<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
          Polyvinyl chloride
             Evaluation of the carcinogenicity and genotoxicity
2013/22
</pre>

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<pre>Polyvinyl chloride
    Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp                 : aanbieding advies Polyvinyl chloride
Uw kenmerk                : DGV/BMO-U-932542
Ons kenmerk               : U-7911/SV/fs/246-Z18
Bijlagen                  :1
Datum                     : 18 oktober 2013
Geachte minister,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
polyvinylchloride.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving
van de Gezondheidsraad.
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
E - m a i l : s r. v i n k @ g r. n l                            w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 5 5 0 8
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<pre></pre>

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<pre>Polyvinyl chloride
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of the
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2013/22, The Hague, October 18, 2013
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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. Polyvinyl chloride. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2013; publication no. 2013/22.
all rights reserved
ISBN: 978-90-5549-969-4
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Data 14
   Polyvinyl chloride 15
.1 Identity and general information 15
.2 IARC conclusion 16
   Carcinogenicity studies 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 23
.3 Conclusion 24
   Contents                              7
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<pre>    Genotoxicity 25
 .1 Gene mutations assays 25
 .2 Chromosomal aberrations 25
 .3 Conclusion 26
    Classification 27
 .1 Evaluation of data on carcinogenicity and genotoxicity 27
 .2 Recommendation for classification 28
    References 29
    Annexes 31
A   Request for advice 33
B   The Committee 35
C   Submission letter 37
D   Comments on the public review draft 39
E   IARC Monograph 41
F   Human studies 43
G   Animal studies 47
H   Carcinogenic classification of substances by the Committee 51
    Polyvinyl chloride
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie polyvinylchlo-
ride onder de loep. Polyvinylchloride wordt geproduceerd uit vinylchloride en
wordt vooral gebruikt in de bouw- en constructie-industrie, in auto-onderdelen,
in consumentenproducten, in verpakkingen en als isolatie van electriciteitsdraad.
Polyvinylchloride wordt gemengd met additieven, zoals weekmakers, stabilisa-
toren, vullers, kleurstoffen, vlamvertragers en biociden.
De commissie concludeert dat de gegevens over polyvinylchloride niet
voldoende zijn om de kankerverwekkende eigenschappen te evalueren
(categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage H).
Samenvatting                                                                      9
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<pre>0 Polyvinyl chloride</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Safety of the Health Council. In this
report, the Committee evaluated polyvinyl chloride. Polyvinyl chloride is
produced from vinyl chloride and is mainly used in the building and construction
industries, in automotive parts, in consumer goods, in packaging and as electrical
wire insulation. Polyvinyl chloride is compounded with additives, such as
plasticisers, stabilisers, fillers, colorants, flame retardants and biocides.
The Committee concludes that the available data are insufficient to evaluate the
carcinogenic properties of polyvinyl chloride (category 3).*
According to the classification system of the Health Council (see Annex H).
Executive summary                                                                  11
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<pre>2 Polyvinyl chloride</pre>

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<pre> hapter 1
        Scope
1.1     Background
        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 (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for a classification are expressed in the form of
        standard sentences (see Annex H).
        This report contains the evaluation of the carcinogenicity of polyvinyl chloride,
        further referred to as PVC.
1.2     Committee and procedure
        The evaluation is performed by the Subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Safety of the
        Health Council, hereafter called the Committee. The members of the Committee
        are listed in Annex B. The submission letter to the Minister can be found in
        Annex C.
        Scope                                                                             13
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<pre>         In 2013, 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
    The evaluation and recommendation of the Committee is based on scientific
    data, which are publicly available. The starting points of the Committees’ reports
    are, if possible, the monographs of the International Agency for Research on
    Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the Committee
    when these are considered most relevant in assessing the carcinogenicity and
    genotoxicity of the substance in question. In the case of PVC, an IARC-
    monograph of vinyl chloride and polymers is available, of which the summary
    and conclusion with regard to PVC are inserted in Annex E.
         More recently published data were retrieved from the databases Medline and
    XToxline, and Chemical Abstracts. The last updated online search was in August
    2013. The relevant new data were included in this report.
 4  Polyvinyl chloride
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<pre> hapter 2
        Polyvinyl chloride
2.1     Identity and general information
        Polyvinyl chloride (PVC) is produced through the polymerisation of vinyl
        chloride. PVC resins for the production of rigid plastics are processed essentially
        without plasticiser: the polymer may be a homopolymer or a copolymer made
        with low levels of comonomer such as vinyl acetate or ethylene. The como-
        nomers are used to aid in the processing of the resulting polymer. Most of the
        flexible and semi-rigid PVC plastics contain plasticisers at a level of 10-100% of
        the resin weight. The plasticisers most commonly used are dialkyl phthalates.
        Other compounding materials (such as pigments, fillers and light- and heat-
        stabilisers) are also used. PVC dispersion or paste resins are used in the form of
        plastisols (PVC resin dispersed in plasticiser).1 PVC is mainly used in the
        building and construction industries, automotive parts, in consumer goods,
        packaging and electrical wire insulation.1,2
        Polyvinyl chloride                                                                  15
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<pre>    The identity of PVC and some of its physicochemical properties are given
    below.1
    Chemical name             : polyvinyl chloride
    CAS registry number       : 9002-86-2
    EC/EINECS number          : not allocated
    Synonyms                  : chloroethene homopolymer; atactic poly(vinyl chloride);
                                chloroethylene polymer; poly(chloroethylene); poly(vinyl chloride);
                                poly(vinylchloride); PVC; vinyl chloride homopolymer; vinyl
                                chloride polymer
    Colour and physical state : white or colourless granules
    Molecular weight          : 60,000-150,000 (average)
    Molecular formula         : (C2H3Cl)n
    Structure                 :
    Relative density          : 1.406
    Solubility                : Solvents for unmodified PVC of high molecular weight are:
                                cyclohexanone, methyl cyclohexanone, dimethyl formamide,
                                nitrobenzene, tetrahydrofuran, isophorone and mesityl oxide.
                                Solvents for lower polymers are: di-n-propyl ketone,
                                methyl amyl ketone, methyl isobutyl ketone, acetonylacetone,
                                methyl ethyl ketone, dioxane and methylene chloride.
    Stability                 : PVC is unstable to heat and light in the absence of added stabilizers.
