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

<pre>www.healthcouncil.nl Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Healthy working conditions How can employees be protected against working conditions that could harm their health? Environmental health Which environmental influences could have a positive or negative effect on health? Healthy nutrition Which foods promote good health and which carry certain health risks? Prevention Which forms of prevention can help realise significant health benefits? Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Areas of activity Advisory Reports The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands Resorcinol diglycidyl ether 2016/03 2017/01 Health-based calculated occupational cancer risk values Vinyl chloride monomer Health Council of the Netherlands</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>Vinyl chloride monomer
    Health-based calculated occupational cancer risk values
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre></pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Vinylchloride monomeer
Uw kenmerk            : DGV/BMO/U-932542
Ons kenmerk           : 1090448/JR/jh/459-A74
Bijlagen              :1
Datum                 : 22 februari 2017
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling
aan vinylchloride monomeer.
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 van vier
per 1.000 en vier per 100.000 door beroepsmatige blootstelling. De conclusies van het
genoemde advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige bloot-
stelling aan stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep
Volksgezondheid.
In dit advies concludeert de commissie dat vinylchloride monomeer een carcinogene stof
is en dat hieraan een stochastisch genotoxisch werkingsmechanisme ten grondslag ligt.
Gebaseerd op humane gegevens schat de commissie de extra kans op kanker voor vinyl-
chloride monomeer op:
• 4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0,65 mg/m3
• en 4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 65,5 mg/m3.
Ik onderschrijf de aanbevelingen en het advies van de commissie.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van VWS
en aan de staatssecretaris van IenM.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                      Postadres
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X      Den Haag                                         2500 BB         Den Haag
E - m a il : jo l a n d a . r i jn k e l s @g r. n l             w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1
</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre></pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>Vinyl chloride monomer
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety (DECOS),
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2017/01, The Hague, February 22, 2017
</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. The Council can publish advisory
reports on its own initiative. It usually does this in order to ask attention for
developments or trends that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Vinyl chloride monomer - Health-based
calculated occupational cancer risk values.The Hague: Health Council of the
Netherlands, 2017; publication no. 2017/01.
all rights reserved
ISBN: 978-94-6281-099-0
</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 14
.3 Data 14
   Identity, toxicity profile and classification 15
.1 Identity, and physical and chemical properties 15
.2 Classification and labelling as a carcinogenic substance 16
.3 Genotoxicity 16
.4 Kinetics and metabolism 17
.5 Non-carcinogenic effects 18
.6 Existing occupational exposure limits 19
   Carcinogenicity studies 21
.1 Human studies 21
.2 Animal experiments 25
.3 Selection of the suitable study for risk estimation in the occupational situation 27
   Contents                                                                             7
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre> .4 Calculation of the HBC-OCRV 28
 .5 Groups with increased risk 31
 .6 Conclusions and recommendation 31
    References 33
    Annexes 41
A   Request for advice 43
B   The Committee 45
C   Letter of submission (in English) 49
D   Comments on the public review draft 51
E   Human studies 53
F   Animal experiments 71
G   Evaluation of the Subcommittee on the Classification of carcinogenic substances 83
H   Carcinogenic classification of substances by the Committee 91
    Calculation of the HBC-OCRV based on animal data (Maltoni et al., 1981) 93
    Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>Samenvatting
Op verzoek van de minister van Sociale zaken en Werkgelegenheid, schat de
Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van
de Gezondheidsraad, de concentraties van een stof in de lucht die overeenkomen
met een vooraf vastgesteld extra risico op sterfte aan kanker door beroepsmatige
blootstelling gedurende het arbeidzame leven. Het gaat om kankerverwekkende
stoffen die door de Gezondheidsraad of de Europese Unie geclassificeerd zijn in
categorie 1A of 1B en die kankerverwekkend zijn via een stochastisch geno-
toxisch mechanisme. Voor de schatting maakt de commissie gebruik van de
Leidraad Berekening ricicogetallen voor carcinogene stoffen van de Gezond-
heidsraad.1 In dit advies doet de commissie zo’n schatting voor vinylchloride
monomeer (VCM). VCM wordt gebruikt in de productie van polyvinylchloride.
Naar schatting van de commissie is de concentratie van VCM in de lucht, die
samenhangt met een extra kans op kanker van
• 4 per 1.000 (4x10-3), bij 40 jaar beroepsmatige blootstelling, gelijk aan
    65,5 mg/m3
• 4 per 100.000 (4x10-5), bij 40 jaar beroepsmatige blootstelling, gelijk aan
    0,65 mg/m3.
Samenvatting                                                                     9
</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>0 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Dutch Expert
Committee on Occupational Safety (DECOS), a committee of the Health Council
of the Netherlands, derives so-called health-based calculated – occupational
cancer risk values (HBC-OCRVs) associated with excess mortality levels of 4
per 1,000 and 4 per 100,000 as a result of working life exposure to substances. It
concerns carcinogenic substances which are classified by the Health Council or
the European Union in category 1A or 1B, and which are considered stochastic
genotoxic carcinogens. For the estimation, the committee uses the Guideline for
the calculation of occupational cancer risk values by the Health Council.2 In this
report the Committee presents such estimates for vinyl chloride monomer
(VCM). VCM is used in the production of polyvinylchloride (plastic).
The Committee estimated that the concentration of VCM in the air, which
corresponds to an excess cancer risk of
• 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 65.5
    mg/m3
• 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to 0.65
    mg/m3.
Executive summary                                                                  11
</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>2 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for genotoxic 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 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 (HBROEL) 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 a
        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 as carcinogens in category
        1A or 1B.
             For the establishment of the HBC-OCRVs, the Committee generally uses a
        linear extrapolation method, as described in the committee’s report Guideline for
        the calculation of occupational cancer risk values.2 The linear model is a default
        method to calculate occupational cancer, unless scientific data would indicate
        that using this model is not appropriate.
        Scope                                                                              13
</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<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.
    In the present report, cancer risk values are calculated for vinyl chloride
    monomer (VCM).
1.2 Committee and procedure
    The present document contains the evaluation of the DECOS, hereafter
    called the Committee. The members of the committee are mentioned in Annex B.
    A submission letter (in English) to the Minister can be found in Annex C.
        In April 2016, 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 advisory report.
1.3 Data
    The Committee’s recommendation has been based on scientific data, which
    are publicly available. Data were obtained from the online databases Chemical
    Abstracts, XToxline, and Medline, using vinyl chloride (monomer), chloro-
    ethylene, carcinogen, cancer, tumour or neoplast and CAS registry number as
    keywords. The literature was searched for the period between 1986 and 2016. In
    addition, in preparing the present report, reviews by IARC3, the WHO4 , US-
    NTP5, and ATSDR6 were consulted. The last search was performed in September
    2016. Criteria for evaluating the quality of human and animal studies are listed in
    Annex E and F respectively.
 4  Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre> hapter 2
        Identity, toxicity profile and
        classification
2.1     Identity, and physical and chemical properties
        VCM is mainly used in the production of polyvinylchloride. The identity and
        some physicochemical properties of VCM are given below.6-13
        Chemical name                   : Vinyl chloride
        CAS registry number             : 75-01-4
        EINECS name                     : Chloroethylene
        EINECS registry number          : 200-831-0
        RTECS number                    :-
        IUPAC name                      : Chloroethene
        Synonyms                        : 1-chloroethylene; ethylene monochloride; monovinyl
                                          chloride; monochloroethene; monochloroethylene; MVCs;
                                          Trovidur; VC; VCM; vinyl chloride monomer
        Molecular formula               : C2H3Cl
        Physical description and colour : Colourless gas (at room temperature), liquid if kept under
                                          high pressure or at low temperatures
        Structure                       : H2C=CH-Cl
        Molar mass                      : 62,5
        Melting point                   : -154°C
        Boiling point                   : -13,3°C
        Relative density (air = 1)      : 0.9195 at 15°C/4°C
        Solubility in water             : 8,800 mg/L at 25°C
        Solubility in organic solvents  : Soluble in alcohol; very soluble in ether
        Identity, toxicity profile and classification                                                15
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>    Log P (n-octanol/water)           : 1,620
    Vapour pressure                   : 2,600 mm at 25°C
    Relative vapour density (air = 1) : 2.15
    Flash point (closed cup)          : -159.7°C
    Odour threshold                   : mild, sweet odour (> 3,000 parts vinyl chloride ppm of air)
    Conversion factor                 : 1 ppm = 2.6 mg/m3; 1 mg/m3 = 0.38 ppm
    (20 °C; 101,3 kPa)
    EU classification                 : Flam.Gas 1: H220; Carc.1A: H350
2.2 Classification and labelling as a carcinogenic substance
    IARC classified VCM as carcinogenic to humans (Group 1) in 1974, 1979, 1987,
    2008 and 2012.3,8-11
    The European Union has classified VCM in carcinogenicity category 1A (known
    to have carcinogenic potential for humans), as listed under index number
    # 602-023-00-7 in Annex VI of Regulation (EC) No 1272/2008 (CLP
    Regulation).13
    VCM is listed in the Dutch SZW-list of carcinogenic substances.14
    In 1986 a committee of the Health Council of the Netherlands concluded that
    VCM should be considered a genotoxic carcinogen in humans.15
2.3 Genotoxicity
    Evidence for the genotoxic properties of VCM has been reviewed by IARC
    (2012)3, ATSDR (2006)6, and NTP (2014)5. The three agencies concluded that
    VCM is a mutagen.
    VCM caused genetic damage in many test systems, including bacteria, yeast,
    insects, cultured human and other mammalian cells, rodents, and in humans. The
    genetic damage included mutations and chromosomal aberrations6. Tables 1 and
    2 in Annex G provide an overview of the in vitro and in vivo evidence of the
    genotoxicity of VCM.
    The Committee concludes, in accordance with the recommendation of the
    DECOS Subcommittee on the Classification of Carcinogenic Substances (see
    Annex G), that VCM induces cancer in experimental animals (rodents) and
 6  Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>    humans via a mutagenic mode-of-action. VCM is therefore considered a
    stochastic genotoxic substance.
2.4 Kinetics and metabolism
    VCM is readily absorbed through the lungs and has also been shown to be almost
    completely absorbed from the gastrointestinal tract after oral exposure6. Animal
    studies indicate that the distribution of VCM is rapid and widespread and may be
    affected by differences in gender, age, and nutritional status6. Storage in the body
    is limited because of rapid metabolism and excretion.
    VCM is primarily and rapidly metabolized in the liver with a saturable
    mechanism. The first step is oxidation, predominantly mediated by the human
    cytochrome P450 (CYP) isoenzyme 2E1. Since CYP2E1 is present in several
    tissues at low levels extrahepatic metabolism of systemically available VCM
    does occur. The primary metabolites of VCM are the highly reactive
    chloroethylene oxide, and its rearrangement product chloroacetaldehyde.
    Conjugation of the primary metabolites with glutathione (GSH) eventually leads
    to the major urinary metabolites N-acetyl-S-(2-hydroxyethyl)cysteine and
    thiodiglycolic acid. Chloroethylene oxide can also be detoxified to
    glycolaldehyde by microsomal epoxide hydrolase, while chloroacetaldehyde can
    be converted to chloroacetic acid by aldehyde dehydrogenase 2 (ALDH2) in the
    urine.3,6
    Both primary metabolites of VCM (chloroethylene oxide and chloroacetaldehyde)
    can bind to proteins, DNA and RNA and form ethenoadducts; chloroethylene
    oxide is the most reactive with nucleotides. Overall, mechanistic animal and in
    vitro data suggest that etheno adducts are probably involved in the initiation of
    hepatocarcinogenesis, but the effects of the observed tissue- and cell-specificity
    and the variability in various biomarkers such as mutant p53 and anti-p53
    antibodies are not completely clear. One source for this variability may be
    explained by differences in polymorphisms in genes (i.e. CYP2E1, GSTT1,
    GSTM1, ALDH2) that encode metabolising enzymes or DNA-repair proteins
    (i.e. the XRCC1 gene).3,6
    In animal studies metabolites of VCM have been found in the liver, kidney,
    spleen, skin, brain, and placenta. The primary route of excretion of VCM is dose-
    dependent: while VCM metabolites are excreted primarily in the urine following
    Identity, toxicity profile and classification                                        17
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>    oral or inhalation exposure to low doses, at higher doses where metabolic
    saturation has been exceeded, VCM is exhaled as the parent compound.6
2.5 Non-carcinogenic effects
    Human data
    Several epidemiological studies have associated chronic occupational exposure
    to VCM with impaired liver function and/or liver damage (including liver
