<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>www.healthcouncil.nl Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Healthy working conditions How can employees be protected against working conditions that could harm their health? Environmental health Which environmental influences could have a positive or negative effect on health? Healthy nutrition Which foods promote good health and which carry certain health risks? Prevention Which forms of prevention can help realise significant health benefits? Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Areas of activity Advisory Reports The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands 2016/07 Health-based recommendation on occupational exposure limits Flour dust from processed, de-hulled soybeans Health Council of the Netherlands Flour dust from processed, de-hulled soybeans 2016/07</pre>

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<pre>Flour dust from processed,
de-hulled soybeans
    Health-based recommendation on occupational exposure limits
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Flour dust from processed, de-hulled soybeans
Uw kenmerk            : DGV/BMO/U-932542
Ons kenmerk           : U-977709/JR/cn/459-X72
Bijlagen              :1
Datum                 : 16 juni 2016
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
meelstof van fijngemalen en gepelde sojabonen.
Het voorliggende advies maakt gebruik van de werkwijze die in 2008 door de Gezondheids-
raad is voorgesteld voor het afleiden van gezondheidskundige advieswaarden of voor het
vaststellen van op risico gebaseerde referentiewaarden voor allergene stoffen (rapportnr.
2008/03, Preventie van werkgerelateerde luchtwegallergieën). De commissie heeft de con-
centratie soja-eiwit antigenen in de lucht berekend waarbij een werknemer een extra kans
van één procent gedurende zijn arbeidszame leven heeft om door beroepsmatige blootstel-
ling gesensibiliseerd te raken ten opzichte van de kans hierop in de niet beroepsmatige
blootgestelde algemene bevolking.
      De conclusies van het genoemde advies zijn opgesteld door de Commissie Gezondheid
en beroepsmatige blootstelling aan stoffen (GBBS) van de Gezondheidsraad en getoetst
door de Beraadsgroep Volksgezondheid.
Ik onderschrijf de aanbevelingen en het advies van de commissie.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van IenM en
aan de minister van VWS.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                            Postadres
Parnassusplein 5                                                       Postbus 16052
2 5 11 V X D e n H a a g                                               2500 BB Den Haag
E - m a il : jo l a n d a . r i jn k e l s @g r. n l                   w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1
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<pre></pre>

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<pre>Flour dust from processed,
de-hulled soybeans
Health-based recommendation on occupational exposure limits
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2016/07, The Hague, June 16, 2016
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. 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.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Flour dust from processed, de-hulled
soybeans. Health-based recommendation on occupational exposure limits. The
Hague: Health Council of the Netherlands, 2016; publication no. 2016/07.
all rights reserved
ISBN: 978-94-6281-078-5
</pre>

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<pre>   Contents
   Samenvatting 9
   Executive summary 15
   Scope 19
.1 Background 19
.2 Committee and procedure 19
.3 Data 20
   Identity, properties and monitoring 21
.1 Identity 21
.2 Physical and biochemical properties 21
.3 EU classification and labelling 23
.4 Validated analytical methods 23
   Sources 27
.1 Natural sources 27
.2 Man-made sources 27
   Exposure 29
.1 General population 29
.2 Working population 29
   Contents                               7
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<pre>    Kinetics 33
    Mechanism of action 35
 .1 Immunological responses 35
 .2 Non-immunological responses 36
    Effects 37
 .1 Irritation 37
 .2 Sensitisation 38
 .3 Other symptoms 44
 .4 Summary 45
    Existing guidelines, standards and evaluation 47
 .1 General population 47
 .2 Occupational population 47
    Hazard assessment 49
 .1 Hazard identification 49
 .2 Selection of study suitable for quantitative risk estimation 51
 .3 Conclusion and recommendation 55
 .4 Groups at extra risk 56
    References 57
    Annexes 63
A   Request for advice 65
B   The Committee 67
C   The submission letter (in English) 69
D   Comments on the public review draft 71
E   Prevalence of sensitisation to soybean flour allergens and respiratory symptoms 73
F   Exposure-response relationships 79
    Flour dust from processed, de-hulled soybeans
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<pre>Samenvatting
Vraagstelling
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid leidt de
Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (Commissie
GBBS; één van de vaste commissies van de Gezondheidsraad) gezondheidskun-
dige advieswaarden af voor stoffen in lucht waaraan mensen blootgesteld kunnen
worden tijdens hun beroepsuitoefening. Deze advieswaarden vormen vervolgens
de basis voor grenswaarden waarmee de gezondheid van werknemers beschermd
kan worden.
    In dit advies bespreekt de commissie de gevolgen van blootstelling aan meel-
stof van fijngemalen en gepelde sojabonen (kortweg aangeduid als sojameelstof)
en probeert zij gezondheidskundige advieswaarden vast te stellen. De conclusies
van de commissie zijn gebaseerd op wetenschappelijke publicaties die vóór mei
2016 zijn verschenen.
Fysische en biochemische eigenschappen
In dit advies is meelstof geëvalueerd afkomstig van sojabonen (Glycine hispida
of Glycine max) die zijn gepeld en fijngemalen.
    Sojameel wordt onder andere toegepast als deegverbeteraar bij de bereiding
van bakkerijproducten. Sojameel bevat lipoxygenase dat carotenoïden bleekt.
Het bevat daarnaast lecithine dat het deeg doet rijzen. Ook de diervoederindustrie
Samenvatting                                                                       9
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<pre>  kent een groot gebruik van sojameel. Sojameel bevat ongeveer 15 allergene gly-
  coproteïnen met een hoge molecuulmassa, waarvan de belangrijkste zijn geïden-
  tificeerd als de opslageiwitten beta-glycinine en glycinine, en trypsineremmers.
       Ingeademde stofconcentraties (gemiddeld over een achturige werkdag) in
  bedrijven waar gewerkt wordt met sojameel, kunnen, over een volledige werk-
  dag, oplopen tot meer dan 35 mg/m3. Het gehalte aan sojaeiwitantigenen in de
  lucht kan oplopen tot in de microgrammen per kubieke meter lucht, afhankelijk
  van de werkzaamheden.
  Monitoring
  De concentratie van de in lucht aanwezige (vaste) stof van bewerkt sojameel kan
  op basis van de massa (gravimetrisch) worden bepaald en gemiddeld over een
  achturige werkdag. In het opgevangen stof kan verder de concentratie van speci-
  fieke sojaeiwitantigenen worden vastgesteld. In Nederland is het gebruikelijk de
  concentratie van de in de lucht aanwezige stof te meten met een gestandaardi-
  seerde techniek (NEN481).
  Grenswaarden
  In Nederland noch in het buitenland zijn grenswaarden voor sojameelstof vastge-
  steld.
  Kinetiek
  Werknemers kunnen aan stof van sojameel worden blootgesteld doordat ze stof-
  deeltjes inademen op hun werk. Daarbij gedragen deze stofdeeltjes in de lucht
  zich waarschijnlijk hetzelfde als andere stofdeeltjes. Afhankelijk van de grootte
  en vorm van de stofdeeltjes, en van de ademhalingsinspanning, komen de deel-
  tjes bij inademing terecht in de neus (grote deeltjes), luchtwegen of longen
  (kleinste deeltjes). Door trilharen in de luchtwegen, slijmproductie en gespeciali-
  seerde cellen in de longen, worden de stofdeeltjes verwijderd uit de luchtwegen
  en longen. Hoe dieper een stofdeeltje in de longen terecht komt hoe moeilijker
  het is het deeltje te verwijderen.
  Effecten
  Inademing van sojameelstof kan klachten geven als rode en jeukende ogen, hoes-
  ten, niezen, opgezette slijmvliezen, verhoogde slijmproductie en benauwdheid
0 Flour dust from processed, de-hulled soybeans
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<pre>(astma). Dergelijke klachten kunnen wijzen op een neus-/keelontsteking en/of
astma. Ze kunnen worden veroorzaakt door irritatie, een ongewenste specifieke
reactie van het immuunsysteem (allergische reactie), of door beide mechanis-
men. Een allergie is een overgevoeligheidsreactie op een lichaamsvreemde stof
bij een blootstelling die normaal gesproken wordt getolereerd. Kenmerkend voor
allergie is dat het ontstaan van klachten wordt voorafgegaan door een klachten-
vrije periode waarin het immuun-systeem door blootstelling in een verhoogde
staat van paraatheid wordt gebracht (sensibilisatie). Een onderscheid tussen irri-
tatie en allergie kan worden gemaakt met behulp van speciale tests voor het aan-
tonen van sensibilisatie voor een specifiek allergeen, in dit geval voor allergenen
die alleen voorkomen in sojameelstof.
     De meeste gegevens over effecten van beroepsmatige blootstelling aan soja-
meelstof zijn afkomstig van onderzoeken onder medewerkers van (banket)bak-
kerijen en meelproducerende of -verwerkende bedrijven. Bij een deel van die
werknemers is ook aangetoond dat zij gesensibiliseerd zijn voor allergenen in
sojameelstof (prevalentie van één tot honderd procent). Ter vergelijking, het aan-
tal gevallen van specifieke sensibilisatie onder niet-blootgestelde controlegroe-
pen lag in die onderzoeken rond de vier à vijf procent en voor de algemene
bevolking op twee procent.
     Er zijn geen onderzoeken uitgevoerd naar mogelijke andere schadelijke
gezondheidseffecten onder werknemers. Ook zijn er geen dierexperimentele stu-
dies uitgevoerd.
Evaluatie
Om een gezondheidskundige advieswaarde te kunnen afleiden, zijn kwantita-
tieve gegevens nodig over de relatie tussen blootstelling en respons, in een zo
laag mogelijk blootstellingsgebied. Op één Amerikaans onderzoek na, is in
andere onderzoeken een dergelijke relatie niet goed onderzocht. In het Ameri-
kaanse onderzoek zijn de gegevens afkomstig van werknemers die vrijwel alleen
blootstonden aan stof van bewerkt sojameel. Als effecteindpunt zijn sensibilisa-
tie en het optreden van (allergische) luchtwegklachten onderzocht; de blootstel-
lingsconcentraties zijn uitgedrukt in ‘totaal ingeademde stof’ of in ‘ingeademde
hoeveelheid sojaeiwitantigenen’.
     Wat het effecteindpunt betreft hecht de commissie de meeste waarde aan de
gegevens over sensibilisatie. Iemand die gesensibiliseerd is, loopt namelijk bij
voortdurende blootstelling een grote kans om allergische klachten te krijgen.
Aangezien sensibilisatie niet omkeerbaar is, zal deze persoon voor de rest van
zijn of haar leven gesensibiliseerd zijn en bij voortzetting van de blootstelling
Samenvatting                                                                        11
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<pre>  allergische klachten kunnen krijgen. Daarnaast kan in tests op sensibilisatie
  bepaald worden door welk allergeen de sensibilisatie is veroorzaakt. Dit is niet
  mogelijk bij tests op aanwezigheid van luchtwegklachten. Voorts heeft de com-
  missie geen bewijs gevonden dat luchtwegklachten bij een lagere blootstelling
  optreden dan sensibilisatie. Dit betekent dat een advieswaarde die gebaseerd is
  op gegevens over sensibilisatie tevens luchtwegklachten zal voorkomen.
      Bij het meten van de blootstelling doet zich een vergelijkbare situatie voor.
  Omdat op de werkplek vaak sprake is van gelijktijdige blootstelling aan verschil-
  lende stofbronnen is het meten van ‘totaal ingeademde stof’ in deze situatie geen
  goede blootstellingmaat. Daarom geeft de commissie de voorkeur aan het meten
  van specifieke sojaeiwitantigenen in de lucht, want voor het meten ervan bestaan
  technieken die onderscheid kunnen maken tussen de antigenen van verschillende
  bronnen.
      Volgens de commissie kan op basis van de beschikbare informatie over sensi-
  bilisatie geen drempelwaarde worden aangewezen, omdat in het uitgangsonder-
  zoek geen blootstellingsniveaus zijn gerapporteerd waaronder geen gevallen van
  sensibilisatie optraden. Dit betekent dat het beste een referentiewaarde kan wor-
  den afgeleid. Een referentiewaarde is een concentratie van sojameelstof (allerge-
  nen) in de lucht waarbij beroepsmatige blootstelling leidt tot een vooraf bepaalde
  extra kans op sensibilisatie ten opzichte van het aantal gevallen in de algemene
  bevolking. Voor allergenen is het extra absoluut risico bepaald op één procent,
  gebaseerd op bescherming gedurende het gehele arbeidzame leven.
      De commissie heeft aan de hand van het voorgaande een referentiewaarde
  voor sojameelstof berekend met behulp van een lineair regressiemodel. Toepas-
  sing van het model leidt tot een referentiewaarde van 0,1 µg sojaeiwit-
  antigeen/m3 als een tijdgewogen gemiddelde concentratie over een achturige
  werkdag.
      De commissie kon geen referentiewaarde afleiden waarmee sensibilisatie
  door piekblootstellingen te voorkomen is. Er zijn weliswaar aanwijzingen dat
  korte hoge blootstelling tijdens het werk ook tot sensibilisatie kan leiden, maar
  de beschikbare gegevens zijn onvoldoende om daarvoor een betrouwbare refe-
  rentiewaarde te kunnen afleiden.
  Referentiewaarde
  De commissie beveelt een referentiewaarde aan voor beroepsmatige blootstelling
  aan stof afkomstig van fijngemalen en gepelde sojabonen, van 0,1 microgram
  sojaeiwitantigeen per kubieke meter (0,1 µg/m3) als een gemiddelde concentratie
  over een achturige werkdag. Bij deze concentratie hebben werkers ten opzichte
2 Flour dust from processed, de-hulled soybeans
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<pre>van de algemene bevolking een extra absoluut risico van één procent op sensibi-
lisatie voor allergenen aanwezig in sojameelstof.
    De gegevens zijn onvoldoende om een referentiewaarde tegen de effecten
van piekblootstellingen af te leiden.
Samenvatting                                                                    13
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<pre>4 Flour dust from processed, de-hulled soybeans</pre>

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<pre>Executive summary
Scope
At the request of the Minister of Social Affairs and Employment, the Dutch
expert Committee on Occupational Exposure Safety (DECOS), one of the
permanent Committees of experts of the Health Council, proposes health-based
recommended occupational exposure limits for chemical substances in the air in
the workplace. These recommendations serve as a basis in setting legally binding
occupational exposure limits by the minister. In this advisory report, the
Committee evaluates the consequences of exposure to dust from processed de-
hulled soybean flour (soybean flour dust), and makes an effort in deriving a
health-based occupational exposure level or reference value. The Committee’s
conclusions are based on scientific papers published before May 2016.