                                Thermal decomposition products can include ethylene and aromatics
                                such as benzene, toluene, 1,3,5-trichlorobenzene and naphthalene.
2.2 IARC conclusion
    In 1979, IARC concluded that the available studies on PVC are insufficient to
    evaluate the carcinogenicity of this compound.1 Therefore, according to the
    IARC criteria, PVC was considered to be not classifiable as to its carcinogenicity
    to humans (Group 3).
 6  Polyvinyl chloride
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<pre> hapter 3
        Carcinogenicity studies
3.1     Observations in humans
        Exposure of humans to PVC often cannot be separated from the exposure to
        vinyl chloride. IARC concluded that there is sufficient evidence in humans for
        the carcinogenicity of vinyl chloride, causing angiosarcoma of the liver and
        hepatocellular carcinoma, and subsequently classified vinyl chloride in Group 1
        (carcinogenic to humans).3 Most studies with PVC workers have focussed on
        exposure to vinyl chloride monomer, but might also provide information on the
        carcinogenicity of PVC. The Committee limits itself to studies specifically
        focusing on the exposure to PVC. These are summarised below, and presented in
        the Table in Annex F.
        Cohort studies
        Gennaro et al.4 reanalysed a VC-PVC production plant cohort previously studied
        by Mastrangelo et al.5, by using an internal reference group. In total, 1,658
        employees had worked in a large petrochemical plant for any period between
        July 1950 and July 1985; follow-up period extended from January 1972 to
        December 1999. Workers were classified according to their job categories (28
        plant sectors) in four large, rather homogeneous groups: autoclave workers (who
        are associated with exposure to relatively high levels of vinyl chloride), PVC
        baggers, PVC compound workers, and other blue collar workers. Technicians
        Carcinogenicity studies                                                         17
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<pre>  and clerks, considered as a group with low (or null) exposure was used as
  internal reference group. The analysis was performed using a Poisson regression
  model including age, calendar period of follow-up, age at hiring, year of hiring,
  duration of employment and latency.
      A statistically increased risk mortality rate was found in autoclave workers
  for liver tumours, including angiosarcoma (relative risk (RR) 9.57; 95% CI
  3.71-24.68). A non-significantly increased RR was found for lung cancer in
  PVC baggers (3.13; 0.96-10.28; p < 0.10) and liver tumours in PVC compound
  workers (2.46; 0.94-6.42; p < 0.10). The fourteen workers with lymphoid and
  haematopoietic cancer could not be compared to the referent group, because
  none were seen in the reference group. When compared to the Italian population
  statistically significant increased standardised mortality ratio (SMRs) were
  estimated for PVC baggers and for the total blue collar workforce, while PVC
  compound workers and other blue collar workers showed more than two-fold
  increase SMRs (not statistically significant).
      The Committee notes that the elevated lung cancer relative risk in the
  baggers is difficult to interpret since it is based on a small internal comparison
  group with only three observed deaths from lung cancer. The comparisons with
  the internal reference group is the more doubtful given the all cause RR of 1.72
  in the baggers and similarly high RR for all causes in the other sub cohorts.
  Another retrospective cohort mortality study was executed in 5,498 male
  workers from nine chemical plants manufacturing or polymerising vinyl chloride
  in the UK.6 Workers had to be employed for at least 1 year in a job that involved
  potential exposure to vinyl chloride for at least 25% of the workweek between
  1940 and 1974, and were followed up to 31 December 1984. Workers were
  divided in 4 categories: autoclave operators, baggers and driers, craftsmen and
  other workers. The hygiene data available indicated that autoclave workers had
  the highest exposure to vinyl chloride, bagger and driers the highest PVC dust
  exposure (0.38-2.88 mg/m3), and craftsmen intermediate exposure for both
  monomer and polymer. Mortality rates were compared to expected mortality
  rates of males in England and Wales matched for age.
      A strong healthy worker effect was observed. A significant excess of
  nonsecondary liver cancer (mainly angiosarcomas) was reported in autoclave
  workers with a median latency period of 25 years from date of first exposure.
  Bagger and driers, and craftsmen showed a deficit of death caused by lung cancer
  (SMR 0.58 and 0.42, respectively; smoking was not considered as confounding
  factor).
8 Polyvinyl chloride
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<pre>Waxweiler et al.7 performed a retrospective cohort study of 4,806 white male
workers ever employed at a synthetic chemicals plant in Kentucky, US, from its
opening in 1942 until 31 December 1973. Many of the workers had concomitant
exposure to vinyl chloride monomer, as well as to chlorinated solvents, PVC
dust, acrylates and acrylonitrile. In this cohort, a statistically significant risk of
death due to malignant tumours of the central nervous system (SMR = 2.09;
p < 0.05) and respiratory system (SMR = 1.49; p < 0.01) was observed compared
to the US white male population. Also, an analysis including 10 years latency
showed a slightly increased risk of death for respiratory system cancer (SMR
1.56).
     To determine whether an excess risk existed for a particular histological type
of lung cancer, Waxweiler et al. conducted a study design which was referred to
as a case-comparand study. In this study the worker case group, consisting of the
27 of the 45 deceased individuals for whom histologic specimens were available,
was compared with a lung cancer comparison group*. An excess of respiratory
system cancer was found to be limited to adenocarcinoma (SMR 1.38; p not
given) and especially, large cell undifferentiated lung cancer (SMR 4.41; p not
given) when compared with the comparison group.
     To evaluate the association between lung cancer and each of 19 chemicals at
the plant, detailed work histories for each cohort member were combined with
exposure ratings for each of 19 chemicals for each job for each calendar year
since 1942. A serially additive expected dose model was then constructed which
compared the doses of each chemical observed for the lung cancer cases to the
doses expected based on subcohorts without lung cancer individually matched to
the cases. PVC dust appeared to be the most likely etiologic agent (p = 0.037).
Time trends of PVC dust exposure indicated a potential latent period of 5-16
years before death.
Wu et al. updated the cohort studied by Waxweiler et al. and extended the
observation period from 1974 to 1986.8 In the total cohort, a statistically
significant increase in cancer risk was observed for liver, lung, and brain. In a
subpopulation exposed to vinyl chloride (but potentially also to PVC), only an
excess risk was observed for liver cancer.