    cirrhosis).
    Ho et al. (1991) reported liver dysfunction in 12 of 271 workers who were
    reportedly exposed to environmental levels of 1 to 20 ppm VCM.16 However,
    this study has been criticised for its weak exposure assessment, small sample
    size, lack of specificity of the liver tests, and the fact that 8 of the 12 affected
    workers were current or ex-drinkers.6 Du et al. (1995) found that serum levels of
    gamma-glutamyl transferase (GGT), but not other indicators of liver function,
    were associated with exposure in a group of 224 VCM workers with time-
    weighted average exposure ranging from 0.36 to 74 ppm (0.92 to 189 mg/m3).17
    Hepatomegaly, altered liver function as shown by biochemical tests, and
    Raynaud’s phenomenon (RP, cold sensitivity and numbness of fingers) were
    reported in chemical plant workers exposed to 25 to 250 ppm VCM (64 to 639
    mg/m3) at levels much higher than those reported by Ho et al.18
    Neurological effects – including dizziness, drowsiness and fatigue, headache,
    euphoria and irritability, nervousness and sleep disturbances, nausea, visual and
    hearing disturbances, and loss of consciousness – have been observed following
    exposure via inhalation. Signs of pyramidal and cerebellar disturbances have also
    been observed. Dizziness has been reported by volunteers acutely exposed to
    20,800 mg/m3, while nausea and subsequent headache resulted from exposures of
    52,000 mg/m3. Peripheral neurological effects have been reported, including
    parasthesia, tingling or warmth in the extremities, numbness or pain in the
    fingers, and depressed reflexes. Human studies into reproductive and
    developmental effects from VCM exposure resulted in equivocal results. Studies
    examining parental employment and/or residential proximity to VCM facilities
    and birth defects reported links to foetal loss and defects of the central nervous
    system, alimentary tract, genitalia, and incidence of club foot. Other studies found
    no such association or suggested that inappropriate or inadequate study designs
    and statistical methodology were employed.4,6,18
 8  Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>    Animal studies
    In animal studies, the lowest observed adverse non-cancer effects in the liver
    included liver cell polymorphisms and development of hepatic cysts resulting
    from chronic oral exposures of 2 mg/kg bw/day; centrilobular hypertrophy and
    fatty liver changes resulted from intermediate-duration inhalation exposures of 26
    and 130 mg/m3, respectively. A variety of effects in animals from single inhalation
    exposure include ataxia, decreased coordination, twitching, tremors, and uncon-
    sciousness. Repeated exposure resulted in damaged nerve tissue, including
    degeneration of brain tissue and fibrosis of peripheral nerve endings. In animals, a
    few studies have identified reproductive and developmental effects. Decreased
    testicular weight, reduced male fertility, and spermatogenic epithelial necrosis
    resulted from intermediate-duration inhalation exposures of 260-1,300 mg/m3, but
    were not observed in rats exposed to up to 2,860 mg/m3. Gestational exposures of
    6,500 mg/m3 resulted in ureter dilation in rat offspring, while delayed ossification
    was observed following 1,300 mg/m3 exposures in mice. This exposure also
    resulted in 17% maternal mortality. No delayed ossification was found for mice
    exposed at 130 mg/m3.6
2.6 Existing occupational exposure limits
    A summary of occupational exposure limits for VCM in various countries is
    given in Table 1.
    In 2002 the scientific committee on occupational exposure limits (SCOEL) of the
    European Commission evaluated risk assessments for VCM including those
    conducted by WHO and US EPA.21 SCOEL concluded that a linear high dose -
    low dose extrapolation of tumour risk was the most appropriate approach for
    VCM and observed that even though different approaches were used, including
    those based on human epidemiological data and those based on extrapolation
    from animal data by means of PBPK modelling, resulting risk estimates were
    essentially consistent. SCOEL concluded that continuous exposure for working
    life to 1 ppm VCM would be associated with a cancer risk for hepatic
    angiosarcoma of about 3 x 10-4.21
    Identity, toxicity profile and classification                                        19
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>  Table 1 Occupational exposure limits.
  Country                  OEL (ppm)     OEL (mg/m3)      TWA                      Type of
  (Organization)                                                                   exposure limita
  The Netherlands19        -               7.77           8h                       OEL
  European Union20         -               7.77           8h                       OEL
  Germany4                 7             18.2             8h (person)              MAK
  Germany4                 3               8              Annual (working area) MAK
  Denmark20                1               3              8h                       OEL
  Finland20                3               7.7            8h                       OEL
  France19                 1               2.59           8h                       OEL
  United Kingdom20         3               7.8            8h                       OEL
  Norway20                 1               3              8h                       OEL
  Sweden20                 1               2.5            8h                       OEL
  Switzerland20            2               5.2            8h                       OEL
  Spain20                  3               7.8            8h                       OEL
  USA (ACGIH)4             1               2.6            8h                       TLV
  USA (NIOSH)4             0             -                -                        TLV
  USA (OSHA)4              5             12.8             15 min                   PEL
  USA (OSHA)4              1             2.6              8h                       PEL
  a    MAK, maximum acceptable concentration; OEL, occupational exposure limit; OES,
       occupational exposure standard; PEL, permissible exposure limit; TLV, threshold limit value.
0 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre> hapter 3
        Carcinogenicity studies
3.1     Human studies
        The Committee finds the current data available on malignancies other than liver
        cancer (especially angiosarcoma of the liver (ASL)) inconsistent (see Annex E).
        The Committee will focus on the key cohorts for exposure-response analysis and
        will not specifically discuss malignancies that are less consistently linked to
        VCM exposure, as these do not influence the carcinogenic classification of VCM
        nor do these provide a basis for a quantitative risk analysis. Details of all the
        studies included in the report are summarized in the Tables 4 en 5 in Annex E.
        Case reports
        The first evidence for an association between exposure to VCM and cancer in
        humans comes from case studies of individuals diagnosed with ASL working in
        VCM producing or processing plants.22 These studies are listed below in Table 2.
        The high incidence of ASL in these plants was remarkable considering the low
        background rate of ASL in the background population (0.0014 cases ASL/
        100,000, or about 25-30 cases per year in the entire US population).23
        Carcinogenicity studies                                                           21
</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<pre>  Table 2 Case studies.
  Number of angiosarcoma  Population/ cohort                                     Reference
  cases
  13 (+2)                 Four vinyl chloride plants (20,000 workers), USA       23,24
  10                      Shawinigan (Canada) population: All ten cases were     25
                          traced to be workers that had been employed at the
                          same vinyl chloride polymerization plant
  173                     Worldwide database for workers exposed to vinyl        26,27
                          chloride
  7                       253 deaths that occurred in seven plants manufacturing 28
                          vinyl chloride monomers and/ or polyvinylchloride and
                          one plant extruding polyvinylchloride in Italy
  Cohort and case-control studies
  The main epidemiological evidence for the carcinogenicity of VCM comes from
  two large multicentre cohort studies from Europe and North America.
  The first report on the European multicentre cohort study was published by
  Simonato et al.29 Collaborators from four countries (Italy, Norway, Sweden and
  the United Kingdom) participated in the cohort study and contributed a total of
  14,351 subjects to the combined database. Both existing studies and newly
  collected cohorts were enrolled from 19 factories in total.14,21,23,25,30,35 The
  pooled analysis revealed no significant excess of total cancer mortality. Mortality
  of cancer of the liver and hepatic bile ducts and cancer of an unspecified site
  were significantly in excess. In a subset of four Nordic factories (for which
  incidence data were available), total cancer incidence was again not in excess,
  but the incidence of cancer of liver and intrahepatic bile ducts was significantly
  in excess. Cancer incidence for several other cancer categories was in excess,
  though not significantly. A positive relation was observed between duration of
  employment or cumulative exposure to VCM and liver cancer mortality. Among
  the 24 liver cancer deaths, 16 were confirmed histopathologically to be
  angiosarcomas, and one was reported as a primary liver cancer without further
  specification. For the remaining 7 a specific histopathological diagnosis was not
  available. Based on the risks observed in this study, the maximum incidence for
  angiosarcoma of the liver (for individuals with ≥ 25 years since first exposure
  and a cumulative exposure of ≥ 10,000 ppm (26,000 mg/m3)-years), was
  calculated to be 280/100,000.
2 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>The most recent publication on the European multicentre cohort study is from
Ward et al.30 In this study the follow-up period was extended with 10 years
compared to the Simonato report. A total of 71 deaths from liver cancer (primary
liver cancer, including 37 angiosarcomas, 10 hepatocellular carcinomas (HCC),
and 24 liver cancers of other and unknown histology were observed. A strong
positive trend for time since first employment, duration of employment, and
cumulative exposure was found with relative risks for all liver cancers,
angiosarcoma, and hepatocellular carcinoma. The highest relative risks were
observed for angiosarcoma of the liver. As the incidence of angiosarcoma of the
liver with unknown etiology in the general population was estimated to be about
0.1 per million population per year, the workers in the study population
experienced a 200-fold higher risk of angiosarcoma than the general population
(based on 4 cases among approximately 200,000 person-years). No other type of
cancer was found in excess. Pirastu et al. and Mastrangelo et al. report a
significant exposure response relationship between cumulative exposure to VCM
and HCC (p<0.001 in both studies) based on an Italian cohort that was included
in the Ward et al. analysis, but for which more follow-up time was accrued.31,32
A number of publications have reported on the North American multicentre
cohort.33-37 In the most recent and complete publication on this cohort by Mundt
et al. 895 cancer deaths were reported. While total cancer mortality was not
elevated, mortality from cancers of the liver and biliary tract was significantly
increased. Modest excesses of brain cancer and cancer of connective and soft
tissue were also observed. Hazard rates from proportional hazard analyses
supported associations with age at first exposure, duration of exposure, and year
of first exposure for cancers of the liver and soft tissues, but not the brain. Hazard
rates for ‘all known angiosarcomas’ (n=48) were associated with duration of
exposure, though not with age at first exposure and year of first exposure.
Results from the European and North American multicentre studies were
combined with six independent studies of cancer among VCM workers (from
(Former USSR, France, Canada, Germany, China, Taiwan) in a meta-analysis by
Boffetta et al.38 Together these studies include 43,810 VCM/PVC workers with
variable follow-up ranging between 1940 and 1997. Most of the smaller cohorts
included in the analysis were published individually and are summarized in
Annex E.15,23-29,31-71 With SMR values ranging from 1.63 to 57.1, all six studies
for which these ratios could be obtained suggested an increased risk of liver
cancer, though these results were deemed too heterogeneous to be included in a
meta-analysis. A significantly increased meta-SMR was also reported for liver
Carcinogenicity studies                                                                23
</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>  cancers other than ASL (based on the 2 multicentre studies) and for soft-tissue
  sarcomas, however, these results may have been influenced by the
  underdiagnosis of true ASL. A meta-analysis for ASL was not conducted as
  relevant SMRs were difficult to estimate due to the extreme rarity of the disease
  in the general population.
  Several studies were published in addition to the cohorts that were included in
  the Boffetta meta-analysis. Many studies suffered from limited statistical power
  (especially for ASL). The details of these studies can be found in Annex E. We
  highlight the most relevant analysis here. An analysis by Beaumont and Breslow
  from 1981 included nine (partially overlapping) early studies conducted in the
  VCM industry.26-33 The combined data revealed a significant risk for liver and
  brain cancer, whereas no significantly increased risk for lung cancer was found.
  Exposure levels in occupational studies
  The highest occupational exposure levels to VCM have generally been incurred
  at VCM/PVC plants and in PVC-processing plants. Only few exposure
  measurements have been reported, but estimates from the chemical industry
  indicate that exposure to VCM amounted to several thousands of milligrams per
  cubic metre in the 1940s and 1950s, and were several hundreds of milligrams per
  cubic metre in the 1960s and early 1970s. Occupational exposure standards were
  set at approximately 13-26 mg/m3 [5-10 ppm] in most countries in the 1970s.3
  Conclusions of the human studies
  The epidemiological literature indicates a strong association between exposure to
  VCM and liver cancer incidence and mortality. The elevated risk for liver cancer
  appears to be primarily driven by ASL and HCC. Studying the exposure-
  response relationship between exposure to VCM and ASL is difficult because
  this form of liver cancer is extremely rare. Studying the association between
  exposure to VCM and liver cancer excluding ASL is also difficult because of the
  risk of misdiagnosis of true ASL. Several other forms of cancer are reported to
  be associated with exposure to ASL in individual studies, but these associations
  are not consistent across studies.
4 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 25 =================================================================