Physical and biochemical properties
In this advisory report dust is evaluated from soybeans (Glycine hispida or
Glycine max), which are de-hulled and finely milled.
    Soybean flour contains lipoxygenase (bleaches carotenoids) and lecithin
(emulsifier). For this reason it is routinely used as dough improver in the
preparation of bakery products. Also, the animal food industry is a large user of
soybean flour. In soybean flour, there are about 15 allergenic high molecular
Executive summary                                                                 15
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<pre>  weight glycoproteins, the most common of which have been identified as the
  storage proteins beta-glycinin and glycinin, and trypsin inhibitors.
      Average inhalable dust concentrations in companies (average concentrations
  measured during an eight hour working day) using soybean flour can reach levels
  of 35 mg/m3 and more, as measured in the breathing zone during a full-shift.
  Monitoring
  Exposure to airborne soybean flour dust can be determined gravimetrically in
  samples of full-shift personal inhalable dust. From the dust samples, the content
  of soy antigens can be determined. In the Netherlands, it is common practice to
  measure exposure using a standardized technique for collection of inhalable dust
  (NEN481).
  Limit values
  In The Netherlands nor in other countries occupational exposure limits have been
  set for soybean flour dust.
  Kinetics
  Exposure to soybean flour dust occurs from dust or aerosols. Most likely, these
  dust particles behave the same as other types of dust particles. The place of
  deposition in the airway system is determined by particle size, aerodynamic
  properties, and the volume of respiration. Macrophages and the mucociliary
  system in the respiratory tract are responsible for the clearance of dust particles.
  Effects
  Inhalation of soybean flour dust may elicit immunological and non-
  immunological responses. Immunological responses, primarily IgE-mediated,
  lead to sensitisation, which may induce allergic reactions with respiratory
  symptoms as rhinitis, rhinoconjuctivitis, asthma (i.e., shortness of breathing,
  cough). These symptoms may also be caused by irritation, a non-immunological
  response. A distinction between the two types of reactions can be made by
  testing on sensitisation.
      Most data on the effects of occupational exposure to soybean flour dust are
  retrieved from human studies on employees working in bakeries, and soybean
  processing and milling companies. Among the employees, symptoms are
6 Flour dust from processed, de-hulled soybeans
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<pre>described which indicate the presence of rhinitis, rhinoconjuctivitis and asthma-
like symptoms. Part of these workers with complaints also showed to be
sensitised to allergens present in the soybean flour (prevalence values of one to
hundred percent). For comparison, in those studies, the number of cases in non-
occupationally exposed control groups averaged around four and five percent,
and for the general population at two percent.
    No studies are available on other possible adverse health effects of soybean
flour dust in humans, nor were there animal studies published.
Evaluation and recommendation
In deriving a health-based occupational exposure limit, quantitative data are
needed on exposure-response relationships in as low as possible exposure range.
Except for one US study, such a relationship has not well been investigated. In
the American study, data were obtained from workers who were unlikely to be
co-exposed to other dust sources or substances then soybean flour. Effect
endpoints in this study were sensitisation and the occurrence of (allergic) airway
symptoms; exposure was expressed as ‘total inhalable dust’ or ‘inhalable soy
antigen’.
    Regarding the health effects, the Committee considered data on sensitisation
as the most relevant. Somebody who is sensitised has a high risk in developing
allergic reactions at (continuing) exposure. Because sensitisation is an
irreversible effect, the person in question will be sensitised for the rest of his or
her life, and at exposure, may show allergic symptoms. In addition, in tests on
sensitisation it is possible to assess which allergen was responsible for the
positive outcome. Such an assessment cannot be made when examining
respiratory symptoms, irrespective the type of response. Moreover, the
Committee did not find evidence that respiratory symptoms caused by irritation,
occur at lower exposure levels than sensitisation. This means that an
occupational exposure limit based on data on sensitisation should prevent also
the development of non-specific respiratory symptoms. Workers who are already
sensitized may develop allergic respiratory symptoms upon continuing exposure
at or perhaps below the OEL for sensitization. However, these workers are
considered a vulnerable group, which are not taken into account in setting an
OEL, because according to the current policy, an OEL should be set for non-
sensitized healthy workers.
    A comparable condition arises in assessing exposure levels. Since in most
workplaces co-exposure to other dust sources is likely, measuring ‘total inhalable
dust’ is in this situation not a good exposure parameter. Therefore, the
Executive summary                                                                     17
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<pre>  Committee prefers measuring airborne soy antigen levels in the air, because
  techniques are available that distinguish airborne antigens from different sources.
      According to the Committee, based on the available information for the
  effect ‘sensitisation’ no threshold level can be assessed, because no exposure
  levels were reported below which no cases of sensitisation to soybean flour
  allergens were found. That implies that the setting of reference values is
  warranted. A reference value is a concentration of soybean flour dust (soy
  antigens) in the air, at which occupational exposure leads to a predefined
  accepted level of extra risk of allergic airway sensitisation, compared to the
  background risk in the general, non-exposed population. In the case of allergens
  the extra (absolute) risk is set at one percent, based on protection during the 40
  years of occupational exposure.
      Based on the preceding, the Committee has calculated a reference value for
  soybean flour dust by using a linear regression model. Using this model, the
  Committee derived a reference value of 0.1 µg inhalable soy antigen/m3 (eight-
  hour time-weighted average concentration).
      The Committee has also discussed whether a reference value could be
  derived to prevent sensitisation due to peak exposure, because it is suggested that
  short exposure during work to high levels of the allergen could lead to
  sensitisation. However, the available data are insufficient to derive a reliable
  short-term reference value.
  Reference value
  The Committee recommends a reference value for occupational exposure to dust
  from processed de-hulled soybean flour of 0.1 µg inhalable soy antigen/m3, as an
  eight-hour time-weighted average concentration (8-hr TWA). At this
  concentration workers have an additional sensitisation risk for dust from
  processed de-hulled soybean flour of one percent compared to the background
  risk in the general population.
       The data are insufficient to derive a short term exposure limit (15-minute
  TWA).
8 Flour dust from processed, de-hulled soybeans
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<pre> hapter 1
        Scope
1.1     Background
        At request of the minister of Social Affairs and Employment, the Dutch expert
        Committee on Occupational Safety (DECOS), a Committee of the Health
        Council of the Netherlands, performs scientific evaluations on the toxicity of
        substances that are used in the workplace (Annex A). The purpose of these
        evaluations is to recommend health-based occupational exposure limits, which
        specify levels of exposure to airborne substances, at or below which it may be
        reasonably expected that there is no risk of adverse health effects.
        In this advisory report, such an evaluation and recommendation is made for flour
        dust from processed, de-hulled soybeans (hereafter called soybean flour dust).
1.2     Committee and procedure
        The present document contains the assessment of DECOS, hereafter called the
        Committee, of the health hazard of soybean flour dust. The members of the
        Committee are listed in Annex B. The submission letter to the Minister can be
        found in Annex C.
             In 2015, the President of the Health Council released a draft of the report for
        public review. The individuals and organisations that commented on the draft are
        listed in Annex D. The Committee has taken these comments into account in
        Scope                                                                                19
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<pre>    deciding on the final version of the report. The received comments, and the
    replies by the Committee, are publicly available on the website of the Health
    Council.
1.3 Data
    The Committee’s recommendations on the health-based occupational exposure
    limit or reference values of soybean flour dust are based on scientific data, which
    are publicly available. Published literature was retrieved from the on-line
    databases Medline and Toxline, supplemented with subject searches in journals
    and internet sources. The final search was carried out in May 2016.
 0  Flour dust from processed, de-hulled soybeans
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<pre> hapter 2
        Identity, properties and monitoring
2.1     Identity
        In this report dust derived from processed, finely-milled and de-hulled soybeans
        (Glycine hispida or Glycine max) is evaluated.
        Additives
        Dust in bakeries and soybean processing companies may contain a variety of
        ingredients, other than soybean flour, such as cereal flour, enzymes (e.g. fungal
        alpha-amylase), and additives (e.g. preservatives, antioxidants, baker’s yeast, egg
        powder). The Committee is aware that these ingredients may contribute to the
        biological effects of soybean flour dust. For instance, cereal flour dust and fungal
        alpha-amylase are known to have sensitising properties, as is suggested also for
        soybean flour dust. However, the present risk evaluation is restricted to soybean
        flour dust.
2.2     Physical and biochemical properties
        About 90% of the whole soybean seed consists of cotyledons and 8% are hulls.
        Grinding or cracking and pressing of de-hulled soybeans result in soybean grit or
        flakes.
        Identity, properties and monitoring                                                  21
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<pre>       Soybean flour is obtained by finely grinding de-hulled soybeans. This so-
  called full-fat soybean flour consists of 46.6% protein, 22.1% fat, 5% moisture,
  2.1% fibre, 5.2% ash. The phospholipid fraction is usually called (soy) lecithin.
  Lecithin is used as a bakery additive because of its emulsifying properties.
       Milling of soybean flakes extracted with solvents results in defatted soybean
  flour, which has nowadays replaced full-fat soybean flour. At least 97% of the
  particles of soybean flour should be smaller than 150 µm. Defatted soybean flours
  typically contain 59% protein, 1% fat, 7% moisture, 2.6% fibre and 6.4% ash.
  Some proteins present in the soybean flour are potential allergens. Immunoblot
  analyses using sera of bakery workers showed sensitisation to at least 16
  glycoproteins (see Table 1). The most common were soybean storage proteins
  Table 1 List of identified allergenic IgE-binding proteins in soybeans.
  Nomenclature            Name(s)                                               Molecular weight
  Cotyledon
  Gly m 3a                Profilin, actin-binding protein                       12-15 kDa
  Gly m 4a                PR-10 protein, SAM22 (starvation associated           16.6 kDa
                          message), group 1 Fagales-related protein
  Gly m 5a                Vicilin, alpha subunit of beta-conglycinin            140-180 kDa
  Gly m 6a                Glycinin, 11S globulin, G1 subunit og glycinin,       320-360 kDa
                          storage protein
  Gly m glycinin G1       11S seed storage protein, G1 subunit of glycinin      40 kDa
  Gly m glycinin G2       11S seed storage protein, G2 subunit of glycinin      22 kDa
  Gly m glycinin G4       11S seed storage protein, G4 subunit of glycinin      61-61 kDa
  Gly m 7a                Seed biotinylated protein                             76 kDa
  Gly m 8a                Gly m 2S Albumin; 2S albumin, storage protein         28 kDa (dimer)
  Gly m Bd 28 k           7S vicilin-like globulin                              28 kDa
  Gly m Bd 30 k           Thiol protease of the papain family                   30-34 kDa
  Gly m Bd 60 k           Cupin (7S vicilin like globulin)                      63-67 kDa
  Gly m TI                Kunitz trypsin inhibitor                              20 kDa
  Gly m Lectin            Gly m Agglutinin; Lectin, an agglutinin, SBA          14.5 kDa
  Gly m IFR               Isoflavone reductase
  Gly m 39 kD             39 kDa protein                                        39 kDa
  Gly m Oleosin           Oleosin, lipid transfer protein                       16/24 kDa (monomer)
                                                                                50 kDa (dimer)
                                                                                76 kDa (trimer)
  Hull
  Gly m 1a                Soybean hydrophobic protein, lipid transfer protein   7 kDa (LMW)
  Gly m 2a                Defensin, storage protein                             7.5 kDa (LMW)
  a    Official allergen nomenclature (WHO/International Union of Immunological Societies).
       Sources: L’Hocine et al. (2007)10, Verma et al. (2013)11, www.allergen.org (May 2016),
       www.phadia.com (May 2016).
  Abbreviations: kDa, kilo Dalton; LMW, low molecular weight.
2 Flour dust from processed, de-hulled soybeans
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<pre>      (beta-conglycinin, glycinin), and soybean trypsin inhibitor (21,000 Dalton). All
      these proteins (range 10,000-94,000 Dalton) are considered high molecular
      proteins.1-5
           In several case studies, allergenic properties have been reported for the
      phospholipid fraction of soybeans, namely lecithin.6-9 However, the positive
      findings upon skin prick testing and serological examination in these studies
      were probably due to contamination of the lecithin preparations with heat
      resistant soybean proteins or alpha-amylase.6,8,9
2.3   EU classification and labelling
      Soybean flour dust has not been evaluated by the European Commission.
2.4   Validated analytical methods
2.4.1 Environmental monitoring
      Dust
      Flour dust exposure is based on personal inhalable gravimetric dust
      measurements. In scientific studies, different types of portable pumps, flow rates,
      filters, and aerosol samplers have been used, depending on the country in which
      the study was carried out. In the Netherlands, inhalable dust is usually collected
      with the PAS6 sampling head. The Institute of Occupational Medicine (IOM) in
      Edinburgh, Scotland, developed the IOM inhalable dust sampling head and
      cassette to meet the sampling criteria for inhalable particulate mass. Within
      Europe, size fractions for measurement of airborne particles in workplace
      atmospheres have been standardized since 1993 (European Standard EN
      481:1993). In this standard, three size fractions have been defined (inhalable,
      thoracic and respirable).12
           The Committee notes that measuring inhalable total dust in assessing
      exposure to airborne soybean flour has limited value in most industries because
      of co-exposure to dust from different sources, except in industries only handling
      soybean flour. Establishing exposure to inhalable soybean flour in, e.g., bakeries
      requires the quantization of soybean flour antigens in the airborne dust.
      Identity, properties and monitoring                                                 23
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<pre>  Antigens in airborne soybean flour dust
  Immunoassays for the determination of soybean flour antigens (proteins) in
  airborne dust were developed within the framework of the six-laboratory
  European research project MOCALEX (Measurement of Occupational Allergen
  Exposure). The methods involve (stationary) collection of dust, followed by
  extraction and analysis of airborne soybean flour antigens. Optimization studies
  for extraction of antigens from airborne (wheat) flour dust were conducted by
  Bogdanovic et al. (2006).13 In the study, stationary parallel sampling devices,
  enabling simultaneous collection of ten identical dust samples, were equipped
  with PAS-6 sampling heads and modified to capture particles with an
  aerodynamic diameter of up to 19 µm. Optimal extraction of flour proteins from
  the filters was achieved using phosphate-buffered saline (pH 7.4) containing
  0.05% (v/v) Tween-20.
      Using the same method for sampling and extraction, Gómez-Ollés et al.