Lung cancer cases most closely preceding and succeeding the chemical plant workers case in the
chronologically ordered hospital pathology logs, matched in age at diagnosis, sex, race, and county of
residence. Smoking was not investigated.
Carcinogenicity studies                                                                                19
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<pre>  Ward combined and updated several cohort studies on vinyl chloride workers in
  Europe, accumulating in a cohort of 12,700 male workers.9 The emphasis of this
  study was on exposure to VCM. No strong relation was observed between
  cumulative vinyl chloride exposure and cancers other than in liver.
      Several additional analyses were done on the subcohort of packers and
  baggers, that was particularly exposed to PVC dust. The Committee notes that
  the reported results in this respect are somewhat ambiguous. Ward et al. report to
  have observed no trend in lung cancer risk with increasing exposure for persons
  ever worked as packer or bagger. However, these authors reported a positive
  trend in lung cancer in the persons who had only worked in these jobs. The exact
  findings with respect to lung cancer and PVC dust are not shown in the
  publication.
  Case-control studies
  Mastrangelo et al.5 conducted a nested case-control study among 543 claimants
  (out of a total cohort of 1658 workers) employed at an Italian vinyl chloride/PVC
  production plant. Thirty-eight cases of histologically confirmed lung cancer and
  224 control subjects without a history of cancer were selected from the claimants.
  Four categories of exposure to PVC dust were determined: (0) subjects with the
  least exposure to PVC dust; (1) compounding workers, never baggers; (2) PVC
  baggers with several jobs at once, date of specific job change not indicated; (3)
  PVC baggers with known length of job, for whom start and end dates were
  available.
      An odds ratio (OR) of 5.6 (95% CI 2.03-16.3) was found for PVC baggers
  with known duration of work. The lung cancer risk increased with the years
  working as a bagger (≥ 3.6 years, OR 7.15; CI 2.55-19.3) and increasing age at
  onset of the job (over 33 years at onset, OR 7.70; CI 2.72-21.1). Both groups of
  baggers with calendar year at onset of job before 1967 or from 1967 onwards
  showed a significant increase of lung cancer compared to workers who had
  never been baggers (before 1967 OR 4.79; CI 1.73-12.5; ≥ 1967 OR 4.55;
  CI 1.38-13.6). Recent rather than historical exposure as a bagger results in a
  stronger association with lung cancer (> 20 years: OR 3.76; CI 1.51-8.99;
  ≤ 20 years: 11.4; CI 2.21-60.7).
      No significant association with lung cancer was found for PVC com-
  pounding, cumulative vinyl chloride exposure, or age at the end of the period of
  observation. Correcting for smoking and age, an excess of lung cancer risk (OR
  1.20; CI 1.08-1.35) was found for each extra year of work as a bagger compared
0 Polyvinyl chloride
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<pre>to workers never exposed to PVC, compounding workers, and baggers with
unknown length of job.
Wu et al. updated the cohort described by Waxweiler et al. and case-control
analyses to 31 December 1986, comprising 4,835 white males.8 Exposure to
PVC dust occurred primarily during the packing of the dried polymer, which was
in the form of a powder. PVC dust exposure occurred in many of the same areas
in which exposure to vinyl chloride occurred. Some workers were also exposed
to butadiene.
    Exposures for each chemical were rated from 0 (no exposure), 1 (exposure
(chemical in building, not handled), 2 (moderate exposure; works around
chemical), 3 (occasional high exposure; spill), 4 (high exposure) and 5 (intimate
contact; e.g. cleaners). Case subjects were matched to 5 control subjects by age.
The excess as reported by Waxweiler (1981) was not confirmed. No association
was found for exposure to PVC dust and lung cancer, since average cumulative
exposure to PVC dust was lower in the lung cancer cases than in the controls.
Hardell et al. reported a case-control study investigating a possible asso-
ciation between testicular cancer and exposure to PVC among the Swedish
population.10,11 Cases (n = 148) with testicular cancer and 30-75 years old were
extracted from the Swedish Cancer Registry between 1989 and 1992. Controls
(n = 315) were selected from the Swedish Population Registry as the next subject
in birth registration order (born the same year) as the cases. Exposures to PVC
plastics were confirmed by contact with the employers or the production
managers.
    Seven cases and two controls had been exposed to PVC resulting in an OR of
6.6 (95% CI 1.4-32) for testicular cancer. The latency period varied between 11
and 35 years. For cumulative exposure to PVC in the lowest exposure group with
3 cases and 2 controls an OR could be calculated of 2.6 (95% CI 0.3-3.2; latency
period not specified).
Hardell et al. conducted a second case-control study for germ cell testicular
cancer.12 Each case (age 20-75 years and recorded in the period 1993-1997) was
matched with one control, resulting in 791 matched pairs. Exposure was assessed
with a questionnaire similar to the previous study, however with more detailed
exposure on plastics exposure. Every work task was classified according to type
of PVC contact with regard to dust levels. The one subject that had been exposed
to vinyl chloride, i.e. had been working with production of PVC plastics, was
excluded from analysis.
Carcinogenicity studies                                                           21
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<pre>  Overall exposure to PVC plastics gave an OR of 1.35 (CI 1.06-1.71) slightly
  increasing with a > 10 years latency period to 1.45 (CI 1.06-1.98). However, no
  increasing response was found at increasing concentration. Rather, an inverse
  relationship with the highest OR in the lowest exposure category was observed
  (independent of latency period). This inverse relationship between exposure and
  response was also apparent using an updated exposure estimation by Westberg et
  al.13
  Selenskas et al. conducted a case-control study for deaths from pancreatic cancer
  from a cohort who had worked 7 months or more at a New Jersey plant between
  1946 and 1967.14 A total of 28 cases were included, and 5 controls per case.
       For the work area vinyl and polyethylene processing with possible exposure
  to PVC for vinyl processing (9 cases; 40 controls) an excess risk was found for
  duration of employment > 16 years (RR 7.15; 95% CI 1.28-40.1). No trend with
  increasing duration was apparent. For resin pulverising, and resins and varnish
  no increased risk was found; for these work areas PVC was not considered as one
  of the major chemicals to which exposure was possible.
  Other
  Chiazze et al.15,16 reported a cross-sectional mortality study with 3,847 deaths of
  white employees of seventeen PVC fabricators during 1964-1973. Several
  exposure categories (no exposure, improbable, possible, definite or unknown
  exposure) separately and combined were compared to not exposed employees.
