<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>             Health Council of the Netherlands
          1,3-Butadiene
             Health-based calculated occupational cancer risk values
2013/08
</pre>

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<pre>1,3-Butadiene
     Health-based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : aanbieding advies 1,3-Butadiene
Uw kenmerk              : DGV/MBO/U-932342
Ons kenmerk             : U-7739/BJB/fs/459-K68
Bijlagen                :1
Datum                   : 31 mei 2013
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling
aan 1,3-butadieen.
Dit advies maakt deel uit van een uitgebreide reeks waarin concentratieniveaus in de lucht
worden afgeleid die samenhangen met een extra kans op overlijden aan kanker door
beroepsmatige blootstelling van 4 per 1.000 en 4 per 100.000 sterfgevallen in de algemene
bevolking. De conclusies van het genoemde advies zijn opgesteld door de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van de Gezondheidsraad
en beoordeeld door de Beraadsgroep Gezondheid en omgeving.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                     Postadres
Rijnstraat 50                                                   Postbus 16052
2515 XP Den             Haag                                    2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1                          Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
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
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<pre></pre>

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<pre>1,3-Butadiene
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2013/08, The Hague, May 31, 2013
</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 & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. 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.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. 1,3-Butadiene; Health-based calculated
occupational cancer risk values. The Hague: Health Council of the Netherlands,
2013; publication no. 2013/08.
all rights reserved
ISBN: 978-90-5549-953-3
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<pre>   Contents
   Samenvatting 9
   Executive summary 15
   Scope 21
.1 Background 21
.2 Committee and procedure 22
.3 Data 22
   General information 23
.1 Identity, and physical and chemical properties 23
.2 IARC conclusion 24
.3 Other conclusions 26
.4 Carcinogenicity studies in humans 26
.5 Carcinogenic activity in experimental animals, lifetime low-dose exposure 40
.6 Kinetics and kinetic models 42
.7 Mechanistic and other relevant data 47
.8 Toxicity profile 59
.9 Overall conclusion 62
   Contents                                                                     7
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<pre>    Risk assessment 63
 .1 Health risk to humans and selection of the suitable study for
    risk estimation in the occupational situation 63
 .2 Calculation of the health-based occupational cancer risk values 64
 .3 Dermal uptake of 1,3-butadiene 68
 .4 Risk values derived by SCOEL 68
 .5 Existing cancer risk values and occupational exposure limits 69
    References 71
    Annexes 79
A   Request for advice 81
B   The Committee 83
C   Letter of submission 85
D   Comments on the public review draft 87
E   Abbreviations 89
F   Human epidemiological studies 91
G   Animal studies 105
H   DNA base-adducts formed from 1,3-butadiene metabolites in vitro 111
    Evaluation of the Subcommittee on the Classification of carcinogenic substances 115
    Carcinogenic classification of substances by the committee 121
    1,3-Butadiene
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<pre>Samenvatting
Vraagstelling
Op verzoek van de minister van Sociale zaken en Werkgelegenheid schat de
Commissie Gezondheid en Beroepsmatige Blootstelling aan Stoffen (GBBS) van
de Gezondheidsraad het extra kankerrisico als gevolg van beroepsmatige bloot-
stelling aan stoffen die door de Europese Unie of door de Commissie GBBS als
stochastisch genotoxisch kankerverwekkend zijn aangemerkt. In dit rapport pre-
senteert de commissie een dergelijke schatting voor blootstelling aan 1,3-butadi-
een. Zij heeft daarbij gebruik gemaakt van de methode die beschreven is in het
rapport ‘Leidraad berekening risicogetallen voor carcinogene stoffen’ van de
Gezondheidsraad (2012).
Fysische en chemische eigenschappen
1,3-Butadieen (CAS nummer 106-99-0; hierna “butadieen”) is een kleurloos gas
met een moleculair gewicht van 54,1 dalton en wordt gebruikt in de bereiding
van verschillende synthetische rubberproducten en -polymeren en als intermedi-
air in de productie van basale petrochemicaliën. Producten gebaseerd op butadi-
een zijn belangrijke componenten van motorvoertuigen, constructiematerialen,
apparaatonderdelen, computers en telecommunicatie-apparatuur, (bescher-
mende) kleding, verpakkingen en huishoudelijke artikelen.
Samenvatting                                                                      9
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<pre>  Grenswaarden
  De huidige grenswaarde voor 1,3-butadieen in Nederland is 46,2 mg/m3 (8-uurs
  tijdgewogen gemiddelde, TGG). Groot-Brittannië heeft een TGG van 22 mg/m3,
  Finland en Noorwegen hebben een TGG van 2,2 mg/m3, Zweden heeft een TGG
  van 1 mg/m3, en de USA hebben TGG’s van 4,4 (‘threshold limit value’ van de
  American Conference of Governmental Industrial Hygienists) en 2,2 mg/m3
  (‘permissible exposure limit’ van de Occupational Safety and Health Adminis-
  tration). De genoemde landen hebben een notificatie dat 1,3-butadieen kanker-
  verwekkend is voor mensen, dan wel verdacht wordt kankerverwekkend te zijn
  voor mensen.
  Kankerverwekkendheid
  Veel epidemiologische onderzoeken tonen een verhoogd risico voor leukemie of
  andere vormen van lymfo-haematopoietische kankers na blootstelling aan 1,3-
  butadieen. Er zijn echter maar drie onderzoeken met werknemers die uitsluitend
  aan de stof zijn blootgesteld. De meeste onderzoeken zijn uitgevoerd met werk-
  nemers blootgesteld aan 1,3-butadieen gedurende de productie van styreen-buta-
  dieen rubber (SBR) en deze mensen waren behalve aan 1,3-butadieen ook
  blootgesteld aan andere potentieel gevaarlijke stoffen. Hoewel er een groot aan-
  tal onderzoeken is gepubliceerd, betreft het vaak actualisaties van eerder uitge-
  voerde onderzoeken; er is dus sprake van dezelfde of overlappende cohorten.
       In twee van de onderzoeken in 1,3-butadieen monomeer-fabrieken vond men
  een iets hogere sterfte door leukemie, in het derde onderzoek werd een kleine
  afname van die mortaliteit gevonden. Het in verhouding hoogste aantal sterfge-
  vallen werd vastgesteld in het onderzoek onder werknemers die waren blootge-
  steld aan hoge concentraties gedurende de eerste productiejaren (Tweede
  Wereldoorlog). In dit cohort werd geen verband gevonden tussen de toename van
  leukemie en de cumulatieve blootstelling of de duur van de blootstelling.
       Met hun langlopend onderzoek onder werknemers in de SBR-productie ver-
  schaften epidemiologen van de Universiteit van Alabama in Birmingham (USA)
  de meeste informatie. Zij onderzochten de mortaliteit van ongeveer 17.000 werk-
  nemers in acht fabrieken (USA en Canada). Een beperking van deze evaluaties
  was dat de diagnose en classificatie van leukemie en andere kwaadaardige
  nieuwvormingen van het lymfatische en haematopoietische systeem zeer com-
  plex zijn en in de loop der jaren diverse veranderingen hebben ondergaan. Hoe-
  wel in de meest recente actualisatie van dit cohort de totale mortaliteit ten
0 1,3-Butadiene
</pre>

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<pre>gevolge van leukemie slechts licht verhoogd was, werden grotere verhogingen
van die mortaliteit gevonden bij mensen werkzaam in delen van de fabrieken met
hoge blootstellingen, alsmede bij werknemers die per uur werden betaald, vooral
bij hen die werkzaam waren in de vroege productiejaren en die daar tien jaar of
langer gewerkt hadden. Voorts werd er een significante associatie vastgesteld
tussen mortaliteit ten gevolge van leukemie en de cumulatieve blootstelling aan
1,3-butadieen. Uit de recente analyses is tevens gebleken dat deze blootstellings-
respons relatie onafhankelijk was van blootstelling aan styreen en dimethyl-
dithiocarbamaat.
    Onderzoek met muizen heeft aangetoond dat zowel mannetjes als vrouwtjes
meer tumoren ontwikkelden nadat ze aan respectievelijk ongeveer 14 mg/m3
(vrouwtjes) en 44 mg/m3 1,3-butadieen (mannetjes) waren blootgesteld. In ratten
blootgesteld aan concentraties tot 2.200 mg/m3 is dit niet waargenomen. Waar-
schijnlijk moet dit worden toegeschreven aan de cruciale rol van het oxidatieve
metabolisme. De carcinogene werking van 1,3-butadieen vereist namelijk active-
ring tot electrofiele epoxiden, en daarin bestaan belangrijke soortverschillen:
muizen zijn efficiënter in de productie van epoxidemetabolieten van 1,3-butadi-
een, terwijl ratten en mensen efficiënter zijn in de hydrolytische detoxificatie van
deze metabolieten.
    Uit vele mutageniteits- en genotoxiciteitstesten, evenals uit onderzoek naar
het carcinogene werkingsmechanisme, is gebleken dat 1,3-butadieen in mensen
en proefdieren het genetische materiaal kan beschadigen.
Algemene toxiciteit
Korte blootstelling aan hoge concentraties 1,3-butadieen leidde bij mensen en
proefdieren tot irritatie van de ogen, neusholte, keel en longen. Tot de klinische
vergiftigingsverschijnselen behoorden hyperventilatie, krampen, opwinding,
anesthesie en narcose. LC50 waarden* varieerden van 270 (muizen) tot 550
(konijnen) g/m3.
    Langdurige blootstelling van proefdieren aan 1,3-butadieen resulteerde
(behalve in kanker) in biochemische veranderingen, zoals depletie van glutathion
in lever, longen en hart; bij muizen was dit ernstiger dan bij ratten. In blootge-
stelde muizen werd ook toxiciteit van het haematopoietische systeem waargeno-
men: subchronische blootstelling aan 2.750 mg/m3 leidde onder meer tot
bloedarmoede en een verminderde hoeveelheid circulerende witte bloedcellen.
De LC50 is de concentratie waarbij 50% van de blootgestelde dieren binnen 24 uur overlijdt.
Samenvatting                                                                                11
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<pre>        Onderzoek naar de voortplantingseffecten met ratten blootgesteld aan 2.200
   mg/m3 lieten een afname van het lichaamsgewicht gedurende de zwangerschap
   zien. In muizen werden testiculaire en ovariële atrofie waargenomen na langdu-
   rige blootstelling aan respectievelijk 1.375 en 13,8 mg/m3. Mannelijke muizen
   blootgesteld aan 2.200 tot 11.000 mg/m3 hadden afwijkende spermamorfologie.
        In ontwikkelingsonderzoek met ratten blootgesteld aan 2.230 of 17.680 mg/
   m3 gedurende dagen 6-15 van de dracht vertoonden de foetussen kleine respec-
   tievelijk grote skeletafwijkingen. Bij muizen blootgesteld aan 88 - 2.210 mg/m3
   gedurende dagen 6-15 van de dracht lieten de mannelijke foetussen een afname
   van het foetale lichaamsgewicht zien. In de groepen blootgesteld aan 442 en
   2.210 mg/m3 nam respectievelijk het aantal gevallen van extra ribben toe en het
   aantal gevallen van verbening van het borstbeen af. Foetale toxiciteit (late dood,
   ontbreken van schedeldak en schedelafwijkingen) werd gevonden wanneer onbe-
   handelde vrouwtjesmuizen werden gepaard met mannetjes die blootstonden aan
   27,5 mg/m3 (6 uur per dag, 5 dagen per week gedurende 10 weken).
        De commissie concludeert dat de LOAEL* (algemene toxiciteit en in het
   bijzonder de voortplantingseffecten) voor blootstelling aan 1,3-butadieen 13,8
   mg/m3 bedraagt (gebaseerd op ovariële atrofie bij muizen). De LOAEL voor ont-
   wikkelingstoxiciteit bedraagt 27,5 mg/m3 (muizen). Niveaus waarbij geen
   toxisch effect optrad (NOAEL’s**) konden uit deze onderzoeken niet worden
   afgeleid.
   Evaluatie
   Op basis van voorgaande informatie beschouwt de commissie het optreden van
   kanker na langdurige blootstelling aan 1,3-butadieen als het kritische effect. Op
   advies van de Subcommissie Classificatie van kankerverwekkende stoffen van
   de Commissie GBBS, concludeert de commissie dat 1,3-butadieen kankerver-
   wekkend is voor de mens (categorie 1A). De stof veroorzaakt kanker via een
   zogenaamd stochastisch genotoxisch mechanisme. De commissie leidt daarom
   voor 1,3-butadieen concentratieniveaus in de lucht af (risicogetallen, HBC-
   OCRV***) die samenhangen met een kans op 4 extra sterfgevallen door kanker
   door beroepsmatige blootstelling per 1.000 en per 100.000 sterfgevallen in de
   algemene bevolking.
   Lowest observed adverse effect level: het laagste niveau waarbij nog juist toxische effecten optreden.
*  No observed adverse effect level: het hoogste niveau waarbij nog juist geen toxische effecten optre-
   den.
** HBC-OCRV: health based calculated occupational cancer risk value.
2  1,3-Butadiene
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<pre>    Voor het afleiden van de risicogetallen gaat de commissie uit van het
onderzoek van Cheng en medewerkers (2007) die een verhoogd aantal gevallen
van leukemie beschreven onder een grote groep werknemers in de SBR-
productie.
Advies
De Commissie GBBS schat dat de 1,3-butadieenconcentratie in de lucht die
samenhangt met een kans op 4 extra sterfgevallen door leukemie:
• per 100.000 sterfgevallen in de algemene bevolking (4x10-5), bij een
    beroepsmatige blootstelling gedurende 40 jaar, 0,1 mg/m3 (0,05 ppm)
    bedraagt
• per 1.000 sterfgevallen in de algemene bevolking (4x10-3), bij een beroeps-
    matige blootstelling gedurende 40 jaar, 10 mg/m3 (5 ppm) bedraagt.
De geadviseerde risicogetallen zijn uitgedrukt als 8-uurs tijdgewogen gemid-
delde concentraties.
Daarnaast beveelt de commissie aan om 1,3-butadieen te classificeren als ‘kan-
kerverwekkend voor de mens’ (categorie 1A).
Samenvatting                                                                   13
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<pre>4 1,3-Butadiene</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; hereafter called
‘the Committee’), a committee of the Health Council of the Netherlands,
estimates the additional cancer risk associated with occupational exposure to
substances that have been classified by the European Union or the Committee as
a stochastic genotoxic carcinogen. In this report the Committee presents such an
estimate for 1,3-butadiene, using the method described in the report ‘Leidraad
berekening risicogetallen voor carcinogene stoffen (in Dutch)’ of the Health
Council of the Netherlands (2012).
Physical and chemical properties
1,3-Butadiene (CAS number 106-99-0; hereafter “butadiene”) is a colourless gas
with a molecular weight of 54.1 dalton and is used for the preparation of a
variety of synthetic rubber products and polymers, and as an intermediate in the
production of basic petrochemicals. Butadiene-based products are important
components of automobiles, construction materials, appliance parts, computers
and telecommunications equipment, (protective) clothing, packaging and
household articles.
Executive summary                                                                15
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<pre>  Guidelines
  Currently, the limit value for occupational exposure to 1,3-butadiene in The
  Netherlands is 46.2 mg/m3 (8-hour time-weighted average: TWA). The UK has a
  TWA of 22 mg/m3, Finland and Norway have a TWA of 2.2 mg/m3. Sweden has
  a TWA of 1 mg/m3, and the USA has TWAs of 4.4 (threshold limit value of the
  American Conference of Governmental Industrial Hygienists) and 2.2 mg/m3
  (permissible exposure limit of the Occupational Safety and Health
  Administration). All mentioned countries either have a notification that 1,3-
  butadiene is carcinogenic to humans or that it is suspected to be carcinogenic to
  humans.
  Carcinogenicity
  Many epidemiological studies show an elevated risk of leukaemia or other
  cancers of the lymphohaematopoietic system following exposure to 1,3-
  butadiene. Only three studies have been conducted on workers employed in 1,3-
  butadiene manufacturing facilities, where exposure is to 1,3-butadiene monomer
  alone. Most studies have been done on workers exposed to 1,3-butadiene during
  styrene-butadiene rubber (SBR) production. Although a relative large number of
  studies has been reported, many of these studies update previously reported
  findings and thus relate to the same or overlapping cohort populations.
      In two of the butadiene monomer industry studies a slight overall excess of
  mortality from leukaemia was observed, whereas in the third study a small
  decrease in mortality from leukaemia was observed. The increased mortality
  from leukaemia in one of the monomer industry cohorts was more pronounced
  among workers who had been exposed at high levels during the first years of
  production (Second World War). In this cohort, no increase in leukaemia was
  observed with duration of exposure or cumulative exposure.
      Studies on SBR workers by researchers of the University of Alabama at
  Birmingham (USA) were considered to be the most informative. In these studies
  the mortality rates of approximately 17,000 workers from eight facilities in the
  USA and Canada were examined. A limiting factor in the evaluations was that
  the diagnosis and classification of lymphatic and haematopoietic malignancies
  are very complex and have undergone several changes over the course of time.
  Although overall mortality from leukaemia was only slightly elevated in the
  most recent update of this cohort, larger increases of mortality from leukaemia
  were seen in workers in the most highly exposed areas of the plants and among
6 1,3-Butadiene
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<pre>hourly paid workers, especially those who had been hired in the early years and
had ten years or longer employment. Furthermore, a significant exposure-
response relationship between cumulative 1,3-butadiene exposure and mortality
from leukaemia was observed in this study. Recent analyses indicate that the
exposure-response relationship for 1,3-butadiene and leukaemia was
independent of exposure to styrene and dimethyldithiocarbamate.
    Studies with mice showed increased tumour formation in various organs in
both sexes at 1,3-butadiene exposures to approximately 14 mg/m3 (females) and
44 mg/m3 (males). This was not observed in rats at exposures up to 2,200 mg/m3,
likely due to the crucial role of oxidative metabolism: 1,3-butadiene requires
metabolic activation to generate electrophilic epoxides in which important
species differences exist (mice are more efficient in the production of epoxide
metabolites of butadiene, while rats and humans are more efficient in the
hydrolytic detoxification of these metabolites).
    Many tests on mutagenicity, genotoxicity and mechanism of action clearly
indicate that 1,3-butadiene is a genotoxic compound in humans and in
experimental animals, requiring metabolic activation to generate electrophilic
and DNA-reactive epoxides (epoxybutene, epoxybutanediol and diepoxybutane),
one or more of which are considered to be the ultimate carcinogens.
General toxicity
Following acute exposure of humans and animals to high 1,3-butadiene
concentrations in air, irritation of the eyes, nasal passage, throat and lungs were
noted. Clinical signs of intoxication of animals included hyperventilation,
twitching, excitation, anaesthesia and narcosis. LC50 values* ranged from 270
(mice) to 550 g/m3 (rabbits).
    Long-term exposure of animals to 1,3-butadiene resulted (in addition to
cancer) in biochemical alterations such as glutathione depletion in liver, lungs
and heart, which was more extensive in mice than in rats. In exposed mice
toxicity of the haematopoietic system also was seen: semi-chronic exposure to
2,750 mg/m3 resulted in anaemia, while also leukopenia and an increase in the
number of circulating erythrocyte micronuclei were seen.
    Reproductive studies with rats exposed to 2,200 mg/m3 showed decreased
weight gain during pregnancy. In mice testicular and ovarian atrophy were
observed following long-term exposure to 1,375 and 13.8 mg/m3, respectively.
The concentration at which 50% of the exposed animals dies within 24 h.
Executive summary                                                                   17
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<pre>  Male mice exposed to 2,200-11,000 mg/m3 showed abnormal sperm head
  morphology.
       In developmental studies with pregnant rats which were exposed to
  concentrations of 2,230 or 17,680 mg/m3 during gestational days (GD) 6-15, the
  fetuses showed minor or major abnormalities, respectively. In mice, a decrease in
  fetal body weight gain in males was observed following exposure of dams to to
  88 - 2,210 mg/m3 during GD 6-15. Increased incidences of of extra ribs and
  reduced ossification of sternebrae were found in groups exposed to 442 and
  2,210 mg/m3, respectively. Fetal toxicity was seen following mating untreated
  female mice with males exposed to 27.5 mg/m3 (6 h/day, 5 days/week, 10
  weeks). Observed effects included increased late fetal death, exencephaly and
  skull abnormalities.
       In conclusion, the overall LOAEL* for reproduction is 14 mg/m3 (based on
  ovarian atrophy in mice). The LOAEL for developmental toxicity is 27.5 mg/m3
  (mice). It was not possible to derive NOAELs** from these studies.
  Evaluation and advice
  Based on the information summarized above the Committee considers the
  induction of cancer following long-term exposure to 1,3-butadiene to be the
  critical effect. Following the advice of the DECOS Subcommittee on the
  Classification of carcinogenic substances the Committee concludes that 1,3-
  butadiene is “carcinogenic to humans” (category 1A). The substance induces
  cancer by a stochastic genotoxic mechanism. Hence the Committee derives risk
  values for concentrations of 1,3-butadiene in ambient air (HBC-OCRV: health
  based calculated occupational cancer risk value) that are related to the risk for 4
  extra cancer deaths due to occupational expusure per 1,000 and 100,000 deaths
  in the general population.
       The Committee uses the epidemiological study of Cheng and coworkers
  (2007), in which the mortality of approximately 17,000 workers in the SBR
  production was examined. From this study the Committee calculates that the
  concentration of 1,3-butadiene in the air, which corresponds to an excess risk of
  cancer mortality of:
  • 4 per 1,000 (4x10-3) deaths in the general population, at 40 years of
       occupational exposure, equals to 10 mg 1,3-butadiene per m3 (5 ppm)
  Lowest observed adverse effect level.
* No observed adverse effect level.
8 1,3-Butadiene
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<pre>•  4 per 100,000 (4x10-5) deaths in the general population, at 40 years of
   occupational exposure, equals to 0,1 mg 1,3-butadiene per m3 (5 ppm).
The recommended values are expressed as 8-hour time-weighted average
concentrations.
The Committee also recommends to classify 1,3-butadiene as “carcinogenic to
man” (category 1A).
Executive summary                                                           19
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<pre>0 1,3-Butadiene</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for chemical substances are set
        using a three-step procedure. In the first step, a scientific evaluation of the data
        on the toxicity of the substance is made by the Dutch Expert Committee on
        Occupational Exposure Safety (DECOS), a committee of the Health Council of
        the Netherlands, at request of the Minister of Social Affairs and Employment
        (Annex A). This evaluation should lead to a health-based recommended
        exposure limit for the concentration of the substance in air. Such an exposure
        limit cannot be derived if the toxic action cannot be evaluated using a threshold
        model, as is the case for carcinogens acting by stochastic genotoxic mechanism.
        In that case, an exposure-response relationship is recommended for use in
        regulatory standard setting, i.e., the calculation of so-called health-based
        calculated occupational cancer risk values (HBC-OCRVs). The Committee
        calculates HBC-OCRVs for compounds, which are classified by the European
        Union or by the Committee in category 1A of 1B.
            For the establishment of the HBC-OCRVs, the Committee generally uses a
        linear extrapolation method, as described in the Committee’s report ‘Calculating
        cancer risk due to occupational exposure to genotoxic carcinogens’. The linear
        model to calculate occupational cancer risk is used as a default method, unless
        scientific data would indicate that using this model is not appropriate.
        Scope                                                                                21
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<pre>    In the next phase of the three-step procedure, the Social and Economic Council
    advises the Minister of Social Affairs and Employment on the feasibility of using
    the HBC-OCRVs as regulatory occupational exposure limits. In the final step of
    the procedure, the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present report is an update of the health-based recommended occupational
    exposure limits for 1,3-butadiene of the Health Council from 19901 and contains
    the derivation of HBC-OCRVs by the DECOS, hereafter called the Committee.
    The members of the Committee are listed in Annex B. The submission letter (in
    English) to the Minister can be found in Annex C.
         In 2012, 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
    deciding on the final version of the report.
1.3 Data
    In order to calculate the HBC-OCRV and to evaluate other toxic effects of 1,3-
    butadiene, the safety evaluation of butadiene by the International Agency for
    Research on Cancer (IARC 20082) has been used as a basis for the update of the
    health-based recommended occupational exposure limit (DECOS 19901). Where
    relevant, the original publications were reviewed and evaluated as indicated in
    the text. In addition, literature was retrieved from the on-line databases Medline,
    Toxline and Chemical Abstracts until September 2012. For the present
    evaluation, only the literature from 2006-2012 was used to update the
    information reviewed in the cited IARC monograph2.
 2  1,3-Butadiene
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<pre> hapter 2
        General information
2.1     Identity, and physical and chemical properties
        1,3-Butadiene (hereafter “butadiene”), a colourless gas, is manufactured
        primarily as a co-product of the steam cracking of hydrocarbon streams to
        produce ethylene. This process accounts for over 95% of global butadiene
        production2. The purity of the technical product is approximately 99.5%.
        Butadiene is used for the preparation of a variety of synthetic rubber products
        and polymers. Butadiene-based products are important components of
        automobiles, construction materials, appliance parts, computers and
        telecommunications equipment, clothing, protective clothing, packaging and
        household articles.
            The synthetic rubbers that are produced from butadiene include styrene-
        butadiene rubber (SBR), polybutadiene rubber, styrene-butadiene latex,
        chloroprene rubber and nitrile rubber. Important plastics that contain butadiene
        as a monomeric component are shock-resistant polystyrene (a two-phase system
        of polystyrene and polybutadiene), polymers that consists of acrylonitrile,
        butadiene and styrene (STYR); and a copolymer of methylmethacrylate,
        butadiene and STYR (which is used as a modifier for polyvinylchloride).
        Butadiene is also used as an intermediate in the production of chloroprene,
        adiponitrile and other basic petrochemicals. It is not known to occur as a natural
        product2.
        General information                                                                23
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<pre>         Butadiene is very reactive: it may form acrolein and peroxides upon exposure
    to air, it can react with oxidizing materials, and it polymerizes readily,
    particularly if oxygen is present. Butadiene is stabilized with hydroquinone,
    catechol, t-butyl catechol or aliphatic mercaptans1,2.
         The identity and most important physicochemical properties of butadiene are
    presented in Table 1.
         The following measured ambient concentrations have been reported3:
    • Air concentrations in urban/suburban areas: 0.02-2 µg/m3
    • Air in heavy traffic area: 2-13 µg/m3
    • Air in homes and restaurants where smoking is allowed: 1.7-4.3 µg/m3
    • Air in homes and restaurants where smoking is not allowed: 0.1-0.9 µg/m3.