<br><br>====================================================================== Pagina 26 ======================================================================

<pre>3.2 Animal experiments
    The carcinogenicity of VCM has been studied extensively in mice, rats, and
    hamsters. These studies have been reviewed in depth by IARC (1974,
    1979,1987, 2008, 2012), ATSDR (2006), and NTP (2014).3,5,6,8-11 The studies
    consistently showed hepatic and extrahepatic angiosarcomas in mice and rats.
    Various other malignant neoplasms also occurred at several anatomical sites.
    However, the reporting of the results has often been incomplete.3 Results from
    all studies are summarized in Annex F of this report. While studies have assessed
    the effects of exposure via inhalation, skin, and ingestion, exposure via
    inhalation is likely the most relevant exposure route for humans. Three relevant
    inhalation studies are described below.
    Hong et al.72 reported on an experiment in which rats and mice were exposed to
    0, 130, 650 or 2,600 mg/m3 VCM via inhalation for 6 hours/day, 5 days/ week
    during 1, 3 or 6 months and describe the development and incidence of
    neoplastic changes and other effects during a 12 month post-exposure follow-up
    period. Unscheduled mortality increased in both species in a dose-related way,
    and occurred at earlier time points at higher concentrations. There was no
    significant sex-related difference in the number of unscheduled deaths (or
    sacrifices). In mice, cumulative incidence of hepatic haemangiosarcomas during
    recovery period was increased at higher VCM concentration. The tumour was
    mostly multiple in site distribution and varied greatly in size. Overall, the
    incidence of this tumour rose as the concentration and duration of VCM
    exposure increased. Also the incidence of bronchioloalveolar tumours was
    greater in mice exposed to increasing levels of VCM and for longer exposure
    periods. In female mice mammary gland adenocarcinoma/carcinoma was
    observed. Metastatic adenocarcinomas originating from the mammary gland
    were also seen in lungs of mice exposed to VCM, but not in lungs of control
    mice.
    Drew et al.73 observed induced haemangiosarcomas and mammary gland
    carcinomas in two strains of mice and lung carcinomas in Swiss mice after six
    months of exposure to 130 mg/m3 VCM. Longer exposure had no significant
    effect on tumour incidence. Incidence was higher when exposure started earlier
    in life. In rats, mainly haemangiosarcomas of the liver, mammary neoplasms and
    hepatocellular carcinomas were found after 6 months of exposure. The incidence
    of haemangiosarcomas was a function of the duration of the exposure. If the
    Carcinogenicity studies                                                           25
</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>  exposure took place early in life, a higher incidence of haemangiosarcomas was
  noted. In hamsters, haemangiosarcomas, mammary gland carcinomas, stomach
  adenomas, and skin carcinomas were produced by exposure to 520 mg/m3 VCM.
  The highest incidence was seen in animals exposed early in life.
  A large series of experiments was performed by Maltoni et al. using rats
  (Sprague-Dawley and Wistar), mice, and hamsters.74-76 In one group of studies,
  Maltoni et al. exposed Sprague-Dawley rats to VCM for 52 weeks at
  concentrations ranging from 1 to 30,000 ppm. Animals were examined at the
  time of their spontaneous death. Statistically significant increases were noted in
  the incidence of mammary gland carcinomas, Zymbal gland carcinomas,
  nephroblastoma, and liver angiosarcoma. Exposure of Swiss mice to 50 ppm
  VCM for 4 hours/day, 5 days/week for 30 weeks also appeared to increase the
  incidence of liver angiosarcoma and angioma. Some variation in the target
  organs that developed tumours was observed when different species were
  exposed to VCM.74 Whereas angiosarcomas of the liver were reported to occur
  in rats, mice, and hamsters, mammary gland carcinomas were found only in rats
  and mice; Zymbal gland carcinomas, neuroblastomas, and nephroblastomas were
  found only in rats; lung tumours were found only in mice; and melanomas,
  acoustical duct epithelial tumours, and leukemias were found only in hamsters.4
  In their review of the Maltoni study, ATSDR noted that limited histopathological
  data were presented and cancer incidences were presented only in summary
  tables. Also, survival of control animals was poor in some of the experiments.
  Furthermore, statistical analyses, where present, appear to be based on a
  compilation of data from several individual studies.6
  Overall, mice seem to be more sensitive to the acute and chronic effects of VCM
  exposure than rats and golden hamsters. In mice, increase in tumour incidence
  was found at all tested concentrations, already at the lowest test concentration of
  130 mg/m3 and exposure for one month. Most studies were performed with rats,
  with concentration ranges differing greatly: between 2.6 mg/m3 and 78 g/m3.73,77
  Basically, all these studies report increased tumour incidence at all test
  concentrations.
  Conclusions of the animal studies
  Based on the available data it can be concluded that tumour incidence (number of
  rats with a tumour) and multiplicity (number of tumours/ rat) following VCM in
  rats was clearly related to exposure concentration and duration. It can therefore
6 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>    be concluded that the carcinogenic effects of VCM in animals and humans are
    similar .
3.3 Selection of the suitable study for risk estimation in the
    occupational situation
    VCM has been shown to induce cancer in both humans and experimental
    animals. As the epidemiological data are of sufficient quality, the Committee
    prefers to estimate the health-based occupational cancer risk value using human
    data rather than animal data.
    The risk calculations on human data are given below. For comparison however,
    risk calculations on animal data are performed and summarized in Annex I.
    In human studies VCM has been consistently associated to liver cancer, in
    particular the subtypes ASL and HCC. The highest relative risks were observed
    for ASL. Two large multicentre cohort studies together incorporate most of the
    evidence available from independent cohorts in which the association between
    VCM and liver cancer (subtypes) was assessed.30,34 Boffetta et al. combined the
    two multicentre cohort studies with several other independent studies, but did not
    report on ASL.38
    The study by Ward et al.30 is the only multi-centre study that reported results
    from quantitative exposure response analysis for cumulative exposure to VCM.
    Two more recent publications report on exposure response analysis for
    cumulative exposure to VCM and HCC based on an Italian cohort.31,32 This
    cohort was included in the Ward analysis and preference was given to base the
    calculation of the HBC-OCRV on the multi-centre analysis. Ward et al.30
    sufficiently describe the methods that were used to assess exposure levels and to
    model the exposure-response relationship. The Committee concludes that the
    Ward et al.30 report provides the best data to estimate health-based occupational
    cancer risk values.
    Study quality limitations and uncertainties potentially affecting the study
    on which the HBC-OCRV will be based
    Several study quality limitations and uncertainties in Ward et al.30 have a
    potential effect on the calculated HBC-OCRV. Considerable uncertainty exists in
    the historical exposure levels that had to be estimated to allow estimation of
    Carcinogenicity studies                                                            27
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>    cumulative exposure to VCM. It may be likely that the historical exposure levels
    are underestimated eventually resulting in an increase in the HBC-OCRV. A
    limitation pertaining primarily to the HCC results is the modest number of cases
    observed in the study population, increasing the uncertainty of the estimated
    relative risks [direction of effect on HBC-OCRV unclear]. Finally, Ward et al.
    controlled only for age and calendar period as confounding factor in their study
    but were not able to control for other potential confounders (e.g. thorotrast
    treatment).
3.4 Calculation of the HBC-OCRV
    The risk analysis for VCM is based on the assumption that VCM is a genotoxic
    carcinogen with a stochastic mode-of-action as described in section 2.3 and
    Annex G. Consequently, it is not possible to determine a threshold level for the
    observed carcinogenicity.
        The Committee used the quantitative exposure-response relationships for VCM
    and ASL, liver cancer (including both ASL, HCC and ‘cancer of other and
    unknown histology’), or HCC reported by Ward et al.30 to derive unit risk
    estimates. For ASL the regression model to derive a unit risk estimate was fit on
    reported exposure group specific incidence rates, while for liver cancer and HCC
    the model was fit on the reported exposure group specific relative risks. For ASL
    and liver cancer a linear model fit the data best, while for HCC an exponential
    model fit the data best. The data and regression models are summarized in Table 3.
    The exposure levels corresponding to the relevant occupational health and safety
    standards were calculated using life tables derived from Dutch mortality data.
    The following assumptions were made for the life table analysis:
    • Workers were assumed to be exposed for 40 years (between 20 and 60)
    • Workers were followed until age 100
    • Excess risk for ASL was calculated using an absolute risk model (linear):
        IR(X=1) = IR(X=0) + AR
    • Excess risk for liver cancer (linear) and HCC (exponential) was calculated
        using a relative risk model:
        IR(X=1) = IR(X=0) * RR.
 8  Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>Table 3 Regression models used to derive unit risk estimate from Ward et al. (2001).30
a Reported cumulative exposure group (in ppm-years).
b Estimated mean cumulative exposure (in ppm-years), for the highest exposure group the mean
  was estimated as 5/3*lower bound, for the other categories the midpoint was used.
c Incidence rate.
d Relative risk.
e Lower confidence limit.
f Upper confidence limit.
Carcinogenicity studies                                                                      29
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>  Based on the life table analysis the Committee estimated an excess ASL
  incidence of
  • 4 per 1,000 (4 x 10-3) for 40 years of exposure to 65.5 mg VCM/m3
  • 4 per 100,000 (4 x 10-5 ) for 40 years of exposure to 0.65 mg VCM/m3.
  Based on the life table analysis the Committee estimated an excess liver cancer
  incidence of
  • 4 per 1,000 (4 x 10-3) for 40 years of exposure to 57.5 mg VCM/m3
  • 4 per 100,000 (4 x 10-5 ) for 40 years of exposure to 0.57 mg VCM/m3.
  Based on the life table analysis the Committee estimated an excess HCC
  incidence of
  • 4 per 1,000 (4 x 10-3) for 40 years of exposure to 127 mg VCM/m3
  • 4 per 100,000 (4 x 10-5 ) for 40 years of exposure to 2.4 mg VCM/m3.
  The Committee agrees that ASL is causally related to VCM exposure and that a
  risk assessment based on human ASL is the most appropriate. ASL incidence is
  however low in the general population potentially resulting in unstable risk
  extrapolations. Therefore, the Committee has performed additional analyses
  using the broader disease definition of ‘liver cancer’ recognizing that the disease
  category is not necessarily causally related to VCM to address the potential
  limitation of low incidence rates in ASL. The Committee observes that the
  calculated risk numbers for both ASL and ‘liver cancer’ are similar. Therefore
  the Committee is of the opinion that the issue of the low ALS background does
  not seem to be a significant methodological problem, and expresses a preference
  for the risk estimate based on ASL.
  For comparison (see Annex I for details) the Committee performed a number of
  risk calculations based on animal data (rat angiosarcoma) published by Maltoni
  et al. (1981).74 The best fitting dose-response curves on the data from three
  respective experiments were established, bench mark doses (BMD10) were
  derived, and health- based calculated cancer risk values were calculated for the
  human situation. Although the calculated values were different per animal
  experiment, they were all in the same order of magnitude (approx. between 1 and
  10 VCM mg/m3 at an extra risk level of 4 per 1,000, and between 0.001 and 0.1
  at 4 per 100,000). The results from the animal data were slightly more
  conservative than the above calculated results from the epidemiological study.
  The Committee is of the opinion that the risk assessment based on the human
0 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>====================================================================== Pagina 32 ======================================================================

<pre>    data should be preferred, and that the animal data may be considered supportive
    to the risk numbers established based on human data.
3.5 Groups with increased risk
    A higher susceptibility for developing HCC due to exposure to VCM among
    workers that are infected with hepatitis B virus, or that report high levels
    alcoholic beverage consumption has been reported.32,78This information is not
    (and can not be) used in the calculation of the occupational cancer risk values
    based on epidemiological evidence for the association between VCM and HCC.
    However, if there are large differences between the population of the
    epidemiological study that was used for derivation of the occupational cancer
    risk values and the current population of the Netherlands in the incidence of
    hepatitis B virus or alcoholic beverage consumption this could lead to an over- or
    underestimation of the actual risk of HCC due to exposure to VCM. A downward
    trend in hepatitis B virus infection in the European Union has been reported for
    the period 1995 - 200779, indicating that current risks for HCC due to exposure to
    VCM might currently be lower than at the time of the study by Ward et al.30
3.6 Conclusions and recommendation
    The Committee endorses the conclusions of the DECOS Subcommittee on the
    Classification of Carcinogenic Substances (see Annex G) that VCM is a human
    carcinogen and that a stochastic genotoxic mechanism underlies its
    carcinogenicity. In addition, the Committee considers cancer of the liver as the
    most critical effect of VCM.
    The Committee is of the opinion that health-based occupational cancer risk
    values (HBC-CRVs) should be calculated for VCM. Therefore, the Committee
    performed a number of risk calculations based on human and animal data using
    different risk models and end-points for liver carcinogenicity.
    The Committee concludes that human angiosarcomas of the liver (ASL) relate
    specifically to VCM exposure and that a risk assessment based on ASL is the
    most appropriate.
    The Committee estimated that the concentration of VCM in the air, which
    corresponds to an excess cancer risk of
    Carcinogenicity studies                                                            31
</pre>

====================================================================== Einde pagina 32 =================================================================

<br><br>====================================================================== Pagina 33 ======================================================================

<pre>  •  4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 65.5
     mg/m3
  •  4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to 0.65
     mg/m3.
2 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 33 =================================================================

<br><br>====================================================================== Pagina 34 ======================================================================

<pre>  References
  Gezondheidsraad. Leidraad berekening risicogetallen voor carcinogene stoffen. Den Haag:
  Gezondheidsraad; 2012: Publicatie nr. 2012/16.
  Health Council of the Netherlands. Guideline for the calculation of occupational cancer risk values.
  The Hague, The Netherlands: 2012: publication no. 2012/16E.
  International Agency for Research on Cancer (IARC). Chemical Agents and Related Occupations.
  IARC Monogr Eval Carcinog Risk Chem Man 100F. 2012.
  World Health Organization (WHO). Environmental Health Criteria. 1999.
  NTP (National Toxicology Program). Report on Carcinogens, Thirteenth Edition. Research Triangle
  Park, NC: U.S. Department of Health and Human Services, Public Health Service.; 2014. Internet:
  http://ntp.niehs.nih.gov/pubhealth/roc/roc13/ consulted: 3-11-2016.
  U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for
  Toxic Substances and Disease Registry. Toxicological profile for vinyl chloride. 2006.
  ChemIDplus Advanced. online source. http://chem.sis.nlm.nih.gov/chemidplus/
  consulted: 3-11-2016.
  International Agency for Research on Cancer (IARC). Some anti-thyroid and related substances,
  nitrofurans and industrial chemical. IARC MonogrEval Carcinog Risk Chem Man 1974; 7: 1-326.
  International Agency for Research on Cancer (IARC). Some monomers, plastics and synthetic
  elastomers, and acrolein. IARC MonogrEval Carcinog Risk Chem Man 1979; 19.
0 International Agency for Research on Cancer (IARC). Summaries & Evaluations. IARC
  MonogrEvalCarcinogen Risk Chem Man 1987; Supplement 7: 373.
  References                                                                                           33
</pre>

====================================================================== Einde pagina 34 =================================================================

<br><br>====================================================================== Pagina 35 ======================================================================

<pre>1 International Agency for Research on Cancer (IARC). 1,3-Butadiene, ethylene oxide and vinyl
  halides (vinyl fluoride, vinyl chloride and vinyl bromide). IARC MonogrEval Carcinog Risk Chem
  Man 2008; 97.
2 Merck Index. 2013.
3 European Parliament and Council. REGULATION (EC) No 1272/2008 OF THE EUROPEAN
  PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on classification, labelling and
  packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and
  1999/45/EC, and amending Regulation (EC) No 1907/2006. 2008.
4 Ministerie van Sociale Zaken en Werkgelegenheid. SZW-lijst van kankerverwekkende stoffen en
  processen. 2016: 43.
5 Health Council of the Netherlands. Advies inzake vinylchloride. Toetsing van een criteriadocument
  en voorstel risico-evaluatie. The Hague, Netherlands: 22-5-1986.
6 Ho SF, Phoon WH, Gan SL, Chan YK. Persistent liver dysfunction among workers at a vinyl chloride
  monomer polymerization plant. J Soc Occup Med 1991; 41(1): 10-16.
7 Du CL, Kuo ML, Chang HL, Sheu TJ, Wang JD. Changes in lymphocyte single strand breakage and
  liver function of workers exposed to vinyl chloride monomer. Toxicol Lett 1995; 77(1-3): 379-385.
8 U.S.Environmental Protection Agency. Toxicological Review of Vinyl Chloride. Washington, DC:
  U.S.Environmental Protection Agency; 2000.
9 RIVM, National Institute for Public Health and the Environment. online source. www.rivm.nl
  consulted: 3-11-2016.
0 SER, Social and Economic Council of the Netherlands. online source. www.ser.nl
  consulted: 3-11-2016.
1 SCOEL, Scientific Committee on Occupational Exposure Limits. Risk Assessment for Vinyl
  Chloride. 2002: SCOEL/SUM/109.
2 Collins JJ, Jammer B, Sladeczek FM, Bodnar CM, Salomon SS. Surveillance for angiosarcoma of the
  liver among vinyl chloride workers. J Occup Environ Med 2014; 56(11): 1207-1209.
3 Heath CWJ, Falk H, Creech JLJ. Characteristics of cases of angiosarcoma of the liver among vinyl
  chloride workers in the United States. Ann N Y Acad Sci 1975; 246: 231-236.
4 Mark L, Delmore F, Creech J, Ogden L, Fadell E, Songster C et al. Clinical and morphologic features
  of hepatic angiosarcoma in vinyl chloride workers. Cancer 1976; 37(1): 149-163.
5 Delorme F, Theriault G. Ten cases of angiosarcoma of the liver in Shawinigan, Quebec. J Occup Med
  1978; 20(5): 338-340.
6 Forman D, Bennett B, Stafford J, Doll R. Exposure to vinyl chloride and angiosarcoma of the liver:
  a report of the register of cases. Br J Ind Med 1985; 42(11): 750-753.
7 Lee FI, Smith PM, Bennett B, Williams DM. Occupationally related angiosarcoma of the liver in the
  United Kingdom 1972-1994. Gut 1996; 39(2): 312-318.
8 Pirastu R, Comba P, Reggiani A, Foa V, Masina A, Maltoni C. Mortality from liver disease
  among Italian vinyl chloride monomer/polyvinyl chloride manufacturers. Am J Ind Med 1990; 17(2):
  155-161.
4 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 35 =================================================================