  Sex-race-cause-specific proportionate mortality ratios (PMRs) were calculated
  by comparing with the US mortality for the individual years 1964-1973. The
  ratios were significantly different from unity for all cancers combined, and for
  cancers of the digestive system and for other, unspecified cancers among both
  white males and white females. In females also PMRs for urinary cancer and
  breast cancer were statistically significantly increased.
       The incidence of deaths due to breast cancer was further investigated by
  case-control analysis. A total of 44 breast cancer deaths and 134 controls
  matched for age and distributed among eight companies were available. Most of
  the cases and controls belonged to the no exposure or improbable exposure
  category (33/44 cases and 114/134 controls), leaving only small numbers that
  have been exposed (2 cases and 6 controls for the definite category). None of the
  relative risks was statistically significantly increased.
2 Polyvinyl chloride
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<pre>    IARC reported a proportional mortality study, using death certificates from
    1970-1972 of 707 male plastic workers (extruding, moulding, cutting, turning or
    otherwise machining plastics, and including PVC fabricating) resulted in a
    statistically significant excess of stomach cancer mortality (24 observed/16.4
    expected; p < 0.05).1
        IARC noted several limitations of the study (i.e. the use of proportionate
    mortality methodology, and the fact that not all deaths studied were among
    workers engaged in PVC activity).
    Summary
    Several epidemiological studies are available, with different designs (i.e.
    retrospective cohort, case-control, cross-sectional mortality). Most of these
    studies do not specifically address – and do not quantify – exposure to PVC. The
    results are inconsistent, as some studies report an association between PVC and
    lung cancer or testicular cancer, while other studies do not.
3.2 Carcinogenicity studies in animals
    Inhalation
    Groth et al. exposed rats, guinea pigs and monkeys by inhalation (6 hour/day,
    5 days/week) for up to 22 months to a concentration of 13 mg PVC dust/m3. The
    treatment and control groups each contained 80 rats, 40 guinea pigs and 10
    monkeys. Autopsies on rats and guinea pigs were performed after 12 months of
    exposure and on monkeys after 22 months of exposure.17
        Aggregates of alveolar macrophages containing PVC particles were found in
    the lungs of all animals. No gross abnormalities were seen in the lungs or other
    organs that could be related to the exposures.
    A group of 48 rats (24 per sex) was exposed to PVC dust, at a concentration
    of 12 mg/m3 for 7 hour/day, 5 days/week for 5 months.18 Cumulative exposure
    amounted to 8,552 mg/m3*hour. Forty-eight control animals were not exposed.
    For each group, 6 rats were sacrificed at the end of the exposure period, 6
    additional animals were sacrificed a year after the start of the exposure and
    the remaining animals were allowed to die of natural causes.
        Widespread distribution of PVC particles was observed in all animals. There
    was evidence of a slight proliferation of reticulin fibers around some foci of
    Carcinogenicity studies                                                          23
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<pre>    macrophages in the spleen, however no progression was observed in any of the
    animals.
    Oral
    No oral studies are available.
    Dermal
    No dermal studies are available.
    Other routes
    A number of carcinogenicity studies with subcutaneously transplanted PVC have
    been reported in 1979 by IARC and hereafter, describing the induction of
    malignant fibrous histiocytomas by the implant.1,19,24,25 No clearly increased
    incidence of tumours was found after intraperitoneal or intrapleural injection of
    granulair PVC.18,20
        As these exposure routes are not relevant for occupational situation, these
    studies are only presented in Annex G.
3.3 Conclusion
    The Committee notes that the available epidemiological data are inconsistent. As
    the exposure of PVC has not been properly assessed, co-exposures or general
    dust toxicity could have attributed to the inconsistent findings. The Committee
    concludes that the human data are insufficient to draw any conclusions on the
    carcinogenic properties of PVC in humans.
        The Committee considers the available animal data not sufficient to draw
    conclusions on the carcinogenicity of PVC in animals.
 4  Polyvinyl chloride
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<pre> hapter 4
        Genotoxicity
4.1     Gene mutations assays
4.1.1   In vitro assays
        PVC did not induce reverse mutations in S. typhimurium TA97, TA98, TA100
        and TA1535 with and without metabolic activation.21
        In vivo assays
        No data are available.
4.2     Chromosomal aberrations
4.2.1   In vitro assays
        No data are available.
4.2.2   In vivo assays
        Suskov and Sazonova (1982) reported a cytogenetic analysis in peripheral
        lymphocytes of 52 workers exposed to synthetic resins, including PVC resin.22
        The average reported concentration of PVC in the air of working areas was
        Genotoxicity                                                                  25
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<pre>    6 mg/m3. Seventy-four healthy individuals with no occupational contacts with
    synthetic resins and matched for sex, smoking, alcohol consumption and
    medication served as controls. A statistically significant increase in the average
    frequency of cells with chromosome aberrations of 6.1% was found for PVC
    compared to 2.4% for the controls. The spectrum of chromosome aberrations, i.e.
    mainly single and paired fragments, was also significantly different from the
    control. The Committee notes the potential of co-exposure and the limitations in
    reporting of the study.
4.3 Conclusion
    The Committee concludes that there are insufficient data available to draw
    conclusions on the genotoxicity of PVC.
 6  Polyvinyl chloride
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        The epidemiological studies available showed no consistent evidence for
        carcinogenicity of PVC in humans. Some studies show an association between
        certain cancer types and workers involved in PVC handling, whereas others do
        not. As these studies show serious methodological limitations (e.g. lacking a
        reliable exposure assessment of PVC, limited correction for confounders
        including co-exposures), the Committee considers the human data insufficient to
        draw any conclusions on the carcinogenic properties of PVC in humans.
            A chronic inhalation study is available in rats, ginea pigs and monkeys, in
        which no (pre-)malignant lesions were observed. This study, however, was not
        aimed to identify carcinogenic effects and shows several methodological
        limitations, such as the use of only one dose level, lack of a sufficient follow-up
        period, and proper histopathologic analysis and reporting. Other carcinogenicity
        studies did not address a relevant route of exposure. Due to the lack of reliable
        carcinogenicity data, the Committee cannot draw conclusions on the
        carcinogenicity of PVC in animals.