         Lovreglio et al. (20064) reported that environmental mean levels of butadiene
    in Italy ranged between 0.2 and 7.9 µg/m3, with lower concentrations measured
    in indoor non-smoking environments and higher concentrations measured in
    indoor smoking environments and in cars. Saborit et al. (20095) reported
    environmental levels of 0.4 ± 0.7 µg/m3 in both urban and suburban, but also in
    rural areas in the UK.
         The highest exposure to butadiene occurs in occupational settings. In general,
    actual workplace exposure levels were not determined until 1970-1980, but it is
    assumed that during early years of butadiene and SBR production (1940 to
    ~1970) workplace butadiene levels were higher (approximately 8-20 mg/m3)
    compared to more recent workplace levels7 (< 2 mg/m3). However, peak
    exposures to high concentrations still occur for some activities in the production
    of butadiene2.
         The average occupational exposure to butadiene in the European Union in
    1995 as reviewed by IARC in 20082 was 3.1-7.5 mg/m3 for exposed production
    workers at 15 monomer production facilities, and 0.06-2.2 mg/m3 for controls
    (supposedly non-exposed) laboratory workers.
         It must be noted that also smoking contributes to butadiene exposure. Hurst
    reported in 20076 that the tobacco smoke of one cigarette contained 0.4 mg
    butadiene. The average breath concentration of butadiene was 0.014 and 0.353
    mg/m3 in nonsmokers and smokers, respectively2.
2.2 IARC conclusion
    In 2008 IARC2 concluded that butadiene is carcinogenic to humans (Group 1),
    because:
    • There is sufficient evidence in humans for the carcinogenicity of butadiene
 4  1,3-Butadiene
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<pre>•     There is sufficient evidence in experimental animals for the carcinogenicity
      of butadiene
•     There is sufficient evidence in experimental animals for the carcinogenicity
      of D,L-diepoxybutane (diepoxybutane is a metabolite of butadiene, see
      Section 2.6).
In 2009 a working group of IARC (IARC 20097) updated the evaluation of 20082
and confirmed the earlier conclusion, pointing to strong evidence of genotoxicity
as the mechanism of carcinogenic effects in workers in the rubber industry.
Table 1 Physical and chemical properties of 1,3-butadiene.
Chemical name                             1,3-butadiene
CAS registry number                       106-99-0
EINECS number                             203-450-8
RTECS number                              EI9275000
IUPAC name                                1,3-butadiene
Synonyms                                  butadiene; biethylene; bivinyl; buta-1,3-diene; divinyl;
                                          erythrene; pyrrolylene; vinylethylene
Molecular weight                          54.1 g/mol
Molecular formula                         C 4H 6
Molecular structure                       H2C=CH–CH=CH2
Physical appearance                       colourless gas (at 100 kPa and 15.5 °C)
Boiling point                             -4.4 °C (100 kPa)
Freezing point                            -108.9 °C (100 kPa); -113 °C 20
Log Pow                                   1.99 (estimation)
Vapour pressure (21 °C)                   240 kPa
Relative density of saturated             3.07
vapour in air (air = 1), 21 °C, 100 kPa
Percentage [vapour in saturated]          237%
air (21 °C, 100 kPa)
Odour threshold                           detection: 1.0-2.1 mg/m3 air
                                          recognition: 2.4-169 mg/m3 air
Flash point                               below -76 °C
Explosion limits in air                   1.1-12.3% (vol/vol)
Solubility                                Water: 2.3 g/L (0 °C); 1.9 g/L (50 °C); 735 mg/L 20;
                                          soluble in ethanol, diethyl ether, benzene and organic
                                          solvents; very soluble in acetone.
Conversion factors                        1 ppm = 2.21 mg/m3
(20 °C, 100 kPa)                          1 mg/m3 = 0.442 ppm
EU classification and labelling (GHS)     Category 1A
                                          May cause cancer (danger) H350
Data from DECOS (19901) and IARC (20082) unless stated otherwise.
General information                                                                                25
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<pre>2.3 Other conclusions
    The Scientific Committee on Occupational Exposure Limits of the European
    Union (SCOEL) evaluated butadiene in 2007 (SCOEL 20078), and concluded
    that ‘butadiene should be treated as a possible human carcinogen, operating via a
    genotoxic mechanism’. No short term exposure limit (STEL) or skin notation
    was considered necessary. Risk values were derived for a number of exposure
    scenarios, see Section 3.4.
         The European Risk Assessment Report of butadiene (EU-RAR 20029)
    classified the substance as a category 1 carcinogen (‘substances known to be
    carcinogenic to humans’), and as a category 2 mutagen (‘substances which
    should be regarded as if they are mutagenic to man’).
         In the extensive reviews of Kirman et al. (2010a10, 2010b11) and Albertini et
    al. (201012) the authors concluded that butadiene has a mutagenic mode of action
    in producing cancer in experimental animals (rodents) and humans. They
    attributed the mutagenicity of butadiene to the formation of the reactive
    metabolites epoxybutene, diepoxybutane and epoxybutane diol.
2.4 Carcinogenicity studies in humans
    In the previous DECOS report (19901) it was concluded that the available human
    studies were inconclusive to determine if butadiene is carcinogenic to humans.
    Many studies showed an elevated risk of leukaemia or other lymphopoietic
    cancers, but either the exposure was not exclusively to butadiene, or the cohort
    was too small to have enough power to detect a two-fold leukaemia excess. The
    Committee concluded that butadiene had to be considered a carcinogen in
    experimental animals but drew no conclusion about any specific mode of action.
    The Committee estimated an additional lifetime cancer risk of 1x10-4 for 40
    years of exposure to 1.18 mg butadiene per m3, and 1x10-6 for 40 years of
    exposure to 0.012 mg butadiene per m3 (DECOS 19901).
         Mortality studies have been conducted both on workers employed in
    butadiene manufacturing facilities where exposure is to butadiene monomer
    alone, and on workers exposed to butadiene during SBR production. Although a
    relative large number of studies has been reported, many of these studies updated
    previously reported findings and thus relate to the same or overlapping cohort
    populations2,9. Epidemiological studies of cancer and exposure to butadiene as
    considered by IARC (20082) are summarized in Annex F, and updated with more
    recent publications.
 6  1,3-Butadiene
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<pre>     In IARC’s evaluation of butadiene2, three independent cohorts of monomer
production workers in the USA were evaluated: the first at three Union Carbide
plants in West Virginia (Ward et al. 199513), the second at a Texaco plant in
Texas (Divine & Hartman 200114), and the third at a Shell plant in Texas (Tsai et
al. 200115). Also two independent groups of SBR production workers have been
studied; one included a two-plant complex in Texas, USA (McMichael et al.
1974, 1976; Meinhardt et al. 1982; in IARC2) studied by the University of
Pittsburgh, and the other included workers from eight facilities in the USA and
Canada studied by researchers from the Johns Hopkins University (JHU;
Matanoski & Schwartz 1987 in IARC2; Matanoski et al. 199016, 199317).
Subsequently, researchers from the University of Alabama at Birmingham
(UAB) studied the two-plant complex originally investigated by the National
Institute for Occupational Safety and Health (NIOSH) plus seven of the eight
plants studied by the JHU (Delzell et al. 199618). The JHU researchers also
conducted nested case-control studies with this working population (Matanoski
et al. 199719, Santos-Burgoa et al. 199220). The UAB group recently updated the
follow-up of the cohort, revising and refining their assessment of exposures to
butadiene, and taking possible confounding co-exposures into account
(Macaluso et al. 200421). A number of largely overlapping publications from
these groups have been reviewed. The most recent results that were evaluated by
IARC2 were published by Graff et al. 200522, Sathiakumar et al. 200523 and
Cheng et al. 200724.
     Compared to exposure to butadiene alone in the monomer production sites,
multiple chemical exposures of SBR workers make interpretation of the results
more difficult. In addition, many employees moved between plants, and have
worked in both the butadiene manufacturing industry and in the SBR industry,
which makes the interpretation of these studies even more complicated.
Industry-based studies - monomer production
Ward and co-workers (199513) identified, among 29,139 workers at three Union
Carbide Corporation facilities in West Virginia (USA), a study population of 364
men who worked in butadiene monomer production from 1940-1979. The
mortality experience of the cohort was compared to USA and to Kanawha
County mortality rates using a modified life-table analysis system, developed by
NIOSH. SMR (standardized mortality ratio), CI (95% confidence interval) and
two-sided p-values were calculated. Mortality from all cancers was not
increased. SMR for lymphohaematopoietic cancers was 1.8 (CI 0.7-3.6), with an
SMR for lymphosarcoma and reticulosarcoma of 5.8 (CI 1.6-14.8). The study
General information                                                               27
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<pre>  has several limitations, the most important of which is that no exposure
  monitoring data are available, so it was not possible to associate mortality from
  lymphosarcoma and reticulosarcoma with exposure data.
      A cohort mortality study of 2,800 male workers employed > 6 months
  between 1943 and 1996 at a butadiene monomer production facility in Texas
  (USA) was described by Divine and Hartman (200114) and also evaluated by
  IARC2. Earlier analyses2 of this cohort showed a significant elevation of deaths
  from cancers of the lymphohaematopoietic system that was mainly due to an
  increase in the deaths from lymphosarcoma. In the most recent update14, a
  follow-up of the patterns of mortality to the end of 1999 was included. The
  overall and cause-specific mortality of the study population was compared to that
  of the US population. The SMR for all lymphohaematopoietic cancers was 1.4
  (CI 1.1-1.9) and was significantly increased. The SMRs for leukaemia and non-
  Hodgkin’s lymphoma were 1.3 and 1.5, respectively (not significantly in-
  creased). As for the previous evaluation of this cohort, the lymphohaemato-
  poietic cancer elevations were found only in workers first employed before 1950.
  Survival analyses for all lymphohaematopoietic cancers, non-Hodgkin’s
  lymphoma and leukaemia were performed using an estimate of cumulative
  butadiene exposure as a time-dependent explanatory variable defined as a
  combination of job exposure class, calendar time, and length of time in job. The
  job/unit exposure classification scheme used in previous reports was used again,
  with a background exposure group (office, utilities, warehouse and transportation
  employees), a low-exposure group (workers partly working on the operating
  units and partly in the office or maintenance shops), and a varied exposure group
  (employees with the potential for exposure to butadiene on a routine basis such
  as laboratory workers, pumpers, pipefitters, and instrument men). The relative
  risks (RRs) for the above causes of death were essentially 1.0, suggesting that
  there was no increase in risk with increasing butadiene exposure. In addition to
  the above mentioned cancers of the lymphohaematopoietic system, non-
  significant positive associations in cancer mortality were observed for larynx-,
  skin- and kidney cancer, lymphosarcoma, and Hodgkin’s disease. Limitations of
  the study were that no industrial hygiene sampling data exist for the plant for the
  years prior to 1981, and no quantitative exposure information was available. In
  addition, the cohort size was small, and the numbers became even smaller for the
  exposure group analyses.
      The report of Cowles (1994, in IARC2) on employees from a petrochemical
  facility in Texas related the cause-specific mortality (1948-1989) of 614
  employees (who had worked in the plant for 5 years or more) with potential
  exposure to butadiene monomer. Butadiene monomer production took place
8 1,3-Butadiene
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<pre>between 1941 and 1948 and from 1970 onwards. Tsai and coworkers (200115,
also evaluated by IARC2) extended this study to 1998 and found the SMR for all
causes of death to be 0.6 (CI 0.4-0.7). None of the cause-specific mortality was
in excess compared with coworkers without butadieen exposure. The findings in
this study suggest that the butadiene exposure at this facility in the last 20 years
does not pose a cancer hazard to employees. However, the mortality and morbi-
dity numbers of the study were based on small numbers of employees and based
on a 8-h time weighted average (TWA) butadiene level with a geometric mean of
less than 6.6 mg/m3 (exposure to butadiene was mostly below 2.2 mg/m3, with
few exposures exceeding 2.2 mg/m3 as an 8-h TWA).
Industry-based studies – styrene-butadiene rubber production
Matanoski et al. (199016, also evaluated by IARC2) followed a cohort of 12,110
male workers employed >1 year in eight SBR polymer manufacturing plants in
the USA and Canada for mortality over a 40-year period (1943-1982). Compared
to the general population, the all-cause mortality of these workers was low (SMR
0.8), whereas the SMRs for some cancers of the digestive tract were higher than
expected, especially oesophageal cancer and stomach cancer in white men. In
this study, individuals were assigned to four work areas (production, main-
tenance, utilities, and others), based on longest job held. There were no measured
exposure data for the different work areas. Production workers showed a signi-
ficantly increased SMR for haematologic neoplasms. Deaths from cancers of the
haematopoietic and lymphopoietic system were higher than expected in produc-
tion workers, with significant excesses for leukaemia and kidney cancer in black
workers and other lymphomas in all workers.
SMR production workers, cancers, white men: kidney 1.66 (95% CI 0.54-3.88),
Hodgkin’s 1.31 (0.16-4.75), lymphatic 2.30 (0.92-4.73); black men: lung 1.23
(0.45-2.67), liver 1.98 (no 95% CI), kidney 5.07 (1.87-11.07), lymphosarcoma
5.32 (no 95% CI), leukaemia 6.56 (1.35-19.06), lymphatic 4.82 (0.59-17.62);
total: kidney 1.53 (0.50-3.57), lymphopoietic 1.46 (0.88-2.27), Hodgkin’s 1.20
(0.15-4.35), leukaemia 1.34 (0.53-2.76), lymphatic 2.60 (1.19-4.94). SMR
maintenance workers, cancers, white men: oesophagus 1.44 (0.53-3.14), stomach
1.66 (0.93-2.75), Hodgkin’s 1.70 (0.35-4.95); black men: rectum 1.37 (no 95%
CI); total: stomach 1.51 (0.90-2.39), Hodgkin’s 1.51 (0.31-4.41). SMR utility
workers, total: large intestine 1.61 (0.44-4.13), respiratory cancers 1.49 (0.79-
2.55) with larynx 5.13 (0.62-8.52) and lung 1.22 (0.58-2.24); lymphopoietic
General information                                                                  29
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<pre>  cancers 2.03 (0.66-4.74), with leukaemia 1.92 (0.23-6.96) and other lymphatic
  3.13 (0.62-6.95).
      In a later analysis of Matanoski and coworkers (199317, also evaluated by
  IARC2) the results of the above cohort study16 were discussed. SMRs for some
  lymphohaematopoietic cancers sometimes were high in early cohort analysis. A
  total of 3,952 samples for butadiene were reported (personal and area
  monitoring). Values indicated upper ranges as high as 1,485 mg/m3 in
  measurements taken in the 1980s, suggesting that previous exposures of some
  workers may have been even higher. In all plants there was a marked variation in
  measurements. The 1993 cohort study17 included workers of eight SBR
  manufacturing plants in North America. All but one (1955) of the plants had
  begun operation in 1943. Four plants had complete personal records from the
  beginning; for three plants that had incomplete records, follow up was begun
  several years after they opened. For the largest plant only workers with >10 years
  of employment were included in the cohort, since follow-up was possible only
  through records of death-benefit claims with the employees group life insurance
  program. The missing records for three of the plants and limitations in follow-up
  in one could lead to underestimation of the workers’ risk. Workers were
  classified in work areas to prevent masking effect of exposure because of
  dilution of the risk in a few people as the result of large numbers of unexposed
  people. New limitations were that workers had to be assigned to a single work
  group, and work areas were assumed to be homogeneous. Despite the continued
  problem of dilution of possible risks due to exposure by the presence of both
  exposed and unexposed workers, workers in production areas showed an
  increased risk for lymphohaematopoietic cancers (SMR 1.6, CI 1.1-2.3), and
  oesophagus cancer (SMR 1.8, CI 0.9-3.4).
      Nested case-control studies within the SBR cohort in the USA and Canada
  were conducted by Matanoski et al. (199317,199719), and Santos-Burgoa et al.
  (199220). Since the presence of large numbers of unexposed workers could
  conceal risks within a cohort, case-control studies were designed to examine the
  relationship between estimated exposures and the mortality due to
  lymphohematopoietic cancers.
      Santos-Burgoa et al. (199220, also evaluated by IARC2) conducted a case-
  control study of 59 cases of lymphohaematopoietic cancers within a cohort of
  male workers employed between 1943 and 1982 in eight North American SBR
  polymer-producing plants (Matanoski et al. 199016). A total of 193 controls were
  matched by plant, age, year of hire, duration worked, and survival to case of
  death. Each job was assigned an estimated exposure rank, and each worker’s
  cumulated rank score was calculated on the basis of time spent in each job during
0 1,3-Butadiene
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<pre>his employment. In the mortality analysis, three subdivisions (process, utilities
and maintenance) were analyzed separately according to the longest job held by
workers in these areas. Matched-pair analysis identified a strong association
between leukaemia and butadiene, with an odds ratio (OR) of 9.4 (CI 2.1-22.9)
and an association between STYR and leukaemia (OR 3.1, CI 0.8-11.2) that did
not achieve statistical significance. When exposure to both STYR and butadiene
was included in a conditional logistic regression model, the OR for butadiene
remained high (OR 7.4), but the estimated association of leukaemia with STYR
was small. The results of this study support the hypothesis that exposure to
butadiene is associated with the risk of leukaemia. The study lacked measured
individual exposures over time; however, there appeared to be an additional risk
from work in specific subdivisions of the industry.
    Matanoski and coworkers (199317, also evaluated by IARC2) studied the
same 59 cases of lymphohaematopoietic cancer and 193 controls from the study
of Santos-Burgoa et al. (199220). Cases and controls were divided into four
cancer groups (leukaemia, other lymphatic cancers, lymphosarcoma and
Hodgkin’s disease), and an average exposure was calculated on the basis of the
log scores (rank assigned to a job multiplied by the number of months worked in
that job, summed over the total work period, and transformed into its logarithm
(log score); method described by Santos-Burgoa et al. 199220). The analysis of
leukaemia cases and controls, using the log mean as a categorical exposure
variable, showed an OR of 7.6 (CI 1.6-35.6) for butadiene alone and 2.9 (CI 0.8-
10.3) for STYR alone. When both variables (butadiene and STYR) were used in
the model, only butadiene was associated with a significantly increased OR (OR
butadiene = 7.4 and OR STYR = 1.1). Three areas seemed to be overrepresented
among the cases: operation services, laboratory, and utility. Limitation of the
study is the use of controls only matching for duration of work. All but one case
had been hired before 1960, 81% had been employed for 10 or more years in the
industry and 73% had worked in only three of the eight plants. The absence of a
risk for workers hired after 1960 may have been due to the long latency period
for this cancer. An average of 24 years between the start of employment and
death was observed. New sets of controls were selected that matched variables
except duration of work. Addition to the model of a variable to account for
duration of work improved the model and demonstrated a risk for leukaemia
associated with exposure to butadiene. The importance of the duration of work
variable suggested that dose per unit time may be the most important exposure
variable to investigate. The same dose given over different time periods may not
carry the same risk. The results suggested that the risk for leukaemia was
associated with exposure to butadiene and with work in specific areas. The SMR
General information                                                               31
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<pre>  for leukaemia among long-term workers hired before 1960 who had worked in
  plants with assumed high butadiene levels was 1.8 times higher than that of the
  US population.
      In the study of Matanoski and coworkers of 199719 (also evaluated by
  IARC2) the population from the Santos-Burgoa et al. (199220) and Matanoski
  et al. (199317) cohort was used for a nested case-control study of lympho-
  haematopoietic cancers occurring in a cohort of synthetic rubber production
  workers to determine the associations of these cancers with exposure to
  butadiene and STYR. Exposures were based on measured values of the two
  chemicals from personal monitoring data in seven of the eight plants under study.
  Plant- and work area-specific exposure estimates were linked to work histories to
  obtain indices of cumulative exposure (mg/m3-months) and average intensity of
  exposure (mg/m3) based on total cumulated exposure in mg/m3-months divided
  by the total time employed for both STYR- and butadiene-related processes for
  each individual. The 59 cases studied previously by Matanoski and coworkers17
  and by Santos-Burgoa and coworkers20 were re-evaluated, resulting in 58
  lymphatic and haematopoietic cancers in this study, together with 1,242 controls
  from the plants. The risk of leukaemia increased with exposure to a TWA
  butadiene measure, with an OR of 1.5 (CI 1.1-2.1) at 2.2 mg/m3 average
  butadiene exposure. Work in specific areas also contributed to the risk, possibly
  because these areas had not been completely characterized for differences in
  butadiene exposure. Hodgkin’s disease was also associated with butadiene
  exposure (OR 1.7, CI 1.0-3.0). Multiple myeloma, lymphosarcoma and all
  lymphomas were associated with exposure to STYR. According to the authors,
  workers in this industry were apparently exposed to two carcinogenic agents, and
  thus they stated that more information is needed on the exposures to each
  chemical over time.
      A retrospective follow-up study of men employed during 1943-1991 in the
  SBR industry in the USA and Canada evaluated the mortality outcome of 15,649
  men employed for more than one year at any of eight North American SBR
  plants (Delzell et al. 199618). The investigation included workers from seven of
  the eight plants previously studied by the JHU16,17,20 and workers from the two
  plants previously investigated by the NIOSH (Meinhardt et al. 1982, in IARC2).
  Due to lack of information to identify individual subjects, it was not possible to
  determine the number of subjects in this study who were included in the earlier
  investigations. The overlap was estimated to be large. Complete work histories
  were available for about 97% of the subjects. Work area groups were combined
  into 5 ‘process main groups’ (rubber production, maintenance, labour, labora-
  tories, and other operations) and seven ‘process subgroups’ (polymerization,
2 1,3-Butadiene
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<pre>coagulation, finishing, shop maintenance, field maintenance, production labour,
and maintenance labour). The subgroup analysis excluded subjects from two
plants (n=1,354) due to lack of information on specific work areas. About 75%
of the men were exposed to butadiene, 83% of the men were exposed to STYR.
The cohort consisted mainly of hourly-paid workers (86%). About 50% of the
workers were hired before 1960 (median year of hire was 1960), 44% had
worked for at least 10 years (median, 7.8 years) and 59% started work before the
age of 30 years. During 1943 to 1992 the cohort had a total of 386,172 person-
years and an average of 25 person-years of follow-up. The overall SMR was 0.87
(CI 0.85-0.90, 3,976 deaths observed, 4,553 deaths expected). More leukaemia
deaths than expected occurred in the overall cohort (48 observed/37 expected,
SMR 1.3, CI 1.0-1.7) and among hourly workers (45 observed/32 expected,
SMR 1.4, CI 1.0-1.9). This increase was observed in hourly workers who worked
more than ten years and who died after more than twenty years since hire (28
observed/13 expected, SMR 2.2, CI 1.5-3.2), and among workers in three areas
with potential for relative high exposure to butadiene or STYR: polymerization
(15 observed/6 expected, SMR 2.5, CI 1.4-4.1), maintenance labour (13
observed/4.9 expected, SMR 2.6, CI 1.4-4.5) and laboratories (10 observed/2.3
expected, SMR 4.3, CI 2.1-7.9). The most likely causal agent was butadiene or a
combination of butadiene and STYR. According to the authors, some cohort
subgroups had slight increases in deaths from lymphopoietic cancers other than
leukaemia, but there was no indication of a causal association with occupational
exposures.
     In an update (an additional 7 years of follow-up and re-examination) of the
study from Delzell et al. (200125), a possible association between exposure to
butadiene, STYR and dimethyldithiocarbamate (DMDTC), and mortality from
lymphohaematopoietic cancer among 16,579 synthetic rubber industry workers
followed up from 1943 to 1998 was evaluated (Graff et al. 200522). All subjects
were men who had worked at any of six study plants (USA and Canada) for at
least one year by the end of 1991. Each of the 7,802 unique work area/job title
combinations was classified into one of 296 work area/job groups. Macaluso et
al. (200421) described in detail the exposure estimation procedures. In short, the
exposure metrics included 8-h TWA intensity, the annual number of peak
exposures (butadiene > 221 mg/m3) and TWA intensity below and above the
peak threshold. butadiene TWAs were approximately 22 mg/m3 during the
1940s-1960s and declined during the 1970s and 1980s. Butadiene peak exposure
accounted for a large proportion of cumulative butadiene exposure. Multiple
correlations among DMDTC, butadiene and STYR exposure estimates made it
difficult to estimate agent-specific effects. Nevertheless, the new exposure
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<pre>  estimates were highly correlated with the old estimates, yielding equivalent
  exposure ranking of workers, and were comparable to limited industrial hygiene
  data published by NIOSH. The cumulative exposure indices used in the study of
  Graff and co-workers (200522) were butadiene mg/m3-years, butadiene mg/m3-
  years due to exposures to intensities ≤ 221 mg/m3, butadiene mg/m3-years due to
  exposures to intensities > 221 mg/m3, and the total number of butadiene peaks
  (> 221 mg/m3 (100 ppm)). Poisson regression analyses were used for lympho-
  haematopoietic cancer rates in relation to butadiene (and STYR and DMDTC)
  exposure. Models provided maximum likelihood estimates of the relative rate for
  the contrast between categories of one agent, adjusting for other agents and for
  additional potential confounders. The results were consistent with the previous
  investigation of Delzell and coworkers25, and indicated that leukaemia was
  positively associated with cumulative exposure to butadiene (relative risks (RRs)
  of 1.0, 1.4 (CI 0.7-3.1), 1.2 (CI 0.6-2.7), 2.9 (CI 1.4-6.4) and 3.7 (CI 1.7-8.0),
  respectively, for exposures of 0, > 0 to < 74, 74 to < 408, 408 to < 939 and ≥ 939
  mg/m3-years), whereas the association of leukaemia with cumulative exposure to
  butadiene together with STYR and DMDTC was observed at higher butadiene
  exposure levels (RRs of 1.0, 1.4 (CI 0.5-3.9), 0.9 (CI 0.3-2.6), 2.1 (CI 0.7-6.2)
  and 3.0 (CI 1.0-9.2), respectively, for exposures of 0, > 0 to < 74, 74 to < 408,
  408 to < 939 and ≥ 939 mg/m3-years). According to Graff et al. (200522) the
  relation between butadiene and leukaemia appeared to be somewhat stronger for
  exposure to butadiene concentrations greater than 221 mg/m3 (in mg/m3-years)
  than for exposure to concentrations of ≤ 221 mg/m3 (in mg/m3-years), but the
  results did not rule out an effect of lower concentrations. Data on specific forms
  of leukaemia were difficult to interpret because of diagnostic uncertainty that
  persisted despite efforts to review medical records. The data do not preclude a
  role of STYR or DMDTC. Recently Graff et al. (200926) reported an uncertainty
  analysis of their earlier findings21,22,27, which overall confirmed the reported
  results.