<br><br>====================================================================== Pagina 36 ======================================================================

<pre>9 Simonato L, L'Abbe KA, Anderson A, Belli S, Comba P, Engholm G et al. A collaborative study
  of cancer incidence and mortality among vinyl chloride workers. Scand J Work Environ Health 1991;
  17(3): 159-169.
0 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.
1 Pirastu R, Baccini M, Biggeri A, Comba P. Epidemiologic study of workers exposed to vinyl chloride
  in Porto Marghera: mortality update. Epidemiol Prev 2003; 27(3): 161-172.
2 Mastrangelo G, Fedeli U, Fadda E, Valentini F, Agnesi R, Magarotto G et al. Increased risk of
  hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: Synergistic effect of
  occupational exposure with alcohol intake. Environmental Medicine 2004; 112(11): 1188-1192.
3 Cooper WC. Epidemiologic study of vinyl chloride workers: mortality through December 31, 1972.
  Environ Health Perspect 1981; 41: 101-106.
4 Mundt KA, Dell LD, Austin RP, Luippold RS, Noess R, Bigelow C. Historical cohort study of 10 109
  men in the North American vinyl chloride industry, 1942-72: update of cancer mortality to 31
  December 1995. Occup Environ Med 2000; 57(11): 774-781.
5 Ott MG, Langer RR, Holder BB, Vinyl chloride exposure in a controlled industrial environment.
  A long-term mortality experience in 594 employees. Arch Environ Health 1975 B.C.; 30(7): 333-339.
6 Tabershaw IR, Gaffey WR. Mortality study of workers in the manufacture of vinyl chloride and its
  polymers. J Occup Med 1974; 16(8): 509-518.
7 Wong O, Whorton MD, Foliart DE, Ragland D. An industry-wide epidemiologic study of vinyl
  chloride workers, 1942-1982. Am J Ind Med 1991; 20(3): 317-334.
8 Boffetta P, Matisane L, Mundt K, Dell L. Meta-analysis of studies of occupational exposure to vinyl
  chloride in relation to cancer mortality. Scand J Work Environ Health 2003; 29(3): 220-229.
9 Beaumont JJ, Breslow NE. Power considerations in epidemiologic studies of vinyl chloride workers.
  Am J Epidemiol 1981; 114(5): 725-734.
0 Belli S, Bertazzi PA, Comba P, Foa V, Maltoni C, Masina A et al. A cohort study on vinyl chloride
  manufacturers in Italy: study design and preliminary results. Cancer Lett 1987; 35(3): 253-261.
1 Buffler PA, Wood S, Eifler C, Suarez L, Kilian D. Mortality experience of workers in a vinyl chloride
  monomer production plant. J Occup Med 1979; 21(3): 195-203.
2 Byren D, Engholm G, Englund A, Westerholm P. Mortality and cancer morbidity in a group of
  Swedish VCM and PCV production workers. Environ Health Perspect 1976; 17: 167-170.
3 Carreon T, Hein MJ, Hanley KW, Viet SM, Ruder AM. Coronary artery disease and cancer mortality
  in a cohort of workers exposed to vinyl chloride, carbon disulfide, rotating shift work, and o-toluidine
  at a chemical manufacturing plant. Am J Ind Med 2014; 57(4): 398-411.
4 Du CL, Wang JD. Increased morbidity odds ratio of primary liver cancer and cirrhosis of the liver
  among vinyl chloride monomer workers. Occup Environ Med 1998; 55(8): 528-532.
5 Duck BW, Carter JT, Coombes EJ. Mortality study of workers in a polyvinyl-chloride production
  plant. The Lancet 1975; 306(7946): 1197-1199.
  References                                                                                               35
</pre>

====================================================================== Einde pagina 36 =================================================================

<br><br>====================================================================== Pagina 37 ======================================================================

<pre>6 Fox AJ, Collier PF. Mortality experience of workers exposed to vinyl chloride monomer in the
  manufacture of polyvinyl chloride in Great Britain. Br J Ind Med 1977; 34(1): 1-10.
7 Gennaro V, Ceppi M, Montanaro F. [Reanalysis of mortality in a petrochemical plant producing vinyl
  chloride and polyvinyl chloride]. Epidemiol Prev 2003; 27(4): 221-225.
8 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.
9 Hagmar L, Akesson B, Nielsen J, Andersson C, Linden K, Attewell R et al. Mortality and cancer
  morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride
  processing plant. Am J Ind Med 1990; 17(5): 553-565.
0 Heldaas SS, Langard SL, Andersen A. Incidence of cancer among vinyl chloride and polyvinyl
  chloride workers. Br J Ind Med 1984; 41: 25-30.
1 Heldaas SS, Andersen AA, Langard S. Incidence of cancer among vinyl chloride and polyvinyl
  chloride workers: further evidence for an association with malignant melanoma. Br J Ind Med 1987;
  44(4): 278-280.
2 Hsieh HI, Chen PC, Wong RH, Du CL, Chang YY, Wang JD et al. Mortality from liver cancer and
  leukaemia among polyvinyl chloride workers in Taiwan: an updated study. Occup Environ Med
  2011; 68: 120-125.
3 Infante PF, Wagoner JK, Waxweiler RJ. Carcinogenic, mutagenic and teratogenic risks associated
  with vinyl chloride. Mutat Res 1976; 41(1 spel. no): 131-141.
4 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.
5 Langard S, Rosenberg J, Andersen A, Heldaas SS. Incidence of cancer among workers exposed to
  vinyl chloride in polyvinyl chloride manufacture. Occup Environ Med 2000; 57(1): 65-68.
6 LaPlanche A, Clavel F, Contassot J-C, Lanouziere C. Exposure to vinyl chloride monomer: report on
  a cohort study. Br J Ind Med 1987; 44: 711-715.
7 LaPlanche A, Clavel-Chapelon F, Contassot J-C, Lanouziere, French VCM group. Exposure to
  vinyl chloride monomer: results of a cohort study after seven year follow up. Br J Ind Med 1992; 49:
  134-137.
8 Lewis R. Use of rank-order analysis of ordinal exposure data: application to vinyl chloride exposure.
  Appl Occup Environ Hyg 2001; 16(2): 188-191.
9 Lewis R, Rempala G. A case-cohort study of angiosarcoma of the liver and brain cancer at a polymer
  production plant. J Occup Environ Med 2003; 45(5): 538-545.
0 Molina G, Holmberg B, Elofsson S, Holmlund L, Moosing R, Westerholm P. Mortality and cancer
  rates among workers in the Swedish PVC processing industry. Environ Health Perspect 1981; 41:
  145-151.
1 Monson RR, Peters JM, Johnson MN. Proportional mortality among vinyl chloride workers. EHP,
  Environ Health Perspect 1975; 11: 75-77.
6 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 37 =================================================================

<br><br>====================================================================== Pagina 38 ======================================================================

<pre>2 Nicholson WJ, Hammond EC, Seidman H, Selikoff IJ. Mortality experience of a cohort of vinyl
  chloride-polyvinyl chloride workers. Annals New York Academy of Sciences 1975.
3 Pirastu R, Bruno C, De SM, Comba P. An epidemiological study of workers exposed to vinyl
  chloride in the plants of Ferrara, Rosignano and Ravenna. Epidemiol Prev 1998; 22(4): 226-236.
4 Scelo G, Constantinescu V, Csiki I, Zaridze D, Szeszenia-Dabrowska N, Rudnai P et al. Occupational
  exposure to vinyl chloride, acrylonitrile and styrene and lung cancer risk (europe). Cancer Causes
  Control 2004; 15(5): 445-452.
5 Smulevich VB, Fedotova IV, Filatova VS. Increasing evidence of the rise of cancer in workers
  exposed to vinyl chloride. Br J Ind Med 1988; 45(2): 93-97.
6 Swaen GMH, Duijts SFA. Epidemiologic evidence for the carcinogenicity of vinyl chloride
  monomer. Scand J Work Environ Health 2005; 31(3): 233-235.
7 Theriault G, Allard P. Cancer mortality of a group of Canadian workers exposed to vinyl chloride
  monomer. J Occup Med 1981; 23(10): 671-676.
8 Waxweiler RJ, Stringer W, Wagoner JK, Jones J, Falk H, Carter C. Neoplastic risk among workers
  exposed to vinyl chloride. Annals New York Academy of Sciences 1976.
9 Weber H, Reinl W, Greiser E. German investigations on morbidity and mortality of workers exposed
  to vinyl chloride. EHP, Environ Health Perspect 1981; 41: 95-99.
0 Wong RH, Chen PC, Du CL, Wang JD, heng TJ. An increased standardised mortality ratio for liver
  cancer among polyvinyl chloride workers in Taiwan. Occup Environ Med 2002; 59: 405-409.
1 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. J Occup Med 1989; 31(6): 518-523.
2 Hong CB, Winston JM, Thornburg LP, Lee CC, Woods JS. Follow-up study on the carcinogenicity
  of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent
  to exposure. J Toxicol Environ Health 1981; 7(6): 909-924.
3 Drew R, Boorman G, Haseman J, McConnell E, Busey W, Moore J. The effect of age and exposure
  duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol Appl
  Pharmacol 1983; 68: 120-130.
4 Maltoni C, Lefemine G, Ciliberti A, Cotti G, Carretti D. Carcinogenicity bioassays of vinyl chloride
  monomer: a model of risk assessment on an experimental basis. Environ Health Perspect 1981; 41:
  3-29.
5 Maltoni C, Lefemine G, Chieco P, Carretti D. Vinyl chloride carcinogenesis: current results and
  perspectives. Med Lav 1974; 65(11-12): 421-444.
6 Maltoni C, Lefemine G, Ciliberti A. Experimental research on vinyl chloride carcinogenesis. In:
  Maltoni and Mehlman, editor. Archives of Research on Industrial Carcinogenesis. Princeton, New
  Jersey: Princeton Scientific Publishers Inc., 1984:
7 Maltoni C, Lodi P. Results of sputum, cytology among workers exposed to vinyl chloride monomer
  and to poly(vinyl chloride). Environ Health Perspect 1981; 41: 85-88.
8 Wong RH, Chen PC, Wang JD, Du CL, Cheng TJ. Interaction of vinyl chloride monomer exposure
  and hepatitis B viral infection on liver cancer. J Occup Environ Med 2003; 45(4): 379-383.
  References                                                                                           37
</pre>

====================================================================== Einde pagina 38 =================================================================

<br><br>====================================================================== Pagina 39 ======================================================================

<pre>9 European Centre for Disease Prevention and Control. ECDC INFORMATION SHEET Hepatitis B
  and C Current situation in the EU/EEA. European Centre for Disease Prevention and Control. http://
  ecdc.europa.eu/en/press/news/Documents/110524_Hepatitis_info_sheet.pdf consulted: 2-11-2016.
0 Van Everdingen J. From consensus to CBO guideline (Van consensus naar CBO-richtlijn).
  Nederlands Tijdschrift Geneeskunde 1999; 143(12): 2086.
1 Mark L, Delmore F, Creech JLJ, Ogden LII, Fadell EH, Songster CL et al. Clinical and morphologic
  features of hepatic angiosarcoma in vinyl chloride workers. Cancer 1976; 37(1): 149-163.
2 Prince MM, Ward EM, Ruder AM, Salvan A, Roberts DR. Mortality among rubber chemical
  manufacturing workers. Am J Ind Med 2000; 37(6): 590-598.
3 Klimisch H. A systematic approach for evaluating the quality of experimental toxicological and
  ecotoxicological data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
4 Suzuki Y. Neoplastic and nonneoplastic effects of vinyl chloride in mouse lung. EHP, Environ Health
  Perspect 1981; 41: 31-52.
5 Suzuki Y. Neoplastic effect of vinyl chloride in mouse lung - lower doses and short-term exposure.
  Environ Res 1983; 32(1): 91-103.
6 Holmberg B, Kronevi T, Winell M. The pathology of vinyl chloride exposed mice. Acta Vet Scand
  1976; 17(3): 328-342.
7 Winell M, Holmberg B, Kronevi T. Biological effects of vinyl chloride: an experimental study.
  Environ Health Perspect 1976; 17: 211-216.
8 Adkins BJ, Van SEW, Simmons JE, Eustis SL. Oncogenic response of strain A/J mice to inhaled
  chemicals. J Toxicol Environ Health 1986; 17(2-3): 311-322.
9 Lee CC, Bhandari JC, Winston JM, House WB, Peters PJ, Dixon RL et al. Inhalation toxicity of vinyl
  chloride and vinylidene chloride. Environ Health Perspect 1977; 21: 25-32.
0 Lee CC, Bhandari JC, Winston JM, House WB, Dixon RL, Woods JS. Carcinogenicity of vinyl
  chloride and vinylidene chloride. J Toxicol Environ Health 1978; 4(1): 15-30.
1 Hehir RM, McNamara BP, McLaughlin J, Jr., Willigan DA, Bierbower G, Hardisty JF. Cancer
  induction following single and multiple exposures to a constant amount of vinyl chloride monomer.
  EHP, Environ Health Perspect 1981; 41: 63-72.
2 Viola PL, Bigotti A, Caputo A. Oncogenic response of rat skin, lungs, and bones to vinyl chloride.
  Cancer Res 1971; 31(5): 516-522.
3 Caputo A, Viola PL, Bigotti A. Oncogenicity of vinyl chloride at low concentrations in rats and
  rabbits. IRCS Libr Compend 1974; 2(9): 1582.
4 Radike MJ, Stemmer KL, Brown PG, Larson E, Bingham E. Effect of ethanol and vinyl chloride on
  the induction of liver tumors: premilinary report. Environ Health Perspect 1977; 21: 153-155.
5 Groth DH, Coate WB, Ulland BM, Hornung RW. Effects of aging on the induction of angiosarcoma.
  Environ Health Perspect 1981; 41: 53-57.
6 Maltoni C, Cotti G. Carcinogenicity of vinyl chloride in Sprague-Dawley rats after prenatal and
  postnatal exposure. Ann N Y Acad Sci 1988; 534(Living Chem. World): 145-159.
8 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 39 =================================================================