            PVC did not induce reverse mutations in S. typhimurium with or without
        metabolic activation. A study in PVC fabrication workers showed an increased
        number of chromosomal aberrations, however this study showed severe
        limitations in reporting and design. The Committee notes that there is insufficient
        information on the potential genotoxic mode of action of PVC.
        Classification                                                                      27
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<pre>5.2 Recommendation for classification
    The Committee concludes that the data on PVC are insufficient to evaluate the
    carcinogenic properties (category 3).*
    According to the classification system of the Health Council (see Annex H).
 8  Polyvinyl chloride
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<pre>References
Vinyl chloride, polyvinyl chloride and vinyl chloride-vinyl acetate copolymers. IARC monographs
on the evaluation of the carcinogenic risk of chemicals to humans 1979; 19: 377-438.
Toxicological profile for vinyl chloride. US Department of Health and Human Services; Public
Health Service; Agency for Toxic Substances and Disease Registry; 2006.
IARC monographs on the evaluation of carcinogenic risks to humans. 1,3-Butadiene, Ethylene Oxide
and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide). 21998: Volume 97.
Gennaro V, Ceppi M, Crosignani P, Montanaro F. Reanalysis of updated mortality among vinyl and
polyvinyl chloride workers: Confirmation of historical evidence and new findings. BMC public
health 2008; 8: 21.
Mastrangelo G, Fedeli U, Fadda E, Milan G, Turato A, Pavanello S. Lung cancer risk in workers
exposed to poly(vinyl chloride) dust: a nested case-referent study. Occupational and environmental
medicine 2003; 60(6): 423-428.
Jones RD, Smith DM, Thomas PG. A mortality study of vinyl chloride monomer workers employed
in the United Kingdom in 1940-1974. Scand J Work, Environ Health 1988; 14(3): 153-160.
Waxweiler RJ, Smith AH, Falk H, Tyroler HA. Excess lung cancer risk in a synthetic chemicals plant.
Environmental health perspectives 1981; 41: 159-165.
Wu W, Steenland K, Brown D, Wells V, Jones J, Schulte P et al. Cohort and case-control analyses of
workers exposed to vinyl chloride: an update. Journal of occupational medicine : official publication
of the Industrial Medical Association 1989; 31(6): 518-523.
Ward E, Boffetta P, Andersen A, Colin D, Comba P, Deddens JA et al. Update of the follow-up of
mortality and cancer incidence among European workers employed in the vinyl chloride industry.
Epidemiology 2001; 12(6): 710-718.
References                                                                                            29
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<pre>0 Hardell L, Ohlson CG, Fredrikson M. Occupational exposure to polyvinyl chloride as a risk factor for
  testicular cancer evaluated in a case-control study. International journal of cancer 1997; 73(6): 828-
  830.
1 Ohlson CG, Hardell L. Testicular cancer and occupational exposures with a focus on xenoestrogens in
  polyvinyl chloride plastics. Chemosphere 2000; 40(9-11): 1277-1282.
2 Hardell L, Malmqvist N, Ohlson CG, Westberg H, Eriksson M. Testicular cancer and occupational
  exposure to polyvinyl chloride plastics: a case-control study. International journal of cancer 2004;
  109(3): 425-429.
3 Westberg HB, Hardell LO, Malmqvist N, Ohlson CG, Axelson O. On the use of different measures of
  exposure-experiences from a case-control study on testicular cancer and PVC exposure. Journal of
  occupational and environmental hygiene 2005; 2(7): 351-356.
4 Selenskas S, Teta MJ, Vitale JN. Pancreatic cancer among workers processing synthetic resins.
  American journal of industrial medicine 1995; 385-398.
5 Chiazze L, Jr., Ference LD. Mortality among PVC-fabricating employees. Environmental health
  perspectives 1981; 41: 137-143.
6 Chiazze L, Jr., Wong O, Nichols WE, Ference LD. Breast cancer mortality among PVC fabricators.
  Journal of occupational medicine : official publication of the Industrial Medical Association 1980;
  22(10): 677-679.
7 Groth DH, Lynch DW, Moorman WJ, Stettler LE, Lewis TR, Wagner WD et al. Pneumoconiosis in
  animals exposed to poly(vinyl chloride) dust. Environ Health Perspect 1981; 41: 73-81.
8 Wagner JC, Johnson NF. Preliminary observations of the effect of inhalation of PVC in man and
  experimental animals. Environ Health Perspect 1981; 41: 83-84.
9 Hansen T, Clermont G, Alves A, Eloy R, Brochhausen C, Boutrand JP et al. Biological tolerance of
  different materials in bulk and nanoparticulate form in a rat model: sarcoma development by
  nanoparticles. Journal of the Royal Society, Interface / the Royal Society 2006; 3(11): 767-775.
0 Pott F, Ziem U, Reiffer FJ, Huth F, Ernst H, Mohr U. Carcinogenicity studies on fibers, metal
  compounds, and some other dusts in rats. Exp Pathol 1987; 32(3): 129-152.
1 Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K. Salmonella mutagenicity tests: IV.
  Results from the testing of 300 chemicals. Environ Mol Mutagen 1988; 11(Suppl. 12): 1-158.
2 Suskov II, Sazonova LA. Cytogenetic effects of epoxy, phenolformaldehyde and polyvinylchloride
  resins in man. Mutation research 1982; 104(1-3): 137-140.
3 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds.
  Health Council of the Netherlands, The Hague; 2010: publication no. A10/07E.
4 Maekawa A, Ogiu T, Onodera H, Furuta K, Matsuoka C, Ohno Y, Tanigawa H, Salmo GS,
  Matsuyama M, Hayashi Y. Malignant fibrous histiocytomas induced in rats by polymers. J Cancer
  Res Clin Oncol. 1984;108(3):364-5.
5 Hatanaka S, Oneda S, Okazaki K, Shong LJ, Yoshida A, Isaka H, Yoshida H. Induction of malignant
  fibrous histiocytoma in female Fisher rats by implantation of cyanoacrylate, zirconia, polyvinyl
  chloride or silicone. In Vivo. 1993; Mar-Apr;7(2):111-5.
0 Polyvinyl chloride
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<pre>A Request for advice
B The Committee
C Submission letter
D Comments on the public review draft
E IARC Monograph
F Human studies
G Animal studies
H Carcinogenic classification of substances by the Committee
  Annexes
                                                             31
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<pre>2 Polyvinyl chloride</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 Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        33
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  committee is given in Annex B.