  (2007) developed several immunoassays for the measurement of airborne
  soybean antigens.14 These included an inhibition enzyme immunoassay (EIA)
  using human anti-soybean flour protein IgG4, a rabbit soybean flour protein
  sandwich EIA, and three EIA’s aimed at the detection of hull proteins in whole
  soybeans.
      Cummings et al. (2010) modified the inhibition ELISA with soybean hull
  extract, developed by Gomez-Olles et al. (2007), using an protein extract
  prepared from de-oiled, de-hulled crushed soybean flakes as reference standard
  and o-phenylenediamine for generating a colored reaction product.15 The optical
  density at 490 nm was compared with the reference standard. The limit of
  detection was 16 ng inhalable soy antigen/mL.
  In order to investigate if soybean trypsin inhibitor or total protein concentrations
  are viable surrogates for airborne soybean dust concentrations, Spies et al. (2008)
  conducted an exposure study in two soybean flour producing factories in South-
  Africa.16 Data for operator exposure in the early phase (n=13), and in the late
  phase (n=19) of soybean processing, were analysed separately. Exposure to
  soybean flour dust occurred exclusively in the late phase. Personal inhalable dust
  (NIOSH method 0050, 60-80% of full shift) was measured gravimetrically. Total
  protein content was determined by means of the bicinchoninic acid assay.
  Trypsin inhibitor content was determined using a polyclonal antibody based
  inhibition enzyme immunoassay developed for food analysis. There was no
  significant correlation between personal inhalable dust and soybean trypsin
  inhibitor concentration. Considering all measurements (early and late phase
4 Flour dust from processed, de-hulled soybeans
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<pre>      combined) in each of the two factories, there was a significant correlation
      between inhalable dust and protein content (Spearman’s r≥0.6, p≤0.01), and
      between protein and trypsin inhibitor contents (Spearman’s r≥0.6, p<0.05).
      However, for exposure in the late phase (relevant for soybean flour dust), the
      only significant correlation found was between inhalable dust and protein
      content in one of the plants. These findings confirm earlier observations, in
      which dust levels were shown to only partially correlate with the actual allergen
      concentration.17
          Soybean flour and wheat or rye flour have few antigens in common,
      complicating the use of wheat or rye flour antigens as a surrogate for soybean
      flour exposure.4,18
2.4.2 Biological exposure monitoring
      No publications were found concerning monitoring of soybean flour (allergens)
      in biological samples.
2.4.3 Biological effect monitoring
      Tests are available to screen for persons who are sensitised against specific
      allergens. A useful clinical method to make a rough approximation of the
      person's sensitivity to an allergen is the skin prick test. In this test, allergens are
      introduced into the skin, after which the extent of local inflammation (wheal and
      flare diameter (mm)) is measured, as a result of the pharmacological effects of
      mediators, such as histamine, on the blood vessels in the skin. Skin prick tests
      resulting in a wheal diameter of at least 3 mm larger than the negative diluent
      (saline) control after fifteen minutes are usually considered positive for
      sensitisation.
          Alternatively, analysis of the presence of relevant specific IgE or IgG-
      antibodies, for instance in blood and nasal secretions, may be carried out. Serum
      concentration of IgE antibodies to soybean flour can be determined by an
      enzyme-allergo-sorbent-test (EAST) using allergen-coated disks. In this assay,
      an anti-IgE-beta-galactosidase conjugate is used for detection.19 Over the years,
      several tests for quantifying specific IgE and IgG antibodies to soybean flour
      allergens in blood have become commercially available, such as a fluorescence
      enzyme immunoassay (CAP-FEIA/ImmunoCAP 1000, Pharmacia Diagnostics/
      Phadia), used in several studies reviewed in this advisory report, and a highly
      sensitive enzyme-enhanced chemiluminescent enzyme immunoassay (Immulite
      2000, Diagnostic Products).2,15,20,21 The cut-off level for considering a test
      Identity, properties and monitoring                                                     25
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<pre>  positive is usually ≥0.35 kU/L. The discriminating power of the ImmunoCAP
  and Immulite tests for the presence of soybean specific IgE in serum was almost
  equal, but precision of the Immulite test was lower.22
      Specific inhalation challenge (SIC) is performed when occupational asthma
  is suspected and there is the need for identification of the causal allergen. The
  test provokes a physical response (rhinitis, asthma), and involves inhalation of a
  low dose of an allergen. Since there is serious risk of the patient suffering an
  asthmatic attack during testing, it is important to perform the test in a good
  clinical setting.
6 Flour dust from processed, de-hulled soybeans
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<pre> hapter 3
        Sources
3.1     Natural sources
        Soybean flour is a product obtained from soybeans. Soybeans are the edible
        seeds (after cooking) of the soybean plant Glycine hispida or Glycine max, which
        is a species of legumes.
3.2     Man-made sources
3.2.1   Production
        According to the Food and Agriculture Organization of the United Nations, the
        worldwide annual production of edible soybean flours and grits is nowadays
        more than 2,000,000 tons (mass).
             In producing soybean flours, in a first step the whole soybeans are roasted,
        removing the coat. Grinding or cracking and pressing of de-hulled soybeans
        result in soybean grit or flakes. Full-fat soybean flour is then obtained by finely
        grinding de-hulled soybeans grit or flakes. Milling of soybean flakes extracted
        with solvents results in defatted soybean flour, which has nowadays replaced the
        full-fat soybean flour.
        Sources                                                                             27
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<pre>3.2.2 Use
      Due to its high protein content it is widely used to produce all kinds of animal
      food, in particular food for pigs and poultry.
          The main use for human consumption being in the soybean processing
      industry and in the bakery industry.23 Soybean flour is a common baking
      additive, routinely added to dough in order to improve its rheology, and for
      bleaching dough carotenoids (lipoxygenase activity).24 In general, the soybean
      flour prepared without heat treatment is added to wheat flour (up to 0.5%) for
      baking white bread and rolls for its lipoxygenase activity. Enzyme de-activated
      (heated) soybean flour is used in dough for baking cakes (3-5%).25 Bread
      improvers typically contain 30-50% soybean flour.26,27 Because it is added to
      baking cereal flour, soybean flour is usually associated with cereal flour dust in
      bakeries and related facilities. The most common tasks associated with flour
      exposure involve dust-generating activities such as dispensing, sieving, weighing
      and mixing.28
          Sources of occupational exposure to soybean flour dust are inhalable dust in
      the atmosphere of the bakeries, flour mills, animal food processing factories, and
      processing factories, and manufacturers of dough improvers.
 8    Flour dust from processed, de-hulled soybeans
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<pre> hapter 4
        Exposure
4.1     General population
        A few outbreaks of asthma have been described, which are associated with
        inhalation of soybean dust, for instance among citizens in the Barcelona
        area.3,29,30 However, these asthma outbreaks were considered to be induced by
        exposure to soybean hull allergens, Gly m 1 and Gly m 2, which are not present
        in soybean flour dust. In addition, the outbreaks concerned environmental
        outdoor exposure with low exposure levels, which is a less relevant exposure
        scenario for the occupational situation.
            No studies have been published concerning the non-occupational exposure to
        airborne processed, de-hulled soybean flour dust or airborne flour dust-
        associated allergens.
4.2     Working population
4.2.1   Airborne allergen levels
        Cummings et al. (2010) reported on airborne soybean antigen (proteins) levels
        from personal dust samples in workers, which were exposed to soybean flour
        dust in a soybean processing plant.15,31 Workers could be divided in three
        exposure categories. The corresponding mean geometric concentrations (full
        shift samples) were: 24-804 ng/m3 (low, n=58); 959-2,297 ng/m3 (medium,
        Exposure                                                                       29
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<pre>      n=57); and 2,634-25,957 ng/m3 (high, n=64). Exposure levels of airborne soy
      flour proteins was determined by an inhibition immunoassay, in which soy flour
      protein extracts, which were prepared from bulk pre-processed de-hulled soy
      flakes, served as a standard.14
          Spies et al. (2008) reported also on total protein levels and soy trypsin
      inhibitor levels in three soybean processing plants.16 Median inhalable dust
      levels ranged between 0.24 and 35.02 mg/m3 (median 2.58 mg/m3), whereas total
      soybean protein ranged between 29.41 and 448.82 µg/m3 (median 90.09 µg/m3),
      and soy trypsin inhibitor between 0.05 and 2.58 µg/m3 (median 0.07 µg/m3;
      sandwich-immunoassay). The investigators did not find a statistically significant
      correlation between total dust levels and total soybean protein levels or soy
      trypsin inhibitor.
4.2.2 Inhalable dust levels
      Inhalable total dust exposure data, taken from studies in which soybean flour
      effects were determined, are shown in Table 2. Overall in bakeries, it is
      inevitable that in total dust not only soy flour dust was present, but also dusts
      from cereal flour and other additives. In none of the studies mentioned in the
      table, a distinction was made between the different dust sources.
 0    Flour dust from processed, de-hulled soybeans
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<pre> able 2 Full-shift personal exposure to airborne inhalable dust in various industries.
 ype of industry             No. of        Median          AM           GM             GSD         Range        Reference
                             personal      (mg/m3)         (mg/m3)      (mg/m3)        (mg/m3)     (mg/m3)
                             samples
 oybean processing plants
  plants, South-Africa:      64a                                                                                Spies et al.
 all processes                             2.58                                                    0.24-35.02 200816
 early process                             1.86-2.90                                               0.44-20.82
 late process                              0.58-3.94                                               0.24-8.83
 administration                            0.25-2.51                                               0.02-4.78
  plant, USA:                178                                                                                NIOSH 200931;
 low                                                                    0.17-0.54                               Cummings
 medium                                                                 0.58-0.73                               et al. 201015
 high                                                                   0.75-1.6
 akeries (use of soybean flour as ingredient in bread improver reported, or use of soybean flour likely when based on cases of
 ensitisation to soybean)
 9 Bread bakeries, UK:                                                                                          Smith &
 with LEV                    49            2.8-10.1                     2.7-8.2        10.3-13.3   0.2-52.6     Wastell Smith
 without LEV                 141           3.2-9.2                      3.3-11.4       19.5-146.7 0.1-770       199827
  Cake bakeries, UK,                                                                                            Smith &
without LEV                  44            3.9-30.6                     3.8-35.7       4.2-26      0.5-90       Wastell Smith
                                                                                                                199827
 8 Small bakeries,                                                                                              Jeffrey et al.
 cotland, exposure:                                                                                             199932
A: directly                  87                            6.7          4.9            2.3         0.6-23.7
  : Indirectly               57                            1.5          1.8            2.7         0.1-5.5
  Bakeries, Norway:          58b                                                                                Storaas et al.
 dough making                                                           3.14                       0.93-16.56 200733
 bread forming                                                          1.51                       0.26-9.15
 confectionary                                                          1.35                       0.41-5.35
 oven work                                                              0.54                       0.17-1.87
 packing                                                                0.29                       0.02-1.81
 administration                                                         0.06                       0-0.26
AM: arithmetic mean; GM: geometric mean; LEV, local exhaust ventilation; GSD: geometric standard deviation.
      60-80% of full-shift. Method of analysis in all studies was gravimetric.
      Total airborne dust.
               Exposure                                                                                                       31
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<pre>2 Flour dust from processed, de-hulled soybeans</pre>

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<pre>hapter 5
       Kinetics
       Exposure to soybean flour occurs as dust particles or liquid aerosols. There are
       no data on absorption, distribution, metabolism, and excretion specifically
       relating to soybean flour, but they are considered to behave as other particulate
       matter. Therefore, below the kinetics of particles (with no or very low toxic
       potential) is summarized.
       Upon inhalation, particles are deposited on the mucous membranes of the
       airways. The place of deposition in the airways is dependent on the size of the
       particle.34 Based on the aerodynamic diameter, particles are divided in inhalable,
       thoracic and respiratory fractions. Inhalable particle (or dust) fractions are
       defined as fractions in which 50% of the particles have an aerodynamic diameter
       of 100 µm. These particles are mainly deposited in the nose and nasopharyngeal
       region of the respiratory tract. In thoracic fractions about 50% of the particles
       have an aerodynamic diameter of 10 µm, and these can be found the trachea and
       bronchial region of the respiratory tract. Finally, particles in the respiratory
       fraction are the smallest, and may reach the lungs (particles with an aerodynamic
       diameter of 3,5-4 µm or smaller).
           The size range of soybean flour particles is from 1 to ~150 µm in diameter.
       Airborne flour dust particle sizes have been measured in the UK plant bakeries
       and Swedish bakeries whilst bakers were dough making and forming bread and
       rolls.35,36 The majority of the particles was larger than 9 µm, and is therefore
       Kinetics                                                                           33
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<pre>  likely to be deposited in the nose, mouth and ciliated airways.37 In wheat bread
  bakeries, 75% of the airborne dust particles was 4.7-5.8 µm in diameter.38
      Dust particles are cleared from the lungs by macrophages and the
  mucociliary system. However, heavy exposure may lower the ability of
  macrophages to eliminate particles, which may result in penetration of dust
  particles into the interstitium. The (anatomic) characteristics of an exposed
  person are also of importance in the development of disease.28,39
4 Flour dust from processed, de-hulled soybeans
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<pre> hapter 6
        Mechanism of action
        Inhalation of soybean flour may induce rhinitis (with frequent sneezing, nasal
        obstruction and rhinorrhea), conjunctivitis (with itching and inflamed, red eyes),
        rhinoconjunctivitis, asthma-like symptoms, and flu-like symptoms. Part of these
        symptoms are allergic in origin and are preceded by sensitisation of the worker
        (immunological response). However, the other part may be explained by non-
        specific irritation responses (non-immunological responses). For interpreting the
        symptoms and its consequences on health, it is important to make a distinction
        between the non-immunological and immunological responses. In practice,
        symptoms are associated with irritation if an immunological response is ruled
        out.
6.1     Immunological responses
        Sensitisation is an immunological mechanism (type I hypersensitivity reaction),
        which may occur at a first exposure, and is characterised by little or no response
        against the sensitising agent, in this case allergens in soybean flour.40 However,
        after a person is sensitised, subsequent exposure may cause intense responses,
        such as asthma, rhinitis and conjunctivitis. This may occur at low exposure
        concentrations. The responses may be life threatening and may have an
        immediate or delayed onset. The key mechanism of sensitisation is the formation
        of specific IgE-antibodies against allergens present in processed, de-hulled
        soybean flour. These IgE-antibodies are incorporated at the surface of mast cells.
        Mechanism of action                                                                35
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<pre>    Following a second encounter with the same allergens, mast cells may overreact
    when these allergens bind to the antibodies presented at the surface of the mast
    cells (elicitation). Mast cells are the starting point of a cascade of chemical
    reactions resulting in clinical symptoms. Specific IgE-antibodies against soybean
    proteins have been demonstrated in workers who were sensitised after inhalation
    of dust (see Chapter 7).