<br><br>====================================================================== Pagina 40 ======================================================================

<pre>7 Feron V, Spit B, Immel H, Kroes R. One-year time-sequence inhalation toxicity study of vinyl
  chloride in rats. III. Morphological changes in the liver. Toxicology 1979; 13: 143-154.
8 Til H, Feron V, Immel H. Lifetime (149-week) oral carcinogenicity study of vinyl chloride in rats. Fd
  Chem Toxic 1991; 29(10): 713-718.
9 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: Publication no. A10/07E.
  References                                                                                            39
</pre>

====================================================================== Einde pagina 40 =================================================================

<br><br>====================================================================== Pagina 41 ======================================================================

<pre>0 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 41 =================================================================

<br><br>====================================================================== Pagina 42 ======================================================================

<pre>A Request for advice
B The Committee
C Letter of submission (in English)
D Comments on the public review draft
E Human studies
F Animal experiments
G Evaluation of the carcinogenicity by the Subcommittee on Classification
  of carcinogenic substances
H Carcinogenic classification of substances by the Committee
  Calculation of the HBC-OCRV based on animal data (Maltoni et al., 1981)
  Annexes
                                                                          41
</pre>

====================================================================== Einde pagina 42 =================================================================

<br><br>====================================================================== Pagina 43 ======================================================================

<pre>2 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 43 =================================================================

<br><br>====================================================================== Pagina 44 ======================================================================

<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:
     Request for advice                                                                                     43
</pre>

====================================================================== Einde pagina 44 =================================================================

<br><br>====================================================================== Pagina 45 ======================================================================

<pre>  •   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
      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 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 45 =================================================================

<br><br>====================================================================== Pagina 46 ======================================================================

<pre>nnex B
     The Committee
     •  RA Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  P.J. Boogaard
        Professor of Environmental Health and Human Biomonitoring, Wageningen
        University and Research Centre; Toxicologist, Shell International BV, The
        Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders (NECORD), Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht
     •  I.M.C.M. Rietjens
        Professor of Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  G.B.G.J. van Rooy
        Occupational Physician, Arbo Unie Expert Centre for Chemical Risk
     The Committee                                                                45
</pre>

====================================================================== Einde pagina 46 =================================================================

<br><br>====================================================================== Pagina 47 ======================================================================

<pre>      Management, and Radboud UMC Outpatient Clinic for Occupational
      Clinical Toxicology, Nijmegen
  •   F. Russel
      Professor of Pharmacology and Toxicology, Radboud University Medical
      Centre, Nijmegen
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
  •   A.H. Piersma, structurally consulted expert
      Professor of Reproductive and Developmental Toxicology, Utrecht
      University, and National Institute for Public Health and the Environment,
      Bilthoven
  •   B.P.F.D. Hendrikx, observer
      Social and Economic Council, The Hague
  •   H. Stigter, observer
      Occupational Physician, Expertise Centre, Ministry of Social Affairs and
      Employment
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of the Netherlands, The Hague
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, persons are asked to submit a form detailing the functions they hold
  and any other material and immaterial interests which could be relevant for the
  Committee’s work. It is the responsibility of the Health Council to assess
  whether or not someone can become a member. An expert who has no financial
  but another clearly definable interest, can become a member under the restriction
  that he will not be involved in the debate on the subject to which his interest
  relates. If a person’s interest is not clearly definable, he can sometimes be
  consulted as an expert. Experts working for a ministry or governmental
  organisation can be structurally consulted. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
6 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 47 =================================================================

<br><br>====================================================================== Pagina 48 ======================================================================

<pre>aware of each other’s possible interests. For permanent committees, possible
conflicts of interest are considered for each topic of advice.
The Committee                                                                47
</pre>

====================================================================== Einde pagina 48 =================================================================

<br><br>====================================================================== Pagina 49 ======================================================================

<pre>8 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 49 =================================================================

<br><br>====================================================================== Pagina 50 ======================================================================

<pre>nnex C
     Letter of submission (in English)
     Subject         : presentation of advisory report Vinyl chloride monomer
     Your reference  : DGV/BMO/U-932542
     Our reference   : 1090448/JR/jh/459-A74
     Enclosure(s)    :1
     Date            : February 22, 2017
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     vinyl chloride monomer.
     This advisory report is part of an extensive series in which carcinogenic
     substances are evaluated for the possibility to establish health-based
     occupational cancer risk values. It involves substances to which people can be
     exposed under working conditions.
     The advisory report was prepared by the Dutch Expert Committee on
     Occupational Safety of the Health Council. The advisory report has been
     reviewed by the Health Council’s Standing Committee on Public Health.
     Letter of submission (in English)                                              49
</pre>

====================================================================== Einde pagina 50 =================================================================

<br><br>====================================================================== Pagina 51 ======================================================================

<pre>  In this report, the Committee concludes that vinyl chloride monomer is a
  carcinogenic substance with a stochastic genotoxic mechanism. The Committee
  estimated that the concentration of VCM in the air, which corresponds to an
  excess cancer risk of
  • 4 x 10-5 for 40 years of occupational exposure to 0.65 mg/m3
  • and 4 x 10-3 for 40 years of occupational exposure to 65.5 mg/m3.
  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)
  Prof. dr. J.L. Severens
  Vice President
0 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 51 =================================================================

<br><br>====================================================================== Pagina 52 ======================================================================

<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in April 2016 for public review. The
     following organizations and persons have commented on the draft document:
     • Kort JH, Shin-Etsu PVC B.V., Rotterdam
     • Lentz TJ, Rice FL, Schubauer-Berigan MK, National Institute for
         Occupational Safety and Health (NIOSH), Cincinnati OH, USA.
     Comments on the public review draft                                             51
</pre>

====================================================================== Einde pagina 52 =================================================================

<br><br>====================================================================== Pagina 53 ======================================================================

<pre>2 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 53 =================================================================

<br><br>====================================================================== Pagina 54 ======================================================================

<pre>nnex E
     Human studies
     If no statistical significance is given, the result was not statistically significant, if
     statistical analysis was performed.
     In parallel to the historical decrease of the worker exposure concentrations, the
     reports are summarized chronologically.
     Quality criteria80:
     Evaluation of therapeutic or preventive studies:
     A1:meta-analysis with at least some A2-level studies with unambiguous results from individual
     studies
     A2: randomised clinical trials (double blind, controlled) of good quality and scale
     B: randomised clinical trial of moderate quality or limited scale, or other comparable study (non-
     randomised study, cohort study, case-control study)
     C: non-comparative study
     D: expert opinion
     Evaluation of diagnostic studies:
     A1: study on the diagnostic effects of clinical results of a prospective well-defined group of patients
     with a defined policy based on test results from clinical tests of A2-level, taking into account mutual
     dependency of the diagnostic tests
     Human studies                                                                                           53
</pre>

====================================================================== Einde pagina 54 =================================================================

<br><br>====================================================================== Pagina 55 ======================================================================

<pre>              A2: study with reference test, with well-defined criteria for test and reference test, with a good
              description of the test and included clinical population; with an adequate number of successive
              patients and well-defined cut-off values and independent assessment of results from test and
              reference standard (in case of multiple diagnostic tests analysis needs to be adjusted for mutual
              dependency, by using e.g. logistic regression)
              B: comparison with a reference test, description of the test and population excluding the A-level
              characteristics
              C: non-comparative study
              D: expert opinion
 able 4 Retrospective/ prospective cohort studies, case reports and nested case-control studies.
 tudy design and population          Data on exposure and health Results                              Remarks
                                     assessment
 etrospective mortality study;       No exposure measurements; EI >1.5: Total malignant               Basic study with sufficient
USA; Vinyl chloride plants;          Exposure Index (duration        neoplasms SMR: 134               number of participants, no
 930s -1972; 7,128 participants (months) x intensity (low,           (41 obs./32.7 exp.); digestive   exposure measurements;
workers exposed for ≥ 1 year); medium or high) resulting in organs and peritoneum                     limited study (only
 ontrol group is US male             <1.5 and ≥1.5); Mortality and SMR:141 (12 obs. /9 exp.);         supportive).
 opulation;                          cause of death recorded;        respiratory system SMR: 135
 abershaw et al., 197436             standard deviation; SMRs        (13 obs. /10.3 exp.); other/     Quality score: B
                                     adjusted for deaths with cause unspecified sites SMR: 190
                                     unknown                         (8 obs./4.52); EI <1.5:
                                                                     SMR146 (9 obs./6.57 exp.);
                                                                     leukemia and aleukemia
                                                                     SMR: 136 (2 obs./1.6 exp.);
                                                                     lymphomas SMR: 212
                                                                     (5 obs./2.54 exp.)
 ase report; USA; PVC industry No exposure measurement               Diagnosis of ASL; Average        Case study, unclear how many
4 different plants, total number data; worker in PVC                 age 48.2 years, length of time   undiagnosed VC-related ASL
 mployees not reported);             production; 0.0014 cases        between first VC work and        occurred among VC workers
 3 diagnosed cases;                  ASL/100,000 in entire           diagnosis ASL: 12-29 years,      of these plants; no exposure
Heath et al., 197523                 population; no statistical      mean total duration of VC        measurements;
                                     analyses; 1 case increased      work: 18 years; calculated risk  Limited study (only
                                     alcohol intake, 1 case          ratio for VC workers >400:1      supportive).
                                     exposure to arsenic             based on estimate of 20,000
                                     insecticides as teenager; no    VC workers in USA;               Quality score: C
                                     exposure to other hepato-       suggestion of dose-response
                                     toxicants                       relation with latency period
 4            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 55 =================================================================

<br><br>====================================================================== Pagina 56 ======================================================================

<pre>   etrospective mortality study;    Four levels of exposure         Significant increase cases of   Well-documented study,
USA; VC industry (5 plants);        defined based on continuous     malignant neoplasms (>200       limited number of cancer
 942-1960; 1974; 594                stationary measurement          ppm: 9 obs/ 5.1 exp, p<0.025    cases; well-documented
 articipants; controls = US white   (1950-59) in 2 plants and job   ); 15 yr after initial exposure estimation of exposure
males (age-specific);               classification (assigned to     to >200 ppm: 8 obs/ 3.2         concentrations (in part based
Ott et al., 1975, partly overlaps   highest level for at least      expected, p<0.01; no deaths     on sampling); potential bias/
with Tabershaw et al., 197435,36    1 month), low (TWA              due to angiosarcoma or          confounding addressed
                                    < 25 ppm), intermediate         hepatic malignancies            (healthy worker effect;
                                    (25-200 ppm), high                                              smoking; family cancer risk;
                                    (>200 ppm) and unmeasured;                                      co-exposure to arsenic).
                                    statistical analysis of high-                                   Limited study only supportive
                                    exposure vs all other exposure
                                    groups with conditional                                         Quality score: B
                                    distribution of independent
                                    Poisson random variables;
                                    arsenic workers were
                                    excluded
   ase report; USA and Canada;      No exposure measurement         Diagnosis of angiosarcoma;      Case study; no exposure
  VC industry; 15 diagnosed         data (estimated to be high);    Average age 47.5 years,         levels estimated;
 ases; Mark et al., 1975, partly workers in PVC production;         average exposure: 16.9 years;   Limited study (only
 verlaps with Heath et al.,         primary angiosarcoma            3-22 months survival after      supportive)
 97523,81                           incidence is                    onse
                                    20-25 in the US per year;                                       Quality score: C
                                    no statistical analysis
   etrospective cohort mortality    No exposure measurement         No increased SMR for cancer     Study with limited number of
 tudy; South Wales (UK); PVC data; Subgroups based on               related deaths in the different participants, no exposure
 lant; 1948-1968; study             occupation, duration of         subgroups (observed 35,         levels estimated;
 erformed Feb, 1975; 2,120 male exposure or time of first           expected 36.4) nor for specific limited study (only
workers; controls: males aged       exposure; Analyses by a         cancers; No ASL cases           supportive)
ess than 75 years in England and “man years at risk” computer
Wales in 1955-1972;                 program                                                         Quality score: B
Duck and Carter, 197545
   etrospective cohort mortality    Peak exposures of               All cancers: 9 observed, 3.9    Study with limited number of
 tudy; New York State, USA;         ≥ 1,000 ppm estimated based     expected; 3 persons with        participants; no exposure
  PVC plant; 1946-1963; 255         on symptoms experienced         haemangiosarcoma; no            measurements; potential bias/
 articipants (exposed for           (up to 10,000 ppm); no          relationship cancer incidence   confounding not addressed;
   5 years, latency period of       statistical analysis; no other  with duration of exposure.      no statistical analyses;
   10 years); control data based on risk factors taken into account                                 study contains several flaws.
mortality in New York State;
Nicholson et al., 1975.62                                                                           Quality score: B
  roportional mortality analysis; No exposure measurement           SMR all cancers 1.5 (obs 41,    Study with limited number of
Kentucky and Louisville, USA data; cause of death based on          exp 28), SMR cancer of liver    participants; no exposure
2 (poly)vinyl chloride plants); death certificate; no other risk    and biliary tract 11 (8 obs,    measurements; potential bias/
ate 1947-1973; 161 participants factors taken into account          0.7 exp), SMR lung cancer       confounding not addressed;
deceased white males); controls                                     1.6 (13 obs, 8 exp), SMR        no statistical analyses
USA white males;                                                    brain cancer 4.23 (5 obs,
Monson et al., 197561                                               1.2 exp); 5 cases of            Quality score: B
                                                                    angioasarcoma
               Human studies                                                                                                    55
</pre>

====================================================================== Einde pagina 56 =================================================================

<br><br>====================================================================== Pagina 57 ======================================================================