      Sathiakumar et al. (200523) updated the mortality study of workers in the
  eight SBR plants in North America and Canada previously described by Delzell
  et al.18,25, Macaluso et al.27 and Sathiakumar et al.2 with an additional 7 years of
  data (1943-1998). They observed that the 16% leukaemia increase was
  concentrated in hourly paid workers with 20-29 years since hire and 10 or more
  years of employment in the industry (SMR 2.6, CI 1.6-4.0) and in workers
  employed in polymerisation (SMR 2.0, CI 1.2-3.2), maintenance labour (SMR
  3.3, CI 1.8-4.6), and laboratory operations (SMR 3.3, CI 1.8-5.5). Uncertainty in
  this study remained about the role of unidentified confounding factors.
4 1,3-Butadiene
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<pre>    Sathiakumar and Delzell (200928) and Sathiakumar et al. (200929)
investigated cancer mortality among female workers in the eight SBR plants in
North America and Canada previously described by Delzell et al. (199618,
200125), Macaluso et al. (199627) and Sathiakumar et al. (1998, cited in IARC2)
for the period 1943-2002. Generally, the number of deaths observed among
exposed females were approximately equal to the expected numbers of deaths,
with the exception of hourly paid women who had more deaths than expected
from lung (SMR 1.6, CI 1.2-2.1) and bladder cancers (SMR 3.3, CI 1.2-7.2).
However, exposure-response analysis (done only for lung cancer) indicated no
trend for butadiene or STYR. The authors concluded that the observed excess of
lung and bladder cancers might be attributable to non-occupational factors rather
than to workplace exposure.
    Cheng et al. (200724) used the Cox regression procedure on the data from
Sathiakumar et al. (200523) and Graff et al. (200522) from the SBR plants in
North America and Canada (1944-1998) to examine further the exposure-
response relationship between several butadiene exposure indices (butadiene mg/
m3-years, the total number of exposures to butadiene peaks > 221 mg/m3, and
average intensity of butadiene), and leukaemia, lymphoid neoplasms and
myeloid neoplasms. By using Poisson regression analysis in which butadiene and
covariates were categorical variables, Sathiakumar et al. (200523) and Graff et al.
(200524) had concluded that cumulative exposure to butadiene was associated
positively with leukaemia, but controlling for STYR and DMDTC attenuated this
association. Subjects included in the study of Cheng et al.12 were 16,579 men,
and exposure to butadiene, STYR and DMDTC was estimated quantitatively by
identifying work/area groups as described by Macaluso et al. (199627, 200421).
All three ways of expressing butadiene exposures (butadiene mg/m3-years, the
total number of exposures to butadiene peaks > 221 mg/m3, and average intensity
of butadiene) were associated positively with leukaemia. Using continuous,
untransformed butadiene mg/m3-years the regression coefficient (β) from
analysis that controlled only for age was 2.9x10-4 (p < 0.01), and was similar in
magnitude (β = 3.0x10-4 (p = 0.04)) when adjusted for all covariates (age, year of
birth, race, plant, years since hire, and DMDTC), though with reduced statistical
significance (more details are shown in Annex F). The analysis of exposure to 11
mg/m3 butadiene over a 20-year period (cumulative exposure, 221 mg/m3)
yielded an RR for leukaemia of 1.0 for the untransformed continuous butadiene
mg/m3-years variable. The analyses indicated that the exposure-response
relationship for butadiene and leukaemia was independent of exposure to
DMDTC. The relevant results are summarized in Table 2.
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<pre>      Sielken et al. (200730) studied the dose-response assessment of the asso-
  ciation between butadiene and leukaemia mortality among workers in the North
  American synthetic rubber industry, based on the recent UAB study and ex-
  posure estimation described by Macaluso et al. (200421), by giving consideration
  to peak exposures to butadiene (a butadiene peak was defined as any exposure,
  regardless of duration, to a butadiene concentration above 221 mg/m3). Exposure
  to butadiene levels above 221 mg/m3 was rather common, in large part inter-
  mittent, frequently of short duration (several seconds to several minutes) and not
  uncommonly to levels of a few hundreds mg/m3. If cumulative butadiene mg/m3-
  years was used as the predictor of the leukaemia rate ratio, the performance of
  this predictor was indeed statistically significantly improved if the slope in the
  predictor was estimated with age and the cumulative number of butadiene peaks
  added as categorical covariates. The cumulative number of butadiene peaks
  counted the number of exposures above 221 mg/m3 and not the magnitude above
  221 mg/m3 nor the duration of time above 221 mg/m3. The inclusion of the
  cumulative number of butadiene peaks as covariate made a statistically signi-
  ficant improvement in the model for leukaemia and myeloid neoplasms, but not
  for lymphoid neoplasms.
      Sielken et al. (200730) used a Poisson regression analysis to assess the
  leukaemia mortality data. The UAB human epidemiological data suggested that
  there was no increasing risk for leukaemia at low cumulative butadiene mg/m3-
  years. Even though the primary focus for regulatory environmental risk assess-
  ment is the best estimate of the slope associated with cumulative butadiene
  mg/m3-years, statistical analysis suggested that cumulative butadiene mg/m3-
  years by itself was not a sufficient explanation of the leukaemia mortality
  observed in the workers. Among the exposure variables reported in the UAB
  study, the observed leukaemia rate ratios were most strongly correlated with the
  number of butadiene peaks (slope of linear rate ratio model 5.77 x 10-4,
  maximum log likelihood -68.75 (peaks included) or -80.50 (peaks excluded), p-
  value of 0.00027). There was no correlation with the cumulative butadiene
  exposure (in mg/m3-years).
      Sielken et al. (200730) mentioned three reasons for the inclusion of butadiene
  peaks in the risk assessment of butadiene: (1) there were large numbers of
  butadiene peaks not only during the early years near the end of World War II but
  also during the entire period up to the 1990s, and a large number of butadiene
  peaks was a prominent part of the work environment throughout the study
  period; (2) all of the statistical analyses of leukaemia herein indicated that
  cumulative number of butadiene peaks was the most important exposure
  covariate which explained a substantial portion of the increase of leukaemia rate
6 1,3-Butadiene
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<pre>ratios with cumulative exposure to butadiene; and (3) the inclusion of butadiene
peaks was consistent with the current biological understanding of the mode of
action of butadiene.
Table 2 Cumulative 1,3-butadiene exposure and rate ratios for leukaemia as reported by Cheng et al.
200724
Butadiene mg/m3-years,         Mean          Number of       RR (95% CI)b         RR (95% CI)c
decile ranges of exposure      exposure      leukaemias
valuesa                        (mg/m3)
0                                   0        10              1.0                  1.0
> 0 - < 26.7                       10.7       7              1.13 (0.43-2.98)     0.98 (0.37-2.61)
26.7 - < 50.6                      38.0       7              2.12 (0.81-5.56      1.67 (0.62-4.50)
50.6 - < 85.7                      67.4       7              2.03 (0.77-5.34)     1.45 (0.53-3.97)
85.7 - < 173                     126          7              1.22 (0.47-3.32)     0.83 (0.30-2.32)
173 - < 408                      274          7              0.94 (0.36-2.46)     0.61 (0.21-1.73)
408 - < 555                      476          7              2.96 (1.13-7.79)     1.77 (0.60-5.24)
555 - < 704                      624          7              4.00 (1.52-10.51)    2.47 (0.82-7.44)
704 - < 996                      829          7              3.37 (1.28-8.86)     1.96 (0.65-5.87)
996 - < 1,833                  1,340          7              2.94 (1.12-7.73)     1.86 (0.62-5.55)
≥ 1.833                        4,094          8              3.84 (1.51-9.76)     2.56 (0.85-7.66)
a    Exposure data are split up into 10 equally large subsections (‘deciles’).
b    Estimated rate ratio (RR) and 95% confidence interval (CI) controlling only for age.
c    Estimated rate ratio (RR) and 95% confidence interval (CI) controlling for age, year of birth,
     race, dimethyldithiocarbamate, years since hire and plant.
In 2011 Sielken and Valdez-Flores31 re-analyzed the earlier mortality data of the
UAB cohort, using Cox regression analyses to estimate exposure-response
models with cumulative butadiene mg/m3-years as the exposure metric. The
authors reported a statistically significant positive correlation between occu-
pational leukaemia and cumulative exposure in butadiene mg/m3-years, i.e. a
significantly positive slope of the cumulative butadiene mg/m3-years in the log-
linear rate ratio model; this slope became less steep if other butadiene exposure
metrics were used. These results are difficult to interpret because the coefficients
for the other exposure metrics are not reported, and confounders were not taken
into account. The correction for plant, e.g., had an increasing effect on the slope
of the model, but could not be interpreted without inclusion of confounders in the
models. The authors argued that there was virtually no risk at low exposures.
However, truncating the ranges of exposure decreases the the number of cases
and hence strongly decreases the statistical power. Due to the complex structure
of the correlation the estimation of the effects of the variables as presented by the
authors is intricate, and it remains possible that the incidence of occupational
leukaemia is fully attributable to butadiene.
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<pre>  Population-based studies
  In addition to industry-based studies, a population-based case-control study in
  Canada (Parent et al. 200032) and a cohort study of students at a high school
  adjacent to a SBR production plant in the USA (Loughlin et al. 199933) were
  reviewed by IARC2. More recent information from Higashino et al. (200734) and
  Mita et al. (200635) is included.
      The risk of mortality from lymphatic and haematopoietic cancers and other
  causes was evaluated among students of a high school adjacent to synthetic
  butadiene-STYR facilities in Texas (producing since 1943). In this study, school
  records, year books and health records for the school years 1963-64 to 1992-93
  were used to construct a cohort of 15,403 students, who attended the school for at
  least 3 consecutive months. No data existed on environmental exposure. The
  SMR for all cause mortality was 0.8 (CI 0.7-1.0) for men and 0.9 (CI 0.7-1.1)
  for women. The SMR for all lymphatic and haematopoietic cancers was 1.6 (CI
  0.8-2.9) for men and 0.5 (CI 0.1-1.7) for women. The slightly positive associa-
  tion for males and lymphatic and haematopoietic cancers was stronger among
  men who attended school for two years or less (Loughlin et al. 199933).
      Grant et al. (200736) provided information on butadiene monitoring data in
  Texas (USA), where several large industrial sources of atmospheric butadiene
  are located. In 2003, annual average concentrations at monitoring sites ranged
  from 0.02 to 7.1 µg/m3 with an overall average of 0.4 µg/m3. Cancer incidence
  data from 1995 to 2002 and cancer mortality data from 1993 to 2003 from
  several areas were investigated by the Texas Cancer Epidemiology and
  Surveillance Branch (TCES). It was concluded that the cancer incidence and
  mortality data from all examined types of cancer in the Houston region were
  within normal ranges. In the Port Neches region, however, a SMR of 5.0 (99%
  CI 1.1-14.2) for subleukaemia and leukaemia not otherwise specified mortality
  was observed, but the TCES could not identify a cause for this elevated
  mortality. Different leukaemia subtypes have varying risk factors, and the
  elevation of various types of leukaemia rather than one predominant subtype is
  generally not indicative of an environmental exposure. However, different
  leukaemia subtypes could not be evaluated independently because non-specific
  descriptions of leukaemia on death certificates are coded to the aleukaemic
  category.
      A population-based case-control study in Montreal, Canada, investigated the
  association between renal-cell carcinoma and a large number of occupational
  exposures among 35-70 years old men diagnosed between 1979 and 1985. A
  total of 142 male patients with renal cell carcinoma were compared with 1,900
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<pre>controls with cancer at other sites and 533 population-based controls. Detailed
job histories and relevant data on potential confounders were obtained (by
interview), and each job was translated into a history of occupational exposures
using a checklist of 294 substances. RRs were estimated by ORs from
unconditional logistic regression models. The OR for exposure to butadiene-
STYR was 2.1 (CI 1.1-4.2) if adjusted for age, family income, smoking and body
mass index, and 1.8 (CI 0.9-3.7) if adjusted for former confounders including
other occupational exposures (Parent et al. 200032).
     Higashino et al. (200734) and Mita et al. (200635) assessed the risk and
consequences of exposure to BTD on human health in Japan. Butadiene in the
general environment originates primarily from automobile emissions. Industrial
emission of butadiene in Japan has decreased in recent years, primarily due to a
voluntary industrial emissions reduction program. The annual mean
concentration of butadiene in residential areas generally amounted to less than
0.5 µg/m3, but exceeded 1.7 µg/m3 at certain sites near industrial sources (data
from 1997-2003). The results indicated that in 2002 the majority of the
population in Japan had an excess lifetime cancer risk of less than 10-5 due to
exposure to butadiene, whereas a small number of people living close to
industrial sources had a cancer risk greater than 10-5.
Summary of human data and conclusion
In two of the three butadiene monomer industry studies a slight overall excess of
mortality from leukaemia was observed, whereas the third study reported a small
deficit in mortality from leukaemia. The excess of mortality from leukaemia in
one of the monomer industry cohorts was more pronounced among workers who
had been exposed at high levels during the first years of production (second
World War). In this cohort, no increase in excess of leukaemia was observed with
duration of exposure or cumulative exposure7.
     A review of the studies of SBR workers by researchers at the UAB (Cheng et
al. (200724) was considered to be the most informative. In this review the
mortality rates of approximately 17,000 workers from eight facilities in the USA
and Canada were examined, and the authors included earlier studies of some of
these facilities. A limiting factor in the evaluation was that the diagnosis and
classification of lymphatic and haematopoietic malignancies are very complex
and have undergone several changes over the course of time. The study used Cox
regression procedures to examine further the exposure-response relationships
between several continuous time-dependent butadiene exposure indices:
butadiene mg/m3-years, the total number of exposures to butadiene peaks > 221
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<pre>    mg/m3, and average intensity of butadiene. All three ways of expressing
    butadiene exposures were associated positively with leukaemia, supporting the
    presence of a causal relationship between high cumulative exposure and high
    intensity of exposure to butadiene and leukaemia. The analyses indicated that the
    exposure-response relationship for butadiene and leukaemia was independent of
    exposure to DMDTC.
2.5 Carcinogenic activity in experimental animals, lifetime low-dose
    exposure
    In the previous DECOS report1 it was concluded that butadiene has a weak
    carcinogenic potential in the rat, but is a carcinogen in the mouse and should be
    regarded as a carcinogen in experimental animals.
        All animal studies with butadiene and its metabolites are presented in
    Annex G.
    Mouse
    In the IARC monograph (20082) two butadiene inhalation studies with mice were
    evaluated which showed increased incidences of lymphoma and neoplasms of
    the heart, lung, forestomach, liver, Harderian gland, preputual gland, and kidney
    in males, and increased incidences of lymphomas and neoplasms of the heart,
    lung, forestomach, liver, Harderian gland, ovary, and mammary gland in females.
    As the first study was terminated due to the high mortality mainly caused by
    malignant lymphomas, the second study was performed at much lower exposure
    levels than the first, comparable to or even lower than historical levels of
    occupational exposure in humans. Tumours developed at the same organ sites in
    both studies. The second study is described below (NTP 199337, Melnick et al.
    199038).
        Groups of 70 (all dose groups except highest) to 90 (highest dose group only)
    B6C3F1 mice were exposed to 0, 14, 44, 138, 440 or 1,380 mg/m3 butadiene
    (purity > 99%), 6 h/day, 5 days/week for 2 years2,37,38. After two years, survival
    was significantly reduced (p < 0.05) in all groups of mice at 44 mg/m3 and
    higher; terminal survivors were: 35/70, 39/70, 24/70, 22/70, 3/70 and 0/90 for
    males and 37/70, 33/70, 24/70, 11/70, 0/70 and 0/90 for females at 0, 14, 44, 138,
    440 or 1,380 mg/m3, respectively. Early occurrence and development of lethal
    lymphocytic lymphomas of thymic origin at 44 mg/m3 and higher reduced the
    number of animals at risk for the expression of later developing neoplasms at
    other sites. Notwithstanding the reduced survival, increased incidence of
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<pre>neoplasms of the lung were found at all exposed levels, neoplasms of the liver
were found at 44 mg/m3 and higher, haemangiosarcomas of the heart, Harderian
gland, mammary gland and ovarian gland at 138 mg/m3 and higher, and
neoplasms of the forestomach and preputual gland at 440 mg/m3 and higher.
Additional studies in which exposure to butadiene was terminated after limited
exposure periods were included to assess the relationship between exposure level
and duration of exposure on the outcome of butadiene-induced carcinogenicity.
In the stop-exposure studies, groups of 50 male mice were exposed to one of the
following regimens: 1,380 mg/m3 for 13 weeks, 440 mg/m3 for 40 weeks, 1,380
mg/m3 for 26 weeks, or 686 mg/m3 for 52 weeks. After exposure, the animals
were held in control chambers for the remainder of the 104 weeks study. The
total exposure (concentration x duration) was approximately equivalent for the
first two groups and provided about half the total exposure given to the last two
groups. Survival was 35/70 for controls (same group as above), 9/50 at 440
mg/m3, 1/50 at 686 mg/m3, and 5/50 and 0/50 at 1,380 mg/m3 exposed for 13 and
26 weeks, respectively. Again increased incidences of lymphomas, heart
haemangiosarcomas, lung alveolar/bronchiolar adenomas and carcinomas, fore-
stomach papillomas and carcinomas, Harderian gland adenomas and adenocar-
cinomas, and kidney tubular adenomas were found at 440 mg/m3, and preputial
gland carcinomas at 686 mg/m3. This exposure protocol revealed additional
tumour sites in males (preputial gland and renal cortex).
     The incidence of thymic lymphomas in mice exposed to higher concentra-
tions of butadiene for a short time was greater than exposure to lower concentra-
tions for an extended period (9/70 at 440 mg/m3 for 2 years compared to 24/50 at
1,380 mg/m3 for 13 weeks). Butadiene-induced neoplastic responses (other than
thymic lymphomas) at multiple organ sites were also observed after only 13
weeks of exposure (Melnick et al. 199038).
     A benchmark dose (BMD) analysis of the main (2-years) study37,38,
performed by the Committee using US-EPA’s BMD software, revealed that the
log-logistic model showed the best fit and resulted in the lowest BMD* and
BMDL at the 10% extra risk level of all models tested, with a BMD of 262 and a
BMDL of 147 mg butadiene per m3. The other models showing equally good fits
resulted in BMDs and BMDLs varying from 330 - 593 and 211 - 401 mg/m3,
respectively.
BMD: benchmark dose; BMDL: benchmark dose at the lower 95% confidence level.
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<pre>    Rat
    Owen and Glaister (199039, also evaluated in DECOS1 and IARC2) reported a
    study with Sprague-Dawley rats (4-5 weeks old, 100/sex/dose) exposed by
    whole-body inhalation to 0, 2,200 or 17,600 mg/m3 butadiene (purity ≥ 92.2%)
    for 6 h/day, 5 days/week for 105 weeks (females) or 111 weeks (males). Survival
    was reduced in low- and high-dose females and in high-dose males. During the
    second year of the study, increased mortality was observed. In males, renal
    lesions were likely the major cause of the increased death rate. Females died as
    result of mammary tumours (80% of subcutaneous masses) and fibrous tumours
    of the skin. Statistically significantly increased incidences in tumours in high
    dose males were observed in the exocrine pancreas (10/100, with 3/100 in
    controls) and the testis (interstitial cells, 8/100, with 0/100 in controls). In high
    dose females increases in the incidence of thyroid follicular-cell tumours (10/
    100, with 0/100 in controls), uterine sarcomas (5/100, with 1/100 in controls),
    Zymbal gland carcinomas (4/100, with 0/100 in controls) and mammary
    adenocarcinomas (26/100, with 18/100 in controls) were observed.
        For the metabolites of butadiene, only inhalation studies with D,L-diepoxy-
    butane were available. These studies confirmed the conclusion from the carcino-
    genic studies on butadiene that mice are far more sensitive than rats (see
    Annex G).
    Conclusion
    In rodents butadiene induced lymphoma, and neoplasms of the heart, lung,
    forestomach, liver, Harderian gland, preputual gland, kidney, ovary and
    mammary gland, starting in mice at exposure to 44 mg/m3, and in rats at
    exposure to 17,600 mg/m3 (exposure duration was 2 years, 6 h/day, 5
    days/week).
2.6 Kinetics and kinetic models
    Kinetics
    In human volunteers exposed to 4.4 mg/m3 butadiene for 20 minutes, the
    absorbed fraction varied from 18 to 74%; this variation was not influenced by
    sex or age. Blood levels approached equilibrium by 5 minutes (ATSDR 200940).
        The uptake of inhaled butadiene by mice and rats was linear up to 4,400 and
    2,200 mg/m3, respectively, above which metabolism appeared to be saturated. In
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<pre>mice and rats inhaling up to 1,380 mg/m3 butadiene, equilibrium in blood levels
was reached by 2 h; butadiene blood levels in mice were 3- to 4-fold higher than
in rats at all times (ATSDR 200940).
    Butadiene distributed to a variety of tissues and organs, as was shown in in
vitro measurements of tissue : blood equilibrium partition coefficients: in
humans these coefficients were highest in fat (18.4) and similar in both well- and
poorly-perfused tissues (0.69 and 0.72, respectively). In rats, partition
coefficients were highest for fat (21.9), similar for liver, kidney, muscle and
spleen (0.87-0.94) and lowest in brain (0.43; ATSDR 200940).
    Following exposure of mice and rats to 14C-butadiene, the elimination of
radioactivity was rapid: 77-99% of the initial tissue concentration was eliminated
with half-lives of between 2 and 10 h. At exposure concentrations of ≤ 2,200
mg/m3 the elimination followed first-order kinetics in both species. The maximal
metabolic elimination rate of butadiene was 400 and 200 µmol/h.kg in mice and
rats, respectively. Urine and exhaled air were the major routes of elimination
(75-85% of total eliminated 14C-butadiene; ATSDR 200940).
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<pre> igure 1 Metabolic pathways of 1,3-butadiene deduced from findings in mammals in vitro and in vivo (copied from IARC
 0082).
 olid frames: electrophilic metabolites that can form DNA or haemoglobin adducts.
Dashed lines: assumed pathways.
A, B, U: metabolites in exhaled air, blood, urine, respectively.
ADH: alcohol dehydrogenase.
DHB: 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane.
HB: 4-(N-acetyl-L-cystein-S-yl)-1-hydroxy-2-butanone.
HMVK: hydroxymethylvinyl ketone.
             Butadiene is oxidized by cytochrome P450 (CYP) to electrophilic epoxides.
             CYP2E1 is one of the enzymes involved in butadiene metabolism. In addition, in
             mouse kidney and liver CYP4B1 plays a major role in butadiene epoxidation.
             The human CYP enzymes forms involved in butadiene conversion to epoxybu-
             tene appear to be CYP2E1 at low and CYP2A6 at high concentrations of
             butadiene (ATSDR 200940). The primary epoxide metabolite formed is
 4           1,3-Butadiene
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<pre>1,2-epoxy-3-butene (also known as epoxybutene, butadiene monoepoxide,
monoepoxybutene or 2-ethyloxirane). The second step in metabolism of
butadiene may be conjugation of the epoxide with glutathione (GSH), hydration
by microsomal epoxide hydrolase (mEH), or further oxidation to 1,2:3,4-
diepoxybutane diastereoisomers (also known as diepoxybutane, diepoxide of
butadiene, butane diepoxide or 2,2’-bioxirane; ATSDR 200940, Filser et al.
201041). All epoxides may be detoxified by GSH conjugation or hydration by
mEH. Additional epoxide forms, including 3,4-epoxy-1,2-butanediol (epoxy-
butanediol) may be involved in butadiene-related carcinogenic processes. This
latter epoxide is of particular concern as it is the most abundant genotoxic
butadiene metabolite in humans (IARC 20082, Hurst 20076), and was suggested
by Jackson et al. (2000, cited in Hurst 20076) to be the most significant meta-
bolite in humans. The metabolic pathways of butadiene, as summarized in IARC
(20082) are shown in Figure 1.
     Comparative in vitro studies conducted with tissues from mice, rats and
humans indicate that the relative rates of oxidation of butadiene to epoxybutene
and of epoxybutene to diepoxybutane are mice > rats ≈ humans. The relative
extent of mEH-catalyzed hydration of epoxybutene or diepoxybutane is humans
> rats > mice, whilst glutathione S-transferase (GST) mediated conjugation of
epoxybutene is mice ≈ rats > humans. Another comparison (activation by initial
oxidation rates versus detoxification as the sum of initial rates for mEH-mediated
hydration and GSH conjugation) among species indicated highest activation/
detoxification ratios for epoxybutene and diepoxybutane in mice, intermediate in
rats and lowest for humans. These observations indicate that the relative carcino-
genicity of butadiene in these species may depend on the balance of activation
versus detoxification (ATSDR 200940).
     Oral or dermal studies regarding absorption, distribution and excretion – in
humans or in experimental animals – were not located.
Physiologically based pharmacokinetic models
Johanson and Filser (1993, cited in ATSDR 200940) simulated absorption and
disposition of butadiene and its metabolite epoxybutene in PBPK models for the
mouse and the rat, including the hepatic conjugation of epoxybutene with GSH.
Tissue compartments included blood, liver, fat, and a lumped compartment for
muscle and richly-perfused tissues. Some, but not all, parameters were optimized
against experimental data. The model predicted epoxybutene levels that were
similar to experimental observations following exposure to butadiene. The model
has not been evaluated for inhalation exposures below 1,100 mg/m3, it does not
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<pre>  simulate other metabolites (such as the diepoxybutane, the diols and the GSH
  conjugation products), nor does it simulate butadiene disposition in humans.
      Also in the model of Kohn and Melnick (1993, 1996, 2000, cited in ATSDR
  200940) the absorption and disposition of butadiene and its metabolite epoxy-
  butene in the mouse and rat were simulated.The body was represented by
  compartments for venous and arterial blood, lung, liver, kidney, fat, GI tract, and
  lumped compartments for richly and poorly perfused tissues. Oxidative meta-
  bolism is represented by the formation of epoxybutene and subsequent oxidation
  to diepoxybutane, further metabolism is represented by hydration and GSH
  conjugation of epoxybutene. Profiles of butadiene and epoxybutene uptake data
  (220- 8,800 mg/m3) in mice and rats, and single time point concentrations of
  butadiene following exposures of mice and rats to 15.5-2,750 mg/m3 were
  predicted correctly, as was the GSH depletion in mice and rats following buta-
  diene exposures of 100-4,400 mg/m3. The model has not been evaluated against
  data for inhalation exposures of humans, and it does not simulate other meta-
  bolites (such as diepoxybutane, the diols and the GH conjugation products.