4 Polyvinyl chloride
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemical NV, Terneuzen (until April 1, 2013);
        Exponent, Menlo Park, United States (from August 15, 2013)
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  S.R. Vink, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              35
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<pre>  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.
6 Polyvinyl chloride
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<pre>nnex C
     Submission letter
     Subject         : Submission of the advisory report Polyvinyl chloride
     Your Reference : DGV/MBO/U-932542
     Our reference : U-7911/SV/fs/246-Z18
     Enclosed        :1
     Date            : October 18, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     polyvinyl chloride.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
     The advisory report was prepared by the Subcommittee on the Classification of
     Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety. The advisory report has been
     Submission letter                                                              37
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<pre>  assessed by the Health Council’s Standing Committee on Health and the
  Environment.
  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
8 Polyvinyl chloride
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in 2013 for public review. The
     following organisations and persons have commented on the draft document:
     •   Mr. T.J.Lentz, National Institute for Occupational Safety and Health, USA.
     Comments on the public review draft                                            39
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<pre>0 Polyvinyl chloride</pre>

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<pre>nnex E
     IARC Monograph
     Excerpt from VOL: 19 (1979)
     Vinyl chloride, polyvinyl chloride and vinyl chloride acetate copolymenrs
     CAS No.: 9002-86-2
     Summary of Data Reported and Evaluation
     Experimental data
     Polyvinyl chloride was tested in rats by subcutaneous and intraperitoneal
     implantation; local sarcomas were induced, the incidence of which varied with
     the size and form of the implant.
     Human data
     In two proportionate mortality studies, in which death certificates of workers
     who had been involved in the fabrication of plastics, including polyvinyl
     chloride, were analysed, there appeared to be an increased proportion of cancer
     of the digestive system in both sexes and possibly of the urinary system and of
     the breast in women.
     IARC Monograph                                                                  41
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<pre>  Evaluation
  The available studies on polyvinyl chloride, which indicate an elevated
  proportion of digestive system cancer in male and female workers and possibly
  of cancers of the breast and urinary organs in female workers involved in the
  fabrication of plastics, including polyvinyl chloride, are insufficient to evaluate
  the carcinogenicity of this compound.
2 Polyvinyl chloride
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<pre> nnex        F
             Human studies
 tudy type     Population        Exposure                  Exposure duration / Effect              Relative Ratio
                                                           Follow-up                               (95% CI)
 ohort         workers from      Classified according to total person-years    liver cancer        RR
Gennaro et al. large             job categories (28 plant 42,253 /             • autoclave workers 9.57 (3.71-24.68)
2008)          petrochemical     sectors) in four large,   Jan 1972 - Dec 1999                     p<0.05
               plant located in  rather homogeneous                            • PVC compound 2.46 (0.94-6.42)
               Porto Marghera    groups: autoclave                                workers          p<0.10
               (Venezia, Italia) workers (n = 210), PVC
               for any period    baggers (n = 198), PVC                        lung cancer (PVC    3.13 (0.96-10.28)
               between July      compound workers                              baggers)            p<0.10
               1950 and July     (n = 404) and technicians
               1985 (n = 1,658)  and clerks (n = 202); one                     lymphatic and
                                 more heterogeneous                            haematopoietic
                                 group was categorized                         cancer (compared to
                                 “other blue collar                            Italian population) SMR
                                 workers” (remaining 24                        • PVC baggers       3.77 (1.03-9.66)
                                 plant sectors; n = 644);                      • total blue collar 2.27 (1.24-2.81)
                                 internal reference =                             workforce
                                 technicians and clerks                        • PVC compound      2.26 (not stat. sign.)
                                                                                  workers
                                                                               • other blue collar 2.29 (not stat. sign.)
                                                                                  workers
             Human studies                                                                                             43
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<pre>etrospective   male workers        0.23-0.46                   ≥1 y /                                  SMR
 ohort         from 9 plants       (autoclave operators)       10-44 y           liver angiosarcoma    autoclave: 18.42
control:       manufacturing or    0.38-2.88                                                           (7.41-37.95)
 opulation of  polymerizing        (baggers and driers)                          lung cancer           autoclave: 0.58
  ngland and   vinyl chloride and  0.52-0.84 (craftsmen)                                               (CI not reported)
Wales) Jones   exposed ≥1 year     ≤0.93 mg/m3                                                         craftsmen: 0.42
 t al. (1988)  between 1940-       (other workers)                                                     (CI not reported)
               1974 (n = 5,498)
etrospective   white male          no data                     no data /                               SMR
 ohort         workers ever                                    until 31 Dec 1973 cancer of central     2.09; p<0.05
control: US    employed at                                                       nervous system
white male     synthetic                                                         cancer of respiratory 1.49; p<0.01
 opulation)    chemicals plant in                                                system
Waxweiler      Kentucky, US                                                      cancer of respiratory 1.56; significant,
 t al. (1981)  from opening in                                                   system                p not given
               1942-1973                                                         (10 y latency)
               (n = 4,806)
etrospective   male workers        PVC dust was not            ≤32 y /           whole cohort:         SMR (90% CI)
 ohort         from a PVC          quantified. Also            until 31 dec 1986 liver cancer          3.00 (1.96-4.49)
control: white polymerization      exposure possible to                          12/18 angiosarcoma
men in US)     plant in the US     butadiene due to                              lung cancer           1.23 (1.04-1.42)
Wu et al.      employed            production of                                 brain cancer          1.62 (1.00-2.50)
1989)          between 1942        styrene-butadiene                             subcohort:
               and 1974            rubber                                        ever exposed to VC
               (n = 4,835)                                                       (n = 3,635)
                                                                                 liver cancer          3.33 (2.02-5.21)
  ohort        12,700 male         No data                     29 y (mean) /     primary liver cancer 2.40 (1.80-3.14)
Ward et al.    workers in the                                  until 1996
2000)          vinyl chloride
               industry in four
               European
               countries
 ested case-   workers selected    (0) subjects with the least no data /         lung cancer
 ontrol study  from 543 claimant   exposure to PVC dust;       no data           variable:             OR
control: 224   s out of a cohort   (1) compounding                               group (3)             5.6 (2.03-16.3)
 ubjects       of 1,658 workers    workers, never baggers;                                             p<0.001
without        at an Italian vinyl (2) PVC baggers with                          ≥3.6 y spent as       7.15 (2.55-19.3)
 istory of     chloride/PVC        several jobs at once, date                    bagger                p<0.0001
 ancer)        production plant    of specific job change                        over 33 y of age at   7.70 (2.72-21.1)
Mastrangelo    (38 cases with      not indicated; (3) PVC                        onset of job          p<0.0001
 t al. (2003)  histologically      baggers with known                            calendar year at
               verified lung       length of job, for whom                       onset of job:
               cancer)             start and end dates were                      before 1967           4.79 (1.73-12.5)
                                   available.                                                          p<0.001
                                                                                 ≥1967                 4.55 (1.38-13.6)
                                                                                                       p<0.001
  4           Polyvinyl chloride
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<pre>                                                                                     time elapsed from
                                                                                     onset of job till end
                                                                                     of follow-up or
                                                                                     death:
                                                                                     >20 y                 3.76 (1.51-8.99)
                                                                                     ≤20 y                 11.4 (2.21-60.7);
                                                                                                           p<0.01
                                                                                     year as bagger        1.20 (1.08-1.35; p
                                                                                     (smoking and age      =0.001
                                                                                     constant)
 ested case     workers from a     no, minimal, moderate,      ≤32 y /               liver cancer          OR not stat. sign.