6.2 Non-immunological responses
    An association between exposure to soybean flour and respiratory symptoms of
    non-immunological origin has been suggested by a few researchers (see Chapter 7).
         As is indicated above (Chapter 5), soybean flour particles are considered to
    behave as dust particles. In general, exposure to large dust particles, irrespective
    to its chemical activity properties, may lead to local irritation to the eyes, nose
    and ears. In addition, inhalable dust particles may lead to irritation and
    inflammation of the bronchioles, alveolar ducts and alveoli. When dust particles
    are deposited in the respiratory system, the body tries to clear the material, in
    which the mucociliary defence system, and/or inflammatory cells, such as
    macrophages, are involved. Macrophages produce inflammatory mediators,
    which induce inflammatory responses with symptoms of irritation.
 6  Flour dust from processed, de-hulled soybeans
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<pre> hapter 7
        Effects
        In general, all available human data on (single and repeated) occupational
        exposure to soybean flour dust were mainly restricted to non-specific irritation
        and allergic reactions in the respiratory tract, eyes, and the skin. No data were
        available on toxicity in other organs, carcinogenic effects or reproductive
        toxicity. Also, no animal data were available.
7.1     Irritation
        Note: The number of studies in which respiratory irritation can be associated
        with certainty to exposure to soybean flour dust is limited, because the majority
        of the studies concern bakeries and other industries, in which co-exposure with
        other potential sources of dust that also may induce irritation (cereal flour dust,
        alpha-amylase, and other additives), is inevitable.
        Zuskin et al. (1990 and 1994) reported on nineteen workers employed in a mill
        processing soybeans (mean exposure duration 4 years), and 20 controls from
        elsewhere, who participated in a study on sensitisation and respiratory changes
        due to exposure to soybean dust.9,41 All participants were smokers. The workers
        were employed in the flaking processing area after extraction of soy oil.
        Sensitisation was determined using the skin prick test with aqueous extracts of
        soybean allergens (prepared from dust in soybean processing workrooms), and
        measuring serum levels of specific IgE. Respiratory symptoms were recorded
        Effects                                                                             37
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<pre>      using a questionnaire and a lung function test. All workers, and all but one
      control, showed to be positive for sensitisation to soybean extract when using the
      skin prick test, but only 3/19 workers had elevated levels of soy-specific IgE.
      The majority of the workers (13/19) were also positive for allergens in house
      dust. In general, the number of persons with respiratory symptoms was higher
      among workers than controls. The authors suggest that because the number of
      control workers positive in the skin prick test to soybean dust was high, the
      symptoms were irritative of origin rather than allergic. The authors also reported
      on high dust exposure levels (mean total dust, 29.5 mg/m3; respirable fraction,
      3.5 mg/m3). The Committee noted that the authors did not report on potential
      exposure to other types of dust. Also, the Committee noted that smoking may
      have influenced the outcome of the study.
          Smith et al. (2000) investigated the prevalence of respiratory symptoms and
      sensitisation (skin prick test) among workers (n=679) in 18 different flour mills,
      who are daily exposed to wheat flour dust and additives, such as fungal alpha-
      amylase, rice flour and soybean flour.42 Prevalence of sensitisation was: 1.2%
      (wheat flour), 0.9% (fungal alpha-amylase), 0.4% (rice flour), and 0.7%
      (soybean flour). However, the prevalence of respiratory symptoms was much
      higher: 22%. The majority of the workers with symptoms (95%) complained of
      transient occasional symptoms (sneezing, blocked/runny nose, chest tightness,
      and/or difficulty breathing), which the authors related to non-specific irritation.
      The flour dust exposure levels (geometric mean, minimum-maximum) were:
      6.1 mg/m3 (0.5-54.7 mg/m3) for production activities, and 17.6 mg/m3 (1.1-217
      mg/m3) for hygiene activities.
7.2   Sensitisation
7.2.1 Prevalence and incidence
      A number of studies have been published on food allergies in the general
      population to soybean as a food ingredient. Care should be taken in comparing
      these data since the general population may also be exposed to potential
      allergens present in the hull of soybeans, whereas occupational exposure in
      bakeries and mills mainly concern flour dust from de-hulled soybeans. Also the
      route of exposure is generally different (oral intake versus inhalation). In at least
      one Swedish population study with data on 1,397 participants, the prevalence of
      serum specific IgE for soybean allergens (high molecular allergens present in de-
      hulled soybeans) was reported to be on average 2%.43
 8    Flour dust from processed, de-hulled soybeans
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<pre>    Some investigators who reported on the prevalence of sensitisation to
soybean flour among bakery workers and millers also reported on reference
groups which were not occupationally exposed to soybean flour dust. For
instance, Baur et al. (1998) reported on a control group of 43 healthy people who
did not work in bakeries. They underwent the same tests as a group of bakers
living in the same area.19 When using the skin prick test none of the controls
scored positive for soybean flour, whereas 5% scored positive for serum soybean
specific IgE (in bakers 1-11% and 19-21%, respectively). Of the controls, 2%
showed respiratory obstruction, and 5% were hyperreactive in the lung function
test (in bakers 17-28% and 13-19%, respectively). Also Cummings et al. (2010)
included in their study a control group of 50 healthcare workers.15 The
prevalence of serum soybean specific IgE was 4% and the levels for soybean
specific IgG was 1.5 mg/L. For soy plant workers the values were 21% and 97.9
mg/L, respectively.
Case reports and patient-based studies
The first who reported on sensitisation to soybean extracts (skin prick test) and
allergic respiratory symptoms was Duke in 1934.44 It concerned five patients
with cough and asthma who worked in a soybean mill in the United States. Bush
and Cohen (1977) described a case of a previously non-allergic worker in a
soybean processing factory who developed immediate and late onset asthma
after breathing soybean flour used in the manufacture of food supplements.45
Skin prick testing to a soybean flour extract showed both an immediate and a late
response. Also the bronchial challenge test to a soybean flour extract was
positive. Heyer (1983) found a positive response in 6/8 bakers with suspected
bronchial disorders upon respiratory challenge testing and skin prick testing to
soybean flour extract.6 Among 202 bakery workers suffering from respiratory
disease, Jorde et al. (1986) found 132 (65%) who reacted positively upon skin
prick testing with soybean flour extract, and 53 (26%) who were positive upon
respiratory challenge testing.46 Bush et al. (1988) reported on a food processing
plant worker who had developed asthma six years after beginning work.47 The
patient reacted positive upon skin prick testing with a soybean flour extract.
Serum soybean flour specific IgE was six times higher than in serum of a control.
     Quirce et al. (2000) demonstrated (skin prick tests) the presence of
sensitisation to high molecular weight soybean proteins (25-55 kDa), and (pure)
soybean trypsin inhibitor, in bakers and confectioners (n=4) with work-related
asthma.3 None of these persons were sensitised to allergens typically present in
soybean hull (Gly m 1, and Gly m 2). In all four persons asthmatic responses
Effects                                                                           39
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<pre>  were elicited when they were challenged with methacholine or soybean flour
  extracts. Later, the same research group reported on two other bakers with work-
  related asthma, who were sensitised to soybean trypsin inhibitor (specific IgE),
  and showed asthmatic responses when challenged to the inhibitor.48
       Specific sensitisation to storage proteins and to soybean trypsin inhibitor
  among bakery workers with work-related symptoms, was reported by several
  other investiga-tors.1,2,4,15
       Baur et al. (1988) found that of the 140 bakery workers 21% were sensitised
  to soybean flour (serum specific IgE).49 The bakers had been employed for at
  least six months, and were selected on showing workplace-related asthma,
  rhinitis and/or conjunctivitis. Subsequently, Bauer et al. (1989) reported an
  incidence of sensitisation of 32% to soybean flour in a group of 260 symptomatic
  bakery workers.50 From the same research group, but from another study, 19% of
  symptomatic bakery workers (6/31) showed to be sensitised (IgE immunoassay)
  to soybean flour.8 Of the sensitised workers 58% were sensitised to trypsin
  inhibitor and 42% to lipoxygenase. Later, Bauer et al. (1996) reported that 86%
  of a group of symptomatic bakers (12/14) and sensitised to soybean flour, scored
  positive for serum soybean trypsin inhibitor specific IgE.1 In addition, Alvarez et
  al. (1996) described three bakers, a miller and a farmer, who were sensitised to
  soybean flour (increased serum soybean flour specific IgE levels).51
       Quirce et al. (2000) examined two bakers and two confectioners who showed
  asthma symptoms (cough, chest tightness, shortness of breath, and wheeze), on
  the presence of specific sensitisation to soybean flour extracts, trypsin inhibitor
  from soybean, and soybean hull extracts.3 Also (specific) bronchial challenge
  test were performed. Using the skin prick test, all four patients showed a positive
  response with soybean flour extracts; two of them were also positive for trypsin
  inhibitor. Serum soybean-specific IgE levels were elevated in three patients; one
  patients showed a positive response for soybean hull allergen ‘Gly m 2’, and
  none for ‘Gly m 1’. In contrast, the authors noted that in a serum pool from
  patients with soybean epidemic asthma (in the general population) specific IgE
  against soybean hull allergen (Gly m 1) was strongly positive. The contents of
  ‘Gly m 1’ in soybean hull and soybean flour extracts were 125 µg/mL and 0.012
  µg/mL, respectively. All patients showed hyperresponsiveness with inhalation of
  metacholine (nonspecific reaction), and soybean flour extract. The investigators
  suggested that soybean allergens causing asthma outbreaks in the general
  population were mainly caused by low molecular weight proteins in soybeans
  (mainly present in hulls), whereas occupational asthma was mainly induced by
  high molecular weight soybean proteins (both present in hull and flour).
0 Flour dust from processed, de-hulled soybeans
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<pre>    The same research group investigated the presence of specific sensitivity in
24 bakers and pastry makers in the baking industry.20 All patients had suspected
occupational asthma (cough, chest tightness, shortness of breath, and wheezing).
They handled routinely cereal flour (wheat and rye), soybean flour and fungal
enzymes. Skin prick tests with soybean flour extracts showed that 42% of the
patients were positive for soybean flour. In 83% of the patients, the tests revealed
sensitivity to more than two occupational allergens (i.e., cereal flour, alpha-
amylase). A positive serum soybean flour specific IgE response was observed in
34% of the patients (in comparison, positive responses were also found for wheat
flour (75%), rye flour (67%), and alpha-amylase (55%)). Nonspecific bronchial
hyperresponsiveness was reported in all but one patient; specific inhalation
challenge tests with soybean flour revealed all but one positive response among
the 6 patients tested. A positive correlation was found between ‘bakery-derived
allergens’ skin prick testing and early asthmatic reaction (r=0.88, 95% CI
0.77-0.94, p<0.001). However, there was a poor correlation between
methacholine challenge testing and specific allergen inhalation testing (r=0.30,
95% CI -0.06-0.59, p=0.07). No correlation was found between specific serum
IgE and allergen-specific inhalation challenge testing. Regarding the
correlations, the Committee noted that no correlations were calculated for
specifically soybean flour-derived allergens.
Cross-sectional studies
A summary of the studies on the prevalence of soybean flour specific
sensitisation is given in Table 3, whereas details of the studies are shown in
Annexes E and F.
    The Committee is aware that the prevalence values may be influenced by the
duration of employment, job tasks, exposure levels, peak exposures and co-
exposure to other types of organic dust. Furthermore, in some studies the number
of participants was very small, which limits the interpretation of the outcomes.
Also potential bias (healthy-worker effect), and the use of different extracts of
soybean (flour) for sensitisation testing may have played a role in the variation of
the outcomes. Taking these potential influencing factors into account, the
Committee concludes that workers who routinely handle soybean flour can get
sensitised to allergens present in the soybean flour.
Effects                                                                              41
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<pre>      Table 3 Prevalence of soybean flour specific sensitisation in workers exposed to soybean flour dust.
      reference                          type of industry          n            skin prick   specific
                                                                                test         serum IgE
                                                                                (% positive) (% positive)
      Soybean milling and processing industry
      • Zuskin et al. 19919                                        19           100          16
      • Roodt and Rees 199552                                      22           36           36
      • Smith et al. 200042                                        678          0.7          -
      • Cummings et al. 201015           soybean processing        135          7            21
      • Harris-Roberts et al. 201253     soybean processing        136          -            14
      Bakery industry
      • Smith et al. 199726              bakery                    383          6            -
      • Baur et al. 199819               bakery                    88/89        1            19
      • Smith & Wastell Smith 199827 bread bakery                  392          7            -
      • Smith & Wastell Smith 199827 cake bakery                   77           1            -
      • Jeffrey et al. 199932            bakery                    205          -            3
      • Storaas et al. 200521            bakery                    183          -            2
      • Baatjies et al. 200954           supermarket bakery        507/513      8            -
      Other industries
      • Zuskin et al. 199255             animal food producer 35                28.6         -
7.2.2 Exposure-response relationships
      The American National Institute for Occupational Safety and Health (NIOSH)
      investigated exposure-response relationships between occupational exposure to
      soybean flour dust and the occurrence of specific sensitisation and respiratory
      symptoms (NIOSH 2007, Cummings et al. 2010).15,31 A detailed description of
      the study design and outcomes are given in Annex F. Briefly, in a US soybean
      factory de-oiled and de-hulled soybean flakes are processed into soybean powder
      products. Co-exposure to other organic dust sources was unlikely. The study
      consisted of 147 workers of the factory, and 50 referents (healthcare workers)
      who were not exposed. To determine exposure levels, full-shift personal
      inhalable dust samples were collected; exposure was expressed as inhalable dust
      and as inhalable soy antigens. Workers were allocated into one of the three
      exposure groups: low, medium and high. Sensitisation was determined by the
      skin prick test, and by measuring serum soybean specific IgE and IgG levels.
      Health information, such as respiratory symptoms, was obtained by interviews
      using a questionnaire. Also lung function tests and bronchial metacholine
      challenge tests were performed.