      The model reported by Brochot et al. (2007, cited in ATSDR 200940)
  simulated absorption and disposition of butadiene and the disposition of
  epoxybutene and diepoxybutane in the blood, fat, and lumped compartments for
  richly- and poorly-perfused tissues in humans. Also the disposition and clearance
  of 3-butene-1,2-diol (butenediol) and epoxybutanediol was modeled for the
  blood and the richly and poorly perfused tissues. All of the metabolic steps were
  described as first-order processes; the metabolic rate constants and physiological
  parameters were optimized against 133 datasets from individual subjects in-
  haling 4.4 mg/m3 butadiene for 20 minutes. The model was intended and thus
  calibrated for low exposures of humans. Extrapolation to higher doses would
  require modification of the metabolic expressions to account for saturation of the
  various metabolic pathways.
      Péry and Bois (200942) developed a (male human) model with 23 compart-
  ments, including arterial and venous blood, lungs, liver, kidney, fat, heart, brain,
  bone marrow, breast, adrenals, thyroid, gonads, pancreas, spleen, stomach, and
  gut. The model simulated absorption and disposition of butadiene and the
  disposition of epoxybutene, and was optimized against human inhalation data of
  butadiene in Japan, with an average environmental concentration of 0,25 µg/m3
  (background in unpolluted areas was 0.06 µg/m3, 0.8 µg/m3 and higher was only
  found in the vicinity of industrial activities).
      Beaudouin et al. (201043) reported a human model to address tissue
  dosimetry over the human lifespan. It had a compartmentalization similar to the
  model of Péry and Bois (200942) described above, extended with compartments
6 1,3-Butadiene
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<pre>    evolving during pregnancy (i.e., placenta and a foetal submodel). The model was
    only evaluated by comparing the predicted butadiene concentrations in exhaled
    air with human experimental data on brief and low level laboratory inhalation
    exposures ( 4.4 mg/m3 for 20 minutes) of volunteers to butadiene and found to
    predict these concentrations quite well. The authors modelled occupational
    exposure by simulating an exposure to 22 mg/m3 for 9 h per day, 5 days per
    week, which resulted in venous blood levels of 0.13-0.28 mM at the beginning
    (slowly increasing during the week) and 6 mM at the end of the simulated
    working day (equalling 7-15 and 325 mg/L, respectively).
2.7 Mechanistic and other relevant data
    The carcinogenicity of butadiene is mediated by its metabolic intermediates,
    since butadiene-induced mutagenicity requires metabolic activation: the DNA-
    reactive epoxides formed during biotransformation of butadiene are direct-acting
    mutagens.
    Biomarkers
    Biomarkers of exposure to butadiene (measurable internal indicators of change at
    the molecular or cellular level that can signal key events between exposure and
    adverse health effects) include water-soluble metabolites of butadiene in urine
    (Hurst 20076, Swenberg et al. 200744). Studies have quantified the presence of
    butadiene-derived metabolites in butadiene-exposed humans. Two urinary
    metabolites have been identified, both mercapturic acids derived from the GSH
    conjugates of electrophilic butadiene metabolites: DHBMA (1,2-dihydroxybutyl
    mercapturic acid; also referred to as DHB, M1, and MI) and MHBMA
    (monohydroxy-3-butenyl mercapturic acid; also referred to as M2 and MII) – see
    Figure 1. In urine of rats and mice two isomeric forms of MHBMA have been
    quantified7. The relative proportions of the metabolites DHBMA and MHBMA
    depend on the species. Since DHBMA shows relatively high background levels,
    this metabolite appears to be a less specific biomarker for butadiene exposure
    than MHBMA, which has relatively low background levels. However, both
    metabolites appeared to be elevated in butadiene exposed humans compared with
    unexposed controls2.
        Besides the urinary biomarkers, there is interest in developing biomarkers
    that are (more) correlated with carcinogenic effects of butadiene, such as
    butadiene-metabolite-DNA adducts. Even though not directly related to
    mutagenic action, covalent adducts of butadiene metabolites with haemoglobin
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<pre>  (Hb) protein may serve as surrogates for DNA adducts and can integrate
  exposure to reactive nucleophilic metabolites over periods up to the lifetime of
  the red cell (120 days in humans)2,6. The metabolite epoxybutene reacts with Hb
  to form N-(2-hydroxy-3-butenyl)valine (MHbVal) adducts, and epoxybutanediol
  and diepoxybutane form N-(2,3,4-trihydroxybutyl)valine (THbVal) adducts2.
  Also the metabolite 3-butene-1,2-diol forms Hb adducts in rats in vivo
  (Barshteyn & Elfarra 200945). At equivalent exposures to butadiene, blood levels
  of the Hb adducts MHbVal and the cyclic adduct N,N-(2,3-dihydroxy-1,4-
  butadiyl)valine (PyrVal) were higher in mice than in rats whereas the level of the
  major adduct, THbVal, was similar in these species. All of these adducts have
  been measured in butadiene-exposed rats and mice at concentrations as low as 6
  mg/m3 (IARC 20082, Swenberg et al. 200744); PyrVal has been demonstrated in
  mice and rats exposed to butadiene at levels of 0.2 and 1.1 mg/m3, respectively
  (Georgieva et al. 201046). Both MHbVal and THbVal have been found in exposed
  workers at occupational exposure levels as low as 0.09 mg/m3. When sampling
  was performed on a limited number of days, correlations between concentrations
  of adducts in blood and butadiene air concentrations were poor, whereas good
  correlations were observed (1) when very frequent air monitoring was
  conducted, and (2) in case of continuous monitoring of an increase in adduct
  concentration over a short period of time and the cumulative exposure during this
  time. The biomarker PyrVal, specific for diepoxybutane, is not available yet in
  humans2,6. Urine metabolite excretion patterns in both sexes revealed GSH
  conjugation to be a minor detoxicification pathway in humans.
       Filser et al. (200747) have measured directly the metabolites epoxybutene,
  diepoxybutane and epoxybutanediol (partial hydrolysis of diepoxybutane), and
  butenediol (hydrolysis product of epoxybutene) in blood from mice and rats. All
  metabolites increased with increasing exposure concentrations; diepoxybutane
  was only found in blood of mice. Butenediol and epoxybutanediol were
  quantitatively predominant in both species. At higher butadiene concentrations
  epoxybutanediol blood concentrations decreased again, which, according to the
  authors, can be explained by a competitive inhibition of the epoxybutanediol-
  producing CYP by butadiene in both species. In mice, epoxybutene blood
  concentrations increased almost linearly with the butadiene exposure concen-
  trations up to 2,210 mg/m3 butadiene. In blood of rats, the increase of epoxy-
  butene deviates from linearity at much lower butadiene concentrations. The
  authors stated that a species-specific saturability of CYP-mediated butadiene
  metabolism may contribute to this observed flattening of the epoxybutene curve.
       In 2011 Swenberg et al.48 reviewed the biomarkers of butadiene exposure.
  They state that the three butadiene epoxides (1,2-epoxy-3-butene, 1,2:3,4-
8 1,3-Butadiene
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<pre>diepoxybutane, and 1,2-epoxy-3,4-butanediol) vary up to 200-fold in their
mutagenic potency, with 1,2:3,4-diepoxybutane being the most mutagenic
metabolite. Mice appeared to form approximately 200 times and 50 times more
1,2:3,4-diepoxybutane than humans and rats, respectively, at exposures of 0.2 –
3.3 mg butadiene per m3.
DNA adducts
Many adducts with epoxybutene, epoxybutanediol and diepoxybutane have been
identified in reactions of these epoxides with nucleosides and DNA in vitro (see
Annex H). Many of these adducts can also block replication by many
polymerases or can cause misincorporation of proper nucleotides. DNA adducts
have been identified in humans exposed to butadiene and in animals exposed to
butadiene and its metabolites. The most abundant DNA adduct measured in
butadiene-exposed rats and mice is N7-trihydroxybutylguanine, which is derived
from either epoxybutanediol or diepoxybutane. N7-guanine adducts can lead to
apurinic sites. Epoxide metabolites of butadiene can also react at base-pairing
sites to form adducts at N3-cytosine, N1-adenine, N6-adenine, N1-guanine and
N2-guanine. The level of DNA adduct N1-(2,3,4-trihydroxybutyl)adenine was
determined in workers from a butadiene monomer production plant in the Czech
Republic. The level of this adduct was significantly increased in exposed
workers compared to control workers. Exposure was not significantly correlated
with DNA single-strand breaks or micronucleus formation (IARC 20082, Hurst
20076, Goggin et al. 200949).
    In a study by Fernandes et al. (200650) the phosphoramidites and subsequent
oligodeoxynucleotides containing N3-2’-deoxyuridine adducts (formed from
diepoxybutane reacted cytosine followed by spontaneous deamination) have
been constructed and characterized. The results indicate that the N3-2’-
deoxyuridine adducts are highly mutagenic lesions that may contribute to
butadiene-mediated carcinogenesis. Thus, the authors have established the
mutagenic effect of the butadiene N3-dU adducts. These are stable adducts that
are blocking to replicative and repair polymerases and mutagenic in mammalian
cells. These data thus suggest the importance of the butadiene N3-dU adducts as
crucial lesions contributing to butadiene carcinogenesis.
    Several authors have reported the formation of DNA-protein adducts by
cross-linking through 1,2:3,4-diepoxybutane (Jelitto et al. 198951; Costa et al.
199752; Loeber et al. 200653; Michaelson-Richie et al. 201054). Potentially such
helix-distorting DNA-protein cross-links may interfere with critical cellular
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<pre>  processes like replication and transcription, ultimately triggering apoptosis or
  genotoxicity.
       The study of Antsypovich et al. (200755) indicates that diepoxybutane-
  induced alkylation of N6-adenine in DNA is unlikely to lead to DNA-DNA
  cross-linking but instead can result in the formation of exocyclic deoxyadenosine
  adducts.
       Loecken and Guengerich (200856) and Loecken et al. (200957) reported
  diepoxybutane-mediated cross-linking between DNA and the enzyme
  glyceraldehyde 3-phosphate dehydrogenase and histones H2b and H3 in
  homogenates of human liver nuclear proteins. These cross-links did, however,
  not induce enhanced mutagenesis in recombinant E. coli systems.
       According to Swenberg et al. (201158) no gender differences have been
  reported for globin adducts or N7 guanine adducts, but female rats and mice had
  2-3 fold higher hprt* mutations and DNA-DNA crosslinks, suggesting a gender
  difference in DNA repair.
  Other data
  According to Swenberg et al. (200744), the findings of the research group at UAB
  suggest that lymphoid neoplasms are more strongly associated with cumulative
  butadiene exposure, whereas myeloid neoplasms show a stronger association
  with peak exposures.
       The International Life Sciences Institute has developed a human relevance
  framework that can be used to assess the plausibility that a mode of action which
  is described for animal models is also valid for humans. The mode of action is
  described as a sequence of key events and processes that result in an adverse
  outcome. A key event is a measurable precursor step that is in itself a necessary
  element of the mode of action or is a bioindicator for such an element. A number
  of key events have been identified whereby DNA-reactive chemicals can pro-
  duce tumours. These include DNA adducts in target tissues, gene mutations and/
  or chromosomal alterations in target tissues and enhanced cell proliferation in
  target tissues. This type of data integration approach to quantitative cancer risk
  assessment can be applied to butadiene, for example, using data on biomarkers in
  exposed Czech workers (Albertini et al. 200359). Using this study, Preston
  (200760) assessed an extensive range of biomarkers of exposure and response,
  including polymorphisms in metabolizing enzymes, urinary concentrations of
  several metabolites of butadiene, Hb adducts, mutations at the hprt locus in T-
  hprt: hypoxanthine guanine phosphoribosyltransferase.
0 1,3-Butadiene
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<pre>lymphocytes, chromosome aberrations (CAs) by fluorescent in situ hybridization
and conventional staining procedures, and sister chromatid exchanges (SCEs).
For the human relevance framework it is necessary to establish key events for a
mode of action in rodents for the induction of tumours by butadiene. There is
clearly a species difference in sensitivity to tumour induction (mice being much
more sensitive than rats); requirement for the identification of a key event is that
it can account for this difference. For butadiene, the weight of evidence from
rodents supports a mode of action of DNA-reactivity and subsequent geno-
toxicity, To evaluate the plausibility of this mode of action in humans, Preston
(200760) considered some key events in human. In general the metabolism in
human liver samples was more similar to that observed in rats than in mice.
Secondly, it was shown that DNA adducts can be measured in human lympho-
cytes following butadiene exposure in an occupational setting. Based on these
observations, the author concluded that the key events in the mode of action are
plausible in humans. There is a large variation in humans for the metabolism of
butadiene but overall the kinetics are more similar to those of rats than to those of
mice. There appears to be no unequivocal evidence for the induction of gene
mutations or CAs in butadiene-exposed humans. However, this lack of response
does not signify a threshold response for tumours, but rather indicates some lack
of sensitivity of such bioindicator assays at relatively low levels of exposure.
Genotoxicity - in vitro and animal data
In the previous DECOS report (19901) it was concluded that the mutagenicity of
butadiene depends mainly on the mutagenic potential of its reactive metabolites.
The mutagenic potential of epoxybutene and diepoxybutane, its most reactive
metabolites, has been proven in several test organisms in vitro. The primary
metabolite epoxybutene was mutagenic in Salmonella typhimurium and
Klebsiella pneumoniae. The secondary epoxide metabolite diepoxybutane was
mutagenic in Klebsiella pneumoniae, Saccharomyces cerevisiae, Drosophila
melanogaster, and induced SCEs in CHO cells.
     In the IARC monograph on butadiene (20082) a comprehensive review of the
genotoxicity of butadiene was reported.
     Butadiene is indirectly toxic to genetic material, as a result of action of its
oxidative metabolites, resulting in a variety of genotoxic effects following
butadiene exposure. Genotoxic effects beyond DNA alkylation involved cyto-
genetic effects including induction of micronuclei in developing erythrocytes and
SCEs in cytogenetic studies of bone marrow cells from mice (not rats) exposed
to butadiene, together with lengthening of average generation time and a
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<pre>  significant depression in the mitotic index. In peripheral blood the proportion of
  polychromatic erythrocytes and micronucleated normochromatic erythrocytes
  had increased. Butadiene was mutagenic in vivo at the hprt locus of splenic T
  cells from mice and weakly mutagenic in rats2,6. A greater hprt mutation
  efficiency was found in rats exposed to 137 mg/m3 or mice exposed to 6.6 mg/m3
  (LOAELs*) compared with exposure of either species to 1,380 or 2,762 mg/m3.
  This may be explained by competition between butadiene and butenediol or
  epoxybutene for CYP oxidation, limiting the secondary oxidation reaction. Thus,
  high-dose studies of butadiene in animals (≥ 1,380 mg/m3) may not adequately
  reveal the full carcinogenic potential of this compound at lower levels of
  exposure2,61.
      The relative genotoxic potency of the butadiene epoxide metabolites
  decreases in the order diepoxybutane > epoxybutene > epoxybutanediol, based
  on effects observed in mice, rats and in human cells. Diepoxybutane has been
  found by means of in vitro studies to be formed at higher levels in mice than in
  rats, which may contribute to the greater susceptibility to tumour formation of
  mouse over rat during chronic butadiene exposure2,6. An overview of results of
  animal genotoxicity tests for in vivo exposure to butadiene or its metabolites is
  shown in Table 3. No in vivo data were available for epoxybutanediol.
      Walker et al. (200762) tested the hypothesis that the hydrolysis
  (detoxification) pathway of butadiene through butenediol is a major contributor
  to mutagenicity at high-level butadiene exposures in the mouse and the rat. To
  determine the relative contribution of butenediol to butadiene-induced
  mutagenicity in rodents, mice and rats were exposed by inhalation directly to
  butenediol at exposure concentrations that produce plasma levels of butenediol
  equivalent to those found after exposure of mice to selected levels of the parent
  compound. Measurements of plasma levels of butenediol showed that exposures
  of mice and rats to 40 mg/m3 butenediol were equivalent to those produced by
  440 mg/m3 butadiene exposures. Measurements of hprt mutant frequencies (via
  T-cell cloning assay) showed that repeated exposures to 40 and 80 mg/m3
  butenediol were significantly mutagenic in mice and rats; mutagenic potency
  was similar between these two concentrations. The resulting data indicated that
  butenediol-derived metabolites (especially 1,2-dihydroxy-3,4-epoxybutane) are
  responsible for nearly all of the mutagenic response in the rat and for a
  substantial portion of the mutagenic response in the mouse following high-level
  (≥ 440 mg/m3) butadiene exposures.
  LOAEL: lowest observed adverse effect level.
2 1,3-Butadiene
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<pre>    Correlations between the efficiency for formation of adducts with the
induction of hprt mutants in butadiene-exposed mice showed poor correlations
between epoxybutene-induced adducts (hydroxybutenyl adducts at N7 of
guanine, epoxybutene-GUA) and mutagenic effects, suggesting that epoxybutene
is not the primary source of butadiene-induced mutations in vivo in the mouse. In
contrast, there were highly positive correlations between the formation of
trihydroxybutyl adducts at N7 of guanine (THB-GUA) as a biomarker of
butadiene exposure, and hprt mutation induction, as a biomarker of butadiene-
induced effect. THB-GUA adducts presumably arise largely from butenediol,
and to a lesser degree from diepoxybutane, and point to the relative importance
of these metabolites in butadiene-induced mutagenesis in the mouse62.
    DNA sequencing revealed that about half of the mutations induced in mice in
vivo by butadiene, epoxybutene and diepoxybutane were frameshift mutations,
while the remaining butadiene-, epoxybutene- and diepoxybutane-induced
mutations were transition and transversion mutations at both AT and GC base
pairs. At the hprt locus in human cells, epoxybutene was genotoxic mainly
through point mutations, while diepoxybutane caused point mutations and partial
deletions2,6.
    Swenberg et al. (200744) reported that rats exposed to diepoxybutane
developed CAs and micronuclei, although butadiene is not clastogenic in rats.
Diepoxybutane is a bifunctional alkylating agent that exhibits both mutagenic
and cytotoxic activity, presumably as a result of its ability to form bifunctional
DNA adducts.
    Kligerman and Hu (200763) investigated SCEs and CAs in vitro in lym-
phocytes from humans, rats and mice after exposure to epoxybutene or diepoxy-
butane at the G0 stage of the cell cycle. Epoxybutene induced no increases in
SCEs or CAs in the cells from the three species. Diepoxybutane was a potent
SCE- and CA-inducer, with the results being similar in each rodent species. The
response for SCEs seen in the human cells was more complex, with genetic
polymorphism for GST possibly modulating the response.
Genotoxicity - human data
In the IARC (20082) monograph a number of genotoxicity tests in humans was
reported, using workers from several butadiene monomer or SBR production
facilities. CAs were significantly increased in 1 out of 6 studies, SCEs in 1 out of
5 studies, and hprt mutations in 4 out of 6 studies. Several studies had separated
the smokers and non-smokers. Only the study of Lovreglio and coworkers
(20064) found a statistically significant increase in the mean SCEs in smokers
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<pre>  Table 3 Results of animal genotoxicity tests for in vivo exposure to 1,3-butadiene or a metabolite
  (derived from IARC 20082).
  Test type                           1,3-Butadiene          Epoxybutene          Diepoxybutane
                                      Result     No of       Result    No of      Result    No of
                                                 studies               studies              studies
  DNA damage, single strand /         +            7         +         1          (+)       1
  double strand breaks, cross-links   –            5
  Gene mutation                       +          15          +         5          +         3
                                      (+)          5         (+)       2          (+)       1
                                                             –         6          –         1
  Comet                                                      +         1          +         1
                                                                                  (+)       1
                                                                                  –         1
  Sister chromatid exchange           +            2
                                      –            1
  Micronucleus                        +          12          +         1
                                      –            2 (rat) –           1
  Chromosome aberration               +            3
  Aneuploidy                          –            1
  Dominant lethal                     +            6
                                      –            2
  Heritable translocation             +            2
  DNA-binding                         +            7
  (N7-guanine, N6-adenine)            –            2
  Sperm morphology                    +            1
  + = positive; – = negative; (+) = weakly positive.
  (6.6 ± 1.2) compared with non-smokers (5.5 ± 0.8; p = 0.001). Exposure to
  butadiene was higher in smokers (mean 7.7) than in non-smokers (mean 2.0;
  p = 0.3). The genotoxic biomarkers (SCEs, CAs, and cells with high frequency of
  SCEs) could not distinguish between the exposed (6.4 ± 14.0 µg/m3) and non-
  exposed group (0.8 ± 1.1 µg/m3) in this study.
       Albertini et al. (200164) found no evidence that low-intensity exposure to
  butadiene was associated with structural changes in chromosomes or gene
  mutations in lymphocytes (as possible indicators for butadiene-induced
  lymphohaematopoietic cancer) among butadiene monomer and synthetic rubber
  workers in the Czech Republic. The relatively small cohort consisted of 83 male
  workers: 24 butadiene monomer production workers with mean butadiene
  exposure of 0.64 mg/m3, 34 polymerization workers with mean butadiene
  exposure of 1.76 mg/m3 and 25 controls with mean butadiene exposure of 0.3
  mg/m3. Their duration of employment was on average 15-18 years.
4 1,3-Butadiene
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<pre>The mutation frequency (MF) at the hprt locus as an intermediate biomarker of
butadiene carcinogenicity was investigated for its relation to mortality and
cancer incidence by Liu et al. (200865). A population of butadiene-exposed
workers and non-exposed control subjects working at the alkenes plant at a
petrochemical products company in Nanjing, China, was analyzed to determine
the MF of the hprt gene in lymphocytes. Exposure of the workers was to an
average butadiene concentration of 21 ± 34 mg/m3. All control group locations
were below 0.44 mg/m3 (detection limit). There was a, not statistically signifi-
cant, increase of 43% in hprt gene MFs in the exposed workers (18 ± 9x10-6) as
compared to controls (13 ± 7x10-6) by using the T-cell cloning assay. The
observed increase in the total number of hprt clones with deletions in exposed
workers (27.4%) was statistically significantly increased compared to control
workers (12.5%). The increase is primarily the result of an increase in multiple
exon deletions (2-8) with 56% and 23% in exposed and controls, respectively,
including both continuous deletions (37% and 17% in exposed and controls,
respectively) and discontinuous deletions (with 19% and 6% in exposed and
controls, respectively).
    Wickliffe et al. (200966) investigated the frequencies of hprt mutant
lymphocytes in workers at a butadiene polymer plant in Texas (USA). Hprt MFs
were not significantly associated with current exposures nor with age. They
were, however, significantly associated with the number of years working in the
butadiene industry at this plant. According to the authors this mutagenic effect
might be the result of chronic and/or past high-level exposures.
DNA repair capacity
To investigate the role of DNA repair in modulating butadiene-induced geno-
toxicity/carcinogenicity, Vodicka et al. (200667) investigated single strand breaks
and endonuclease III-sensitive sites in DNA along with γ-irradiation-specific
DNA-repair activity in hepatocytes and frequencies of micronuclei in poly-
chromatic bone marrow erythrocytes of male NMRI mice (6/experimental point)
during sub-acute inhalation exposure to butadiene (28 days, 500 mg/m3) and up
to 28 days after exposure. Concentrations of butadiene in blood (indicator of
internal exposure) were 0.08-0.10 mg/L during the exposure period. The
γ-irradiation-specific DNA repair activity gradually increased during exposure,
reaching a maximum on day 1 after the termination of exposure and then
returning to control levels. A significant correlation between γ-irradiation-
specific DNA repair activity and the concentration of butadiene in blood
supports a possible induction of DNA-repair activity by the exposure to
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<pre>  butadiene and formation of its metabolites. The initial increase in micronucleus
  frequency in the exposed mice continuously decreased from 20.4 (day 3) to 15
  (day 28) within the exposure period and subsequently from 12 to 4.6 in the
  period following termination of the butadiene exposure, while micronucleus
  frequencies in control animals were significantly lower (1.7-4.2 micronuclei per
  1,000 cells).
  Alterations in oncogenes and suppressor genes in tumours
  The mechanistic link between animal and human neoplasia induced by butadiene
  is supported by the identification in mice of genetic alterations in butadiene-
  induced tumours that are frequently involved in the development of a variety of
  human cancers. The K-ras, H-ras, p53, p16/p15 and b-catenin mutations detected
  in tumours in mice probably occurred as a result of the DNA reactivity and
  genotoxic effects of butadiene-derived epoxides. A consistent pattern of K-ras
  mutations (G→C transversions at codon 13) was observed in butadiene-induced
  cardiac haemangiosarcomas, neoplasms of the lung and forestomach and
  lymphomas2,68. Alterations in the p53 gene in mouse brain tumours were mostly
  G→A transition mutations. Inactivation of the tumour-suppressor genes p16 and
  p15 may also be important in the development of butadiene-induced lymphomas.
  Mammary gland adenocarcinomas induced by butadiene in mice had frequent
  mutations in the p53, H-ras and b-catenin genes.
      Together these observations point to a genotoxic mechanism that underlies
  the development of butadiene-induced cancers. Although genotoxicity data
  indicate that diepoxybutane is the most genotoxic of the butadiene epoxides, the
  relative contribution of these metabolic intermediates to the mutagenicity and
  carcino-genicity of butadiene is not known2,6.
  Polymorphism
  Metabolic activation and inactivation rates of butadiene in humans exhibit a high
  degree of variability and appear to span the range of activation rates between
  mice and rats when evaluated with in vitro systems measuring enzyme kinetics
  (greater than ten-fold). Other in vitro studies and in vivo molecular
  epidemiological studies indicate the range of increased sensitivity due to human
  genetic polymorphisms is approximately two- to four-fold (IARC 20082, ATSDR
  200940).
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<pre>     The basis of species differences between rats and mice may be related to the
greater production of toxic intermediates, specifically diepoxybutane, and a
lower capacity for detoxification of these intermediates in mice3.
     Several epidemiological studies (references in IARC 20082 and Wickliffe et
al. 200769) examining human sensitivity to butadiene following occupational
exposures have found an association between somatic mutations and exposures.
They also found an association between specific polymorphisms in biotrans-
formation and DNA repair genes and increased genetic damage. These studies
addressed the role of polymorphisms in biotransformation genes such as the
GSTs GSTT1 and GSTM1, and the gene EPHX1, coding for the principal
detoxifying enzyme mEH, and in DNA repair genes involved in nucleotide
excision repair (NER) and base excision repair (BER). Polymorphisms in
biotransformation and DNA repair proteins may modulate genetic suscep-
tibility69. Vacek et al. (201070) studied production and accumulation of the
metabolite 1,2:3,4-diepoxybutane in exposed and non-exposed males and
females of the Czech cohort of workers in the SBR industry (described by
Albertini et al. 200164) by measuring THbVal adducts, and found that exposed
men had significantly higher THbVal concentrations than non-exposed men, but
exposed and non-exposed women did not differ significantly. THbVal con-
centrations were significantly correlated with mean 8-h TWA exposures to
butadiene for both males and females. However, the rate of increase with
increasing butadiene exposure was significantly lower for females, and the size
of the differences increased with exposure. The authors concluded that
apparently females absorb or metabolize less butadiene than males per unit
exposure.