 ontrol         PVC                occasional peak, high       untill 31 Dec 1986    (16 cases, 81         different from 1.00
control:        polymerization     and intimate exposure                             controls)
 nexposed       plant in the US    (not quantified)                                  brain cancer
 ersons from    employed                                                             (13 cases, 62
 ame plant)     between 1942 and                                                     controls)
Wu et al.       1974 ever                                                            lung cancer
1989)           exposed to PVC                                                       (98 cases, 456
                dust                                                                 controls)
 ase-control    patients with                                 11-35 years latency    testicular cancer     OR
 tudy (control: testicular cancer                              • low and high        (7 cases/ 2 controls) 6.6 (1.4-32)
male Swedish    and 30-75 years                                  exposure
 opulation; n   old from Swedish                                 combined
  315)          Cancer Registry                                • low exposure        (3 cases/2 controls) 2.6 (0.3-3.2)
Hardell et al.  between 1989 and                                                                           (not clear if 1 or 5
1997);          1992 (148 cases)                                                                           year latency period)
Ohlson and
Hardell (2000)
 ase-control    patients with      every work task was         no data /             testicular cancer     OR
 tudy (control: testicular cancer  classified according to     no data               >1 y latency          1.35 (1.06-1.71)
male Swedish    (only germ cell    type of PVC contact with                          >10 y latency         1.45 (1.06-1.98).
 opulation;     tumours) and       regards to dust levels
 ge- matched;   20-75 years old
  = 791)        from Swedish
Hardell et al.  Cancer Registry
2004)           between 1993 and
                1997 (791 cases)
 ested case-    employees died     • vinyl and polyethylene    >16 y /               pancreatic cancer     7.15 (1.28-40.1);
 ontrol study   from pancreatic      processing (9 cases; 40   no data                                     p<0.05
control:        cancer and           controls)
 nexposed       worked 7 months • resin pulverizing                                                        no increased risk
 ersons from    or more at New       (10 cases; 55 controls),
 ame plant;     Jersey plant         and resins and varnish
  = 140)        between 1946 and (5 cases; 32 controls)
  elenskas      1967 with at least • sub-department vinyl      >18 y                                       8.98 (0.90-98.8)
 t al. (1995)   one hourly job       and polyethylene          (4 cases, 6 controls)
                assignment (cases processinga (8 cases
                = 28)                and 34 controls)
               Human studies                                                                                                    45
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<pre> ross-            white women         no, improbable, possible, no data /             breast cancer         RR: all 4 exposure
 ectional         employees from 5 definite and unknown           none                                      categories vs no
mortality         PVC fabricators exposure to PVC                                                           exposure: 1.94 (CI
 tudy (control:   (44 cases)                                                                                not given; not
workers                                                                                                     significant)
matched for
 ge (and
 ompany, if
 ossible);
  = 134)
  hiazze et al.
1980)
“case-            27 white male       no data                     no data /                                 SMR
 omparand” workers from                                           till 31 Dec 1973    cancer of respiratory
 ontrol:          above cohort                                                        system:
matched for                                                                           • adenocarcinoma 1.38; p not given
 ge at                                                                                • large cell          4.41; p not given
 iagnosis, sex,                                                                          undifferentiated
ace, and
 ounty of
esidence
Waxweiler
 t al. (1981)
 roportional male plastic             no data                     no data /           stomach cancer        O/E: 24/16.4;
mortality         workers (n = 707)                               no data                                   p<0.05)
 tudy             died in 1970-1972
ARC (1979)
 roportional      white employees no data                         no data /                                 PMR (p = 0.05)
mortality         from 17 PVC                                     no data             all cancers           male 1.16; female
 tudy             fabricators during                                                                        1.30
control: US       1964-1973                                                           digestive system      male 1.27; female
mortality)                                                                            cancer                1.48
  hiazze and                                                                          urinary cancer        female 2.84
  erence                                                                              breast cancer         female 1.34
1981)                                                                                 other unspecified     male 1.60; female
                                                                                      cancers               1.96
      comprises: vinyl rigid; vinyl rigid planished; rigid vinyl liquid molding compounds; vinyl granular; vinyl fabrication;
      vinyl flexible, calendered; polyethylene fabrication.
  6            Polyvinyl chloride
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<pre> nnex       G
            Animal studies
species /      dose                   freq Xpo /          no.         no.        comments/specified      Ref.
sex                                        Xpe            survivors   animals    skin tumours unless
(no./group)                                                           with       stated otherwise
                                                                      tumours
Implant (subcutaneous, intrapleural)
rat            implant in abdominal once   189-727 days / at          17         fibrosarcomas and 1     Oppenheimer
Wistar         wall of square or disc      189-727 days appearance    malignant  liposarcoma (a similar  et al.,
sex not        of commercial PVC                          of first    tumours at but perforated film:    1952/55 in
specified (45) known to contain                           tumour: 44  site after 0/27 local tumours; sc  IARC (1979)
               some additives (0.04                       animals     189-727    implant of cotton:
               mm thick and 15 mm                         still alive days       0/50 local tumours);
               wide)                                                             preliminary reporting
                                                                                 and final results never
                                                                                 reported
rat            implant in abdominal once   533 days /     not         4          preliminary reporting   Oppenheimer
Wistar         wall of pure PVC film       533 days       indicated   malignant and final results were   et al.
sex not        (0.03 mm thick)                                        tumours    never forthcoming       (1952/55) in
specified                                                                                                IARC (1979)
(similar
group)
rat            implant into abdomen once   800 days /     after 300 after 580 one sarcoma and one        Russell et al.