<pre>  etrospective mortality study;   No exposure measurement          Brain cancer SMR 612            Study on mortality of total
  weden; 1 PVC plant;             data (peak exposures of up to    (2 observed /0.33 expected;     PVC employee group
 940-1971; 750 participants;      10,000-15,000 ppm estimated      p 0.043); cancer of liver/      (number of cases too limited),
 ontrol is population of Sweden   for autoclave cleaners based     pancreas SMR 413 (4 obs. /      no refinements, no exposure
1969); Byren et al., 197642       on unconsciousness);             0.97 exp.; 0.017); no           measurements;
                                  one-tailed Poisson               relationship with time of       Limited study (only
                                  distribution                     exposure                        supportive)
                                                                                                   Quality score: B
  etrospective cohort mortality   VC exposure determined by        SMR (all malignant              Well-documented study with
 tudy; USA; Vinyl chloride        survey, review of company        neoplasms) increased            intermediate cohort; no
 olymerization industry (4        process, engineering control,    significantly (35 obs/ 23.5     exposure measurements; no
 lants); follow-up from time of   and air-sampling data (not       exp, p<0.05); Hepatic system    potential bias/confounding
ermination of employment 1941     further specified); Mortality,   ≥10-y latency SMR: 1,155        taken into account, statistical
o Dec 1973; 1,294 participants    cause of death and               (7 obs/0.6 exp, p<0.01) and     analyses not described;
≥ 5 years exposure and latency    histopathology were recorded;    ≥15-y latency SMR: 1,606        only supportive study.
 eriod of at least 10 years);     type of statistical analyses not (7 obs/0.4 exp, p<0.01);
 ontrol = US white males (same    described                        Brain and CNS ≥15y latency      Quality score B
 ge, calendar year of death and                                    SMR: 498 (3 obs/0.6 exp,
 ause of death);                                                   p<0.05); Respiratory system
Waxweiler et al., 1976 and                                         ≥15y latency SMR: 194
 nfante et al., 197653,68                                          (11 obs/5.7 exp, p<0.05));
                                                                   Lymphatic and hematopoietic
                                                                   system (≥15y latency SMR:
                                                                   176, not significant); 11 cases
                                                                   of angiosarcoma within 14
                                                                   cases of confirmed liver
                                                                   cancer (average latency = 19
                                                                   years)
  etrospective cohort mortality   No exposure measurements, SMR primary liver cancer 141           Study on large cohort,
 tudy; UK; VCM industry           exposure estimated based on (1 obs/ 0.71 exp); SMR other         differentiated for exposure
including 4 PVC plants);          job history (>200 ppm “high”, liver cancers 323 (3 obs (2        estimate; Number of cases too
 940-1974; 7,409 workers; sex 25-200 ppm “medium”,                 angiosarcomas)/ 0.93 exp);      limited; No potential bias/
 nd age standardized death rates >25 ppm “low”, constant or both liver angiosarcoma cases          confounding taken into
or England and Wales;             intermittent); statistical       at high/constant exposure       account;
  ox and Collier, 197746          analyses not described; no       (SMR: 1,538 (2 obs/0.13         Limited study only supportive
                                  other risk factors taken into    exp))
                                  account                                                          Quality score B
  ase report; Canada; 10 cases of No exposure measurements, All cases worked in VC                 Well-documented case study.
ASL diagnosed between             exposure in PVC plant is         polymerization plant with       Clear experimental set-up. No
 955-1974 in Shawinigan,          estimated as very high in the direct contact with VC for         exposure measurements
Quebec; study in 1974;            past, in 1974 <3 ppm;            5-26 years (average 17 years),  performed.
Delorme et al., 1978.25           Questionnaires on                average age at death 50.5
                                  occupational history of          years; latency time 11-28       Quality score C
                                  patients, past and present       years from first exposure
                                  residence, medical history,      (average 20.5 years)
                                  smoking and drinking habits;
                                  no statistical analyses; authors
                                  have taken into account
                                  smoking and alcohol intake
  6           Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 57 =================================================================

<br><br>====================================================================== Pagina 58 ======================================================================

<pre>  etrospective cohort mortality   No exposure measurement         SMR all cancers 122            Well-documented study,
 tudy; Canada; VCM/ PVC           data; job and exposure history  (20 obs/ 16.4 exp); SMR        limited number of
ndustry (1 plant); 1948-1972;     assessed via questionnaires;    cancer of digestive system:    participants/ limited number
 tudy performed in 1977; 451      statistical analyses via        259 (14 obs/ 5.4 exp, p<0.01); of cases; No exposure levels.
 articipants (exposed to VCM for  “man-years-at-risk” method      SMR cancer of bone, skin and   Limited study only supportive
  5 years); control = entire                                      connective tissue 526 (2 obs/
 opulation of the Province of                                     0.4 exp); SMR respiratory      Quality score B
Quebec (age- and sex-matched;                                     cancer 187 (6 obs/ 3.2 exp);
  heriault et al., 1981; Delorme                                  8 angiosarcomas/ 20 total
 nd Theriault 197825,67                                           cancer cases
  etrospective cohort analyses of No exposure measurements, Respiratory system cancer:           Well-documented study,
mortality patterns; USA; VCM      exposure estimated based on SMR: 289 (5 obs/1.73 exp,          limited number of
 roduction plant; 1948-1975; 464  company personnel records: p=0.032); latency period            participants. Limited number
 articipants (white males, ≥ 2    job and exposure history; jobs 5 years: SMR: 268 (4 obs/       of cases; Exposure levels only
 onsecutive months of exposure);  classified in 7 exposure        1.49 exp (p=0.06)); group      based on estimation.
 ontrol population is age-        groups; one-sided test of       longer exposed SMR: 381        Limited study only
matched, white males from         significance, based on Poisson (4 obs/1.05 exp, p=0.023);      supportive.
  exas; Buffler et al., 197941    distribution; corrected for     high average level of exposure
                                  effects of smoking, duration SMR: 441(3 obs/0.68 exp,          Quality score B
                                  and level of exposure           p=0.032); 4/5 persons with
                                  (combined or separate)          `lung cancer smoked
  etrospective cohort study;      No exposure measurements, Workers >2-y exposure (10 y          Too many subcohorts; number
  weden; PVC processing           exposure estimated based on latency): SMR: malignant           of cases too small; no
ndustry; 1945-1974; study in      job history: high (mixing       tumours 1.51 (9 obs/6 exp),    potential bias/confounding
 976; 1,970 workers (at least 3   department), medium (heat       SMR: digestive organ           taken into account in analysis;
months employed); control =       treatment machines) or low      tumours 1.85 (4 obs/2.2 exp);
 ational population;              (other departments), exposure workers > 6 months exposure:     only supportive study
Molina et al., 198160             time subcohorts based on        SMR: digestive organ
                                  individual employment           tumours 1.29 (11 obs/8.5 exp); Quality score B
                                  history; endpoints: mortality all SMRs not significant
                                  and morbidity; no details on
                                  type of statistical analyses;
                                  other risk factors not taken
                                  into account
  etrospective cohort study; USA  No exposure measurements, SMR brain and CNS                    Number of cases too small;
mainly South USA); PVC/VCM        exposure estimated based on malignant neoplasms 203            other risk factors not taken
ndustry (37 plants in total, 11   job history (high/ medium/      (12 obs / 5.9 exp, p<0.05);    into account
 roduced only VCM, 18 only        low); Statistical significance SMR leukemia and aleukemia      limited study only supportive.
  VC, 3 both and 5 produced       calculated following Chiang 143 (9 obs/ 6.7 exp); 8 cases
 omopolymers and copolymers,      (1961); not corrected for other of liver angiosarcoma in       Quality score B
with or without VCM and PVC);     risk factors                    cohort (4-23 years of
 tart VC production; 1978; 9,677                                  exposure, 16-24 years from
male workers (>1 year exposure                                    first exposure to death)
o vinyl chloride before 31 Dec
 972); controls were age-
matched males from USA
 eneral population; Cooper,
 981; Tabershaw, 197433,36
              Human studies                                                                                                   57
</pre>

====================================================================== Einde pagina 58 =================================================================

<br><br>====================================================================== Pagina 59 ======================================================================

<pre>  etrospective cohort study;         No exposure measurement          Malignant tumours of:           No exposure measurements or
Germany (West); PVC                  data; statistical method:        Lymphatic and hematopoietic     estimations included,number
 rocessing industry; from            Poisson test; other risk factors tissues: SMR 214 (15 obs/6      of cases too small; Limited
 eginning of VCM/PVC                 by additional cohort of PVC      exp, p<0.01; SMR decreased      study (only supportive)
 roduction industry-1974; date       processing workers not           in PVC processing);
 tudy not mentioned; 7,021 male      exposed to vinyl chloride        GI tract and peritoneum SMR     Quality score B
workers, German or Austrian,         (4,007 participants)             149 (45 obs/27 exp, p<0.05;
VCM/ PVC production; 4,910                                            SMR decreased in PVC
 ontrols (West German male                                            processing); Liver SMR 1,523
 opulation);                                                          (12 obs/4 exp, p<0.01; no
Weber et al., 198169                                                  increase in PVC processing);
                                                                      Brain: SMR 162 (2 obs/2
                                                                      exp); for PVC processing:
                                                                      SM 535 (5 obs/2 exp, p<0.05);
                                                                      Latency period taken into
                                                                      account: Lymphatic and
                                                                      hematopoietic tissues, GI tract
                                                                      and peritoneum and brain: no
                                                                      significantly increased SMR
                                                                      for any latency period); Liver
                                                                      SMR 874 for 13-16 months
                                                                      (p<0.05), 1,525 for 61-120
                                                                      months and 2,528 for
                                                                      >121 months exposure (both
                                                                      p<0.01)
  ohort study; Norway (Telemark      No exposure measurements, All cancers: SMR 114                   Number of cases too small,
 ounty); Vinyl chloride industry;    exposure estimated based on (23 obs/20 exp); For high VC         exposure levels estimated, no
 953-1979; 454 participants          interviews and sporadic          exposure (VC/PVC                statistical analyses performed.
employed ≥ 1 year, before            ‘explosion meter’                production, autoclave           Supporting study
 970); age-matched control           measurements: 2,000 ppm          cleaning, maintenance,
 ohort from Norwegian                (1950-1954), 1,000 ppm           packing/drying): Malignant
 opulation;                          (1955-1954), 500 ppm             melanoma of the skin: SMR       Quality score B
Heldaas et al., 198450               (1960-1967), 100 ppm             590 (3 obs/0.51 exp);
                                     (1968-1974, <1 ppm (since        Cancer of thyroid gland: SMR
                                     1975, monitored)); study         1820 (2 obs/0.11 exp);
                                     differentiates nine job          Bronchial cancer: SMR 220
                                     classifications based on         (4 obs/1.82 exp);
                                     estimated exposure level; no Colon cancer: SMR 330
                                     statistical analyses; 53% of     (3 obs/0.92 exp); data indicate
                                     the workers was estimated to dose-related effect on risk of
                                     smoke (comparable to             cancer; For group with
                                     control: 42%)                    ≥ 500 ppm-years: all cancers
                                                                      23 obs/ 20 exp
  ase reports: register of all cases Principal occupation; no         Angiosarcoma incidence          Descriptive study with only
 f angiosarcoma in the liver         statistical analyses             peaks 20-29 years after         limited data per case.
histologically confirmed); 118                                        exposure: Production worker/    Supporting study
 ases in total, all men working in                                    operator and autoclave
he PVC industry; worldwide;                                           cleaners most at risk           Quality score C
 974-1984 (dates back to 1955);
  orman et al., 198526
  8            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 59 =================================================================

<br><br>====================================================================== Pagina 60 ======================================================================

<pre>  ohort study; Norway (Telemark Study set-up essentially the        High exposure: Colon cancer     Number of cases too small,
 ounty); Vinyl chloride industry; same to Heldaas et al., 1984      (5 obs/1.4 exp); Bronchial      exposure levels estimated, no
 953-1984; 430 participants        (only extended study period)     cancer (6 obs/2.5 exp);         statistical analyses reported.
employed ≥ 1 year, before                                           Malignant melanoma of skin      Supporting study
 970); age-matched control                                          (4 exp/0.7 obs), 1 additional
 ohort from Norwegian                                               case in each high and medium
 opulation;                                                         group compared to Heldaas et    Quality score B
Heldaas et al., 1987;                                               al, 1984, cases equally divided
Heldaas et al., 198450,51                                           between 3 latency groups in
                                                                    workers employed between
                                                                    1950 and 1964
 rospective exposed/non-           No exposure measurements,        No significant change in        Number of cases too small
 xposed cohort study; France; 12   exposure estimated high          cancer incidence related to     No exposure measurements;
VCM polymerization plants;         before 1970, moderate            Vinyl chloride exposure; One    Several potential bias/
 980-1985; 1,100 participants      1970-1976, low since 1976,       case of angiosarcoma was        confounding taken into
40-55 years old); 1,100 controls   data combined resulted in        found, in the group of exposed  account ;
non-exposed, age-matched,          7 exposure levels; data          workers                         Limited study (supportive
 ame plant and physician);         collected on job history,                                        only)
  aPlanche et al., 198756          amount of exposure and
                                   medical history, smoking and                                     Quality score B
                                   drinking habits of participants
                                   and controls; Data analysed
                                   by PIGAS system;
                                   confounding factors
                                   (smoking, alcohol
                                   consumption and socio-
                                   economic status) were
                                   controlled for by Mantel-
                                   Haenszel procedure
  etrospective cohort study;       No exposure measurements,        Ferrara cohort: All tumours:    Number of cases too small;
taly; VC/PVC industry (3 plants exposure levels estimated           SMR 155 (23 obs/14.8 exp,       no potential bias/confounding
ncluded); 1953/1959-1983/          (> 1,000 ppm in ‘50s en ‘60s     90% CI 106-220);                taken into account; Limited
 984; 437+181+638 workers          to 1-5 ppm mid ‘70); vital       Lung cancer: 217 (9 obs/        study (only supportive)
 mployed ≥ 6 months); controls status/ cause of death from          4.1 exp, 90% CI 113-379);
Italian population, age-, cause of administrative sources (when     other two plant cohorts         Quality score B
 eath- and calendar time-          available, clinical and          showed no increased risk for
 pecific);                         pathological data collected);    any malignant tumour
  elli et al., 198740              statistical analyses not
                                   described, performed per
                                   plant (confidence intervals
                                   calculated by procedure by
                                   Liddel); other risk factors, not
                                   taken into account
                Human studies                                                                                                    59
</pre>

====================================================================== Einde pagina 60 =================================================================

<br><br>====================================================================== Pagina 61 ======================================================================