     Tan et al. (201071) studied micronucleus frequencies in peripheral
lymphocytes of butadiene-exposed workers in a polybutadiene latex production
plant in Ningbo, China, and reported that (1) the frequency in workers was
significantly higher than in controls, (2) male workers had lower frequencies
than female workers, and (3) workers who carried the genotypes of GSTM1 (+),
CYP2E1 (c1c2/c2c2) and the mEH intermediate group had significantly higher
frequencies than those carrying the genotypes of GSTM1 (-), CYP2E1 (c1c1) or
the mEH high group. The same group studied the same workers with respect to
polymorphism of NER (Wang et al. 201072) using micronucleus frequencies in
peripheral lymphocytes, and reported multiple NER polymorphisms (an ADPRT
and several XRCC1 genotypes) and a XRCC1 haplotype to be associated with
differential levels of frequencies.
     To investigate the role of genetic polymorphisms in mEH or NER in the
mutagenicity of butadiene, experiments were conducted in which mice lacking
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<pre>  mEH (Ephx1-null) or NER activity (Xpc-null) were exposed to butadiene by
  inhalation or to epoxybutene by intraperitoneal injection. Xpc-null mice were
  significantly more sensitive to epoxybutene exposure, exhibiting an average
  2.8-fold increase in hprt mutant frequency relative to those of exposed wild-type
  mice69,73. This study with the Ephx1-null mice supports the hypothesis that
  humans with a diminished mEH activity are more susceptible to relatively high
  levels of butadiene exposure, whereas the study with the Xpc-null mice provides
  initial insights into the recognition and repair pathways involved in maintaining
  genomic integrity in vivo.
  Other data
  Diepoxybutane, the most potent metabolite of butadiene, is a bifunctional
  alkylating agent that exhibits both inter-strand and intra-strand DNA cross-
  linking ability, and DNA-protein cross-linking ability. Diepoxybutane also
  generates reactive oxygen species that can damage DNA or produce H2O2.
  Apoptosis in reponse to diepoxybutane exposure has also been observed in Big
  Blue Rat cultured cells, mouse L929 cultured cells, as well as in human CD34+
  bone marrow cells.
       Fred et al. (200874) studied whether the large differences in outcome of
  cancer tests with butadiene could be predicted quantitatively on the basis of the
  concentration over time in blood (area under the curve: AUC) of the epoxide
  metabolites, their mutagenic potency, and a multiplicative cancer risk model
  which has earlier been used for ionizing radiation. Published data on Hb adduct
  levels from inhalation experiments with butadiene were used for the estimation
  of the AUC of the epoxide metabolites in the cancer tests. The estimated AUC of
  the epoxides were then weighed together to a total genotoxic dose, by using the
  relative genotoxic potency of the respective epoxide interferred from in vitro hprt
  mutation assays using epoxybutene as standard. The tumour incidences predicted
  with the risk model on the basis of the total genotoxic dose correlated well with
  the earlier observed tumour incidences in the cancer tests. The total genotoxic
  dose that leads to a doubling of the tumour incidences was estimated to be the
  same for rat and mouse, 9 to 10 mmol/L.h epoxybutene-equivalents.
  Conclusion
  Butadiene, taken up by inhalation, is metabolized into DNA-reactive epoxides
  (stereoisomers of epoxybutene, epoxybutanediol and diepoxybutane). Both in
  vitro and in vivo animal studies have demonstrated the presence of butadiene
8 1,3-Butadiene
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<pre>    metabolites after exposure. Metabolite-specific Hb adducts have been found in
    workers. Both animal and in vitro studies indicate that (combinations of)
    metabolites from butadiene are clastogenic and may bind to DNA. In human
    studies, no explicit butadiene-induced genotoxic effects have been observed:
    results on cytogenetic endpoints and on hprt mutations in workers exposed to
    butadiene are not conclusive. This may be due to interindividual differences in
    metabolic activity and/or in DNA-repair capacities. Although the genotoxicity
    data indicate that diepoxybutane is the most genotoxic epoxide formed from
    butadiene, the relative contribution of all epoxide metabolites to the mutagenicity
    and carcinogenicity of butadiene is not known. The enzymes involved in the
    formation and further biotransformation of epoxides are polymorphic in human
    populations, but the extent to which the variabilities of these enzymes modulate
    the carcinogenicity of butadiene is not known (IARC 20082).
2.8 Toxicity profile
    In Hurst (20076), the DECOS report of 19901, and the evaluation of the Agency
    for Toxic Substances and Disease Registry (ATSDR, 200940) overviews of the
    toxicity of butadiene were presented, which are summarized below.
    Human data
    Irritation of eyes, nasal passages, throat, and lungs was noted in workers exposed
    to butadiene during early manufacture of rubber (Wilson 1944, in Hurst, 20076).
         De Jong et al. 1983 (cited in Decos 19901) reported the following short-term
    effects of different butadiene at concentrations in air to industrial workers
    (exposure period is not mentioned):
    • 2,200 mg/m3: no effects
    • 4,400-8,800 mg/m3: slight irritation of the eyes and bronchi
    • Volunteers exposed for 8 hours to a concentration of 17,600 mg/m3 butadiene
         showed no other effects than irritation of the eyes and bronchi.
    Animal data
    Lethality* as a consequence of acute exposure in animals have been reported to
    vary between 3.2 and 5.5 g butadiene per kg bw (LD50s for orally exposed mice
    LC50/LD50: lethal concentration / lethal dose at which 50% of the exposed animals die within 24 h.
    General information                                                                                59
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<pre>  and rats), and between 270 and 550 g butadiene per m3 (LC50s for inhalatory
  exposed mice, rats and rabbits).
      The clinical signs of intoxication by butadiene following inhalation exposure
  included hyperventilation, twitching, excitation, anaesthesia and narcosis.
      Irritation of the mucous membranes resulting in conjunctivitis, nasal and
  bronchial irritation leading to respiratory obstruction were the outcome of
  exposure of mice and rats, for unspecified times, to atmospheres containing
  198,000-308,000 mg/m3 butadiene.
      Ophthalmoscopic examination of the rabbit eye revealed no signs of injury
  during or following exposure to atmospheres containing up to 14,740 mg/m3
  butadiene for 7.5 h/day, 6 days/week during 8 months. A similar result was
  obtained in a limited study performed concurrently on dogs (Shell 1986, in
  DECOS1).
      Early studies noted that inhalation of high concentrations of butadiene was
  anaesthetic in animals, as a concentration of 550,000 mg/m3 was lethal to rabbits
  within 30 minutes. A 50% mortality was observed in rats and mice after
  exposure to 269,000 mg/m3 and 285,000 mg/m3 after 4- and 2-h exposures,
  respectively. These acute exposures resulted in irritation of eye, respiratory tract
  and skin, as well as in effects on the central nervous system (reviewed in Hurst
  20076).
      Himmelstein et al. 1997 (in Hurst 20076) reviewed the toxic effects (other
  than cancer) in animals. Higher inhaled concentrations butadiene were related to
  biochemical alterations, including glutathione depletion in liver, lung and heart.
  This depletion was noted to be more complete and at lower inhaled concentra-
  tions in mice than in rats, and was correlated with increased concentrations of the
  metabolites butadiene monoepoxide and butadiene diepoxide.
      Reproductive and developmental studies of the US National Toxicology
  Program (NTP) showed mice being more sensitive to butadiene inhalation than
  rats. Exposure of rats to 2,200 mg/m3 resulted in decreased weight gain during
  pregnancy, but no fetal developmental toxicity was observed. In Swiss CD-1
  mice exposure to 440 and 2,200 mg/m3 resulted in anomalies including extra ribs
  and decreased ossification of sternebrae in fetuses. Additional NTP studies
  showed abnormal sperm head morphology in male mice exposed to concentra-
  tions of 2,200-11,000 mg butadiene/m3 and an increased ratio of dead to total
  implanted fetuses in dominant lethal assays in female mice. These observations
  are indicative for butadiene, or its metabolites, being mutagenic to germ cells in
  mice at high concentrations. Testicular atrophy was observed in B6C3F1 mice
  exposed to 1,375 mg/m3 butadiene, and atrophy of ovaries was observed at 13.8
0 1,3-Butadiene
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<pre>mg/m3 (LOAEL; a NOAEL* could not be derived)37. ATSDR (200940)
characterized the effect at this LOAEL to be a serious reproductive effect.
    Fetal toxicity was observed following the mating of untreated female mice
with males exposed to 27.5 mg/m3 butadiene for 10 weeks (6 h/day, 5 days/
week). Observed effects included an increase in late fetal death, exencephaly and
skull abnormalities. Early fetal death occurred in untreated female mice mated to
males exposed to 144 mg/m3 for 4 weeks, 6 h/day, 5 days/week (ATSDR 200940).
    When exposed to concentrations up to 17,680 mg/m3 butadiene during days
6-15 of gestation (GD 6-15), Sprague-Dawley rats showed signs of dose-related
maternal and fetal toxicity. Depressed body weight gain amongst dams was
observed at ≥ 442 mg/m3, and fetal growth was significantly decreased in the
17,680 mg/m3 group. A significantly increased incidence of skeletal abnormali-
ties (wavy ribs, irregular rib ossification) occured in the 2,210 mg/m3 group and
major abnormalities (defects of the skull, spine, sternum, long bones and ribs)
were observed in the 17,680 mg/m3 group. In mice, a 5-23% decrease in fetal
body weight gain in males was observed after exposure of dams during GD 6-15
to 88-2,210 mg/m3 butadiene, and increased incidences of extra ribs and reduced
ossification of sternebrae were found in fetuses from groups exposed to 442 mg/
m3 and 2,210 mg/m3, respectively (ATSDR 200940).
    In butadiene-exposed mice, also toxicity of the haematopoetic system was
observed. In two strains of male mice exposed to 2,750 mg/m3 for 6-24 weeks,
macrocytic-megablastic anaemia was observed. In addition leukopenia and an
increase in the number of erythrocyte micronuclei were observed (IARC 199975,
Hurst 20076).
Conclusion
At the time that the industrial manufacture of butadiene was started (thus
occupational exposure to relatively high concentrations), irritation of eyes and
respiratory tract was noted in humans. Repeated dose toxicity resulted in
biochemical alterations and haematopoietic disturbance. At high concentrations
butadiene is lethal to animals. A LOAEL of 13.8 mg/m3 was derived from a
chronic study in mice, based on ovarian atrophy (LOAEL reproduction and
overall LOAEL); at this dose level also respiratory adenomas and carcinomas
were found in female mice. Developmental toxicity (late fetal death, exence-
phaly and skull abnormalities) was observed at 27.5 mg/m3 in mice (LOAEL).
NOAEL: no observed adverse effect level.
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<pre>2.9 Overall conclusion
    The Committee agrees with the conclusion of the Subcommittee on the
    Classification of carcinogenic substances (see Annex I) that butadiene is a
    stochastic genotoxic carcinogen, expressing its genotoxicity through its reactive
    metabolites (1,2-epoxy-3-butene, 1,2:3,4-diepoxybutane and 3,4-epoxy-1,2-
    butanediol), which are alkylating agents. This conclusion is in line with similar
    conclusions by others (IARC 20082, 20097; Kirman et al. 2010a10, 2010b11;
    Albertini et al. 201012).
        Butadiene expresses its carcinogenicity at lower exposures compared to the
    lowest exposure at which toxic effects other than carcinogenicity become
    manifest.
 2  1,3-Butadiene
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<pre> hapter 3
        Risk assessment
3.1     Health risk to humans and selection of the suitable study for risk
        estimation in the occupational situation
        Inhalation studies with animals exposed to butadiene showed increased tumour
        incidences in many tissue types.
            However, to estimate health-based occupational cancer risk values, the
        Committee prefers to use human data above animal data. In case of exposure to
        butadiene many human data are published. The data mainly concern mortality
        due to lymphatic and/or haematopoietic tumours; no distinctly increased
        incidence of mortality was found for tumours in other tissues in the few studies
        in which this was investigated.
            The human studies showed a dose-related association between butadiene
        exposure and tumour development2,19,21-25,27,30. Generally, these associations
        were still statistically significant when the data were corrected for age (leu-
        kaemia with cumulative exposure), peak exposure, and average intensity of
        exposure24.
            Eight epidemiological studies on leukaemia mortality among workers
        exposed to butadiene were of interest. The papers concern Delzell et al. (199618,
        200125), Cheng et al. (200724), Graff et al. (200522), Macaluso et al. (199627),
        Matanoski et al. (199719), Sielken et al. (200730) and Sielken and Valdez-Flores
        (201131).
        Risk assessment                                                                   63
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<pre>        Most of the studies found cumulative exposure to butadiene to fit best with
    the observed extra leukaemia deaths following occupational exposure to this
    substance. Only Sielken et al. (200730) and Sielken and Valdez-Flores (201131)
    used the cumulative number of butadiene peaks during the occupational expo-
    sure period as a co-variable to estimate the risks, which resulted in relatively low
    risks compared with the other studies. It is difficult to understand that the
    relationship between cumulative butadiene exposure, and risk of leukaemia
    found in the other studies, would only be the result of exposure to butadiene
    peaks, the more because Sielken and Valdez-Flores assigned to all butadiene
    peaks > 100 ppm (221 mg/m3) the same weight, without accounting for peak
    height or peak duration. Dominant influence of butadiene peaks is also question-
    able in view of the results of Graff et al. (200522), who found significant
    exposure-response relationships for cumulative (occupational) exposures to both
    < 100 ppm butadiene, and ≥ 100 ppm butadiene. Therefore the Committee
    decided not to use assumptions on peak exposure.
        Reviewing all studies, Cheng et al. (200724) provided the most extensive set
    of quantitative data, and was most transparent in the methods used regarding
    exposure data and exposure-response modelling, including corrections for co-
    exposure to STYR and DMDTC. In Figure 2 the data on relative risk and
    cumulative exposure (see Table 2) from this study are depicted. These exposure
    and response data were used to estimate health-based occupational cancer risk
    values.
3.2 Calculation of the health-based occupational cancer risk values
    According to the ‘Guideline for the calculation of carcinogenic risks’ of the
    Health Council of The Netherlands76, the Committee used a survival analysis,
    also called ‘life-table’ analysis, in estimating the cancer risk values. Survival
    analysis is a statistical methodology to describe mortality or survival rates
    (expressed as the number of deaths per 100,000 person-years) in populations
    during a specified time. By comparing mortality rates between an exposed
    population and a non-exposed population, the number of extra deaths that
    corresponds to a certain exposure level can be estimated. This ‘number of extra
    deaths’ serves as a point of departure to estimate cancer risk values.
 4  1,3-Butadiene
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<pre>Figure 2 Relative risk of leukaemia mortality following occupational exposure to 1,3-butadiene,
according to Cheng et al. (200724).
In case of leukemia and occupational butadiene exposure, the Committee used
the following principles and assumptions:
1 The Committee calculated leukaemia mortality of the general population on
    the basis of national data on leukaemia mortality in five-year age bands,
    obtained through Statistics Netherlands (Centraal Bureau voor de Statistiek).
    Mortality data for the years 2000 to 2010 were used, separated by age and
    sex. Rates for women and men were averaged, so that the calculations would
    describe the average risk for the population. To soften the transitions between
    age categories, the mortality data were ‘smoothed’. These ‘modelled’
    mortality data were employed in the Committee’s analysis.
2 For the occupational exposure to butadiene, it is assumed that exposure of the
    cohort starts at the age of 20, and lasts until the age of 60 years. Every year,
    the cohort reduces in size, through death as a result of the cause of death
    under study and other causes; the cohort is followed until it reaches the age of
    100 years76.
3 Assuming a given average annual exposure to butadiene, every year that a
    person in the cohort is exposed is another year contributing to his/her
    cumulative exposure. This approach employs cumulative exposure because
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<pre>      studies of workers exposed to high levels of butadiene always work with
      cumulative exposure; the formulae employed are also based on cumulative
      exposure. Using this cumulative exposure, which is recalculated for each
      year, and the assumed exposure-response relationship between exposure to
      butadiene and death from leukaemia, the number of extra deaths is calculated
      for each year that the cohort ages. Using this information, first the additional
      risk of death per year associated with exposure to butadiene can be
      calculated, and then the lifelong additional risk of death associated with
      exposure.
  Leukaemias included in the analysis are listed in the 10th International Code of
  Diseases of the WHO, categories C81-C96 (“malignant neoplasms, stated or
  presumed to be primary, of lymphoid, haematopoietic and related tissue;
  excluded: secondary and unspecified neoplasm of lymph nodes”; WHO 200377).
  In applying this approach the Committee extrapolates data on leukaemia as
  reported by Cheng et al. (200724) to include more forms of lymphohaema-
  topoietic cancers. The Committee is of the opinion that there is sufficient
  information indicating the risk of various lymphohaematopoietics cancers
  following butadiene exposure (see, e.g., IARC 20082). The diagnosis and
  classification of lymphatic and haematopoietic malignancies is very complex,
  and has undergone several changes in the course of time (as outlined in section
  2.4). Thus, limiting the risk evaluation to leukaemia only would certainly result
  in an underestimation of the risk of developing cancer following butadiene
  exposure. The exposure-response data published for myeloid (implicitly also
  covered in the exposure-response of leukemia) and lymphoid neoplasms are
  more limited than for leukaemia. The Committee noted that the exposure-
  response association as published in Cheng et al. (200724) is not noticeably
  different from the published association for leukaemia, albeit that the slope-
  factor is lower. Given these uncertainties, the Committee prefers to use the
  leukaemia data of Cheng c.s., and to extrapolate these to the malignancies listed
  in WHO’s ICD codes 81-96. The Committee is aware of the resulting possible
  slight overestimation of the risk, but prefers this rather than ending up with an
  underestimation by limiting the risk to leukaemia only.
  Results of the analysis
  First, using the data by Cheng et al. (200724; see Table 2), the Committee derived
  the model with the best fit regarding exposure-response relationships. Using the
  software programme SAS, and with PROC NLMIXED the following two
6 1,3-Butadiene
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<pre>  relationships with the best fits were obtained (RR = 1 means no difference in
  mortality when compared to the general population):
  • RR = 1 + 0.001159 x (cumulative exposure)                             (linear additive model)
  • RR = 1 + 0.005934 x (cumulative exposure)0.7626                       (exponential model)
  Of these two models the linear additive model has a slightly better fit*, and
  hence this model was chosen for the next step, the survival analysis.
       The survival analysis was performed using the software R (in Windows). For
  the derivation of health-based calculated occupational cancer risk values (HBC-
  OCRV), an additional risk of one extra cancer death due to occupational
  exposure per 250 (4 x 10-3) and 25,000 (4 x 10-5) is taken into account. The
  results are shown in Table 4.
  Table 4 Exposure-response modelling and survival analysis.
  Study                                        Cheng et al. 200724
  Model                                        RR = 1 + 0.001159 x (cum. exp.)
  Original unit                                butadiene ppm-years
  Mean exposure at risk 4x10-3                 4.7 ppm = 10 mg/m3
  Mean exposure at risk 4x10-5                 0.047 ppm = 0.1 mg/m3
  Health-based calculated occupational cancer risk values (HBC-OCRVs)
  The Committee calculates that the concentration of 1,3-butadiene in the air,
  which corresponds to an excess risk of cancer mortality of:
  • 4 per 1,000 (4x10-3) deaths in the general population, at 40 years of
       occupational exposure, equals to 10 mg 1,3-butadiene per m3 (5 ppm)
  • 4 per 100,000 (4x10-5) deaths in the general population, at 40 years of
       occupational exposure, equals to 0,1 mg 1,3-butadiene per m3 (5 ppm).
  The recommended values are expressed as 8-hour time-weighted average
  concentrations.
  Other (toxic) effects have been reported in experimental animals: the lowest
  overall LOAEL was 13.8 mg/m3, based on ovarian atrophy observed in mice in
  the two-years carcinogenicity/toxicity inhalation study of the US National
  Toxicology Program (NTP 199337, Table 5). The Committee performed a
  benchmark dose (BMD) analysis on the data of this study using the BMD
* The linear additive model has an AIC of 50.3, the exponential model has an AIC of 51.9. The AIC
  value (Akaike's Information Criterion; Akaike 197478, 198079) is -2L+2p, where L is the log-
  likelihood at the maximum likelihood estimates for the parameters, and p is the number of model
  parameters estimated. It is used to compare different types of models which use a similar fitting
  method, The model with the lowest AIC is presumed to be the better model.
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<pre>    Table 5 Inhalation study with B6C3Fl mice exposed to 1,3-butadiene, 6 h/day, 5 days/week during
    103 weeks (NTP 199337)
    Exposure (mg/m3)                        0        13.8       44.2    138       442      1381
    Animals with ovarian atrophya           4/49     19/49      32/48   42/50     43/50    69/79
    Percentage animals affected             8        39         67      84        86       87
    a   animals with ovarian atrophy / total number of animals.
    software of the US-EPA (US-EPA 201280). Taking into account the seriousness
    of the effect, the 10% extra risk level was taken as the point of departure. This
    analysis resulted in a BMDL (BMD at lower risk level with 95% confidence
    interval) of 1.0 mg/m3. To derive a health based occupational limit value for
    humans, two uncertainty factors of 3 were applied, one to correct for interspecies
    differences, and one to correct for intraspecies differences. Since the exposure of
    the experimental animals in the cited study was for 6 h/day, 5 days/week during
    103 weeks, additional uncertainty or uncertainty factors were not needed. This
    resulted in a human occupational limit value of 1.0/9 = 0.11 mg/m3. This value is
    practically equal to the 4 x 10-5 risk HBC-OCRV of 0.1 mg/m3 that the
    Committee derived above. Hence this HBC-OCRV is not expected to result in
    effects other than carcinogenicity.
3.3 Dermal uptake of 1,3-butadiene
    To decide whether a skin notation should be recommended to the substance, the
    Committee uses the ECETOC criteria for assigning a skin notation81.
        Butadiene is a gas with a boiling point of -4.4°C. As the vapour pressure at
    21°C is 240 kPa, the compound is not expected to give rise to skin exposure by
    direct contact. Therefore, the Committee indicates no skin notation for butadiene
    on the basis that exposure to gases requires a different protection regime.
3.4 Risk values derived by SCOEL
    The Committee noted that the European Scientific Committee on Occupational
    Exposure Limits (SCOEL) presented also data on extra cancer risks (SCOEL
    20078). At occupational exposure of 5 ppm (11 mg/m3) SCOEL estimated the
    extra risk of leukaemia mortality at -0.05-11.7 deaths between the age of 25-85
    years, per 1,000 males occupationally exposed during working life from 25-65
    years. The Committee, however, did not use these extra cancer risk data for
    several reasons, including (1) the availability of more recently published data, (2)
    lack of clarity on the criteria used by SCOEL to model the data (SCOEL used
 8  1,3-Butadiene
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<pre>    various models to calculate the upper and lower risk levels at the different
    exposure levels, without explanation), and (3) SCOEL’s use of out-of date
    mortality data of a local population, whereas national or European and up-to-date
    date are preferred.
3.5 Existing cancer risk values and occupational exposure limits
    Table 6 summarizes the risk values of a number of (inter)national organisations
    for dying from leukaemia following occupational exposure to butadiene.
    Table 6 Risk values of other organisations for dying from leukaemia following occupational
    exposure to 1,3-butadiene
    Organisationa        1,3-Butadiene concentration         Risk level   Reference
    France (ANSES), 0.08 mg/m3                               1 x 10-4     Health Canada 200081,
    201182               0.008 mg/m3                         1 x 10-5     BAuA 201080
                         0.0008 mg/m3                        1 x 10-6
    Germany (BAuA), 5 mg/m3 (2 ppm)                          4 x 10-3b    Graff et al. 200522,
    201083               0.5 mg/m3 (0.2 ppm)                 4 x 10-4 c   Cheng et al. 200724
    Canada (Health       7.8 mg/m3                           1 x 10-2 d   Delzell et al. 199618
    Canada), 200084
    a    ANSES, BAuA and Health Canada are (semi)governmental organisations responsible for
         independent scientific advice of their respective governments.
    b     “Akzeptanzrisiko”
    c    “Toleranzrisiko”
    d    Tumorigenic concentration for 1% of the occupationally exposed people (TC01)
    ANSES: Agence Nationale de Sécurité Sanitaire de l’Alimentation,
    de l’Environnement et du Travail, France.
    BAuA: Bundesanstalt für Arbeitsschutz und Arbeitsmedizin, Germany.
    Existing occupational exposure levels for butadiene, other than the ones
    summarized in Table 6, are presented in Table 7.
         Like the Committee, the organisations cited in Table 5 used mortality data
    from leukaemia of approximately 17,000 workers in the North-American
    butadiene industry as reported by a number of investigators (Delzell et al.
    199618, 200125, Graff et al. 200522, Cheng et al. 200724). The risk values derived
    are all in the same order of magnitude as the values derived above (Section 3.2)
    by the Committee. Differences between the various risk values can be attributed
    to (1) the epidemiological dataset used, (2) the types of leukaemia that are
    included, (3) the model applied to estimate an exposure-response relationship,
    (4) the life tables applied, and (5) the age to which mortality is analysed.
    Risk assessment                                                                             69
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<pre>  Table 7 Existing occupational exposure limits (OELs) for 1,3-butadiene.
  Country - organisation              OEL (mg/m3)                   Type of OEL Note
  The Netherlands                     46.2                          TWA         Car
  (Ministry of Social Affairs and
  Employment)
  Denmark                             22                            TWA         Car
  Norway                              2.2                           TWA         Car
  Sweden                              1                             TWA         Car
                                      10                            STEL
  Finland                             2.2                           TWA         Car
  United Kingdom                      22                            TWA         Car
  USA
  - ACGIH                             4.4 (TLV)                     TWA         Car
  - OSHA                              2.2 (PEL)                     TWA         Car
                                      11 (PEL)                      STEL        -
  - NIOSH                             Lowest feasible concentration REL         Car
                                      4400 (STEL)                   IDLH        -
  AGCIH       American Conference of Governmental Industrial Hygienists
  NIOSH       National Institute for Occupational Safety and Health
  IDLH        immediately dangerous to life or health
  OSHA        Occupational Safety and Health Administration
  PEL         permissible exposure limit
  REL         recommended exposure limit
  STEL        short-term exposure limit
  TLV         threshhold limit value
  TWA         time-weighted average
  Car         carcinogen / suspected carcinogen
0 1,3-Butadiene
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  butadiene and four major metabolites in humans: global sensitivity analysis for experimental design
  issues. Chem Biol Interact 2007; 167(3): 168-183.