 2    Flour dust from processed, de-hulled soybeans
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<pre>     The investigators found prevalence values of soybean-specific sensitisation
(IgE levels) of 21% (low exposure), 33% (medium exposure), 6% (high
exposure), and 4% (referents). The prevalence values for asthma-like symptoms
were: 9% (low), 20% (medium) and 8% (high). No clear relationship was found
between exposure levels (expressed as soybean allergen exposure) and serum
specific IgE levels or asthma-like symptoms. Most likely this was due to a
healthy-worker effect, which would also explain why they found an inverse
relation between duration of employment and skin rash (15%, short duration;
13%, medium duration; and, 2%, long duration). There was a positive
association between work-related asthmatic symptoms and specific IgE-based
sensitisation to soybean flour (OR 5.9; 95% CI, 2.0-17.6). No data on exposure-
response relationship were presented for the prevalence of sensitisation by the
skin prick test, nor for exposure levels expressed as inhalable dust. Overall, the
correlation between personal inhalable dust and soybean flour dust allergen was
fair (Spearman’s r=0.35; n=178, p<0.001).
     Furthermore, the authors reported on real-time personal and static peak
exposure measurements of inhalable dust in relationship with the occurrence of
symptoms. Also for these peak exposures workers were divided in three
exposure categories (low, non-production workers; medium, support production
workers; and, high, production workers). Prevalence values for asthma-like
symptoms were: 2% (low), 15% (medium), and 19% (high). For skin rash the
values were: 5% (low), 6% (medium), and 21% (high). The increase in
prevalence values for both type of symptoms was statistically significantly
associated with increased peak exposure.
     The authors did not find an association between work-related asthma and
other health outcomes, and several confounding risk factors, such as race/
ethnicity, gender, age, smoking status, soy IgG level, elevated total IgE, and soy
IgE positivity. In addition they did not find an association between peanut and
storage mite IgE positivity, positive skin response to other extracts (e.g.,
soybean, house dust mite).
     Overall, in the study by Cummings et al., exposure-response relationships
were found for peak exposure only, and not for average exposure. The
Committee noted several flaws, such as that exposure-response analyses on
specific soy IgE levels and exposure levels were carried out without adjustment
for potential confounders. In addition, the Committee noted that the analysis on
peak exposure shows mainly a difference between non-production and
production workers, whereas the difference between production supporting work
and production work is small.
Effects                                                                            43
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<pre>7.2.3 Cross-reactivity
      A cross-reaction involves a specific antibody, which binds an allergen other than
      the target allergen.40 It usually involves allergens that are structurally very
      similar, but not always. The phenomenon may indicate that sensitisation of an
      allergen in for instance cereal flour may also lead to sensitisation of a
      comparable allergen in soybean flour without previous exposure to dust of
      soybean flour. Overall, only a few data are available on the possible cross-
      reactivity regarding soybean flour. At least it appears that soybean flour and
      cereal flour have some allergens in common. For instance, Sandiford et al.
      (1995) reported on a major common protein of soybean and wheat flour with a
      molecular weight of 21 kDalton (trypsin inhibitor), which would suggest that
      they have common enzyme inhibitors.4 However, the same authors reported on a
      poor correlation between several other allergens present in cereal flour and
      allergens present in soybean flour. This would indicate that a large number of
      potentially cross-reacting proteins in cereal flour are absent in soybean flour. In
      addition, Smith and Wastell Smith (1998) concluded from their study among
      bakery workers that fungal alpha-amylase does not cross-react with wheat and
      soybean allergens.27
          Regarding food allergy in the general population, a number of studies has
      investigated the potential of cross-reactivity among legumes, because they have
      structurally homologous proteins and share common epitopes.11,56,57 Like
      peanuts, lentils and lupins, also soybeans are legumes. All these legumes are
      known to have allergenic potential. However, only low frequencies of cross-
      reactivity in humans have been reported between for instance peanut and
      soybean.10,11 In addition, Mittag et al. (2004) showed a high degree of cross-
      reactivity between the soybean allergen ‘Gly m 4’ and birch pollen allergen in an
      inhibition immunoassay.58
7.3   Other symptoms
      Reports are available on flu-like symptoms among workers in the soy processing
      industry. For instance, Harris-Roberts et al. (2012) associated flu-like illness
      (fever, aching, tiredness after work) with off-loading of whole soybeans among
      workers in South Africa (n=25/114), of which 7/57 (12.3%) were nor currently
      exposed to dust during soybean off-loading, and 18/57 (31.6%) were currently
      exposed (OR 2.7, 95% CI 1.0-7.2).53 However, the etiology of these flu-like
      symptoms was unclear, and the authors could not exclude that the presence of
 4    Flour dust from processed, de-hulled soybeans
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<pre>    high concentrations of endotoxin (in the hulls) may have been the cause, and/or
    the antigens in the hull of the soybeans.
        In 2013, Cummings et al. reported on flu-like symptoms (fever, aching, pain,
    chills, and night sweats during the past 12 months) in their study (see Section
    7.2.2).59 In this case, workers were mainly exposed during the processing of de-
    hulled soy beans. Of the 147 participants, 55 (37%) reported flu-like illness, and
    20 (14%) work-related flu-like illness (flu-like illness that was better away from
    work). Production workers had a higher odds ratio for work-related flu-like
    illness than non production workers (OR 4.4; 95% CI 0.9-21.0). However, the
    work-related flu-like illness could not be associated with soy specific IgE (OR
    1.6; 95% CI 0.5-4.9), soy-specific IgG, or with exposure categories (inhalable
    dust, inhalable soy antigen, peak dust). The latter was most likely due to immune
    tolerance of a health-worker effect. Since workers were not exposed to the hulls
    of whole soybeans, also the concentrations of endotoxin in the samples were low.
7.4 Summary
    Data on the adverse health effects of occupational exposure to soybean flour dust
    are mainly restricted to respiratory symptoms in humans. No animal data have
    been presented nor data on carcinogenicity and reproductive toxicity.
        Respiratory symptoms (cough, dyspnea, wheezing, chest tightness, shortness
    of breath) are associated with rhinitis, rhinoconjunctivitis and asthma. The
    etiology of these symptoms may be (non-specific) irritation or allergic reactions,
    or a combination of both. A way to discriminate between the two mechanisms is
    determining specific immune responses (sensitisation) against allergens present
    in soybean flour.
        A number of case reports, hospital-based studies, and cross-sectional studies
    report on workers in bakeries, soybean mills and processing factories, who are
    sensitised specifically to allergens present in soybean flour, indicating that
    allergic responses do occur. Part of these workers also showed respiratory
    symptoms. However, prevalence values on soybean specific sensitisation vary
    widly among the cross-sectional studies. This is partly explained by variations in
    job history and exposure circumstances, and by variations in test systems used to
    determine sensitisation. In one cross-sectional study among workers in a soybean
    processing factory, also exposure-response relationships were investigated.
    However, no clear correlation was found between levels of exposure (airborne
    soy antigens) and the prevalence value of sensitisation. This was probably due to
    a healthy-worker effect. In contrary, a statistically significant positive
    Effects                                                                            45
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<pre>  correlations was found between levels of peak exposure (inhalable dust), and
  asthma-like symptoms and skin rash.
      It is inevitable that most of the workers who participated in the
  epidemiological studies are exposed simultaneously to organic dust from other
  sources than soybean flour, such as cereal flour dusts, and fungal alpha-amylase
  in bakeries. All these sources may have induced respiratory symptoms by
  themselves, and thus may have influenced the outcomes of the studies on
  soybean flour dust exposure. In soybean processing and manufacturing plants,
  co-exposure with dust from other sources than soybeans is less likely. There are
  some indications that cross-reactivity with allergens that are present in cereal
  flour dust and fungal alpha-amylase, does not play a role in sensitisation to
  allergens that are present in processed soybean flour.
6 Flour dust from processed, de-hulled soybeans
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<pre> hapter 8
        Existing guidelines, standards and
        evaluation
8.1     General population
        Not available.
8.2     Occupational population
        In the Netherlands and in other countries no occupational exposure limits have
        been set specifically for soybean flour dust.
        Existing guidelines, standards and evaluation                                  47
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<pre>8 Flour dust from processed, de-hulled soybeans</pre>

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<pre> hapter 9
        Hazard assessment
        The Committee specified soybean flour dust as dust from processed, de-hulled
        soybeans.
9.1     Hazard identification
        Available studies have shown that the main health effects of inhalation to
        soybean flour dust are symptoms in the respiratory tract and eyes, such as
        rhinitis, rhinoconjunctivitis, asthma (baker’s asthma), and flu-like symptoms.
        Upon contact with the skin also rash is recorded. Part of the symptoms has been
        shown to be of allergic origin, mediated by immunoglobulin E (IgE) antibodies
        to proteins present in soybean flour. This is a concern to the Committee, because
        once allergic, the person in question may express allergic symptoms for the rest
        of his or her life upon exposure to soybean flour dust. However, the symptoms
        may also be explained by non-allergic irritation responses, as is shown in a few
        studies among bakery workers, and flour milling and processing workers.
            No relevant human and animal data were available on other adverse health
        effects, nor were there data presented on the carcinogenic potential and
        reproductive toxicity.
        In the bakery and animal food industry where soybean flour is handled, it is
        inevitable that workers are simultaneously exposed to organic dust from other
        sources, such as dust from whole soybeans, cereal flour dusts, fungal alpha-
        Hazard assessment                                                                 49
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<pre>  amylase, and additives that improve bread baking. Part of these sources are
  known for their allergic and irritation potential, which may induce the same
  symptoms as described for soybean flour. This makes it difficult to distinguish
  the symptoms caused by soybean flour dust from other dust sources. Therefore,
  co-exposure hampers the use of data on symptoms in deriving a health-based
  occupational exposure level. The same applies for using dust (inhalable or
  respirable) levels as exposure parameter, since dust present in the air in those
  types of workplaces may contain particles from different sources. The problem
  may be overcome by using specific sensitisation (see below) and airborne
  antigen levels as effect and exposure parameter, respectively. Co-exposure in the
  processing and manufacturing industry, in which only soybeans are used is less
  likely.
      Regarding allergic symptoms, these are preceded by and coincide with
  sensitisation. Sensitisation is an immunologic response to a specific allergen.
  Soybean flour, and also cereal flour and fungal alpha-amylase, contains proteins
  that may induce IgE mediated immune responses. In contrast to recording
  symptoms, tests like the skin prick test and determination of serum specific IgE
  levels can distinguish sensitisation caused by soybean flour allergens from
  sensitisation caused by allergens from other sources. In addition, the available
  data indicate that there is no or only a low frequency of cross-reactivity. For these
  reasons, in assessing a health-based occupational exposure limit, the Committee
  is of the opinion that data on sensitisation to dust from processed soybean flour
  can be used as critical effect endpoint. Furthermore, since sensitisation often
  precedes the onset of allergic symptoms, by preventing sensitisation also allergic
  symptoms will be prevented.40
      The available data clearly show that occupational exposure to soybean flour
  dust is associated with an increased risk for developing sensitisation and allergic
  symptoms. However, there is a considerable heterogeneity in the prevalence
  estimates of sensitisation to soybean flour dust among soybean flour handling
  workers (see Section 7.2.1). The heterogeneity may be explained by differences
  in job history, job tasks, working conditions, the use of different extracts of
  soybean flour for testing sensitisation, the use of different tests, potential bias,
  such as the healthy-worker effect, and personal factors (smoking habits, atopy).
  The highest prevalence estimates are made in the soybean milling and processing
  industry (16-36%; see Table 3). The prevalence for serum soy-specific IgE in the
  general population is 2 percent.43
0 Flour dust from processed, de-hulled soybeans
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<pre>9.2   Selection of study suitable for quantitative risk estimation
      In many studies no exposure levels were assessed, but when it was done, mainly
      levels of inhalable dust were reported. So far two studies have been published
      with data on airborne soybean flour antigens. In the study by Spies et al. (2008)
      exposure levels on soybean antigens were reported (Spies et al. 2008).16 A few
      years later, in the same soybean processing plants also investigations on health
      effects were performed (Harris-Roberts et al. 2012). However, no exposure-
      response relationships were assessed.53 This leaves one study in which an
      exposure-response analysis was performed with the preferred exposure and
      effect parameters (Cummings et al. 2010, NIOSH 2009).15,31 In this cross-
      sectional study, data were obtained from workers in a soybean processing
      factory. The plant processed de-oiled, de-hulled soybean flakes into soybean
      powder products. Combined exposure to other organic dust sources was unlikely,
      and although the Committee focuses on airborne allergen levels and specific
      sensitisation, in this particular study also inhalable dust levels and airway
      symptoms were recorded. Study details and results are shown in Annex F. The
      participants (n=135) showed a significantly higher prevalence of serum soy-
      specific IgE than controls (21% versus 4%; PR 52; 95% confidence interval
      1.3-21.0). Also, the participants with a positive soy-specific IgE outcome
      showed significantly more symptoms of asthma than participants with a negative
      outcome. The Committee examined the possibility of using the data from this
      study for its quantitative risk analysis.
9.2.1 Reference value (8-hour TWA)
      Suitability of the study
      Regarding full shift exposure measurements, the investigators did not find a
      significant association between inhalable soy antigen exposure and soy-specific
      sensitisation (see Table 4). In particular participants in the highest exposure
      group showed the lowest prevalence of soy-specific sensitisation. According to
      the investigators this may be due to the healthy-worker effect, in which workers
      with a positive score on the soy-specific IgE test may have left the workplace to
      avoid further exposure before this study started. This would explain the bell-
      shaped exposure-response relationship (see Figure 1). Theoretically, it may also
      be explained by the occurrence of tolerance, i.e, with continued exposure the
      soy-specific IgE levels decrease over time. Furthermore, the authors noticed the
      Hazard assessment                                                                 51
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<pre>  Table 4 Exposure-response analysis based on full shift inhalable soy antigen exposure.15,31
                    Exposure level (ng/m3)             Prevalence of sensitisation Prevalence ratio
                    Range            Median            (serum specific IgE levels)
  Control           0                  0                4%                           No statistically
  Low               24-804           400               21%                           significant positive
  Medium            959-2,297          1,628           33%                           association
  High              2,635-25,958       4,296            6%
  Figure 1 Association between soy exposure in ng/m3 and soy sensitisation (in percentages).
  Reference sensitisation level from Björnsson et al. (1996)43; point estimates from the exposure
  categories as given by Cummings et al. (2010).15
  small number of participants in the groups, which may have limited the ability to
  detect associations. Including the large differences in exposure levels within the
  groups, the Committee confirms that these points may have considerably limited
  the power of the study. In addition, the Committee has noticed that in the lowest
  exposure group, the prevalence for soy-specific IgE is relatively high compared
  to the control group (21% versus 4%). This may indicate that in the lowest
  exposure group the exposure to soybean dust allergens was already rather high.