Wistar         of PVC film 4x5x0.16        800 days       days: 20/30 days: 0/30 fibroma in PVC-         (1959) in
M/F (35;       mm; control implant                        and 30/35 and 2/35 treated rats                IARC (1979)
control 25     of glass of similar
rats)          size
            Animal studies                                                                                          47
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<pre>rat            PVC capsules, whole once    not specified  not       5/16, 2/5 sarcomas                   Kogan and
strain not     PVC films or                not specified  specified and 1/5 for                          Tugarinova
specified      perforated PVC films                                 PVC                                  (1959) cited
not specified  implanted in kidney                                  capsules,                            in IARC
                                                                    whole                                (1979)
                                                                    PVC films
                                                                    or
                                                                    perforated
                                                                    PVC films
rat            implants (of unstated once  3, 10, 15, 30, not       see         of rats that survived    Raikhlin and
albino         size) of PVC film by        90, 195, 285,  specified comments 285-375 days, 6/16          Kogan (1961)
sex not        laparotomy to               300 and 380                          developed                cited in IARC
specified (80) surround the kidney         days                                 fibrosarcomas at site of (1979)
                                           380 days                             implantation
rat            inoculated             once lifetime       12-18     6/24 PVC 5 tumours of the liver Wagner and
Wistar         intrapleurally with 20      lifetime       months:               and 1 tumour             Johnson
M/F (24/sex) mg PVC dispersion                            39/48 PVC             originating from site of (1981)
               polymer in saline;                                               inoculation: poorly
               controls: 20 mg UICC                                             differentiated sarcomas
               crocidolite, Min-U-                                              (3 possibly of Kupffer
               Sil (quartz) in saline                                           cell origin); none of
               or saline                                                        animals with PVC after
                                                                                18 months nor any of
                                                                                control animals
                                                                                developed this type of
                                                                                tumour; a new study
                                                                                with commercial
                                                                                dispersion polymer
                                                                                produced no tumours
                                                                                within 18 months
                                                                                (information limited to
                                                                                the above; study
                                                                                ongoing and final
                                                                                results never reported)
rat            0 or one of three      once 2 years        not       Control: 8/ subcutaneous tumours Maekawa
Wistar         plasticizes PVCs            2 years        specified 10 M and    (mostly malignant        (1984)
M/F (20/sex    (PVC-1, -2 and -3),                                  5/12 F;     fibrous histiocytomas)
(control 12/   subcutaneous implant                                 PVC-1:      at implantation site:
sex))          in interscapular                                     11/17 M     Control: none; PVC-1:
               region of 10-20 mm                                   and 10/20   3 M and 5 F; PVC-2: 5
               piece, 0.3-0.5 mm                                    F;          M and 6 F; PVC-3: 8
               thick                                                PVC-2:      M and 13 F;
                                                                    12/15 M     polyhydroxyethyl
                                                                    and 13/20   methacrylate had
                                                                    F;          similar amount of
                                                                    PVC-3:      subcutaneous tumours
                                                                    13/18 M     and dimethyl
                                                                    and 16/20   polysiloxane also
                                                                    F           showed some
                                                                                subcutaneous tumours
 8           Polyvinyl chloride
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<pre> rat              subcutaneous implant once       741 days       not         6/11         seven subcutaneous     Hatanaka
 Fisher           of PVCa (10x20x0.3              741 days       specified                tumours (similar       (1993)
 F (12)           mm) in lateral                                                          morphological
                  abdominal region                                                        characteristics to
                  (2x) and on back                                                        human malignant
                                                                                          fibrous histiocytoma)
                                                                                          at site appearing 85
                                                                                          weeks after
                                                                                          implantation; author
                                                                                          concludes extremely
                                                                                          high incidence of
                                                                                          tumours compared to
                                                                                          controls from a
                                                                                          previous study
 rat              subcutaneous implant once       6(4) or 12 (6) all animals none                                Hansen et al.
 Sprague-         of bulk PVC on 1 side           months                                                         (2006)
 Dawley           of vertebral column             12 months
 M (10)           or intramuscular with
                  nanoparticles on
                  contralateral sideb
 Intraperitoneal injection
 rat              0 or 500 (5x100) mg weekly 5 weeks             29 and 14   2/102 and    preliminary results,   Pott et al.
 Wistar           granular PVCc                   28 months      for control 5/51 for     final results never    (1987)
 F (51; control  (particle size: 90% <                           and         control and  reported; average
 102)            2.5 µm) in saline; ip                           treated,    treated,     lifespan similar to
                 injection                                       resp.       resp.        control; author
                                                                                          concludes no clear
                                                                                          carcinogenic effect
     4 groups with other materials were investigated.
     ratio of surface area to volume (mm-1): 4.2 for bulk and 5x104 for nanoparticles (50-60 mg).
     PVC was administered as one of 50 dusts in this study in order to say something on the relation between length, diameter
     and biopersistence and tumour incidence.
Abbrevations used: M= male; F= female; mg = milligramme; mm = millimeter; µm = micrometer; freq= frequency;
Xpo = duration of exposure; Xpe = duration of the experiment; bw = body weight; no. = number.
               Animal studies                                                                                                49
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<pre>0 Polyvinyl chloride</pre>

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<pre> nnex        H
             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
                                                                                    67/548/EEC         EC No 1272/2008
                                                                                    (before            (as from
                                                                                    12/16/2008         12/16/2008
A             The compound is known to be carcinogenic to humans.                   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, it is unclear whether the compound is genotoxic.
B             The compound is presumed to be as carcinogenic to humans.             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, it is unclear whether the compound is genotoxic.
              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.23
             Carcinogenic classification of substances by the Committee                                                51
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<pre>2 Polyvinyl chloride</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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