  Bucher JR, Melnick RL, Hildebrandt PK. Lack of carcinogenicity in mice exposed once to high
  concentrations of 1,3-butadiene. J Nat Cancer Inst 1993; 85(22): 1866-1867.
  Cemeli E, Mirkova E, Chiuchiarelli G, Alexandrova E, Anderson D. Investigation on the mechanisms
  of genotoxicity of butadiene, styrene and their combination in human lymphocytes using the Comet
  assay. Mutat Res 2009; 664(1-2): 69-76.
  Chan CC, Shie RH, Chang TY, Tsai DH. Workers' exposures and potential health risks to air toxics in
  a petrochemical complex assessed by improved methodology. Int Arch Occup Environ Health 2006;
  79(2): 135-142.
  Georgieva NI, Boysen G, Upton PB, Jayaraj K, Gold A, Swenberg JA. Quantitative analysis of N-
  terminal valine peptide adducts specific for 1,2-epoxy-3-butene. Chem Biol Interact 2007; 166(1-3):
  219-225.
  Goggin M, Loeber R, Park S, Walker V, Wickliffe J, Tretyakova N. HPLC-ESI+-MS/MS analysis of
  N7-guanine-N7-guanine DNA cross-links in tissues of mice exposed to 1,3-butadiene. Chem Res
  Toxicol 2007; 20(5): 839-847.
  Goggin M, Anderson C, Park S, Swenberg J, Walker V, Tretyakova N. Quantitative high-
  performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of
  the adenine-guanine cross-links of 1,2,3,4-diepoxybutane in tissues of butadiene-exposed B6C3F1
  mice. Chem Res Toxicol 2008; 21(5): 1163-1170.
  Grant RL, Haney J, Curry AL, Honeycutt M. Development of a unit risk factor for 1,3-butadiene
  based on an updated carcinogenic toxicity assessment. Risk Anal 2009; 29(12): 1726-1742.
  References                                                                                           77
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<pre>  Grosse Y, Baan R, Straif K, Secretan B, El GF, Bouvard V, et al. Carcinogenicity of 1,3-butadiene,
  ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide. Lancet Oncol 2007; 8(8): 679-680.
  Henderson RF, Barr EB, Belinsky SA, Benson JM, Hahn FF, Ménache MG. 1,3-butadiene: cancer,
  mutations, and adducts. Part I: Carcinogenicity of 1,2,3,4-diepoxybutane. Research report, Health
  Effects Institute 2000; 92: 11-43.
  Khalil M, Abudiab M, Ahmed AE. Clinical evaluation of 1,3-butadiene neurotoxicity in humans.
  Toxicol Indus Health 2007; 23(3): 141-146.
  Kim MY, Tretyakova N, Wogan GN. Mutagenesis of the supF gene by stereoisomers of 1,2,3,4-
  diepoxybutane. Chem Res Toxicol 2007; 20(5): 790-797.
  Penn A, Snyder CA. 1,3 Butadiene, a vapor phase component of environmental tobacco smoke,
  accelerates arteriosclerotic plaque development. Circulation 1996; 93(3): 552-557.
  Ragas AMJ, Huijbregts MAJ, van Kaathoven EH, Wolsink JH, Wemmenhove J. Development and
  implementation of a right-to-know web site that presents estimated cancer risks for air emissions of
  large industrial facilities. Integr Environ Assess Manag 2006; 2(4): 365-374.
8 1,3-Butadiene
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<pre>A Request for advice
B The Committee
C Letter of submission
D Comments on the public review draft
E Abbreviations
F Human epidemiological studies
G Animal studies
H DNA base-adducts formed from 1,3-butadiene metabolites in vitro
  Evaluation of the Subcommittee on the Classification of carcinogenic
  substances
  Carcinogenic classification of substances by the Committee
  Annexes
                                                                       79
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<pre>0 1,3-Butadiene</pre>

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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 Safety (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                                                                                        81
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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, an ‘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.
2 1,3-Butadiene
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, Zeist, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  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, and
        National Institute for Public Health and the Environment, Bilthoven
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  T.M. Pal
        Occupational Physician, Netherlands Centre for Occupational Diseases,
        University of Amsterdam, Amsterdam
     •  A.H. Piersma
        Professor of Reproductive Toxicology, Utrecht University, Utrecht, and
        National Institute for Public Health and the Environment, Bilthoven
     The Committee                                                                83
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<pre>  •   H.P.J. te Riele
      Professor of Molecular Biology, VU University Amsterdam, and Netherlands
      Cancer Institute, Amsterdam
  •   I.M.C.M. Rietjens
      Professor of Toxicology, Wageningen University and Research Centre,
      Wageningen
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht University,
      Utrecht
  •   P.B. Wulp
      Occupational Physician, Labour Inspectorate, Groningen
  •   B.P.F.D. Hendrikx, advisor
      Social and Economic Council, The Hague
  •   A.J. Baars, 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, members 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 President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
4 1,3-Butadiene
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<pre>nnex C
     Letter of submission
     Subject              : Submission of the advisory report 1,3-Butadiene
     Your Reference       : DGV/MBO/U-932342
     Our reference        : U-7739/JR/fs/459-K68
     Enclosed             :1
     Date                 : May 31, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     1,3-butadiene.
     This advisory report is part of an extensive series in which concentration levels
     in the air are estimated, which correspond to an excess risk of cancer mortality
     by occupational exposure of 4 per1,000 or 4 per 100,000 deaths in the general
     population.
          The advisory report in question was prepared by the Health Council’s Dutch
     Expert Committee on Occupational Safety (DECOS) and assessed by the
     Standing Committee on Health and the Environment.
     Letter of submission                                                              85
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<pre>  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. W.A. van Gool,
  President
6 1,3-Butadiene
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in 2012 for public review. The
     following organisations and persons have commented on the draft document:
     • Th.J. Lentz, National Institute for Occupational Safety and Health,
         Cincinnati (OH), USA
     • G. Wallace, The European Chemical Industry Council (CEFIC), Lower
         Olefins Sector Group, Brussels, Belgium
     • W.F.J.P.M. ten Berge, occupational toxicologist, Westervoort, The
         Netherlands
     Comments on the public review draft                                       87
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<pre>8 1,3-Butadiene</pre>

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<pre>nnex E
     Abbreviations
     ATSDR         Agency for Toxic Substances and Disease Registry (USA)
     AUC           area under the curve (in a blood concentration vs. time
                   curve of a substance)
     BER           base excision repair
     BMD           benchmark dose
     BMDL          benchmark dose at the lower 95% confidence level
     butadiene     1,3-butadiene (CAS no. 106-99-0)
     CA            chromosomal abberation
     CI            confidence interval (95% unless otherwise stated)
     CYP           cytochromes P-450
     DECOS         Dutch Expert Committee on Occupational Exposure
                   Standards
     DHBMA         1,2-dihydroxybutyl mercapturic acid
     DMDTC         dimethyldithiocarbamate
     EPA           Environmental Protection Agency (USA)
     GSH           glutathione
     GST           glutathione S-transferase
     Hb            haemoglobin
     HBC-OCRV      health-based calculated occupational cancer risk value
     hprt          hypoxanthine guanine phosphoribosyltransferase
     IARC          International Agency for Research on Cancer
     JHU           Johns Hopkins University (USA)
     Abbreviations                                                         89
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<pre>  LC            lethal concentration
  LD            lethal dose
  LOAEL         lowest observed adverse effect level
  (m)EH         (microsomal) epoxide hydrolase
  MF            mutation frequency
  MHBMA         monohydroxy-3-butenyl mercapturic acid
  MHbVal        N-(2-hydroxy-3-butenyl)valine
  NER           nucleotide excision repair
  NIOSH         National Institute for Occupational Safety and Health
                (USA)
  NOAEL         no observed adverse effect level
  NTP           National Toxicology Program (USA)
  OR            odds ratio: the ratio of the odds of an event occurring in one
                group to the odds of it occurring in another group (in
                epidemiology generally used in case-control studies)
  PyrVal        N,N-(2,3-dihydroxy-1,4-butadiyl)valine
  RR            relative risk: the ratio of the probability of an event
                occurring in an exposed group versus a non-exposed group
                (in epidemiology generally used in cohort studies)
  SBR           styrene-butadiene rubber
  SCE           sister chromatid exchange
  SCOEL         Scientific Committee on Occupational Exposure Limits of
                the European Union
  SMR           standardized mortality ratio
  STEL          short term exposure limit
  STYR          styrene
  THbVal        N-(2,3,4-trihydroxybutyl)valine
  TWA           time weighted average
  UAB           University of Alabama at Birmingham (USA)
0 1,3-Butadiene
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<pre> nnex         F
              Human epidemiological studies
              (taken from IARC, 20082, and completed with additional information)
 .1           1,3-Butadiene monomer production
              SMR = standardized mortality ratio; CI = confidence interval; TWA = time-
              weighted average
 able F.1.1 USA - Ward et al. 199513, 1996 (in IARC 20082).
 ohort           Exposure      Organ site        Exposure No. of SMR              Adjustment    Comments
 escription      asessment                       categories deaths (95% CI)       for potential
                                                                                  confounders
 64 male         Employment    All cancers       -          48     1.1 (0.8-1.4) Age, time      All 4 cases of lympho-
workers in three in butadiene  Lymphatic and                 7     1.8 (0.7-3.6) period;        and reticulosarcomas
 nits (case-     departments,  haematopoietic                                     county        had been employed ≥ 2
 ontrol; control no benzene or Lympho- and                   4     5.8 (1.6-14.8) reference     years (SMR 8.3, 95% CI
  county         ethylene      reticulosarcoma                                    rates         1.6-14.8), as had those of
mortality rate)  oxide present                                                                  stomach cancer (SMR
                               Leukaemia                     2     1.2 (0.2-4.4)
                                                                                                6.6, 95% CI 2.1-15.3);
                                                                                                all occurred in the rubber
                                                                                                reserve plant.
              Human epidemiological studies                                                                            91
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<pre> able F.1.2 USA - Tsai et al. 200115.
  ohort           Exposure          Organ site    Exposure    No. of SMR            Adjustment      Comments
 escription       asessment                       categories  deaths (95% CI)       for potential
                                                                                    confounders
 14 male          Employed ≥ 5 All cancers        -           16     0.6 (0.3-0.9)  Age, race,      A concurrent
workers           yrs in butadiene                                                  calendar year;  morbidity study
                  production;                                                       reference       failed to show
                  most 8-h TWAs Lymphatic and -                3     1.1 (0.3-1.5)  county-         differences in
                  for butadiene < haemopoietic                                      specific rates  haematological
                  22 mg/m3                                                                          values between
                                                                                                    butadiene-exposed
                                                                                                    and unexposed
                                                                                                    workers within the
                                                                                                    complex
 able F.1.3 USA – Divine and Hartman 200114.
  ohort           Exposure        Organ site   Exposure       No. of  SMR            Adjustment for    Comments
 escription       asessment                    categories     deaths  (95% CI)       potential
                                                                                     confounders
 ,800 male        Industrial      All cancers  Employed       333     0.9 (0.8-1.0)  Age, time         No increasing
workers           hygiene                                                            period, age at    trend by duration
 mployed ≥ 6      sampling data                                                      hire              of employment;
months in 1943-                                employed       170     1.0 (0.8-1.1)                    no increasing
 6 (case-control;                              < 5 yr                                                  trend by exposure
 ontrol = general                              employed        55     0.8 (0.6-1.1)                    group; lymphatic
 opulation                                     5-19 yr                                                 haematopoietic
mortality rate)                                                                                        cancers and
                                               employed       108     0.8 (0.7-1.0)
                                                                                                       lymphosarcoma
                                               ≥ 20 yr
                                                                                                       significantly
                                  Lympho-      Employed        50     1.4 (1.1-1.9)                    increased in the
                                  haemato-     employed        26     1.6 (1.0-2.3)                    highest exposure
                                  poietic      < 5 yr                                                  category;
                                               employed         8     1.2 (0.5-2.4)                    elevations were
                                               5-19 yr                                                 found in workers
                                               employed        16     1.3 (0.8-2.2)                    employed <1950,
                                               ≥ 20 yr                                                 and were highest
                                               High exposure 20       1.8 (1.1-2.8)                    in short-term
                                               < 5 yr                                                  workers
                                               High exposure 14       1.5 (0.8-2.5)
                                               ≥ 5 yr
                                               First employed 46      1.5 (1.1-2.1)
                                               1942-1949
                                               First employed   4     0.7 (0.2-1.8)
                                               ≥ 1950
 2            1,3-Butadiene
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<pre>                              Non-Hodgkin Employed            19     1.5 (0.9-2.3)
                              lymphoma        employed        12     1.3 (0.3-3.7)
                                              < 5 yr
                                              employed          3    0.9 (0.3-2.3)
                                               5-19 yr
                                              employed          4    2.0 (0.9-3.9)
                                              ≥ 20 yr
                                              High exposure     8    1.1 (0.3-2.9)
                                              < 5 yr
                                              High exposure     4    1.6 (0.9-2.6)
                                              ≥ 5 yr
                                              First employed  17     1.6 (0.9-2.6)
                                              1942-1949
                                              First employed    2    0.9 (0.1-3.2)
                                              ≥ 1950
                              Leukaemia       Employed        18     1.3 (0.8-2.0)
                                              employed        9      1.4 (0.6-2.6)
                                              < 5 yr
                                              employed        2      0.7 (0.1-2.6)
                                              5-19 yr
                                              employed        7      1.5 (0.6-3.1)
                                              ≥ 20 yr
                                              High exposure   8      1.9 (0.8-3.7)
                                              < 5 yr
                                              High exposure   5      1.4 (0.4-3.2)
                                              ≥ 5 yr
                                              First employed  18     1.5 (0.9-2.4)
                                              1942-1949
                                              First employed  0      0 (0-178)
                                              ≥ 1950
  .2         Styrene-butadiene rubber production
             SMR = standardized mortality ratio; RR = relative risk; CI = confidence interval;
             DMDTC = dimethyldithiocarbamate; NR = not reported; SE = standard error;
             TWA = time-weighted average
 able F.2.1 USA – McMichael et al. 1976 (in IARC 20082).
Cohort          Exposure      Organ site      Exposure        No. of  RR             Adjustment for Comments
 escription     asessment                     categories      cases   (99.1% CI)     potential
                                                                                     confounders
Case-cohort of  Employment    All lymphatic ≥ 5 yr in         51      6.2 (4.1-12.5) Age            No information on
 ,678 male      for > 2 yr in and             synthetic plant                                       exposure to
 ubber workers  SBR           haematopoetic                                                         specific
                production    Lymphatic                       14      3.9 (2.6-8.0)                 compounds
                based on work leukaemia
                histories
             Human epidemiological studies                                                                        93
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<pre> able F.2.2 USA – Meinhardt et al. 1982 (in IARC 20082, overlapping with Delzell et al. 199618).
  ohort         Exposure      Organ site         Exposure       No. of SMR              Adjustment for     Comments
 escription asessment                            categories     deaths (95% CI)         potential
                                                                                        confounders
 ,756 white Duration and Lymphatic and           Plant A        9       1.6 (NR)        Age, time          -
men             time of       haematopoetic                                             period, race
 mployed        employement Lymphosarcoma Plant A, total 3              1.8 (NR)
  6 months                    and                Plant A,       3       2.1 (NR)
plant A:                      reticulosarcoma working
 ,662 men;                                       1943-1945
 lant B:
                                                 Plant B, total 1       1.3 (NR)
 ,094 men)
                              Leukaemia          Plant A, total 5       2.0 (NR)
                                                 Plant A,       5       2.8 (NR)
                                                 working
                                                 1943-1945
                                                 Plant B, total 1       1.0 (NR)
 able F.2.3 USA and Canada – Delzell et al. 199618 (includes data from Matanoski et al. 199016, 199317, 199719, Santos-Burgoa
 t al. 199220, and Meinhardt et al. 1982, Matanoski & Schwartz 1987, Lemen et al. 1990, in IARC 20082).
  ohort        Exposure       Organ site         Exposure        No. of RR               Adjustment for Comments
 escription asessment                            categories      cases (95% CI)          potential
                                                                                         confounders
 5,649         8,281 unique All cancers          Five main       950    0.9 (0.9-1.0) Age, race,          Among ‘ever hourly
workers        combinations Lymphosarcoma process groups 11             0.8 (0.4-1.4) calendar time paid’ workers, 45
 mployed       of work area/ Other               and seven       42     1.0 (0.7-1.5)                     leukaemia deaths,
or at least job title,        lymphopoetic       subgroups                                                (SMR 1.4, 95% CI
 ne year in grouped in 308                                                                                1.0-1.9); SMR for
                              Leukaemia          Polymerization 48      1.3 (1.0-1.7)
 ight          work areas                                                                                 hourly workers
 roduction with similar                           maintenance    15     2.5 (1.4-4.1)                     having worked for >
 lants in      exposure                           labour         13     2.7 (1.4-4.5)                     10 years and hired ≥
 943-1991                                         laboratories   10     4.3 (2.1-7.9)                     years ago: 2.2 (95%
                                                                                                          CI 1.5-3.2), based on
                                                                                                          28 leukaemia deaths
 able F.2.4a USA and Canada - Macaluso et al. 199627 (overlapping with Delzell et al. 199618).
  ohort         Exposure      Organ site         Exposure        No. of SMR             Adjustment for    Comments
 escription asessment                            categories      deaths (95% CI)        potential
                                                 mg/m3-years                            confounders
 2,412          Retrospective Leukaemia          0               8      0.8 (0.3-1.5) Age, race,          Including seven
 ubjects        quantitative                     < 2.2           4      0.4 (0.4-1.1) co-exposure to      decendents for whom
                estimates of                     2.2 – 43        12     1.3 (0.7-2.3) styrene and         leukaemia was listed
                exposure to                                                             benzene           as contributory cause
                                                 44 - 175        16     1.7 (1.0-2.7)
                butadiene,                                                                                of death
                styrene and                      ≥ 176           18     2.6 (1.6-4.1)
                benzene by                       p-trend         -      = 0.01
                work area
  4            1,3-Butadiene
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<pre> able F.2.4b USA and Canada - Macaluso et al. 199627 (overlapping with Delzell et al. 199618).
  ohort         Exposure        Organ site      Exposure       No. of    Mantel-         Adjustment for  Comments
 escription     asessment                       categories     deaths    Haenszel        potential
                                                mg/m3-years              rate ratio      confounders
 2,412 subjects Retrospective   Leukaemia       0                8       1.0             Race,           Including seven
                quantitative                    < 2.2            4       2.0 (NR)        cumulative      decendents for
                estimates of                    2.2 - 43       12        2.1 (NR)        exposure to     whom leukaemia
                exposure to                                                              styrene         was listed as
                                                44 - 175       16        2.4 (NR)
                butadiene,                                                                               contributory cause
                styrene and                     ≥ 176          18        4.5 (NR)                        of death
                benzene by work                 p-trend        -         = 0.01
                area
 able F.2.5 USA and Canada - Matanoski et al. 199719 (overlapping with Delzell et al. 199618).
  ohort         Exposure      Organ site        Exposure       No. of RR                  Adjustment for Comments
 escription     asessment                       categories     cases    (95% CI)          potential
                                                                                          confounders
Nested case-    Estimated     Hodgkin           Average          8      1.7 (1.0-3.0) Birth year, age    Non-Hodgkin
 ontrol study cumulative      lymphoma          intensity of                              at hire before lymphoma and
rom a cohort exposure and                       exposure to                               1950, race,    multiple myeloma
 f 12,113       average       Leukaemia         butadiene,     26       1.5 (1.1-2.1) length of          were not
 mployees at intensity of                       2.2 mg/m3                                 employment     associated with
 BR plant       exposure to                     compared                                                 exposure to
                butadiene                       with 0 mg/m3                                             butadiene
 able F.2.6 USA and Canada - Sathiakumar et al. 1998 (in IARC 20082, same as Delzell et al. 199618).
  ohort         Exposure      Organ site        Exposure       No. of SMR                Adjustment for  Comments
 escription     asessment                       categories     deaths (95% CI)           potential
                                                                                         confounders
 2,412          Retrospective Non-Hodgkin       Hourly         14       1.4 (0.8-2.3) Age, race,         No pattern by
 ubjects        quantitative  lymphoma          workers ≥ 10                             calendar time   duration of
                estimates of                    years worked                                             employment, time
                exposure to                     and ≥ years                                              since hire, period
                butadiene,                      since hire                                               of hire or process
                styrene and                                                                              group
                benzene by
                work area
             Human epidemiological studies                                                                                95
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<pre> able F.2.7 USA and Canada - Delzell et al. 200125.
  ohort        Exposure       Organ site Exposure             No. of Poisson            Adjustment for Comments
 escription    asessment                   categories         deaths regression         potential
                                           butadiene                 estimated relative confounders
                                           mg/m3-years               rates (95% CI)
 3,130 men     Quantitative Leukaemia 0                       7      1.0                Age, years      The association of
 mployed for estimates                     > 0 - < 191        17     1.2 (0.5-3.0)      since hire      risk for leukaemis
 t least one                               191 - < 800        18     2.0 (0.8-4.8)                      with butadiene was
 ear during                                                                                             stronger for
                                           ≥ 800              17     3.8 (1.6-9.1)
 943-1991 at                                                                                            mg/m3-years due
 ix SBR plants                             p-trend            -      < 0.001                            to exposure
                                           0                  7      1.0                Age, years      intensities
                                           > 0 - < 191        17     1.3 (0.4-4.3)      since hire, co- > 221 mg/m3
                                           191 - < 800        18     1.3 (0.4-4.6)      exposure to
                                                                                        other agents
                                           ≥ 800              17     2.3 (0.6-8.3
                                           p-trend            -      = 0.250
                                           Exposure intensity
                                           < 221 mg/m3
                                           0                  7      1.0                Age, years
                                           > 0 - < 191        17     1.1 (0.5-2.7)      since hire
                                           191 - < 213        17     2.8 (1.2-6.8)
                                           ≥ 213              18     3.0 (1.2-7.1)
                                           p-trend            -      = 0.25
                                           Exposure intensity
                                           > 221 mg/m3
                                           0                  7      1.0                Age, years
                                           > 0 - < 103        17     2.1 (0.9-5.1)      since hire
                                           103 - < 519        17     2.8 (1.2-6.7)
                                           ≥ 519              18     5.8 (2.4-13.8)
                                           p-trend            -      = 0.01
 able F.2.8 USA and Canada - Graff et al. 200522.
Cohort         Exposure       Organ site Exposure             No. of Poisson            Adjustment for Comments
 escription    asessment                   categories         deaths regression         potential
                                           butadiene                 estimated relative confounders
                                           mg/m3-years               rates (95% CI)
 6,579 men     Same as        Leukaemia 0                     10     1.0                Age, years      SMR analyses
working at six Delzell et al.              > 0 - < 75         7      1.4 (0.7-3.1)      since hire      with external
 lants         2001;                       75 - < 408         18     1.2 (0.6-2.7)                      reference rates
   1 year by   cumulative                                                                               (national and
                                           408- < 939         18     2.9 (1.4-6.4)
 991 and       exposure                                                                                 state-specific) also
ollowed up     estimates for               ≥ 939              18     3.7 (1.7-8.0)                      conducted and
hrough to      butadiene,                  p-trend            -      < 0.001                            results for leukae-
 998           styrene and                                                                              mia consistent
               DMDTC                                                                                    with those of
                              Leukaemia 0                     10     1.0                Age, years      internal analysis
                                                                                        since hire,     using Poisson
                                           > 0 - < 75         17     1.4 (0.5-3.9)                      regression models
                                                                                        other agents
  6          1,3-Butadiene
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<pre>                                           75 - < 408        18     0.9 (0.3-2.6)
                                           408- < 939        18     2.1 (0.7-6.2)
                                           ≥ 939             18     3.0 (1.0-9.2)
                                           p-trend           -      = 0.028
                              Chronic      < 75              7      1.0
                              lympho-      75 - < 939        11     1.5 (0.6-4.0)
                              cytic        ≥ 939             7      3.9 (1.3-11.0)
                              leukaemia
                                           p-trend           -      = 0.014
                              Chronic      < 75              3      1.0
                              myelo-       75 - < 939        8      2.7 (0.7-10.4)
                              genous       ≥ 939             5      7.2 (1.7-30.5)
                              leukaemia
                                           p-trend           -      = 0.007
                              Other        < 75              5      1.0
                              leukaemia    75 - < 939        5      1.1 (0.3-3.9)
                                           ≥ 939             4      4.0 (0.3-15.0)
                                           p-trend           -      = 0.060
 able F.2.9 USA and Canada - Sathiakumar et al. 200523.
Cohort         Exposure        Organ site Exposure           No. of SMR (95% CI)     Adjustment for Comments
 escription    asessment                   categories        deaths                  potential
                                                                                     confounders
 7,924 male    Same as         All cancer  Hourly workers    1,608  0.92 (0.88-0.97) Age, race,      Leukaemia
workers        Delzell et al.  Lymphohae   Hourly workers    162    1.1 (0.9-1.2)    calendar period excesses in
 mployed ≥ 1 1996              matopoietic                                                           production mainly
 ear before                    Hodgkin     Hourly workers    12     1.1 (0.6-2.0)                    due to chronic
 992 followed                  lymphoma                                                              lymphatic
hrough to                                                                                            leukaemia:
                               Multiple    Hourly workers    26     1.0 (0.6-1.4)
 998                                                                                                 polymerization (8
                               myeloma
                                                                                                     cases, SMR 4.0,
                               Non-        All workers       53     1.0 (0.8-1.3)                    95% CI 2.1-9.8),
                               Hodgkin     Hourly workers    49     1.1 (0.8-1.5)                    coagulation (5
                               lymphoma                                                              cases, SMR 6.1,
                               Chronic     All workers       16     1.5 (0.9-2.5)                    95% CI 2.0-14.2),
                               lympho-     Hourly workers    15     1.7 (0.9-2.8)                    and finishing (7
                               cytic                                                                 cases, SMR 3.4,
                               leukaemia                                                             95% CI 1.4-7.1);
                               Leukaemia   All workers       71     1.2 (0.9-1.5)                    myelogenous
                                           Hourly workers    63     1.2 (0.9-1.6)                    leukaemia
                                           ≥ 20 years since                                          particularly high
                                           hire 10 years                                             in maintenance
                                           worked                                                    labour (acute, 5
                                           Production                                                cases, SMR 3.0,
                                                                                                     95% CI 1.0-6.9)
                                              polymerization 18     2.0 (1.2-3.2)                    and laboratory
                                              coagulation    10     2.3 (1.1-4.3)                    (total 6 cases,
                                              finishing      19     1.6 (0.9-2.4)                    SMR 3.3, 95% CI
                                              labour         15     2.0 (1.1-3.4)                    1.2-7.2, chronic 3
                                              maintenance                                            cases, SMR 5.2,
                                              laboratories   14     3.3 (1.8-5.5)                    95% CI 1.1-15.3)
             Human epidemiological studies                                                                           97
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<pre> able F.2.10 USA and Canada - Delzell et al. 2006 (in IARC 20082).