      Overall, despite these limiting factors, the Committee is of the opinion that
  the data in the study can be used in assessing a health-based occupational
  exposure level, since: data concerns exposure to soybean flour dust only (no
  interference due to co-exposure); measurements are performed on specific
  endpoints (antigens in soybean flour, specific sensitisation); the prevalence on
2 Flour dust from processed, de-hulled soybeans
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<pre>sensitisation is rather high; and, in the lower exposure range a steep exposure-
response relationship is observed. The lower exposure range is the most relevant
range in assessing an occupational exposure limit.
Linear Poisson regression analysis
The Committee did not observe a level below which no additional cases of
sensitisation to soybean flour allergens were found. This means that an exposure
level, at which sensitisation to airborne soybean flour allergens will not occur,
cannot be identified; thus no threshold-based occupational exposure level can be
attained. Earlier, the Health Council reported on this issue.40 The Council
concluded that in theory a threshold level exists for allergic sensitisation by
inhaled allergens. This implies that a health-based recommended occupational
exposure limit can be calculated, using the same procedures and methods as for
other non-carcinogenic substances. However, the Council emphasized that for
most allergens, in practice it will not be possible to calculate a reliable health-
based recommended occupational exposure limit. The reason being that the
threshold level will be too low to discern using the techniques presently
available. For those allergens, the Health Council proposed an alternative
approach, involving determination of reference values, i.e., concentration levels
that correspond to predefined accepted levels of extra risk of allergic
sensitisation.
The risk analysis method used in the Cummings/NIOSH-study is very
sophisticated. To cope with the bell-shaped relationship, data on the highest
exposure group could be omitted in the analysis. However, the other limiting
factors are still remaining. Alternatively, several robust risk analysis methods are
available that have been used for many years. For example, the approach using a
No-Observed-Adverse-Effect-Level (NOAEL) or the Lowest-Observed-
Adverse-Effect-Level (LOAEL) as starting point. Also, a straightforward linear
relationship can be assumed, making use of more data points instead of one as
with the NOAEL/LOAEL-approach. The Committee emphasises that none of
these methods cope with the limitations of the data set, rather they indicate
approximately the level of an exposure limit. Alternatively, another (less
preferential) effect endpoint may be chosen. However, using work-related
symptoms as an effect endpoint instead of specific sensitisation, is obstructed by
missing data on the control group, number of persons per group, and missing
data on prevalence for symptoms other than work-related asthma-like symptoms
(see Annex F).
Hazard assessment                                                                    53
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<pre>      Overlooking the alternatives, the Committee proposes to estimate a health-
  based occupational exposure limit by assuming a linear exposure-response
  relationship.
  The data from all exposure groups were combined. The Committee estimated the
  average exposure level by taking the midpoint (median) of the exposure range
  per group, and weighting this midpoint with the number of participants in the
  concerning groups. This leads to a weighted average exposure level of 2,324 ng
  inhalable soy antigen/m3.
      Regarding setting a reference value, the Ministry of Social Affairs and
  Employment has requested the council to base a reference value on an additional
  absolute sensitisation risk to an allergen of 1 percent due to occupational
  exposure, compared to the background risk in the general population.
      The reference value was estimated by using a simple linear Poisson
  regression model and by fitting the line through the intercept (zero). The slope
  coefficient of the regression model is calculated to be 0.0039 (p=0.041). This
  resulted in the equation:
      RR = 1 + 0.0039 × exposure concentration
  in which RR is the relative risk, ‘1’ is the relative risk at the baseline, and
  exposure concentration is expressed in ng inhalable soy antigen/m3. The
  background risk (risk level of the non-exposed population) is set at 2 percent.43
  An additional absolute risk of 1% corresponds to an RR of (2 +1)/2 = 1.5. Using
  the formula, this results in a reference value of 0.1 µg inhalable soy antigen/m3
  (128 ng inhalable soy antigen /m3, rounded-off).
  The Committee discussed whether the estimated exposure concentrations should
  be adjusted for inter-individual differences in vulnerability among humans. In
  case of developing allergies, a group of vulnerable people are the atopics. Since
  atopics were included in the study populations, no adjustments are needed.
      The available literature does not suggest that non-allergic symptoms occur at
  lower exposure levels than allergic symptoms. Therefore, the Committee is of
  the opinion that a risk assessment based on sensitisation not only protects against
  allergic symptoms, but most likely against the development of non-allergic
  symptoms as well.
4 Flour dust from processed, de-hulled soybeans
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<pre>9.2.2 Health-based short-term exposure limit (STEL; 15-minutes TWA)
      When peak exposure to total inhalable dust was taken into account, positive
      correlations were found for asthma-like symptoms, airway obstruction, and rash
      or other skin problems (see Table 5). According to Cummings et al. (2010), this
      means that prevention of peak exposure will most likely lower the risk for
      development of specific sensitisation and symptoms.
           Since peak exposure is a risk factor in developing work-related respiratory
      allergies, the Committee evaluated whether it is possible to derive a STEL. In the
      study by Cummings et al. (2010; NIOSH 2009) effect data on peak exposure
      were reported. Statistically significantly positive correlations were found for
      work-related asthma-like symptoms, airway obstruction, and rash or skin
      problems (see Table 5 and Annex F). The strongest correlations were found for
      asthma-like symptoms.
           However, the Committee noted also incomplete reporting of peak exposure
      data that are needed in deriving a STEL. For instance, data on the non-exposed
      control group are missing, and no data are presented as to how many persons per
      exposure group were included. In addition, no data are given on the prevalence
      of sensitisation, the most sensitive effect parameter in assessing the risk on
      allergy development. Overall, the Committee is of the opinion that data on peak
      exposure are too limited to be useful in deriving a STEL.
      Table 5 Exposure-response analysis based on peak total inhalable dust exposure measurements.15,31
      Effect parameter           Exposure levels           Prevalence             Prevalence ratio
      Work-related asthma-like Low: <1 mg/m3                2%                    1.0
      symptoms                   Medium: 1-10 mg/m3        15%                    6.96 (1.22-131)
                                 High: ≥10 mg/m3           19%                    9.37 (1.61-178)
      Airway obstruction         Low: <1 mg/m3              -                     1.0
      (spirometry)               Medium: 1-10 mg/m3         -                     4.9 (0.79-94.5)
                                 High: ≥10 mg/m3            -                     8.49 (1.41-163)
      Rash or skin problems      Low: <1 mg/m3              -                     1.0
                                 Medium: 1-10 mg/m3         -                     1.38 (0.26-10.3)
                                 High: ≥10 mg/m3            -                     5.29 (1.26-36.3)
      Correlation expressed as odds ratio (95% confidence interval). No data on control group reported.
9.3   Conclusion and recommendation
      The Committee recommends a reference value for occupational exposure to de-
      hulled soybean flour dust allergens of 0.1 µg inhalable soy antigen/m3, as an
      eight-hour time-weighted average concentration (TWA). At this concentration
      Hazard assessment                                                                                 55
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<pre>    workers have an additional absolute sensitisation risk for allergens in soybean
    flour dust of 1 percent compared to the background risk in the general (not
    exposed) population.
        Data are insufficient to derive a short term exposure limit (15-minute TWA).
9.4 Groups at extra risk
    Some people are more likely to develop allergies, as a result of genetic
    susceptibility, or other factors such as atopy.40 As stated by the World Allergy
    Organization atopy is “a personal or familial tendency to produce IgE antibodies
    in response to low doses of allergens, usually proteins, and to develop typical
    symptoms such as asthma, rhinoconjunctivitis, or eczema/dermatitis”.60-62 Atopy
    is not considered an illness, but a predisposition. It is estimated that up to 45% of
    the general population can show any form of atopic sensitisation to a panel of
    aeroallergens, which means that they are sensitised to one or more ‘every day’
    common allergen. In an earlier report by the Health Council on work-related
    respiratory allergies, the council stated that “atopy is not seen as a good predictor
    of specific sensitisation or of the development of allergic symptoms, because a
    high proportion of atopic people are not sensitised by exposure to work-related
    allergens and do not develop allergic symptoms”.40,63
        Workers with pre-existing asthma or those with more general respiratory
    symptoms may have an increased risk to develop symptoms (i.e., work-
    aggravated asthma). Also, it is possible that workers who are already sensitized
    to soybean allergens may experience allergic symptoms with continuing
    exposure at very low exposure levels.
 6  Flour dust from processed, de-hulled soybeans
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<pre>References
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Quirce S, Polo F, Figueredo E, Gonzalez R, Sastre J. Occupational asthma caused by soybean flour in
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Sandiford CP, Tee RD, Newman-Taylor AJ. Identification of crossreacting wheat, rye, barley and
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Smith TA, Lumley KPS. Work-related asthma in a population exposed to grain, flour and other
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Lavaud F, Perdu D, Prevost A, Vallerand H, Cossart C, Passemard F. Baker’s Asthma Related to
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Wüthrich B, Baur X. Backmittel, insbesondere alpha-Amylase, als berufliche Inhalationsallergene in
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8 Flour dust from processed, de-hulled soybeans
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  References                                                                                            59
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5 Bush RK, Cohen M. Immediate and late onset asthma from occupational exposure to soybean dust.
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7 Bush RK, Schroeckenstein D, Meier-Davis S, Balmes J, Rempel D. Soybean flour asthma: detection
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8 Quirce S, Fernández-Nieto M, Polo F, Sastre J. Soybean trypsin inhibitor is an occupational inhalant
  allergen. J Allergy Clin Immunol 2002; 109(1): 178.
9 Baur X, Sauer W, Weiss W. Baking additives as new allergens in baker’s asthma. Respiration 1988;
  54(1): 70-72.
0 Baur X, Sauer W, Weiss W, Fruhmann G. Inhalant allergens in modern baking industry. Immunol
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2 Roodt L, Rees D. Tests for sensitisation in occupational medicine practice--the soy bean example.
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3 Harris-Roberts J, Robinson E, Fishwick D, Fourie A, Rees D, Spies A et al. Sensitization and
  symptoms associated with soybean exposure in processing plants in South Africa. Am J Ind Med
  2012; 55(5): 458-464.
4 Baatjies R, Lopata AL, Sander I, Raulf-Heimsoth M, Bateman ED, Meijster T et al. Determinants of
  asthma phenotypes in supermarket bakery workers. Eur Respir J 2009; 34(4): 825-833.
5 Zuskin E, Kanceljak B, Schachter EN, Witek TJ, Maayani S, Goswami S et al. Immunological and
  respiratory changes in animal food processing workers. Am J Ind Med 1992; 21(2): 177-191.
6 Lehrer SB, Reese G, Malo JL, Lahoud C, Leong-Kee S, Goldberg B et al. Corn allergens: IgE
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7 Vinje NE, Namork E, Lovik M. Cross-allergic reactions to legumes in lupin and fenugreek-sensitized
  mice. Scand J Immunol 2012; 76(4): 387-397.
8 Mittag D, Vieths S, Vogel L, Becker WM, Rihs HP, Helbling A et al. Soybean allergy in patients
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0 Flour dust from processed, de-hulled soybeans
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<pre>9 Cummings KJ, Gaughan DM, Green BJ, Beezhold DH. Flu-like illness among workers at a soy
  processing plant. Am J Ind Med 2013; 56(5): 520-521.
0 Gerth van Wijk R, van Cauwenberge PB, Johansson SG. [Revised terminology for allergies and
  related conditions]. Ned Tijdschr Geneeskd 2002; 146(48): 2289-2293.
1 Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T et al. A
  revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task
  force. Allergy 2001; 56(9): 813-824.
2 Johansson SG, Bieber T, Dahl R, Friedman PS, Lanier BQ, Lockey RF et al. Revised nomenclature
  for allergy for global use: report of the nomenclature review Committee of the World Allergy
  Organization, October 2003. J Allergy Clin Immunol 2004; 113: 832-836.
3 Meijer E, Heederik D, Grobbee DE. Diagnostiek en preventie van allergische beroepsziekten als
  gevolg van blootstelling aan hoogmoleculaire allergenen. Een handleiding ten behoeve van de
  bedrijfsgeneeskundige praktijk. Institute for Risk Assessment Sciences, Division Environmental and
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  BV, Enschede; 2002.
4 Storaas T, Irgens A, Florvaag E, Steinsvag SK, Ardal L, Van Do T et al. Bronchial responsiveness in
  bakery workers: relation to airway symptoms, IgE sensitization, nasal indices of inflammation, flour
  dust exposure and smoking. Clin Physiol Funct Imaging 2007; 27(5): 327-334.
5 Baatjies R, Meijster T, Lopata A, Sander I, Raulf-Heimsoth M, Heederik D et al. Exposure to flour
  dust in South African supermarket bakeries: modeling of baseline measurements of an intervention
  study. Ann Occup Hyg 2010; 54(3): 309-318.
  References                                                                                           61
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<pre>A Request for advice
B The Committee
C The submission letter (in English)
D Comments on the public review draft
E Prevalence of sensitisation to soybean flour allergens and respiratory
  symptoms
F Exposure-response relationships
  Annexes
                                                                         63
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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        65
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
6 Flour dust from processed, de-hulled soybeans
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        toxicologic pathologist, TNO Innovation for Life, Zeist; professor of
        translational toxicology, Wageningen University and Research Centre
     •  P.J. Boogaard
        toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        professor of risk assessment in occupational epidemiology, Institute for Risk
        Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        occupational hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders, Utrecht
     •  H. van Loveren
        professor of immunotoxicology, Maastricht University, Maastricht
     •  I.M.C.M. Rietjens
        professor of toxicology, Wageningen University and Research Centre,
        Wageningen
        G.B.G.J. van Rooy
     •  occupational medicin specialist, ArboUnie Expert Centre for Chemical Risk
        Management, Utrecht; Outpatient Clinic for Occupational Clinical
        Toxicology, Radboud University Medical Centre, Nijmegen
     The Committee                                                                    67
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<pre>  •   F.G.M. Russel
      professor of pharmacology and toxicology, Radboud University Medical
      Centre, Nijmegen
  •   R.C.H. Vermeulen
      epidemiologist, Institute for Risk Assessment Sciences, Utrecht University,
      Utrecht
  •   A.H. Piersma, structurally consulted expert
      professor of reproductive toxicology, Utrecht University, Utrecht; National
      Institute for Public Health and the Environment, Bilthoven
  •   B.P.F.D. Hendrikx, observer
      Social and Economic Council, The Hague
  •   H. Stigter, observer
      Labour Inspectorate, Utrecht
  •   J.M. Rijnkels, scientific secretary
      Health Council of the Netherlands, The Hague
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, persons are asked to submit a form detailing the functions they hold
  and any other material and immaterial interests which could be relevant for the
  Committee’s work. It is the responsibility of the Health Council to assess
  whether or not someone can become a member. An expert who has no financial
  but another clearly definable interest, can become a member under the restriction
  that he will not be involved in the debate on the subject to which his interest
  relates. If a person’s interest is not clearly definable, he can sometimes be
  consulted as an expert. Experts working for a ministry or governmental
  organisation can be structurally consulted. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
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<pre>nnex C
     The submission letter (in English)
     Subject         : Submission of the advisory report Flour dust from processed,
                       de-hulled soybeans
     Your reference : DGV/BMO/U-932542
     Our reference : U-977709/JR/cn/459-X72
     Enclosure(s) : 1
     Date            : June 16, 2016
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     flour dust from processed, de-hulled soybeans.