<pre> etrospective cohort study; UK;   No exposure measurements.        Nonsecondary liver cancer:      Number of cases small; no
VC industry; 1940-1974; 5,498     Four occupational categories     SMR 567 (11 obs/1.9 exp;        potential bias/confounding
 articipants (males, employed for with estimated and measured      95% CI 283-1,015,               taken into account; Limited
  1 year with VCM exposure for    VCM exposure levels (not         7 angiosarcoma); Highest        study (supportive)
  25% of work shift); controls    further specified): Autoclave    exposure group (autoclave
rom England and Wales, same       operators (500-800 ppm and       operators):                     Quality score B
ive-year age group;               150-500 ppm), baggers and        Liver malignant neoplasm
 ones et al., 1988;               driers (<400 ppm and             (prim or sec): 6 obs/ 0.1 exp
 ox and Collier 197746,54         <40 ppm), craftsmen              (p<0.5), in this group
                                  (240 ppm-440 ppm and             incidence non-secondary liver
                                  50-300 ppm) for 1940-955         cancer increased with latency
                                  and 1956-1974 resp., and         (2 obs/ 0.16 exp for 10-19
                                  other workers (<100 ppm);        years and 4 obs/0.13 exp for
                                  mortality and cause of death     ≥ 20 years, both p<0.05) and
                                  via death certificate; mortality length of exposure (2 obs/
                                  analysis by OCMAP                0.08 exp ofor 5-9 years and
                                  computer program (Poisson        4 obs/ 0.15 exp for ≥10 years);
                                  distribution assumed); other     other cancers not increased
                                  risk factors not taken into
                                  account
 etrospective cohort study;       No exposure measurements,        Leukaemia/ aleukaemia in        Number of cases small,
 oviet Union; VC industry;        exposure estimated (> 300        both sexes: SMR 500             exposure levels only
 939-1977; 3232 participants      mg/m3 (high), 30-300 mg/m3       (5 obs/1 exp; p<0.05);Other     estimated; no potential bias/
2,195 male and 1,037 female       (moderate), <30 mg/m3 (low);     malignancies of lymphatic       confounding taken into
VC workers (> 1 month             significance determined by       and haematopoietic tissue:      account;
 mployed)); control (mean death confidence limits of the           both sexes: SMR 417 (both       Limited study (only
ates in city where relevant plant variation of cancer frequency,   5 obs /1.2 exp, p<0.05);        supportive.
was located for years 1959, 1969 effect of duration and level of   females: SMR 2,000
 nd 1975 (15-74 y old));          treatment calculated by          (4 obs/0.2 exp; p<0.05);        Quality score B
 mulevich et al., 198865          factorial dispersion technique   Both sexes high level group:
                                                                   Lymphomas/ leukaemias:
                                                                   SMR 636 (7 obs/1.1 exp,
                                                                   p<0,05);
                                                                   Females in high level group:
                                                                   (Stomach cancer: SMR 385
                                                                   (5 obs/1.3 exp; p<0.05);
                                                                   Lymphomas/ leukaemias
                                                                   SMR 4,000 (4 obs/0.1 exp,
                                                                   p<0.05)
 0            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 61 =================================================================

<br><br>====================================================================== Pagina 62 ======================================================================

<pre>  etrospective cohort mortality  No exposure measurements; Total cohort:                           Number of cases limited
 tudy; USA; vinyl chloride       vital status determined via       Liver cancer: SMR 300 (18 obs except for lung cancer; no
 olymerization industry; 1974-   administrative records; cause (12 cases angiosarcoma) /           exposure measurements, no
 986; total cohort 4835 (VCM     of death via death certificate or 6 exp; 90% CI 196-449);         potential bias/confounding
 ubcohort 3635) participants     hospital records; statistical     Lung cancer: SMR 123            addressed (potential co-
whites, employed between         significance tested assuming (115 obs/ 94.5 exp,                  exposure to butadiene only
 942-1973); control (US white    Poisson distribution              90% CI 104-142);                mentioned);
men); Wu et al., 1989;                                             Brain cancer: SMR 162 (15       Limited study (only
Waxweiler et al 197668,71                                          obs/ 9.2 exp, 90% CI 100-250); supportive)
                                                                   VCM-exposed cohort: Liver Quality score B
                                                                   cancer: SMR 333 (14 obs/
                                                                   4.2 exp, 90% CI 202-521);
                                                                   Lung cancer: SMR 115
                                                                   (80 obs/ 69.2 exp,
                                                                   90% CI 95-139);
                                                                   Brain cancer: SMR 145
                                                                   (10 obs/ 6.8 exp,
                                                                   90% CI 79-248); risk of
                                                                   mortality due to liver cancer
                                                                   was consistently elevated for
                                                                   all duration categories from
                                                                   5-25 years of exposure.
Nested case-control study; USA;  No exposure measurements, Odds ratio cumulative                   Study with limited number of
 inyl chloride polymerization    cumulative exposure/worker exposure to VCM and liver              cases; No exposure
ndustry; 1974-1986; each death   was estimated based on level angiosarcoma (n=12) for              measurements, PVC and
rom cause of interest was        of exposure (0 to 5) job1 x       5 years at level 5 exposure:    butadiene potential bias/
matched with 5 control subjects  duration of job1 + level of       109.9 (p=0.03); no relationship confounding addressed.
 y age (whites, employed         exposure job2 x duration of       between VCM and other           Limited study (supportive
 etween 1942-1973, subcohort     job2 + … ; vital status           cancers or PVC and specific only)
with workers exposed to VCM);    determined via administrative cancers or butadiene and
Wu et al., 1989; Waxweiler et al records; cause of death via       specific cancers                Quality score B
 97668,71                        death certificate or hospital
                                 records; Data analyses
                                 conditional logistic regression
                                 (variables for sex, year of first
                                 employment, cumulative dose
                                 of VCM, cumulative dose of
                                 PVC and butadiene taken into
                                 account
              Human studies                                                                                                   61
</pre>

====================================================================== Einde pagina 62 =================================================================

<br><br>====================================================================== Pagina 63 ======================================================================

<pre> etrospective cohort study;      No exposure measurements, No stat. significant relationship Low number of observed/
 weden; PVC processing           exposure estimated (none, low between mortality and a            cancer, exposure only
ndustry; 1945-1980; 2,031        (0.1 ppm), moderate (1 ppm), specific tumour; all tumour         estimated; co-exposure to
 articipants (male, employed     high (10 ppm)); job and           morbidity similar with (or     fibers and plastics explained
  3 months); about 75,000        exposure history derived from without) ≥10 y latency: SMR the respiratory cancers
 ontrols (males in same county,  plant records; cause of death 138 (55 obs/ 39.8 exp,
 ge-matched);                    from death certificates; two- 95% CI 105-181);                   Limited study (only
Hagmar et al., 199049            tailed statistical analyses,      Respiratory cancer morbidity supportive)
                                 assuming Poisson distribution; without ≥10 y latency: SMR
                                 effects of co-exposure to fibers 213 (17 obs/ 8.0 exp,
                                 and plastics were addressed 95% CI 127-346); no
                                                                   significant liver tumour
                                                                   morbidity (2 liver tumours
                                                                   were not haemangiosarcoma);
                                                                   no significant association
                                                                   between respiratory cancer or
                                                                   total cancer incidence and
                                                                   length of employment, or
                                                                   individual cumulative exposure
                                                                   VCM estimates; only
                                                                   significant increase of SMR
                                                                   respiratory cancers in
                                                                   subcohort exposed to asbestos
                                                                   and plasticizers (not to
                                                                   VCM):1,070
                                                                   (95% CI 220-3,120)
 ase mortality study; Italy;     No exposure measurement           14 primary liver cancers were Paper describing causes of
VCM/ PVC industry (3 plants); data; causes of death (and           identified: 7 angiosarcoma and death related to liver for
 53 deaths;                      other personal information)       2 hepatocellular carcinoma,    VCM/ PVC workers; no
 irastu et al., 1990;            collected from death              others not further specified;  comparison to control;
 elli et al., 198728,40          certificates and/or hospital      For resp. angiosarcoma and     Supportive study
                                 records (clinical and             primary nonangiosarcoma liver
                                 pathological data collected       cancer the mean age of death Quality score C
                                 where available                   was 48 years and 53 years,
                                 (3 plants only)                   mean duration of exposure
                                                                   16 and 18 years, mean latency
                                                                   19 and 20 years
                                                                   Note: next to highly VCM
                                                                   exposed angiosarcoma cases
 etrospective cohort study;      No exposure measurements, Cancer of liver and biliary            Basic epidemiological study
USA; Vinyl chloride industry     exposure estimated by             tract: SMR 641 (37 obs/        on mortality and cause of
32 plants); 1942-1982; study in occupation (high/ medium/          5.77 exp, p=0.01); 20+ y       death, sufficient number of
 990; 9,370 participants (males, low) and duration of              exposure: SMR 1285 (11 obs; participants from different
 xposed for ≥ 1 year prior to    employment (<10 years,            p=0.01); <20 y latency: SMR plants, but limited number of
 1 Dec 1972 and employed         10-20 years and >20 years); 386 (10 obs, p=0.01); 20-30 y cases. No exposure
 uring or after 1942); controls= demographic information,          latency: SMR 59 0 (11 obs,     measurements (only
US population;                   vital status and employment p=0.01); 30+ y latency; SMR estimated); healthy worker
Wong et al., 1991; Cooper, 1981, history collected via question- 1218 (16 obs, p=0.01);           effect or other factors not taken
 abershaw et al., 197433,36,37   naires; cause of death collected Cancer of brain and CNS:        into account; Study with minor
                                 via death certificates; Statisti- SMR 180 (23 obs/ 12.8 exp, flaws, supporting
                                 cal analyses with standard        p=0.05); 20+ y exposure: SMR
                                 computer package (OCMAP; 386 (6 obs, p=0.05); none of Quality score B
                                 95% confidence limits)            latency periods significant
 2             Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 63 =================================================================

<br><br>====================================================================== Pagina 64 ======================================================================

<pre> rospective cohort study; France; No exposure measurements,        RR malignant tumour 1.3,       Small number of cases,
VC industry (12 plants);          exposure estimated based on      95% CI 0.8-2.10); Liver cancer exposure estimated; no
 980-1988; 1,100 participants employment history; data             (all angiosarcoma): 3 exposed statistical analyses;
40-55 y old in 1980); 1,100       analysed with the GLIM           group/ 0 control group         limited study (supportive only)
 ontrols (age-matched, same       package
 lant and same physician);                                                                        Quality score B
  aplanche et al., 1992;
 aplanche et al., 198756,57
  ase study; United Kingdom;      Unclear how cases were           Twenty cases of liver          Twenty case reports from the
 VC industry; 1972-1994; 20       identified: from public          angiosarcoma in male VC        UK, source unknown
 atients; Lee et al., 199627      databases or from industry       workers reported (all in 2
                                  records; incidental exposure     plants); Average age 54 years Quality score C
                                  of up to 10,000 ppm (19          (37-71), average exposure 15
                                  workers, autoclave operators     years (3-29), average latency
                                  and polycleaners), moderate      25 years (9-35), mean survival
                                  exposure up to 200 ppm           from diagnosis to death 3.5
                                  (1 worker, premix, blow          months (1.5-13 months)
                                  down and stripping operator).
                                  Exposure low after 1975
                                  Background level of liver
                                  angiosarcoma in UK is around
                                  2-7 cases/ year
Morbidity cohort study, case-     No exposure measurement          Primary liver cancer: MOR 4.5 Limited number of cases; no
 ontrol design; Taiwan; PVC       data; health examinations        (vs motor; 95% CI 2.3-18.4) exposure measurements;
ndustry (5 plants); follow-up     including 5 liver function tests and 6.5 (vs optical;           several potential bias/
 989-1995; 2,224 participants and interview on occupational        95% CI 1.5-13.3);              confounding taken into
current and former male           and medical history              Haematopoieic cancer: MOR account by choice of relevant
workers); 3,667 and 5,861 male (714 current workers only);         3.4 (vs motor,                 control group;
 ontrols (workers from optical information from 1,510              95% CI 1.0-11.8) and 3.1 (vs Limited study (only
 quipment and motorcycle          former PVC workers from          optical, 95% CI 0.8-11.8);     supportive)
ndustry 1985-1994 resp.);         hospital records; Morbidity      Incidence haematopoietic
Du et al., 1998.44                odds ratio (MOR) statistically   cancer related with age (MOR Quality score B
                                  analysed by multiple logistic    18.1 for <40 vs >50
                                  regression on the SAS            (95% CI 2.3-138); In total, 6
                                  package, 6.08 edition;           cases of primary liver cancer
                                  incidence of primary liver       and 6 cases of hepatocellular
                                  cancer in males is 28.4 per      carcinoma in PVC worker
                                  100,000 (Cancer Registry         group (latency 8-29 years, age
                                  Report Taiwan, 1994); by         at admission 41-68 years,
                                  selecting reference population   working duration 5-30 years)
                                  with similar socio-economic
                                  status, effects of smoking,
                                  drinking were minimized
              Human studies                                                                                                   63
</pre>

====================================================================== Einde pagina 64 =================================================================

<br><br>====================================================================== Pagina 65 ======================================================================