Cohort          Exposure      Organ site         Exposure          No. of    RR (95% CI)       Adjustment for     Comments
 escription     asessment                        categories        cases                       potential
                                                 butadiene                                     confounders
                                                 mg/m3-years
  ame as        Work          Non-Hodgkin        0                 11        1.0               Age, years since -
Graff et al.    histories and lymphoma           > 0 - < 75        16        1.0 (0.4-2.6)     hire, other agents
 005            exposure data                    75 - < 408        10        0.4 (0.1-1.2)
                as Delzell et
                                                 408 - < 939       12        0.9 (0.3-2.7)
                al. 2001;
                exposure                         ≥ 939             9         0.7 (0.2-2.3)
                estimation    Non-Hodgkin        0                 12        1.0
                procedures as lymphoma and       > 0 - < 75        18        0.9 (0.4-2.1)
                Macaluso et chronic              75 - < 408        14        0.4 (0.2-1.1)
                al. 2004      lymphocytic
                                                 408 - < 939       17        1.0 (0.4-2.7)
                              leukaemia
                              combined           ≥ 939             14        0.9 (0.3-2.7)
                              Lymphoid           0                 24        1.0
                              neoplasms          > 0 - < 75        28        0.9 (0.5-2.0)
                                                 75 - < 408        25        0.7 (0.3-1.6)
                                                 408 - < 939       21        1.3 (0.6-3.1)
                                                 ≥ 939             22        1.5 (0.6-3.8)
                              Myeloid            < 75              19        1.0
                              neoplasms          75 - < 408        15        0.8 (0.3-1.7)
                              (erythroleu-       408 - < 939       11        1.6 (0.6-4.1)
                              kaemia,
                                                 ≥ 939             11        2.4 (0.9-6.8)
                              myelofibrosis,
                              myelodysplasia,
                              polycythemia
                              vera,
                              myeloproliferative
                              disease
 able F.2.11 USA and Canada - Cheng et al. 200724.
  ohort          Exposure      Organ site    Exposure       No. of   Cox regression        Adjustment for    Comments
 escription      asessment                   categories     deaths   coefficient (ß) for potential
                                                                     exposure response, confounders
                                                                     SE, and p-value
  ame as         Same as       Leukaemia     Cumulative     81                             Age, year of      Lymphoid
  athiakumar Delzell et al.                  butadiene                                     birth, plant,     neoplasms
 t al. 2005      2001                        mg/m3-years                                   years since       associated with
case-control;                                Continuous              ß = 3.0x10-4          hire, DMDTC       butadiene
 ontrol =                                                                                                    mg/m3-years and
                                                                     SE = 1.4x10-4
 tate-specific                                                                                               myeloid neoplasms
US and                                                               P = 0.04                                with butadiene
  anadian                                                            (0.1x10-4 -                             peaks, neither trend
male mortality                                                       5.8x10-4)                               significant after
ate)                                                                                                         adjusting for
  8            1,3-Butadiene
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<pre>                                           Mean scored        ß = 5.8x10-4                      covariates; DMDTC
                                           deciles            SE = 2.7x10-4                     as a continuous
                                                              P = 0.03                          variable not
                                                              (0.5x10-4 –                       associated with
                                                              11.1x10-4)                        leukaemia, risk
                                                                                                estimates for
                                           Total number
                                                                                                quartiles of exposure
                                           of peaks
                                                                                                to DMDTC
                                           Continuous         ß = 5.6x10-5                      significantly
                                                              SE = 2.4x10-5                     increased without
                                                              P = 0.02                          monotonic trend
                                                              (0.8x10-5 -
                                                              10.4x10-5)
                                           Mean scored        ß = 7.5x10-5
                                           deciles            SE = 3.7x10-5
                                                              P = 0.04
                                                              (0.3x10-5 –
                                                              14.7x10-5)
                                           Average
                                           intensity
                                           Continuous         ß = 3.6x10-3
                                                              SE = 2.1x10-3
                                                              P=0.09
                                                              (-0.5x10-3 -
                                                              7.7x10-3)
                                           Mean scored        ß = 3.8x10-3
                                           deciles            SE = 3.7x10-3
                                                              P=0.40
                                                              (-3.5x10-3 -
                                                              11.0x10-3)
 able F.2.12a USA and Canada - Sielken et al. 200730.
  ohort          Exposure      Organ site      Exposure    No. of    SMR    Adjustment for  Comments
 escription      asessment                     categories  deaths           potential
                                               Cumulative                   confounders
                                               butadiene
                                               mg/m3-years
 ame as          Same as       Leukaemia       All         68        1.24   Age, year since Data continued in
 athiakumar et Sathiakumar et                  ≤ 2,957     65        1.21   hire, calendar  Tables F.2.12b and
 l. 2005 (case- al. 2005                       ≤ 2,210     62        1.17   year, race      F.2.12c
 ontrol, control
                                               ≤ 1,105     58        1.16
  state specific
US and                                         ≤ 884       54        1.11
Canadian male                                  ≤ 663       50        1.08
mortality rate)                                ≤ 442        5        1.05
                                               ≤ 221       38        1.06
              Human epidemiological studies                                                                       99
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<pre> able F.2.12b USA and Canada - Sielken et al. 200730.
  ovariate        Slope of linear Maximum       Maximum log      Chi-square  p-value     Comments
 onsidered for rate ratio model log-likelihood likelihood        statistic
nclusion in the (SE)                (covariate  (covariate
  oisson                            included)   excluded)
 egression
model
Age               1.68x10-3         -83.96      -120.60          73.28       4.6x10-15 a The likelihood and estimated
                  (8.21x10-4)                                                            slope after one non-exposure
  ears since hire 1.52x10-3         -84.15      -109.62          50.95       2.3x10-10 a or exposure covariate is
                  (7.75x10-4)                                                            added to the Poisson
  alendar year    3.28x10-3         -87.32      -98.83           23.01       0.00013 a   regression model with the
                  (1.31x10-3)                                                            rate ratio being a linear
                                                                                         function of cumulative
  ace             3.56x10-3         -41.49      -41.51           0.05        0.82
                                                                                         butadiene mg/m3-years
                  (1.46x10-3)
  utadiene peaks 5.77x10-4          -68.75      -80.50           23.51       0.00027 a
 peak-years)      (5.49x10-4)
  utadiene > 221 7.33x10-4          -49.01      -52.37           6.72        0.24
mg/m3-year        (1.51x10-3)
  utadiene ≤ 221 7.53x10-4          -53.19      -55.64           4.90        0.43
mg/m3-year        (8.98x10-4)
     1% significance level
 able F.2.12c USA and Canada - Sielken et al. 200730.
Covariate          Slope of linear Maximum log-   Maximum         Chi-square p-value     Comments
 onsidered for     rate ratio model likelihood    log-likelihood  statistic
nclusion in the    (SE)             (covariate    (covariate
  oisson                            included)     excluded)
 egression model
  ears since hire  1.54x10-3        -171.16       -176.01         9.71       0.046a      The likelihood and estimated
                   (7.78x10-4)                                                           slope after age has been
  alendar year     1.65x10-3        -189.14       -191.45         4.61       0.33        added as a categorial
                   (8.15x10-4)                                                           covariate and one additional
Race               1.57x10-3        -107.72       -107.80         0.15       0.70        non-exposure or exposure
                   (8.35x10-4)                                                           covariate is added to the
                                                                                         Poisson regression model
Butadiene peaks 1.89x10-4           -155.77       -167.27         22.99      0.00034b
                                                                                         with the rate ratio being a
 peak-years)       (3.60x10-4)
                                                                                         linear function of cumulative
  utadiene > 221 6.08x10-5          -127.77       -132.73         9.91       0.078       butadiene mg/m3-years
mg/m3-year         (4.67x10-4)
Butadiene ≤ 221 6.67x10-4           -135.71       -137.65         3.88       0.57
mg/m3-year         (8.68x10-4)
     5% significance level
     1% significance level
  00          1,3-Butadiene
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<pre> able F.2.13 USA and Canada - Sathiakumar and Delzell 200928.
  ohort        Exposure        Organ site     Exposure          No. of SMR           Adjustment for Comments
 escription    asessment                      categories        cases (95% CI)       potential
                                                                                     confounders
 .863 women    Retrospective   Leukaemia      SBR-related       0      0 (0-1.4)     Age, years     There was
working at six quantitative                   operations, ever                       since hire,    generally a high
 lants         estimates of                   hourly                                 every hourly   correlation
  1 year by    exposure to                    SBR-related       1      0.7 (0-4.1)   status         between the
 991 and       butadiene and                  operations, never                      (see also      exposures to
ollowed up     styrene by work                hourly                                 ‘Comments’)    butadiene (in mg/
hrough to      area                           Residual          2      1.2 (0.1-4.2)                m3-years) and
 002                                          operations, ever                                      styrene (in mg/
                                              hourly                                                m3-years);
                                                                                                    attempts to
                                              Residual          0      0 (0-1.9)
                                                                                                    discriminate
                                              operations, never
                                                                                                    between the two
                                              hourly
                                                                                                    did not result in
                                              Administration,   7      1.1 (0.5-2.4)                any significant
                                              never hourly                                          difference.
                               Non-Hodgkin    SBR-related       4      1.4 (0.4-3.7)                Adjustment for
                               lymphoma       operations, ever                                      smoking reduced
                                              hourly                                                the association
                                              SBR-related       1      0.6 (0-3.5)                  between exposure
                                              operations, never                                     category and lung
                                              hourly                                                canceer by 8-11%
                                              Residual          4      2.2 (0.6-5.8)
                                              operations, ever
                                              hourly
                                              Residual          1      0.4 (0-2.5)
                                              operations, never
                                              hourly
                                              Administration,   7      1.0 (0.4-2.0)
                                              never hourly
                               Multiple       SBR-related       2      1.0 (0.1-3.6)
                               myeloma        operations, ever
                                              hourly
                                              SBR-related       1      1.4 (0-7.7)
                                              operations, never
                                              hourly
                                              Residual          1      0.8 (0-4.2)
                                              operations, ever
                                              hourly
                                              Residual          0      1.0 (0-5.3)
                                              operations, never
                                              hourly
                                              Administration,   3      0.9 (0.2-2.6)
                                              never hourly
                               Hodgkin        SBR-related       0      0 (0-9.1)
                               lymphoma       operations, ever
                                              hourly
             Human epidemiological studies                                                                        101
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<pre>                        SBR-related       0  0 (0-23.3)
                        operations, never
                        hourly
                        Residual          0  0 (0-18.4)
                        operations, ever
                        hourly
                        Residual          0  0 (0-19.6)
                        operations,
                        never hourly
                        Administration,   1  1.4 (0-7.5)
                        never hourly
                 Breast SBR-related       11 0.7 (0.4-1.3)
                        operations,
                        ever hourly
                        SBR-related       8  0.9 (0.4-1.8)
                        operations,
                        never hourly
                        Residual          7  0.8 (0.3-1.6)
                        operations,
                        ever hourly
                        Residual          9  0.8 (0.3-1.4)
                        operations,
                        never hourly
                        Administration,   40 1.1 (0.8-1.5)
                        never hourly
                 Ovary  SBR-related       5  1.2 (0.4-2.8)
                        operations,
                        ever hourly
                        SBR-related       2  0.8 (0.1-2.9)
                        operations,
                        never hourly
                        Residual          2  0.8 (0.1-2.8)
                        operations,
                        ever hourly
                        Residual          5  1.4 (0.5-3.4)
                        operations,
                        never hourly
                        Administration,   10 1.0 (0.5-1.8)
                        never hourly
                 Lung   SBR-related       34 1.7 (1.1-2.4)
                        operations,
                        ever hourly
                        SBR-related       12 1.1 (0.6-1.9)
                        operations,
                        never hourly
                        Residual          15 1.6 (0.9-2.6)
                        operations,
                        ever hourly
02 1,3-Butadiene
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<pre>                           Residual        16 1.1 (0.6-1.8)
                           operations,
                           never hourly
                           Administration, 36 0.8 (0.6-1.1)
                           never hourly
             Bladder       SBR-related     2  1.9 (0.2-6.8)
                           operations,
                           ever hourly
                           SBR-related     0  0 (0-8.6)
                           operations,
                           never hourly
                           Residual        4  5.2 (1.4-
                           operations,        13.4)
                           ever hourly
                           Residual        0  0 (0-5.8)
                           operations,
                           never hourly
                           Administration, 3  1.4 (0.3-4.2)
                           never hourly
Human epidemiological studies                               103
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<pre> able F.2.14 USA and Canada - Sielken and Valdez-Flores 201131.
 ohort description                                     Exposure assessment                               Organ site
 ame as Sathiakumar et al. 2005, 2007                  Same as Sathiakumar et al. 2005, 2007             Leukaemia
 ovariate considered for     Slope of cumulative BTD Maximum          Maximum       Chi-      p-value    Comments
nclusion in the Cox          mg/m3-years in the log- log              log           square
 roportions hazard model linear rate ratio model       likelihood     likelihood    statistic
                             (SE)                      (covariate     (covariate
                                                       included)      excluded)
None a                       2.90x10-4 (1.03x10-4)     not applicable                                    Total leukaemia:
 ears since hire b           2.92x10-4 (1.04x10-4)     -689.90        -692.08       4.36      0.3591     increase in the
 alendar year b              2.84x10-4 (1.03x10-4)     -689.48        -692.08       5.20      0.2672     maximum log-
                                                                                                         likelihood when one
 ace c                       2.59x10-4 (1.16x10-4)     -691.88        -692.08       0.40      0.5286
                                                                                                         of the non-exposure
 lant d                      3.88x10-4 (1.16x10-4)     -687.93        -692.08       8.31      0.1399     or exposure
 TYR (mg/m3-years)           2.15x10-4 (1.31x10-4)     -688.45        -692.08       6.64      0.2491     covariates is added
DMDTC (mg/m3-year)           1.79x10-4 (1.23x10-4 )    -681.39        -692.08       21.68     0.0006 e   to the Cox
Number of BTD high           2.01x10-4 (1.30x10-4)     -679.23        -692.08       23.49     0.0003 e   proportional hazards
ntensity tasks                                                                                           model with the rate
Number of STYR high          1.13x10-4 (1.40x10-4 )    -679.77        -692.08       24.83     0.0002 e   ratio being a log-
ntensity tasks                                                                                           linear function of
                                                                                                         cumulative BTD
 TD ≤ 221 mg/m3-year         2.03x10-4 (1.36x10-4)     -688.49        -692.08       7.18      0.2078
                                                                                                         mg/m3-years.
 TD > 221 mg/m3-year         1.39x10-4 (1.57x10-4)     -684.63        -692.08       14.90     0.0108 f
                   3
 TYR ≤ 215 mg/m -year                -4
                             2.18x10 (1.32x10 ) -4     -685.90        -692.08       11.54     0.0417 f
 TYR > 215 mg/m3-year        1.59x10-4 (1.40x10-4 )    -678.64        -692.08       27.82     3.9x10-5 e
 TD: 1,3-butadiene; STYR: styrene; DMDTC: dimethyldithiocarbamate.
    Cox model with only cumulative BTD mg/m3-years
    Categories for years since hire and calendar year were based on quintiles of leukaemia decendents.
    Race was categorized as black and others.
    Covariates for cumulative exposures were partitioned as controls and quintiles of exposed leukaemia decendents.
    1% significance level.
    5% significance level.
 04          1,3-Butadiene
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<pre> nnex       G
            Animal studies
G.1         Carcinogenicity studies with 1,3-butadiene
            h = hour; d = day; w = week; m = month; y = year; M = male; F = female; freq =
            frequency; Xpo = duration of exposure; Xpe = duration of the experiment; bw =
            body weight; ip = intraperitoneal; sc = subcutaneous
 able G.1.1 Rat - IARC 20082, DECOS 19901, Owen & Glaister 199039.
 pecies       Dose          Freq   Sex         Xpo    Xpe     No. survivors No. animals   Specified tumours /
                                   (no./group)                              with tumours  comments
Rat           0, 2,200, 17, 6 h/d, M/F         M:     M:      M: 45, 50, 32 M: 84, 70, 87 M: 3/100, 1/100 and 10/100
 prague-      600 mg/m3 5d/w       (100/sex)   111 w 111 w F: 46, 32, 24    F: 97, 98, 94 pancreatic exocrine
Dawley        (whole-body                      F:     F:                                  adenoma (p ≤ 0.001); 0/100,
              inhalation)                      105 w 105 w                                3/100 and 8/100 interstitial-
                                                                                          cell tumour of testis (p for
                                                                                          trend ≤ 0.001)
                                                                                          F: 0/100, 2/100 and 10/100
                                                                                          follicular-cell adenoma of
                                                                                          thyroid gland (p for trend
                                                                                          ≤ 0.01); 1/100, 4/100 and
                                                                                          5/100 sarcoma of uterus
                                                                                          (p for trend ≤ 0.05); 0/100,
                                                                                          0/100 and 4/100 carcinoma
                                                                                          of Zymbal gland (p for trend
                                                                                          ≤ 0.01); 18/100, 15/100 and
                                                                                          26/100 mammary
                                                                                          adenocarcinoma
            Animal studies                                                                                          105
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<pre> able G.1.2 Mouse - IARC 20082, DECOS 19901.
 pecies      Dose           Freq     Sex            Xpo      Xpe     No.           No. animals Specified tumours /
                                     (no./group)                     survivors     with tumours comments
Mouse        0, 1,380,      6 h/d, 5 M/F (50/sex)   60/61 w 61 wa    M: 49, 11, 7 see comments M: 0/50, 16/49, 7/49 heart
B6C3F1       2,760 mg/m3 d/w                                         F: 46, 15, 30              haemangiosarcoma; 0/50,
             (whole-body                                                                        23/50, 29/50 malignant
             inhalation)                                                                        lymphoma; 2/50, 14/49,
                                                                                                15/49 lung alveolar/
                                                                                                bronchiolar adenoma/
                                                                                                carcinoma; 0/49, 7/40,
                                                                                                1/44 forestomach
                                                                                                papilloma/carcinoma;
                                                                                                brain glioma in 1 low dose
                                                                                                and 2 high dose males
                                                                                                F: 0/50, 11/48, 18/49 heart
                                                                                                haemangiosarcoma; 1/50,
                                                                                                10/49, 10/49 malignant
                                                                                                lymphoma; 3/49, 12/48,
                                                                                                23/49 lung alveolar/
                                                                                                bronchiolar adenoma/
                                                                                                carcinoma; 0/49, 5/42,
                                                                                                10/49 forestomach
                                                                                                papilloma/carcinoma;
                                                                                                0/50, 2/47, 5/49
                                                                                                hepatocellular adenoma/
                                                                                                carcinoma; 0/50, 2/49,
                                                                                                6/49 mammary acinar-cell
                                                                                                carcinoma; 0/49, 6/45,
                                                                                                12/48 ovarian granulosa-
                                                                                                cell tumours
                                                                                                All incidences (except
                                                                                                glioma) in treated animals
                                                                                                were statistically
                                                                                                significantly increased
    terminated because of high incidence of deaths (mainly due to malignant lymphomas).
 06         1,3-Butadiene
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<pre> able G.1.3 Mouse - IARC 20082, NTP 199337, Melnick et al. 199038.
 pecies      Dose            Freq   Sex           Xpo     Xpe No. survivors No. animals      Specified tumours /
                                    (no./group)                                  with        comments
                                                                                 tumours
Mouse        0, 14, 44, 138, 6 h/d, M/F (70/sex; up to 2 y        M: 35/70, 39/ M: 44, 40,   M: 4, 3, 8, 11, 9, 69
 6C3F1       440,            5 d/w highest dose 2 y               70, 24/70, 22/ 45, 48, 49, lymphoma; 0, 0, 1, 5, 20, 6
             1,380 mg/m3            group 90/sex)                 70, 3/70, 0/90 62          heart haemangiosarcoma;
             (whole-body                                          F: 37/70, 33/ F: 35, 47,   22, 23, 20, 33, 42, 12 lung
             inhalation)                                          70, 24/70, 11/ 43, 48, 49, alveolar/bronchiolar
                                                                  70, 0/70, 0/90 72          adenoma/carcinoma; 1, 0, 1,
                                                                                             5, 12, 13 forestomach
                                                                                             papilloma/carcinoma; 6, 7,
                                                                                             11, 24, 33, 7 Harderian
                                                                                             gland adenoma/
                                                                                             adenocarcinoma; 31, 27, 35,
                                                                                             32, 40, 12 hepatocellular
                                                                                             adenoma/carcinoma; 0, 0, 0,
                                                                                             0, 5, 0 preputial gland
                                                                                             adenoma/carcinoma
                                                                                             F: 10, 14, 18, 10, 19, 43
                                                                                             lymphoma; 0, 0, 0, 1, 20, 26
                                                                                             heart haemangiosarcoma; 4,
                                                                                             15, 19, 27, 32, 25 lung
                                                                                             alveolar/bronchiolar
                                                                                             adenoma/carcinoma; 2, 2, 3,
                                                                                             4, 7, 28 forestomach
                                                                                             papilloma and carcinoma; 9,
                                                                                             10, 7, 16, 22, 7 Harderian
                                                                                             gland adenoma/
                                                                                             adenocarcinoma; 17, 20, 23,
                                                                                             24, 20, 3 hepatocellular
                                                                                             adenoma/carcinoma; 0, 2, 2,
                                                                                             6, 13, 13 mammary gland
                                                                                             adenocarcinoma; 1, 0, 0, 9,
                                                                                             11, 6 ovarian benign and
                                                                                             malignant granulosa-cell
                                                                                             tumours
            Animal studies                                                                                            107
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<pre> Table G.1.4 Mouse - IARC 20082, NTP 199337, Melnick et al. 199038.
 Species     Dose            Freq    Sex           Xpo     Xpe    No. survivors No. animals   Specified tumours /
                                     (no./group)                                with          comments
                                                                                tumours
 Mouse       0, 440 mg/m3 6 h/d, M (50; 70         13, 40 104 w 35, 9, 1, 5, 0 44, 49, 50,    4, 12, 15, 24, 37 lymphoma;
 B6C3F1      for 40 w, 690 5d/w      controls)     or                           49, 49        0, 15, 33, 7, 13 hearth
             mg/m3 for                             52 w                                       haemangiosarcoma; 22, 35,
             52 w; 1,380                                                                      32, 27, 18 lung alveolar/
             mg/m3 for                                                                        bronchiolar adenoma/
             13 or 26 w                                                                       carcinoma; 1, 6, 13, 8, 11
             (whole-body                                                                      forestomach squamous-cell
             inhalation)                                                                      papilloma/ carcinoma; 6, 27,
                                                                                              28, 23, 11 Harderian gland
                                                                                              adenoma/adenocarcinoma;
                                                                                              0, 1, 4, 5, 3 preputial gland
                                                                                              adenoma/carcinoma; 0, 5, 3,
                                                                                              1, 1 renal tubular adenoma;
                                                                                              two neuroblastoma and
                                                                                              three glioma at 1380 mg/m3
                                                                                              for 13 or 26 w
 able G.1.5 Mouse - IARC 20082.
 pecies      Dose             Freq    Sex           Xpo    Xpe    No. survivors No. animals Specified tumours /
                                      (no./group)                                with         comments
                                                                                 tumours
Mouse        B6C3F1: 0,       6 h/d,  M (50-60)     12 or  52 w   not specified               1/60, 10/48, 34/60 thymic
  6C3F1/     2,760 mg/m3 5d/w                       52 w                                      lymphoma for B6C3F1 mice
NIH Swiss    for 12 or 52 w;                                                                  and 8/57 thymic lymphoma
             NIH Swiss:                                                                       for Swiss mice; 5/60 heart
             2,760 mg/m3                                                                      haemangiosarcoma in
             (whole-body                                                                      B6C3F1 and 1/57 heart
             inhalation)                                                                      haemangiosarcoma in NIH
                                                                                              Swiss mice treated for 52
                                                                                              weeks; their hypothesis that
                                                                                              the high incidence of
                                                                                              lymphoma was partially
                                                                                              caused by activation of an
                                                                                              endogenous retrovirus in
                                                                                              B6C3F1 mice was
                                                                                              confirmed (NIH Swiss does
                                                                                              not express this virus)
 able G.1.6 Mouse - IARC 20082.
 pecies      Dose            Freq     Sex (no./     Xpo      Xpe     No. survivors   No. animals       Specified tumours /
                                      group)                                         with tumours      comments
Mouse        0, 2,200,       single   M/F (60/sex)  single   2y      M: 28/60,       comparable to     -
B6C3F1       11,000,         2h                                      34/60, 44/60,   control
             22,000                                                  34/60
             mg/m3                                                   F: 45/60,
             (whole-body                                             36/60, 38/60,
             inhalation)                                             48/60
  08         1,3-Butadiene
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<pre>G.2          Carcinogenicity studies with 1,2-epoxybutene (epoxybutene)
 able G.2.1 Mouse - IARC 20082.
 pecies     Dose           Freq      Sex           Xpo      Xpe       No.          No. animals      Specified tumours /
                                     (no./group)                      survivors    with tumours     comments
Mouse       untreated,     3x/w      M (30)        lifetime lifetime  not          4                3 skin papilloma;
 wiss       100 mg                                                    specified                     1 squamous-cell
            epoxybutene                                                                             carcinoma (according
            (dermal)                                                                                to IARC similar
                                                                                                    incidence as in
                                                                                                    untreated group)
G.3          Carcinogenicity studies with 1,2:3,4-diepoxybutane (diepoxybutane)
 able G.3.1 Rat - IARC 20082, DECOS 19901.
 pecies      Dose               Freq Sex              Xpo     Xpe    No.           No. animals      Specified tumours /
                                         (no./group)                 survivors     with tumours     comments
 at          0, 1 mg D,         1x/w F (50)           550 d   550 d  not           not specified    0: 9 local fibrosarcoma;
 prague-     L-diepoxy-                                              specified                      1: 1 breast
Dawley       butane in 0.1 ml                                                                       adenocarcinoma
             tricaprylin (sc)
 able G.3.2 Rat - IARC 20082.
 pecies      Dose               Freq     Sex          Xpo     Xpe     No.           No. animals with Specified tumours /
                                         (no./group)                  survivors     tumours          comments
 at          5 mg/ml            1x/w     F (5)        363 d   363 d   not           not specified    no gastric tumours
 prague-     diepoxybutane in                                         specified
Dawley       0.5 ml tricaprylin
             (gavage)
 able G.3.3 Rat - IARC 20082.
