
                           Styria (A)
Saleh et al.   lactating   women liv- determination       average district concentrations of Pb in breast women (aged 20-40) had been living in the
(1996)         women       ing in 20      of Pb content   milk ranged from 9.0-101.4 µg/l (individual     same area for at least 10 years and had
               from 20     urban and      in breast milk  range 0-158 µg/l) with highest concentrations   given birth to their 1st or 2nd child, which
               different   rural areas in                 in urbanic areas                                was healthy
               areas (n=6) Egypt                                                                          85% of the women was a housewife
                                                                                                          none of the women smoked
Frkovic et     lactating   residence in   determination   Pb content of milk averaged 7.3 µg/l (range     women were 17-45 years of age and had
al. (1997)     women       urban or       of Pb concen-   0.3-44 µg/l) significant differences in milk Pb normal pregnancy
               (n=29)      rural area     tration in milk concentration exist due to residence (urban     parity 1-7, weight gain 7-22 kg, gestation
                           (Croatia)      PN days 2 and   10.6 vs region 4.7 µg/l)                        36-41 w newborns weight 2200-4400 g,
                           (annual mean   12              no differences due to age, parity or smoking    length 46-53 cm, Apgar score (1/5 min) 5-
                           0.054-0.151                    habits                                          10/7-10
                           vs. 0.013-
                           0.026 µg Pb/
                           m3)
Vavilis et al. healthy     rural and      determination   mean milk Pb concentrations were 90 µg/l        women were aged 18-41 and had gestation
(1997)         lactating   urban (Thes-   of Pb concen-   (range 50- 250 µg/l) and 84 µg/l (range 50-     periods of 37-41 weeks the pregnancies,
               women       saloniki)      tration in milk 140 µg/l) for urban and rural areas, respec-    deliveries and infants were normal air Pb
               (n=40-51)   areas in       from PN days    tively (non-significant difference)             concentrations in the two year prior to
                           Greece         4-5 (colostrum)                                                 study ranged from 0.54-0.67 µg/m3 in the
                                                                                                          city; in rural areas they were 15 times
                                                                                                          lower
70              Metallic lead
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<pre>Table 3.6 Human studies on effects of Pb on lactation
authors      subjects     exposure      design           effects/observation                       remarks
Gulson et healthy lac-    women         determination    Pb content in maternal blood (all sub-    women were 18-35 years of age
al. (1998) tating         belonged to   of Pb content by jects) was <0.5 mg/l, in cord blood of
             women        Australian    isotope ratio    immigrants 9.1-36.1 µg/l (mean 20.2
             (n=15)       immigrants    measurement in   µg/l) and of Australians 9.6-36.7 µg/l
                          or to the 2nd venous blood     (mean 25.1 µg/l)
                          generation    PN day 60, and   Pb concentration milk averaged 0.73
                          Australian    breast milk col- µg/l (range 0.09-3.1 µg/l) (all subjects,
                          women         lected monthly   no difference in groups)
Friel et al. healthy lac- no particu-   determination    Pb concentration in milk from women       none of the women (aged 20-35)
(1999)       tating       lar exposure  of Pb in milk    with a premature child varied from 0-1    was vegetarian
             women,       women         collected PN     µg/l and in milk from women with a        ca. 95% of the women was of
             who deliv-   lived in      days 2 to 56     full-term child from 0-4 µg/l             European origin and no aboriginal
             ered pre-    Newfound-     weekly with                                                women participated
             mature (wk   land, Can-    one final sam-                                             birth weight was 1312 and 3672 g
             29.4)        ada           ple taken PN                                               for premature and full-term
             (n=24) and                 day 84                                                     infants, respectively
             full-term
             (wk 39.8)
             (n=29)
             infants
Tripathi et lactating     no particu- determination      geometric mean milk level amounted to
al. (1999) women          lar exposure of Pb content in  1.9 µg/l and 1.7 µg/l for human and cow
             (n=30)       Mumbai        milk samples     milk, respectivelydaily intake for a 6-12
                          area (India)                   month old infant from human milk was
                                                         estimated to be 1.3 µg, from formulae
                                                         up to 9.4 µg
PN = postnatal; BLL = blood Pb level
               Fertility and developmental toxicity studies                                                                       71
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<pre>72 Metallic lead</pre>

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<pre>Annex E
      Calculation safe levels of lead in (human)
      breast milk
      Assumptions
      • body weight woman: 60 kg
      • body weight infant: 4.5 kg (4-5 kg)
      • Intake breast milk: 900 ml (800-1000 ml)
      • An infant is as sensitive for the effects of lead as an adult
      Calculation safe levals of lead in (human) breast milk
      The FAO/WHO (FAO93) recommends a PWTI (provisional tolerable weekly intake) of
      25 µg/kg body weight. This corresponds to:
      • a tolerable intake level of 3.6 µg/kg body weight per day.
      • a safe intake level per infant of 14 µg/ infant /day
      • a safe level of lead in breast milk of 16 µg/l
      In conclusion, the committee consideres 16 µg lead/ liter breast milk as a safe level.
      Calculation safe levels of lead in (human) breast milk                                 73
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<pre>74 Metallic lead</pre>

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<pre>Annex F
      Abbreviations
      Abbreviations used:
      bw        body weight
      CI        confidence interval
      CNS       central nervous system
      d         day
      F         female(s)
      GD        gestation day
      i.p.      intraperitoneal
      IRPC      increased renal pelvic cavitation
      i.v.      intravenous
      M         male(s)
      n         number
      NOAEL     no adverse effect level
      OECD      Organisation for Economic Cooperation and Development
      OR        Odds ratio
      OT        Operating theatre
      PN        postnatal
      RR        relative risk
      Abbreviations                                                   75
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<pre>76 Metallic lead</pre>

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<br><br>