     The present advisory report makes use of the method, which is proposed by the
     Health Council to derive health-based occupational exposure limits, or on risk-
     based reference values for allergenic substances (report No. 2008/03E,
     Prevention of work-related airway allergies). The Health Council has calculated
     the concentration of soybean protein antigens in the air, at which occupational
     exposure leads to an additional sensitisation risk of 1%, compared to the
     background risk in the non-exposed, general population.
     The submission letter (in English)                                              69
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<pre>      The conclusions in the advisory report were drawn by the Health Council’s
  Dutch Expert Committee on Occupational Safety (DECOS), and included the
  reviews by the Health Council’s Standing Committee on Public Health.
  I confirm the recommendations made by the Committee.
  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor J.L. Severens
  Vice President
0 Flour dust from processed, de-hulled soybeans
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in 2015 for public review. The
     following persons and organisations have commented on the draft review:
     • Lentz, Green and Cummings, National Institute for Occupational Safety and
         Health, Cincinnatti OH, USA
     • Passchier, Georganiseerd Overleg van werkgevers- en werknemers-
         organisaties in het bakkersbedrijf, Gouda
     • Flipsen, Nederlandse Vereniging Diervoederindustrie (Nevedi), Rijswijk.
     The comments received, and the reply by the committee can be found on the
     website of the Health Council.
     Comments on the public review draft                                         71
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<pre>2 Flour dust from processed, de-hulled soybeans</pre>

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<pre> nnex         E
              Prevalence of sensitisation to
              soybean flour allergens and
              respiratory symptoms
 tudy design and Exposure information          Health information    Results                                      Reference
 opulation
nformation
 tudies with exposure data on total inhalable dust levels
  ross-sectional Mean environmental dust Questionnaire on            Prevalence of sensitisation, skin prick test Zuskin et al.
 esign; 19        levels (full-shift):         respiratory           (soybean workers vs control group (n=20)): 19919, 199441
workers in a      • total inhalable:           symptoms; lung        • soybean dust: 100% vs 95%
 oybean              29.5 mg/m3                function tests; skin  • soybean after separation of oil: 94.7% vs
 rocessing mill, • respirable: 3.5 mg/m3. prick test with              100%
 ugoslavia.                                    extracts of soybean   • soy lecithin: 15.8% vs 0%
 tudy included    Mean exposure duration dust, soybean after         • soy oil: 5.3% vs 0%
 0/31 controls    was 4 years (1-6 years).     separation of oil,    • house dust: 68.4% vs 20%.
transport                                      soy lecithin and soil
workers not       Cracking of soybean          oil; serum soybean    Prevalence of sensitisation, specific IgE
 xposed to        produces soy flakes from specific IgE levels.      (soybean workers versus control group
ndustrial dust or which oil is extracted. The                        (n=20)): 15.8% vs 5%.
umes).            remaining material is dried
                  and ground into flour, then                        Respiratory symptoms, workers versus
                  packed and store. Workers                          control group (n=31)):
                  who participated in the                            • chronic cough: 36.8% vs 19.4%
                  study worked in the soy                            • chronic phlegm: 31.6% vs 16.1%
                  flake processing areas.                            • chronic bronchitis: 21.1% vs 16.1%
                                                                     • asthma: 10.5% vs 0%
                                                                     • dyspnea: 47.4% vs 9.7%
                                                                     • nasal catarrh: 15.8% vs 6.5%
                                                                     • sinusitis: 10.5% vs 6.5%.
                                                                     Only for dyspnea the difference between the
                                                                     two groups was statistically significant.
              Prevalence of sensitisation to soybean flour allergens and respiratory symptoms                                73
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<pre>                                                                    Authors suggest that the irritant effect of soy
                                                                    dust may have played a role.
 ross-sectional Environmental dust            Questionnaire on      Prevalence of sensitisation, skin prick test, Zuskin et al.
 esign: 35         measurements (full-shift; respiratory            all workers:                                    199255,
workers in an      range):                    symptoms; lung        • soybean: 28.6%                                199441
 nimal food        • total dust: 0.77-10.62   function tests; skin • fish flour: 82.9%
 rocessing            mg/m3                   prick test with       • carotene: 77.1%
actory,            • respirable dust:         extracts of soybean; • corn dust: 65.7%.
 ugoslavia.           0.34-2.94 mg/m3.        serum soybean         Prevalence of sensitisation, IgE assay, all
 tudy included                                specific IgE levels. workers:
 0/39 controls     Food for pigs and chickens                       • total IgE: 40%
clerical office    was prepared with                                • IgE soybean: 2.8% (1/35)
workers, not       different components                             Prevalence of sensitisation, IgE assay,
 ccupationally     including soybeans and                           control group:
 xposed to         wheats.                                          • total IgE: 2.6% (1/39).
 nimal food        Workers were exposed to
 omponents).       food aerosols during                             Respiratory symptoms, workers versus
                   grinding, weighing,                              control group (n=36)):
                   mixing, and packaging.                           • chronic cough: 54.3% vs 26.7%
                                                                    • chronic phlegm: 51.4% vs 23.3%
                                                                    • chronic bronchitis: 42.9% vs 23.3.1%
                                                                    • asthma: 5.7% vs 0%
                                                                    • dyspnea: 31.4% vs 6.7%
                                                                    • chest tightness: 48.6% vs 6.7%
                                                                    • rhinitis: 25.7% vs 6.7%.
                                                                    For chronic cough, chronic phlegem,
                                                                    dyspnea, and chest tightness, the difference
                                                                    between the two groups was statistically
                                                                    significant.
 ross-sectional Exposure includes wheat Structured                  Prevalence of sensitisation to soybean flour: Smith and
 esign; 392        flour dust and fungal      interview (3          • bread baking: 7% (26/392)                     Wastell Smith
 mployees from alpha-amylase. The use of occupational               • ake baking: 1% (1/77)                         199827
 9 bread           soybean flour was not      physicians with       (difference marginally significant, p=0.045).
 akeries, and 77 specified.                   prior agreed criteria
workers from 3                                for diagnosis); skin Prevalence of sensitisation to other bakery
 ake bakeries, the Personal sampling of       prick tests to        allergens:
UK.                respirable dust at various common and work- Wheat flour:
                   times between 1990 and related allergens         • bread baking: 6%
                   1996. Soybean flour        (wheat, soybean and • cake baking: 3%.
                   allergen content of dust   rice flour, and       Rice flour:
                   was not determined. No     fungal alpha-         • bread baking: 4%
                   data presented on the use amylase). Extract of • cake baking: 1%.
                   of soybean flour.          soybean flour for     Fungal alpha-amylase:
                                              skin prick test was • bread baking: 16%
                   The 1990-1996 dust         not specified.        • cake baking: 1%.
                   exposure measurements
                   were collated (no local    Workers were          Prevalence of work-related respiratory
                   exhaust ventilation, 8-h   allocated to 4        symptoms:
                   TWA GM±SD and range): categories:                • bread baking: 20.4% (80/392,
                   Bread bakeries:            • occupational          occupational asthma, occupational rhinitis
                   • sieving (n=35):             asthma               or respiratory irritation);
                      11.4±73.1 mg/m3         • occupational        • cake baking:10.4% (8/77, only respiratory
                      (range, 0.9-349.5)         rhinitis             irritation).
 4            Flour dust from processed, de-hulled soybeans
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<pre>                  • weighing (n=26):         • respiratory        No effect data presented based on type of
                    8.2±146.7 mg/m3             irritation        activity.
                    (range, 1.0-770)         • asymptomatic
                  • dough making (n=80):
                    3.3±19.5 mg/m3 (range,
                    0.1-142.2)
                  Cake bakeries:
                  • sieving (n=12): 35.7±26
                    mg/m3 (15.9-90)
                  • weighing (n=8):
                    19.2±20.7 mg/m3
                    (7.4-68.5)
                  • mixing (n=24): 3.8±4.2
                    mg/m3 (0.5-16.3).
 ross-sectional   Use of soybean flour not   Physician-           Prevalence of sensitisation: Soybean flour: Jeffrey et al.
 esign; 224       specified. Exposure        administered         3% (6/205)                                      199932
workers in 18     includes wheat flour dust  questionnaire on     Wheat flour: 24% (49/205)
 mall bakeries    and fungal alpha-amylase.  work-related         Rye flour: 16% (33/205)
<50 employees),                              symptoms, past       Barley flour: 16% (32/205)
 cotland.         Job-based exposure         medical history,     Amylase: 15% (71/205)
                  categories:                smoking status and   Oat flour: 4% (9/205).
                  A - workers handling flour occupational history The authors did not present job-title specific
                  directly (dough break/roll (n=224); serum IgE   sensitisation prevalence rates for soybean
                  machine, cleaning, bag     to common and        flour.
                  collection, weighing and   bakery allergens,
                  mixing, dividing and       including an extract Work-related symptoms:
                  moulding, cake mixing);    of soybean flour     Chronic bronchitis
                  B - workers exposed from   (IgE measured by     A: 9.3% (10/108)
                  general contamination of   RAST; threshold for  B: 4.3% (5/116)
                  spaces.                    positive sera was    Asthma
                                             defined as mean      A: 25% (27/108)
                  Full-shift personal        plus 2.5 standard    B: 17.4% (20/116)
                  inhalable dust (geometric deviations of the     Nasal/eye
                  mean ± standard            background level,    A: 33.3% (36/108)
                  deviation):                established in       B: 20.8% (24/116)
                  A: 4.9±2.3 mg/m3 (range workers in an           Specific IgE to wheat flour
                  0.6-23.7 mg/m3)            electronic factory). A: 30% (31/103)
                  B: 1.0±2.7 mg/m3 (range                         B: 18% (72/400).
                  0.1-5.5 mg/m3).
 ross-sectional Milling of wheat. Authors Screening by            Prevalence of sensitisation:                    Smith et al.
 esign; 679       report on use of fungal    occupational         Soybean flour: 0.7% (5/678)                     200042
 mployees of 18 alpha-amylase. Use of        physician, using     Wheat flour: 1.2% (8/679)
lour mills, the   soybean flour not          structured interview Amylase: 0.9% (6/679)
UK; workers       specified, but in some     on type, time of     Rice flour: 0.4% (3/679)
were regularly    mills bread improvers are onset and duration    Atopy: 37% (248/678).
 xposed to flour added to the flour for      of work-related
 ust (workers     bread baking. Potential of respiratory          Work-related respiratory symptoms were
nvolved in        exposure to grain dust     symptoms; skin       reported by 147/679 workers (22%), mostly
milling,          present.                   prick testing to     occasional and transient, which were
 roduction or                                common allergens,    classified as non-specific irritation. Allergic
 acking           Full-shift personal total  and to typical       respiratory symptoms were reported by 8/
 ctivities)       inhalable dust             bakery allergens,    679 workers (1%, 4 rhinitis and 4 asthma).
                  measurements between       such as present in
              Prevalence of sensitisation to soybean flour allergens and respiratory symptoms                                75
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<pre>                 1990 and 1998. Exposure    wheat flour,         Authors did not present effect data based on
                 by job category (geometric soybean and rice     job categories.
                 mean and range):           flour and to fungal
                 • -production (n=78):      alpha-amylase.
                    6.1 mg/m3 (0.5-54.7)
                 • -hygiene (n=38):         Mean duration of
                    17.6 mg/m3 (1.1-217).   employment: 12.5
                                            years (2 months - 47
                 Exposure to inhalable dust years).
                 (median, 8-h TWA, all
                 workplaces): 8.1 mg/m3
                 (range, 0.5-217).
 ross-sectional  Exposure includes wheat Interview focusing      Prevalence of sensitisation:                   Storaas et al.
 esign; 197      and rye flour dust, and    on occupational      Soybean flour: 2% (3/183)                      200521,
 mployees of 6   fungal alpha-amylase. No rhinitis (n=181) and   Wheat flour: 11% (20/183)                      200733,
 akeries,        data on the use of soybean self-administered    Rye flour: 10% (18/183)                        200764
Norway.          flour.                     questionnaire on     Barley flour: 8% (14/183)
                                            work tasks, family   Oats: 5% (9/183)
                 Breathing zone personal history,                Amylase: 2% (4/183).
                 total inhalable dust       occupational
                 samplers (n=58). Four      symptoms, smoking    Occupational rhinitis, preceded lower airway
                 exposure groups:           habits and           symptoms and was associated with asthma
                 • <1.0 mg/m3 (packers,     prevalence of        symptoms.
                    oven workers,           allergy and atopic
                    administration)         dermatitis/eczema    Bronchial hyperresponsi-veness (BHR),
                 • 1.0-1.9 mg/m3 (mainly (n=180).                determined by methacholine challenge, was
                    confectionary workers, Specific serum IgE    associated with smoking and work-related
                    bread formers)          for occupational     asthma. BHR, corrected for baseline lung
                 • 2.0-3.9 mg/m3 (mainly and common              function, was not associated with
                    dough makers)           allergens (n=183).   occupational IgE sensitisation (defined as
                 • >3.9 mg/m3 (mainly       Spirometry,          positive to wheat, alpha-amylase, oats,
                    dough makers).          bronchial            barley, rye, soybean, storage mites, mold or
                                            provocation test     cockroach). It is concluded that IgE
                                            with methacholine,   sensitisation is not the main causative factor
                                            nasal challenge and  for airway hyperresponsive-ness and
                                            lavage.              occupational rhinitis in bakery workers.
                                                                 BHR was not associated with current flour
                                            Categorisation of    dust exposure level, with number of working
                                            workers in job       hours in a bakery, or with a history of dough-
                                            titles:              making.
                                            • dough makers
                                            • bread formers      No effect data presented based on exposure
                                            • oven staff         categories.
                                            • packers
                                            • confectionary
                                               workers
                                            • administration
                                               and cleaning
                                               workers.