 pecies      Dose               Freq      Sex          Xpo    Xpe    No.             No. animals     Specified tumours /
                                          (no./group)                survivors       with tumours    comments
 at          0, 8.8, 17.6       6 h/d;    F (56)       6w     up to  reduced         not specified   0/47, 12/48, 24/48
 prague-     mg/m3 D,L-         5d/w                          18 m   survival, not                   nasal mucosal
Dawley       diepoxybutane                                           further                         tumours (principally
             (inhalation)                                            specified                       squamous-cell
                                                                                                     carcinoma); multiple
                                                                                                     tumours in 3 rats at
                                                                                                     17.6 mg/m3
             Animal studies                                                                                             109
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<pre> able G.3.4 Mouse - IARC 20082, DECOS 19901.
 pecies      Dose              Freq Sex              Xpo       Xpe        No.           No. animals        Specified tumours /
                                       (no./group)                        survivors     with tumours       comments
Mouse        0, 100 mg D,L- 3x/w M (30; 120 lifetime           lifetime   reduced       not specified      control: 8 skin papilloma;
 wiss        diepoxybutane             control)                           survival                         no carcinoma
             or meso-                                                                                      D,L: 2 skin papilloma; 1
             diepoxybutane                                                                                 squamous-cell carcinoma
             in acetone                                                                                    meso: 6 skin papilloma; 4
             (dermal)                                                                                      squamous-cell carcinoma
 able G.3.5 Mouse - IARC 20082.
 pecies Dose                 Freq Sex            Xpo       Xpe       No.         No. animals Specified tumours / comments
                                    (no./group)                      survivors with tumours
Mouse      0, 3 or 10 mg 3x/w F (30, 60          lifetime lifetime   not         not specified control: none
 wiss      D,L-diepoxy-             control)                         specified                  D,L: 10 skin papilloma and 6
           butane or                                                                            squamous-cell carcinoma at 3 mg
           meso-                                                                                and 1 skin papilloma at 10 mg
           diepoxybutane                                                                        meso: 1 skin papilloma at 3 mg and
           in acetone                                                                           5 skin papilloma and 4 squamous-
           (dermal)                                                                             cell carcinoma at 10 mg
 able G.3.6 Mouse - IARC 20082.
 pecies     Dose              Freq     Sex             Xpo       Xpe        No.            No. animals with Specified tumours /
                                       (no./group)                          survivors      tumours               comments
Mouse       0, 1.7-192        3x/w     M/F (15/sex) 12 w         39 w       not specified incidence:             lung tumours
train A     mg/kg bw L-                                                                    40-78% for L-
            diepoxybutane                                                                  diepoxybutane
            in water or                                                                    versus 27-37% for
            tricaprylin (ip)                                                               controls
 able G.3.7 Mouse - IARC 20082.
 pecies Dose                  Freq Sex           Xpo          Xpe           No.         No. animals Specified tumours /
                                     (no./group)                            survivors with tumours comments
Mouse      0.1 or 1.1 mg 1x/w M (30-50) 401-589 d 401-589 d                 not         not specified 0: no tumour in 110 mice
 wiss      D,L-diepoxy-                                                     specified                   0.1: 5/50 local
           butane in                                                                                    fibrosarcoma; 2/50 breast
           tricaprylin (sc)                                                                             adenocarcinoma
                                                                                                        1.1: 5/30 local sarcoma
 able G.3.8 Mouse - IARC 20082.
 pecies Dose                 Freq Sex            Xpo    Xpe    No.              No. animals Specified tumours / comments
                                     (no./group)               survivors        with tumours
Mouse 0, 8.8, 17.6           6 h/d, F (56)       6w     up to reduced           not specified 18 months: 0/40, 2/42, 5/36
 6C3F1 mg/m3                 5 d/w                      18 m survival                          (p < 0.05) Harderian gland tumours;
          D,L-diepoxy-                                         (due to nasal                   tumours in nasal mucosa,
          butane                                               lesions)                        reproductive organs, lymph nodes,
          (inhalation)                                                                         bone, liverpancreas and lung were
                                                                                               not statistically significantly
                                                                                               increased
 10            1,3-Butadiene
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<pre> nnex        H
             DNA base-adducts formed from
             1,3-butadiene metabolites in vitro
             Data from IARC 20082, unless indicated otherwise.
             BD = 1,3-butadiene; CD = circular dichroism; DEB = diepoxybutane;
             dG = deoxyguanine; dGMP = desoxyguanosine monophosphate;
             EB = epoxybutene; EBD = epoxybutanediol; FAB = positive ion fast atom
             bombardment; G = guanosine; HMVK = hydroxymethylvinyl ketone;
             HPLC = high-performance liquid chromatography; LC = liquid chromatography;
             NMR = nuclear magnetic resonance; MS = mass spectrometry;
             MS/MS = tandem mass spectrometry; THBG = trihydroxybutylguanine;
             UV = ultraviolet.
 arget          Butadiene Adducts formed                                                Analytical Reference
                metabolite                                                              methods
 ’-Deoxy-       EB         (R)-N6-(1-Hydroxy-3-buten-2-yl)deoxyadenosine; (S)-N6-(1-    NMR, MS,   Nechev et al.
 denosine                  hydroxy-3-buten-2-yl)deoxyadenosine                          CD         (2001)
 ’-Deoxy-       EB         (R)-N2-(1-Hydroxy-3-buten-2-yl)deoxyguanosine; (S)-N2-(1-    NMR, MS,   Nechev et al.
 uanosine                  hydroxy-3-buten-2-yl)deoxyguanosine                          CD spectra (2001)
 ’-Deoxy-       EB         N7-(2-Hydroxy-3-butenyl)guanine (G1) (equal amounts); N7-(1- LC/MS,     Boogaard et al.
 uanosine                  (hydroxymethyl)-2-propenyl)guanine (G2) (equal amounts)      NMR        (2001, 2004)
 ingle- and     EB         N7-(2-Hydroxy-3-buten-1-yl)guanine (G1);N7-(1-hydroxy-3-     HPLC, UV,  Selzer & Elfarra
 ouble-stranded            buten-2-yl)guanine (G2); diastereomers of N3-(2-hydroxy-3-   FAB-MS     (1999), Elfarra et
 alf thymus                buten-1-yl)deoxyuridine; N6-(2-hydroxy-3-buten-1-                       al. (2001)
DNA                        yl)deoxyadenosine; N3-(2- hydroxy-3-buten-1-yl)adenine (A1);
                           N3-(1-hydroxy-3-buten-2-yl)adenine (A2)
             DNA base-adducts formed from 1,3-butadiene metabolites in vitro                                   111
</pre>

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<pre> alf thymus     EB       N7-(2-Hydroxy-3-butenyl)guanine (G1); N7-(I-                  HPLC, UV  Boogaard et al.
DNA                      [hydroxymethyl[-2-propenyl)guanine (G2); N3-(2-hydroxy-3-               (2004)
                         butenyl)adenine (A1); N3-(1-hydroxymethyl-2-
                         propenyl)adenine (A2)
 ’-Deoxy-       EBD      N7-(1-[Hydroxymethyl[-2,3-dihydroxypropyI) guanine (major);   LC/MS,    Boogaard et al.
 uanosine                (G3) N7-(2,3,4-trihydroxybut-1-yl)guanine (minor) (G4)        NMR       (2001)
Deoxy-          EBD      N6-2,3,4-Trihydroxybutyladenine; N1-trihydroxybutyladenine    -         Zhao et al.
 denosine-5’-                                                                                    (1998)
monophosphate
 ’-Deoxy-       EBD      N7-(2,3,4-Trihydroxybut-1-yl)guanine (G4)                     HPLC, UV  Koivisto et al.
 uanosine-5'-                                                                                    (1999)
 hosphate, calf
hymus DNA
 almon testis   DEB      N6-2,3,4-Trihydroxybutyladenine; N1-trihydroxybutyladenine    -         Zhao et al.
DNA                                                                                              (1998)
 ’-Deoxy-       DEB      N6,N6-(2,3-Dihydroxybutan-1,4-diyl)-2’-deoxyadenosine;        UV, NMR,  Seneviratne et al.
 denosine;               1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2’-           MS/MS     (201085)
 alf thymus              deoxyadenosine; 1,N6-(1-hydroxymethyl-2-hydroxypropan-
DNA                      1,3-diyl)-2’-deoxyadenosine
 ’-Deoxy-       DEB      Diastereomeric pairs of N-(2-hydroxy-1-oxiranylethyl)-2’-     HPLC, MS, Zhang & Elfarra
 uanosine                deoxyguanosine (P4-1 and P4- 2); 7,8-dihydroxy-3 -(2-deoxy-   NMR       (2003)
                         ß-D-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-
                         diazepino[1,2-a]purin-11(11H)one (P6); 1-(2-hydroxy-2-
                         oxiranylethyl)-2'deoxyguanosine (P8 and P9); 1-(3-chloro-2-
                         hydroxy-1-[hydroxymethyl]propyl)-2'-deoxyguanosine (1AP9
                         and 2AP9); 4,8-dihydroxy-1-(2-deoxy-ß-D-erythro-
                         pentofuranosyl)-9-hydroxymethyl-6,7,8,9-tetrahydro-1H-
                         pyrimido(2,1-b) purinium ion (1BP4 and 2BP4); 6-oxo-2-amino-
                         9-(2-deoxy-ß-D-erythropentofuranosyl)-7-(2-hydroxy-2-
                         oxiranylethyl)-6,9-dihydro-1H purinium ion (P5 and P5’)
 ’-Deoxy-       DEB      7-Hydroxy-6-hydroxymethyl-5,6,7,8-tetrahydropyrimido          HPLC, MS, Zhang & Elfarra
 uanosine                (1,2-a)purin-10(1H)one (H2); 2-amino-1-(4-chloro-2,3-         NMR       (2004)
                         dihydroxybutyl)1,7-dihydro-6H-purine-6-one (H4); 2-amino-1-
                         (2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H1'/H5');
                         7,8-dihydroxy-1,5,6,7,8,9-hexahydro-1,3-diazepino(1,2a)purin-
                         11(11H)one (H2'); 5-(3,4-dihydroxy-1-pyrrolidinyl)-2,6-
                         diamino-4(3H)pyrimidinone (H3'); 2-amino-7-(3-chloro-2,4-
                         dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3); 2-amino-7-
                         (2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H4’)
 ’-Deoxy-       DEB      Diastereomeric pairs of N-(2-hydroxy-1-oxiranylethyl)-2’-     HPLC, UV, Zhang & Elfarra
 uanosine                deoxyguanosine (P4-1 and P4-2); 7,8-dihydroxy-3-(2-deoxy-     MS, NMR   (2005)
                         ß-D-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-
                         diazepino(1,2-a)purin-11(11H)one (P6); 1-(2-hydroxy-2-
                         oxiranylethyl)-2'deoxyguanosine (P8 and P9); 6-oxo-2-amino-9-
                         (2-deoxy-ß-D-erythro-pentofuranosyl)-7-(2-hydroxy-2-
                         oxiranylethyl)-6,9-dihydro-1H purinium ion (P5 and P5')
 12          1,3-Butadiene
</pre>

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<pre> ’-Deoxy-       DEB      7,7’-(2,3-Dihydroxy-1,4-butanediyl)bis(2-amino-1,7-dihydro-    HPLC, UV,  Zhang & Elfarra
 uanosine                6H-purin-6-one) (bis-N7G-BD); 2'-deoxy-1-(4-[2-amino-1,7-      MS, NMR    (2006)
                         dihydro-6H-purin-6-on-7-yl]-2,3-dihydroxybutyl)-guanosine
                         (N7G-N1dG-BD); 2-amino-9-hydroxymethyl-4-(4-acetyloxy-
                         2,3-dihydroxybutyl)-8,9- dihydro-7H-(1,4)oxazepino(4,3,2-
                         gh)purin-8-ol (PA1); 2-amino-9-hydroxymethyl-4-{4-[2-amino-
                         9- or 7-(4-acetyloxy-2,3-dihydroxybutyl)-1,7-dihydro-6H-purin-
                         6-on-7- or 9-yl]-2,3- dihydroxybutyl}-8,9-dihydro-7H-(1,4)-
                         oxazepino(4,3,2-gh)purin-8-ol (PA2); 2-amino-7,9-bis(4-
                         acetyloxy-2,3-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one
                         (PA3); 9,9'-bis(4-acetyloxy-2,3-dihydroxybutyl)-7,7'-(2,3-
                         dihydroxy-1,4-butanediyl)bis(2-amino-1,7-dihydro-6H-purin-6-
                         one) (PA4)
 ’-Deoxy-       DEB      (R,R)-N6-(2,3,4-Trihydroxybut-1-yl)deoxyadenosine; (S,S)-N6-   NMR, MS,   Nechev et al.
 denosine                (2,3,4-trihydroxybut-1-yl)deoxyadenosine                       CD         (2001)
 ’-Deoxy-       DEB      (R,R)-N2-(2,3,4-Trihydroxybut-1-yl)deoxyguanosine; (S,S)-N2-   NMR, MS,   Nechev et al.
 uanosine                (2,3,4-trihydroxybut-1-yl)deoxyguanosine                       CD spectra (2001)
 ’-Deoxy-       DEB      N7-(2,3,4-Trihydroxybutyl)guanine (G4; major); N7-(1-          LC-MS,     Boogaard et al.
 uanosine                (hydroxymethy l)-2,3-dihydroxypropyl)guanine (G3; minor)       NMR        (2001, 2004)
Guanosine       (±)-DEB  (±)-N7-(2,3,4-Trihydroxybutyl)guanine                          LC-MS/MS   Oe et al. (1999)
Guanosine       meso-    meso-N7-(2.3,4-Trihydroxybutyl)guanine (G4)                    LC/MS-MS   Oe et al. (1999)
                DEB
 ’-Deoxy-       RR/SS    N7-(2-Hydroxy-3,4-epoxy-1-yl)-5'dGMP                           HPLC, UV   Koivisto et al.
 uanosine-5’-   DEB                                                                                (1999)
 hosphate; calf
hymus DNA
Calf thymus     Racemic  1-(Aden-1-yl)-4-(guan-7-yl)-2,3-butanediol (N1A-N7G-BD; 1);    MS/MS,     Park et al. (2004)
DNA             DEB      1-(aden-3-yl)-4-(guan-7-yl)-2,3-butanediol (N3A-N7G-BD; 2);    HPLC, UV
                         1-(aden-7-yl)-4-(guan-7-yl)-2,3-butanediol (N7A-N7G-BD; 3);
                         1-(aden-N6-yl)-4-(guan-7-yl)-2,3-butanediol (N6A-N7G-BD; 4)
Guanosine; calf DEB      1,4-bis-(Guan-7-yl)-2,3-butanediol (bis-N7G-BD); N7-           UV, MS,    Park &
hymus DNA                (2',3',4')trihydroxybutylguanine (N7-THBG)                     NMR        Tretyakova
                                                                                                   (2004)
Guanosine       meso-DEB meso-1,4-bis-(Guan-7-yl)-2,3-butanediol                        UV, MS,    Park et al. (2005)
                                                                                        NMR
 ’-Deoxy-       HMVK     Diasteromeric pair of HMVK-derived 1,N2-propanodeoxy-          UV, MS,    Powley et al.
 uanosine; calf          guanosine C-6 adducts, as well as a diastereomeric pair of     NMR        (2003)
hymus DNA                C-8 HMVK-derived 1,N2 -propanodeoxyguanosine adducts
             DNA base-adducts formed from 1,3-butadiene metabolites in vitro                                     113
</pre>

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<pre>14 1,3-Butadiene</pre>

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<pre> nnex I
      Evaluation of the Subcommittee on
      the Classification of carcinogenic
      substances
.1    Scope
      On request of the Dutch Expert Committee on Occupational Safety of the Health
      Council, the Subcommittee on the Classification of carcinogenic substances
      evaluates the carcinogenic properties of 1,3-butadiene.
          In the Netherlands a special policy is in force with respect to occupational
      use and exposure to carcinogenic substances. Regarding this policy, the Minister
      of Social Affairs and Employment has asked the Health Council of the
      Netherlands to evaluate the carcinogenic properties of substances, and to propose
      a classification with reference to an EU-directive (see Annex J). In addition to
      classifying substances, the Health Council also assesses the genotoxic properties
      of the substance in question.
          The members of the Subcommittee on the Classifaction of carcinogenic
      substances are listed at the end of this Annex. This evaluation is based on the
      data summarized in Chapter 2 of the present report.
.2    Carcinogenicity of 1,3-butadiene
      1,3-Butadiene (butadiene) was classified previously as a human carcinogen by
      the International Agency for Research on Cancer (category 1; IARC 2008, 2009)
      and by the European Commission (category 1A; EU-RAR 2002).
      Evaluation of the Subcommittee on the Classification of carcinogenic substances   115
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<pre>       Many human studies show an elevated risk of leukaemia or other cancers of
   the lymphohaematopoietic system following exposure to butadiene. Only three
   of these studies have been conducted on workers employed in butadiene
   manufacturing facilities, where exposure is to butadiene monomer alone. Most
   studies, however, have been done on workers exposed to butadiene during
   styrene-butadiene rubber (SBR) production. Although a relative large number of
   studies has been reported (fully reviewed in DECOS 1990, IARC 2008, ATSDR
   2009), many of these studies update previously reported findings and thus relate
   to the same or overlapping cohort populations.
       Compared to exposure to butadiene alone in the monomer production sites,
   multiple chemical exposures of SBR workers makes interpretation of the results
   more difficult. In addition, have worked in both the butadiene manufacturing
   industry and in the SBR industry, which makes the interpretation of these studies
   even more complicated.
       In two of the butadiene monomer industry studies a slight overall excess of
   mortality from leukaemia was observed, whereas in the third study a small deficit
   in mortality from leukaemia was observed. The increased mortality from
   leukaemia in one of the monomer industry cohorts was more pronounced among
   workers who had been exposed at high levels during the first years of production
   (second World War). In this cohort, no increase in leukaemia was observed with
   duration of exposure or cumulative exposure.
       Two studies of SBR workers by researchers at the University of Alabama at
   Birmingham, USA (Delzell et al. 2001, Cheng et al. 2007) were considered to be
   the most informative. In these study the mortality rates of approximately 17,000
   workers from eight facilities in the USA and Canada were examined, and
   included earlier studies of some of the facilities. Limiting factors in the
   evaluations were that the diagnosis and classification of lymphatic and
   haematopoietic malignancies are very complex and have undergone several
   changes over the course of time. Although overall mortality from leukaemia was
   only slightly elevated in the most recent update of this cohort, larger increases of
   mortality from leukaemia (chronic lymphocytic and chronic myelogenous
   leukaemia) were seen in workers in the most highly exposed areas of the plants
   and among hourly paid workers, especially those who had been hired in the early
   years and had longer (≥10 years) employment. Furthermore, a significant
   exposure-response relationship between cumulative butadiene exposure and
   mortality from leukaemia was observed, and the most recent analyses indicate
   that the exposure-response relationship for butadiene and leukaemia was
   independent of exposure to styrene and dimethyldithiocarbamate (Cheng et al.
16 1,3-Butadiene
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<pre>   2007, Sielken et al. 2007, Graff et al. 2009, Sathiakumar and Delzell 2009,
   Sathiakumar et al. 2009).
       The Subcommittee concludes that the human studies provide limited
   evidence regarding the carcinogenicity of butadiene: there is a positive
   association between exposure to butadiene and cancer, but coincidences, bias and
   confounders cannot fully be excluded.
       Several studies with mice showed increased tumour formation in various
   organs in both sexes at exposures to approximately 1 ppm (2.2 mg/m3)
   butadiene. This was not observed in rats at exposures up to 1,000 ppm (2,200
   mg/m3), likely due to the crucial role of oxidative metabolism: butadiene
   requires metabolic activation to generate electrophilic epoxides in which
   important species differences exist (mice are more efficient in the production of
   epoxide metabolites of butadiene, while rats and humans are more efficient in the
   hydrolytic detoxification of these metabolites) (reviewed in IARC 2008, EU-
   RAR 2002, ATSDR 2009, Kirman et al. 2010b). Although carcinogenicity has
   been observed in one animal species only, positive results have been obtained in
   several studies, including a number of studies by the US National Toxicology
   Program. The Subcommittee concludes that the animal studies provide sufficient
   evidence for the carcinogenicity of butadiene.
       Many tests on mutagenicity, genotoxicity and mechanism of action clearly
   indicate that butadiene is a genotoxic compound in humans and in experimental
   animals, requiring metabolic activation to generate electrophilic and DNA-
   reactive epoxides (stereoisomers of epoxybutene, epoxybutanediol and
   diepoxybutane; reviewed in IARC 2008, EU-RAR 2002, ATSDR 2009, Albertini
   et al. 2010, Kirman et al. 2010a, 2010b). The Subcommittee considers butadiene
   therefore as a stochastic genotoxic carcinogen, and advises to calculate health
   based occupational cancer risk values.
.3 Recommendation for classification
   Based on the available data, the Subcommittee recommends classifying 1,3-
   butadiene in category 1A (‘the compound is known to be carcinogenic to man’),
   and considers the substance as a stochastic genotoxic carcinogen.
   Evaluation of the Subcommittee on the Classification of carcinogenic substances   117
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<pre>   References
   Albertini RJ, Carson ML, Kirman CR, Gargas ML, 2010. 1,3-Butadiene: II. Genotoxicity profile. Crit
   Revs Toxicol 40(S1): 12-73.
   ATSDR, 2009. Toxicological profile for 1,3-butadiene (draft). Agency for Toxic Substances and
   Disease Registry, US Department of Health and Human Services, Public Health Service.
   Cheng H, Sathiakumar N, Graff J, Matthews R, Delzell E. 1,3-Butadiene and leukemia among
   synthetic rubber industry workers: exposure-response relationships. Chem Biol Interact 2007; 166(1-
   3): 15-24.
   DECOS, 1990. Health-based recommended occupational exposure limits for 1,3-butadiene. Dutch
   Expert Committee on Occupational Standards; Health Council of the Netherlands, report no. RA5/
   1990.
   Delzell E, Macaluso M, Sathiakumar N, Matthews R, 2001. Leukemia and exposure to 1,3-butadiene,
   styrene and dimethyldithiocarbamate among workers in the synthetic rubber industry. Chem-Biol
   Interact 135-136: 515-534.
   EU-RAR, 2002. European Union Risk Assessment Report 1,3-Butadiene.
   Graff JJ, Sathiakumar N, Macaluso M, Maldonado G, Matthews R, Delzell E, 2009. The effect of
   uncertainty in exposure estimation on the exposure-response relation between 1,3-butadiene and
   leukemia. Int J Environ Res Public Health 6(9): 2436-2455.
   IARC, 2008. Monographs on the evaluation of the carcinogenic risk of chemicals to humans: 1,3-
   Butadiene. Vol. 97: 45-184. International Agency for Research on Cancer.
   IARC, 2009. Working Group, International Agency for Research on Cancer. Special report: policy. A
   review of human carcinogens, part F: chemical agents and related occupations. Lancet Oncol 10(12):
   1143-1144.
   Kirman CR, Albertini RJ, Gargas ML, 2010a. 1,3-Butadiene: III. Assessing carcinogenic modes of
   action. Crit Revs Toxicol 40(S1): 74-92.
   Kirman CR, Albertini RJ, Sweeney LM, Gargas ML, 2010b. 1,3-Butadiene: I. Review of metabolism
   and the implications to human health risk assessment. Crit Revs Toxicol 40(S1): 1-11.
   Sathiakumar N, Brill I, Delzell E, 2009. 1,3-Butadiene, styrene and lung cancer among synthetic
   rubber industry workers. J Occup Environ Med 51(11): 1326-1332.
   Sathiakumar N, Delzell E, 2009. A follow-up study of mortality among women in the North
   American synthetic rubber industry. J Occup Environ Med 51(11): 1314-1325.
   Sielken RL, Valdez-Flores C, Gargas ML, Kirman CR, Teta MJ, Delzell E, 2007. Cancer risk
   assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective. Chem-
   Biol Interact 166(1-3):140-149.
18 1,3-Butadiene
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<pre>The Subcommittee
•  G.J. Mulder, chairman
   Emeritus Professor of Toxicology, Leiden University, Leiden
•  M.J.M. Nivard
   Molecular Biologist and Genetic Toxicologist, Leiden University Medical
   Center, Leiden
•  R.A. Woutersen
   Toxicologic Pathologist, TNO Innovation for Life, Zeist, and Professor of
   Translational Toxicology, Wageningen University and Research Centre,
   Wageningen
•  A.A. van Zeeland
   Emeritus Professor of Molecular Radiation Dosimetry and Radiation
   Mutagenesis, Leiden University Medical Center, Leiden
•  E.J.J. van Zoelen
   Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
•  A.J. Baars, scientific secretary
   Health Council of the Netherlands, The Hague
Meeting date: 3 December 2010
Evaluation of the Subcommittee on the Classification of carcinogenic substances 119
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<pre>20 1,3-Butadiene</pre>

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<pre> nnex        J
             Carcinogenic classification of
             substances by the Committee
             The committee expresses its conclusions in the form of standard phrases:
 ategory         Judgement of the committee (GRGHS)                                   Comparable with EU Category
                                                                                      67/584/EEC        EC No 1272/2008
                                                                                      before 12/16/2008 as from 12/16/2008
A               The compound is known to be carcinogenic to man.                      1                 1A
                • It acts by a stochastic genotoxic mechanism.
                • It acts by a non-stochastic genotoxic mechanism.
                • It acts by a non-genotoxic mechanism.
                • Its potential genotoxicity has been insufficiently investigated.
                Therefore, the mechanism of action is not known.
B               The compound is presumed to be carcinogenic to man.                   2                 1B
                • It acts by a stochastic genotoxic mechanism.
                • It acts by a non-stochastic genotoxic mechanism.
                • It acts by a non-genotoxic mechanism.
                • Its potential genotoxicity has been insufficiently investigated.
                Therefore, the mechanism of action is not known.
                The compound is suspected to be carcinogenic to man.                  3                 2
3)              The available data are insufficient to evaluate the carcinogenic      Not applicable    Not applicable
                properties of the compound.
4)              The compound is probably not carcinogenic to man.                     Not applicable    Not applicable
ource: Health Council of The Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.
             Carcinogenic classification of substances by the Committee                                                121
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<pre>22 1,3-Butadiene</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 and              realise significant                 which carry certain
opportunities?                        health benefits?                    health risks?
Environmental health                  Healthy working                     Innovation and
Which environmental                   conditions                          the knowledge
influences could have                 How can employees                   infrastructure
a positive or negative                be protected against                Before we can harvest
effect on health?                     working conditions                  knowledge in the
                                      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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