 6           Flour dust from processed, de-hulled soybeans
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<pre>  ross-sectional   Exposure includes wheat    Self-administered      Prevalence of sensitisation                   Baatjies et al.
 esign; 517        and rye flour dust, and    questionnaire on       Soybean flour                                 200954,
 mployees of 31    fungal alpha-amylase. No   respiratory            all: 8% (42/507)                              201065
 upermarket        data on the use of soybean symptoms,              atopics: 15% (32/213)
 akeries, South-   flour.                     employment history     nonatopics: 3% (10/294)
Africa.                                       and job title,         Wheat flour
                   Full-shift personal        degrees of exposure    All: 16% (79/507)
                   airborne dust was sampled to flour dust, baking   atopics: 24% (52/213)
                   (PAS6) in 18 bakeries on 2 activities at home     nonatopics: 9% (270/294)
                   days (n=211). Inhalable    and smoking habits.    Fungal alpha-amylase
                   dust in each job category Skin prick tests to     All: 3% (17/507)
                   (GM±GSD):                  common and work-       atopics: 6% (13/213)
                   • bread baker (n=112):     related allergens,     nonatopics: 1% (4/294)
                      1.33±2.25 mg/m3         including soybean      Atopy: 42% (whole population).
                   • confectioner (n=38):     flour.
                      0.65±2.08 mg/m3         Pulmonary function     The authors did not present job-title (or
                   • supervisor (n=13):       testing (spirometry    exposure) specific sensitisation prevalences.
                      0.56±2.05 mg/m3         and metha-choline
                   • manager (n=13):          challenge).            Work-related symptoms (all workers,
                      0.51±2.34 mg/m3                                n=517):
                   • counterhand (serving     Average duration of    Asthma diagnosed: 13%
                      customers, n=35):       employment in a        Tight chest, wheeze or cough: 13%
                      0.28±1.89 mg/m3.        bakery: 6±5 years.     Chest symptoms: 17%
                                                                     Upper airway symptoms, ocular-nasal: 31%.
 tudies without exposure information
  ross-sectional Low-exposure: clerical       Questionnaire on       Sensitisation, specific IgE:                  Roodt and
 esign; 22 day- and maintenance workers       clinical work-         • all workers: 36% (8/22)                     Rees 199552
 hift workers in a (n=10); high-exposure:     related symptoms;      • high exposure: 25% (3/12)
 oybean mill,      millers and packers        test for sensitisation • low exposure: 50% (5/10)
 outh Africa       (n=12). Exposure category  (skin prick test and   • control group: 5% (1/20)
                   based on job activities.   serum specific IgE     Sensitisation, skin prick test:
                   Study included 20 control  levels; extracts from  • all workers:36% (8/22)
                                              full fat and defatted  • high exposure: 25% (3/12)
                   Exposure to full-fat and   soybean powder).       • low exposure: 50% (5/10)
                   defatted soybean powder. Also smoking status      • control group: 0% (0/20).
                                              and soybean
                                              consumption was        Authors reported that the prevalence of
                                              recorded.              work-related cough and breathlessness was
                                                                     higher in the exposed groups than in
                                                                     controls. However, this differences was not
                                                                     statistically significantly different.
                                                                     The Committee noted the low number of
                                                                     participants.
  ross-sectional Workers currently exposed Interview on work- Prevalence of sensitisation to soybean flour: Smith et al.
 esign; 383        to dust from bread         related symptoms • all workers: 6% (24/383)                          199726
workers in 19      improver, wheat flour and by physician; skin • atopics: 11% (15/132)
 akeries, the UK. other ingredients, such as prick tests to          • non-atopics: 4% (9/257)
                   fungal alpha-amylase, on a common and work- Diagnostic categories:
                   regular basis.             related allergens,     • asthma: 50% (1/2)
                                              including soybean • rhinitis: 80% (8/10)
                   Exposure to soybean flour flour (source of        • respiratory irritation: 14% (9/66)
                   possible by the use of     extract and            • asymptomatic: 2% (6/305).
              Prevalence of sensitisation to soybean flour allergens and respiratory symptoms                                 77
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<pre>                  bread improver. Normal     composition not       Prevalence of sensitisation to other allergens
                  content of bread improver: specified).           (all workers):
                  • soybean flour: 40-50%                          • wheat flour: 6%
                  • wheat flour: up to 20%   Workers were          • rice flour: 4%
                  • fungal amylase:          allocated to the      • fungal alpha-amylase: 16%.
                     maximum of 0.1%.        following groups:
                                             • occupational        The authors explain the low prevalence of
                                                asthma (alone or   asthmatics by healthy worker effect.
                                                in combination
                                                with rhinitis);
                                             • occupational
                                                rhinitis;
                                             • respiratory
                                                irritation (non-
                                                specific);
                                             • asymptomatic
                                                (= no work-related
                                                symptoms).
  ross-sectional Exposure includes wheat Skin prick tests to       Prevalence of sensitisation to soybean flour Baur et al.
 esign; 89 bakery flour dust and fungal      common and bakery     Skin prick test:                               199819
workers, 104      alpha-amylase. No data on allergens, including   bakery workers: 1% (1/88)
 ersons with      the use of soybean flour. soybean flour          asthmatics: 11% (11/103)
 akers’ asthma,                              (extract used not     control subjects: 0% (0/43)
 nd 43 control    No data on job activities. specified);           Specific IgE:
 ubjects (not                                Measurement of        bakery workers: 19% (17/89)
working in a                                 specific IgE          asthmatics: 21% (22/104)
 akery),                                     antibodies (EAST -    control subjects: 5% (2/41).
Germany.                                     enzyme-allergo-
                                             sorbent-test); lung   Authors reported also on sensitisation to
                                             function tests.       other bakery allergens, such as wheat flour,
                                                                   rye flour, and fungal alpha-amylase.
                                                                   Lung function tests:
                                                                   Obstructive:
                                                                   bakery workers: 17% (13/76)
                                                                   asthmatics: 28% (26/94)
                                                                   control subjects: 2% (1/39)
                                                                   Hyperreactive:
                                                                   bakery workers: 13% (10/76)
                                                                   asthmatics: 19% (18/94)
                                                                   control subjects: 8% (3/39)
                                                                   Normal:
                                                                   bakery workers: 70% (1/76)
                                                                   asthmatics: 53% (11/94)
                                                                   control subjects: 90% (0/39).
 8            Flour dust from processed, de-hulled soybeans
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<pre> nnex        F
             Exposure-response relationships
             Cross-sectional study by Cummings et al. (2010)15 and NIOSH (2009)31.
 tudy design and  Exposure information                  Health information            Results
 opulation
nformation
 47 workers of a  Plant receives de-oiled, de-hulled    Interviewer-administered      See separate Table at the end of this
 oybean           crushed soy flakes for further        questionnaire (n=147) on      Annex for exposure-response analysis
 rocessing plant, processing. Flakes are processed into work-related respiratory and
USA. Study        soybean powder.                       dermatological symptoms,      Prevalence of sensitisation:
ncluded                                                 physician-diagnosed asthma    All workers:
eferents (n=50,   Full-shift personal inhalable dust    and eczema, smoking history   • skin prick test: 7% (9/132)
 ealthcare        (n=178, IOM samplers and              and employment and            • specific IgE: 21% (28/135)
workers) not      gravimetric analysis) and total soy   demographic information;      Referents:
 ccupationally    antigen (protein) concentrations      lung function (n=140) and     • specific IgE: 4% (2/50).
 xposed to        measured (inhibition immunoassay).    methacholine challenge tests.
 oybean flour.    Real-time photometric measurements                                  Prevalence of sensitisation to soybean
                  of personal (n=23) and area (n=47)    Skin prick tests (n=132) to   flour dust (specific IgE):
                  peak airborne dust levels.            commercially available        By job category:
                                                        extracts of soybean food, and • production: 20%
                  Job-title categories: inhalable soy   common allergens (positive if • production support: 24%
                  antigen (geometric mean±standard      wheal diameter at 15 min      • non-production: 18%.
                  deviation):                           reading ≥3 mm larger than
                  • production support (n=39 workers): negative control and ≥25% of   Authors did not find an association
                    2,991±15 ng/m3                      positive control).            between sensitisation (IgE) and the
                  • production (n=66 workers):          Analysis of soybean-specific  level of inhalable soybean antigens or
                    2,782±5.4 ng/m3                     IgG and IgE in blood (n=135)  job categories. This was possible due
                  • non-production (n=42 workers):      ImmunoCAP, positive if        to a healthy worker effect. The
                    235±9.1 ng/m3.                      specific IgE >0.35 kU/L)      suggestion is strengthened by the
                                                        n=135).                       inverse relation between duration of
             Exposure-response relationships                                                                              79
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<pre>     Job-title categories by inhalable soy      employment and skin rash:
     antigen exposure:                          • short: 15% (OR 1.0; 95% CI -)
     • low: 24-804 ng/m3                        • medium: 13% (OR 0.9; 95%
     • medium: 959-2,297 ng/m3                    CI 0.3-2.7)
     • high: 2,635-25,958 ng/m3                 • long: 2% (OR 0.1; 95% CI 0.01-
     (low, autopack assistants, maintenance       0.7).
      workers, office staff, warehouse
      workers; medium, autopack operators,      Detection of soybean-specific IgG
      feed dryer operators, spray dryer         levels (all workers had detectable IgG
      operators, laboratory technicians; high,  to soybean):
     curd operators, production leads,          • low: 60 mg/L
     sanitation operators, unloading            • medium: 46 mg/L
     operators).                                • high: 219 mg/L
                                                • referents: 1.5 mg/L
     Job-title categories: inhalable dust       Work-related asthma symptoms,
     (geometric mean ± standard                 outcome (OR; 95% CI):
     deviation):                                IgE to soy
     • non-production: 0.29±2.6 mg/m3           • negative: 7% (1.0; -)
     • production support: 0.60±3.2 mg/m3       • positive: 32% (5.9; 2.0-17.6)
     • production: 0.77±2.9 mg/m3.              Current work classification
                                                • non-production: 2% (1.0; -)
      Peak dust exposure categories             • prod. support: 13% (6.0; 0.9-118)
      (maximum concentration during real-       • production: 18% (9.1; 1.7-169).
      time sampling, 23 personal and 47 area
      samples):                                 Work-related nasal allergies, outcome
      • low: <1 mg/m3                           (OR; 95% CI):
     • medium: 1-10 mg/m3                       Current work area
     • high: ≥10 mg/m3                          • non-production: 2% (1.0; -)
     (low, non-production workers -             • prod. support: 15% (7.5; 1.2-144)
      laboratory technicians, office staff and  • production: 8% (3.4; 0.5-65.6).
      warehouse workers; medium, curd
      operators, production leads, spray        The Committee noted that in the
      dryer operators, maintenance workers;     analysis of the data, no corrections
      high, autopack operators, autopack        were made for confounding, and that
      assistants, feed dryer operators,         the results on peak exposure mainly
      sanitation operators, unloading           show a difference between the
      operators).                               production and non-production
                                                workers (the difference between the
                                                two production groups is small).
0 Flour dust from processed, de-hulled soybeans
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<pre>               Exposure-response analysis (data from Cummings et al. and NIOSH).
 ffect parameter                         Exposure levels                       Prevalence Correlation
                                                                                          (Odds ratios)
 xposure parameter: Inhalable soy antigen (full shift)
 ensitisation (serum specific IgE)       Low: 24-804 ng/m3                     21%        No significant positive
                                         Medium: 959-2,297 ng/m3               33%        correlation
                                         High: 2,635-25,958 ng/m3                6%
                                         Control: not exposed                    4%
Work-related asthma like symptoms        Low: 24-804 ng/m3                       9%       No significant positive
                                         Medium: 959-2,297 ng/m3               20%        correlation
                                         High: 2,635-25,958 ng/m3                8%
Cough                                    Low: 24-804 ng/m3                       -        1.0
                                         Medium: 959-2,297 ng/m3                 -        3.13 (1.09-9.80)
                                         High: 2,635-25,958 ng/m3                -        2.18 (0.67-7.33)
 inusitis or sinus problems              Low: 24-804 ng/m3                       -        1.0
                                         Medium: 959-2,297 ng/m3                 -        0.99 (0.46-2.17)
                                         High: 2,635-25,958 ng/m3                -        1.40 (0.62-3.29)
Nasal allergies                          Low: 24-804 ng/m3                       -        1.0
                                         Medium: 959-2,297 ng/m3                 -        0.34 (0.14-0.79)
                                         High: 2,635-25,958 ng/m3                -        0.43 (0.17-1.01)
Rash or skin problems                    Low: 24-804 ng/m3                       -        1.0
                                         Medium: 959-2,297 ng/m3                 -        1.58 (0.63-3.96)
                                         High: 2,635-25,958 ng/m3                -        1.34 (0.50-3.56)
 xposure parameter: total inhalable dust (peak exposure, maximum level measured)
Work-related asthma like symptoms        Low: <1 mg/m3                           2%       1.0
                                         Medium: 1-10 mg/m3                    15%        6.96 (1.22-131)
                                         High: ≥10 mg/m3                       19%        9.37 (1.61-178)
Airway obstruction (spirometry)          Low: <1 mg/m3                           -        1.0
                                         Medium: 1-10 mg/m3                      -        4.9 (0.79-94.5)
                                         High: ≥10 mg/m3                         -        8.49 (1.41-163)
 inusitis or sinus problems              Low: <1 mg/m3                           -        1.0
                                         Medium: 1-10 mg/m3                      -        2.16 (0.75-7.17)
                                         High: ≥10 mg/m3                         -        2.86 (0.95-9.83)
Nasal allergies                          Low: <1 mg/m3                           -        1.0
                                         Medium: 1-10 mg/m3                      -        0.64 (0.09-2.94)
                                         High: ≥10 mg/m3                         -        1.08 (0.26-4.01)
Rash or skin problems                    Low: <1 mg/m3                           -        1.0
                                         Medium: 1-10 mg/m3                      -        1.38 (0.26-10.3)
                                         High: ≥10 mg/m3                         -        5.29 (1.26-36.3)
Correlation expressed as odds ratio (95% confidence interval).
               Exposure-response relationships                                                                   81
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<pre>2 Flour dust from processed, de-hulled soybeans</pre>

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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory opinions that    cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks                  realise significant                 which carry certain
and opportunities?                    health benefits?                    health risks?
Environmental                         Healthy working                     Innovation and
health                                conditions                          the knowledge
Which environmental                   How can employees                   infrastructure
influences could have                 be protected against                Before we can harvest
a positive or negative                working conditions                  knowledge in the
effect on health?                     that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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