<pre>  etrospective mortality study;  No regular exposure             Lung cancer: 11 obs/ 8 exp;     Study with small cohort, no
Norway (Telemark county); PVC    measurement data (estimated     Melanomas of the skin: 7 obs/   exposure levels measured; no
ndustry 91 plant); follow-up     based on measurements with      2.07 exp (5 cases in highest    confounding factors taken
 953-1993; 428 participants      explosion meters in the 50s     exposure group ≥5 ppm-years     into account;
employed > 1 year, first         and 60s, interviews (odour      vs 0.7 exp (95%CI 2.3-16.7);    Supporting study
 mployment between 1950 and      threshold): constant decrease   Total number of skin cancers,
 970); age-matched control       in VC concentration over the    melanomas and spinocellular     Quality score B
 ohort from Norwegian            years, therefore, cumulative    cancers combined: 12 obs/ 3.7
 opulation; Langard et al.,      exposure: <1 ppm-years,         exp (95% CI 1.7-5.7); during
 000, Heldaas et al., 1984 and   1-5 ppm-years, ≥5 ppm-years;    observation period 1985-93
Heldaas et al., 198750,51,55     nine job classifications based  no new cases of liver
                                 on estimated exposure level;    haemangiosarcoma, thyroid
                                 cause of death based on
                                 Cancer Registry of Norway
                                 (also used to calculate
                                 expected incidence of
                                 cancers); Poisson distribution
  etrospective mortality cohort  No exposure measurement         Malignant neoplasm of the       Well-performed study
 tudy; Taiwan; PVC industry;     data; Vital status and/or cause liver (mostly hepatocellular    (sufficient number of
 985-1997; 3,293 participants    of death via National health    carcinoma, no ASL): SMR         participants), no exposure
male workers, employed ≥ 1       Insurance/National Mortality    1.78 (25 obs/14.1 exp,          measurements; only one other
 ear between 1950-1992, alive    Registry; statistical analyses  95% CI 1.15-2.62);              risk factor addressed
 n 1st January 1985)); reference assuming Poisson                Cancer of lymphatic and         (hepatitis infection); well-
 eneral male population of       distribution; potential         haematopoietic tissue: SMR      performed study with
  aiwan; Wong et al., 2002;      hepatitis infection addressed   2.6 (7 obs/2.6 exp, 9           limitations
Du et al., 199844,70                                             5% CI 1.09-5.6); SMR for
                                                                 liver cancer specifically       Quality score B
                                                                 increased in group exposed
                                                                 <10 years (2.45, 95% CI 1.30-
                                                                 4.19), age at first exposure
                                                                 <30 years (4.5,
                                                                 95% CI 1.07-4.12), year of
                                                                 first exposure before 1970
                                                                 (4.82, 95% CI 2.41-8.63) and
                                                                 latency period ≥ 25 years
                                                                 (3.13,
                                                                 95% CI 1.5-5.75), all p≤0.05
  etrospective mortality study;  No exposure measurement         SMR for primary liver cancer    Since only the summary is
taly (Venice area, 1 plant);     data (differentiated per job)   increased (SMR 2.78             available of this study in
VC industry; 1973-1999;                                          90% CI 1.86-4.14); Mortality    English, the reliability of the
 ,658 participants (from 1950,                                   rates for liver angiosarcoma (6 data cannot be assessed
 resent in 1956 or successively                                  cases) increased with latency
 ired until 1985);                                               and cumulative exposure
  irastu et al., 2003 (only                                      (both p<0.001); Mortality
  nglish abstract, main text in                                  rates for hepatocellular
talian)31                                                        carcinoma
                                                                 (12 cases) showed similar
                                                                 pattern for cumulative
                                                                 exposure
  4            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 65 =================================================================

<br><br>====================================================================== Pagina 66 ======================================================================

<pre>   etrospective mortality study;    No exposure measurement         Excess mortality for all      Since only the summary is
taly (Venice area, 1 plant); VC     data (differentiated per job);  tumours (RR=1.53),            available of this study in
ndustry; 1972-1995; 1,658           statistical analyses by Poisson lung cancer (RR=2.05),        English, the reliability of the
 articipants (males); two           regression, adjusting for age,  liver tumours (RR=4.08), and  data cannot be assessed
eference groups: “technicians       age at hiring, calendar period, lymphomas and leukaemia
 nd employees” and “other blue      length of exposure and          (RR=2.97)
 ollar workers”;                    latency
Gennaro et al., 2003 (only
  nglish abstract, main text in
talian)48
   etrospective case-cohort study;  No exposure measurement         Angiosarcoma incidence        Moderate number of cases, no
USA (Kentucky); VC/PVC              data, exposure estimated from   related to year of hire and   exposure measurements;
ndustry (1 plant); 1942-2002;       year, building and job with     years employed (p=0.09 and    potential effects of
 ,817 participants in total, 23     VC exposure by qualitative      p<0.05), all cases worked in  co-exposure to acrylonitrile,
 ases of angiosarcoma, 16 cases     ranking system (6 ranks);       PVC building, and all exposed 1,3-butadiene and styrene
 f brain cancer (white males,       stratified nonparametric        in two highest ranks          addressed; control cohort not
 ired prior to 1967, employment     analysis of case exposure       (p<0.001); Brain cancer       described; Limited, study
   1 year);                         ranks (Fisher’s exact),         incidence related to year of  (only supportive)
   ewis and Rempala, 2003;          calculations with SAS           hire (p=0.09); Angiosarcoma
Waxweiler et al, 1976,              software or LogXact 2.1         and brain cancer cases not    Quality score B
Wu et al., 1989,                    (for small size calculations)   exposed to highest levels of
  ewis et al., 200158,59,68,71                                      acrylonitrile, 1,3-butadiene
                                                                    and styrene
   etrospective case- control       No exposure measurement         Strong association of         Moderate number of cases, no
 tudy; USA (Kentucky); VC           data, exposure estimated from angiosarcoma with exposure      exposure measurements;
ndustry (1 plant); 1942-2002; 23    year, building and job with     to VC (p<0.001), not with     potential bias/confounding for
 ases of angiosarcoma, 16 cases     VC exposure by qualitative      vinyl acetate, vinylidene     vinyl acetate, vinylidene
 f brain cancer (all white males,   ranking system (6 ranks);       chloride or PVC; no           chloride or PVC investigated;
 ired prior to 1967, employment     rank order and logistic         association of brain cancer   Limited study (only
   1 year); 160 and 98 controls for regression analyses,            with any of the substances    supportive)
 ngiosarcoma and brain cancer       weighted sum of the case        used
 ases resp.;                        percentile ranks by the van                                   Quality score B
   ewis and Rempala, 2003;          Elteren-Cuzick statistic,
Waxweiler et al., 1976, Wu et al.,  calculations with SAS
 989, Lewis et al., 200358,59,68,71 software or LogXact 2.1 (for
                                    small size calculations)
   etrospective case-control study; No exposure measurement         No significant correlation    Moderate number of cases, no
  urope (Romania, Hungary,          data; job and exposure history incidence lung cancer and      exposure measurements;
  oland, Russia, Slovakia, Czech    assessed by questionnaires      vinyl chloride exposure       several potential bias/
epublic, UK); 1998-2002;            analysed by industrial                                        confounding taken into
 ,861 cases (recruited from         hygienists for vinyl chloride,                                account; limited study (only
 linical and pathological           acrylonitrile and styrene for                                 supportive)
 epartments); age- and gender       each job held by each subject;
matched controls (total number      stratified statistical analyses                               Quality score B
 ,118);                             (unconditional logistic
  celo et al., 200464               regression models); effect of
                                    smoking, age and gender was
                                    taken into account
                Human studies                                                                                                   65
</pre>

====================================================================== Einde pagina 66 =================================================================

<br><br>====================================================================== Pagina 67 ======================================================================

<pre>Nested case-referent study; Italy; No exposure measurement data Hepatocellular carcinoma:           Small number of cases, well-
VC industry; 1987-1999;            (cumulative exposure              odds ratio for VC exposure     documented statistical
 3 cases of hepatocellular         estimated based on job            >2500 ppm years 29.3 (9 cases, analyses; no exposure
 arcinoma and 139 controls(total history); cancer cases through 95% CI 3.61-1,298, p<0.001 measurements; Several
 ohort of 1,658 participants);     hospital records and cancer       for trend)                     potential bias/confounding
Mastrangelo et al., 2004.2         registry; physical examination                                   taken into account.
                                   of 643 cohort members 1999-                                      Limited study (only
                                   2002 (liver sonography or                                        supportive)
                                   serum biochemistry); interval
                                   variables analyzed by Student’s                                  Quality score B
                                   t-test and frequency variables
                                   by Fisher’s exact test; Odds
                                   ratio and 95% Confidence
                                   Interval by StatXact statistical
                                   package; Chi-square test for
                                   linear trends; authors
                                   addressed effect of alcohol
                                   intake and viral hepatitis
                                   infection
  etrospective case-cohort         No exposure measurement           Relative risk for liver cancer Low number of cases; no
mortality study; Italy (Veneto     data, exposure estimated based among autoclave workers           exposure measurements;
 rea); VC-PVC production plant; on work history: autoclave           (9.57, 95% CI: 3.71-24.7,      potential bias taken into
 972-1999; 1,658 participants workers (n=210), PVC baggers 7 obs, significant); Increased account by use of internal
male workers, employed             (n=198), PVC compound             SMR (compared to Italian       comparison group;
 etween 1950-1985); internal       workers (n=404), and              population) for                confounding factors not taken
eference group: technicians and technicians and clerks (n=202, haemolymphopoietic system into account. Limited study
 lerks (202 workers) or Italian low to null exposure), other tumours for PVC baggers                (only supportive)
 opulation;                        blue collar workers (n=644); ; (3.77, 95% CI 1.03-9.66) and
Gennaro et al., 2008; Gennaro et Internal comparison through total blue collar workforce            Quality score B
 l., 2003, Pirastu et al., 2003,   two-sided, Poisson regression (2.27 95% CI 1.24-2.81)
 irastu et al.,199831,47,48,63     model, multivariate regression
                                   analysis adjusted for age,
                                   calendar period, employment
                                   duration and latency
  etrospective cohort study;       No exposure measurement data Liver cancer: SMR 1.93 for          Moderate/low number of
 aiwan; PVC industry (6 plants); (estimated TWA: 150 ppm             1980-1997 (33 obs/16, 6exp, cases; no exposure
 980-2007; 3,336 participants (1973-1974), 25 ppm                    95% CI 1 37-2.79, p<0.01); measurements (only
male workers); reference is        (1974-1975), 10 ppm               Leukaemia: SMR 3.93 for        estimated); no potential bias/
 eneral Taiwanese population; (1975-1994), 5 ppm                     1908-1997 (6 obs/1.53 exp,     confounding taken into
Hsieh et al., 2011;                (1995-2002), 3 ppm (203-          95% CI 1.4-8.5; p<0.01); both account; Limited study (only
Wong et al., 199137,52             2007); Vital status, cause of SMRs for 1998-2007                 supportive)
                                   death and other personal          non-significant
                                   information via National                                         Quality score B
                                   Household Registration
                                   System or National Mortality
                                   Registry; statistical analyses by
                                   Byar’s approximation of the
                                   exact Poisson test, non-
                                   parametric test for several risk
                                   factors (all two-sided);
                                   confounding factors not taken
                                   into account
  6            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 67 =================================================================

<br><br>====================================================================== Pagina 68 ======================================================================

<pre> abel 5 Multi-centric cohort studies and meta-analysis of previously published data on the effects of VCM exposure.
 tudy design and population           Data on exposure and health Results                            Remarks
                                      assessment
  e-analysis of retrospective         Statistical power of median     Combined relative risk for     Well-documented re-analysis
mortality studies; original studies SMRs found in the studies         liver cancer 5.17 (p<0.00001), of historical data sets
rom USA (Texas), UK, Sweden, were calculated with respect for brain cancer 1.74 (p<0.01)
Germany; Vinyl chloride               to liver, brain or lung cancer                                 Quality score B
ndustry; studies published            to relate positive (excess risk
 974-1978); studies differed in for a specific cancer at
 umber of participants                p=0.05) and negative findings
255-9,677), exposure time of          to power; One- sided Poisson
 articipants (1 day - >5 years),      test
 ge of participants, different
 ontrol populations (standard
 opulation of Texas or study’s
 ountry was conducted);
  eaumont and Breslow, 1981;
 abershaw et al., 1974,
Ott et al., 1975, Nicholson et al.,
 975, Byren et al., 1976,
Waxweiler et al., 1976, Fox and
  ollier, 1977, Buffler et al.,
 97935,36,39,41,42,46,62,68
Multicentric cohort study; Italy, No exposure measurements, All malignant neoplasms:                 Well-documented study with
Norway, Sweden, United                exposure estimated based on SMR 104 (445 obs/ 428 exp, sufficient number of
Kingdom; VCM/ PVC industry; industrial hygiene sources and 95% CI 95-114)                            participants, from 4 different
 955-1986; 12,706 participants occasional air measurements Cancer of liver and                       countries and several plants;
rom 19 plants (males with             (regular measurements from intrahepatic bile ducts: SMR no exposure measurements;
  1 year employment); controls mid-1970s (low: <50 ppm;               286 (24 obs/ 8.4 exp, 95% CI possible co-exposure to other
 re national incidence of             intermediate: 50-449 ppm;       183-425);                      substances only mentioned;
mortality rates (men only)            high: ≥ 500 ppm); background ≥15 y latency: SMR 445            Well-performed study
 pecific for age and 5-year           data through nation-based       (95% CI 285-663);
 alendar periods;                     cancer registries or WHO        16 confirmed angiosarcoma/
 imonato et al., 1991;                databases; Poisson              17 histologically identified;  Quality score B
  yren et al., 1976,                  distribution; authors           Duration of exposure, level of
Molina et al., 1981,                  mentioned possibility of co- exposure, and cumulative
Heldaas et al., 1984,                 exposure to other compounds exposure related to increased
  elli et al., 1987,                                                  mortality from liver cancer
 irastu et al., 199028,29,40,42,50,60                                 (p<0.001, p<0.01 and p<0.001
                                                                      resp.), risk unaffected by age
                                                                      of first exposure and calendar
                                                                      period of exposure;
                                                                      Liver and intrahepatic bile
                                                                      cancer: SIR 303 (7 obs/
                                                                      2.3 exp, 95% CI 122-623,
                                                                      Norway and Sweden only,
                                                                      2643 participants); Data show
                                                                      clear dose-dependency for
                                                                      liver cancer incidence
                Human studies                                                                                                    67
</pre>

====================================================================== Einde pagina 68 =================================================================

<br><br>====================================================================== Pagina 69 ======================================================================

<pre>  etrospective cohort study;      No exposure measurement or      Liver and biliary tract cancer:  Study with large number of
USA/ Canada (1 plant, Ontario);   estimates; vital status/ cause  SMR 359 (95%CI 284-446);         participants; statistical
VCM or PVC industry               of death from National Death    Brain and CNS cancer: SMR        analyses to identify variables
37 plants); 1942-31 Dec 1995;     Index and the death records of  142, (95%CI 100-197);            of influence; no exposure
 0,109 participants (males        the Social Security             Connective and other soft        measurements or estimates;
 mployed for ≥ 1 year in          Administration; for Canada      tissue cancer: SMR 270           potential bias/confounding
 942-1972); reference rates for   from Ontario Office of the      (95%CI 139-472);                 taken into account; Limited
white men, SMRs calculated both   Registrar General;              Lung cancer: SMR 82              study (only supportive)
 ation-wide and state-specific by Standardized mortality ratio    (95% CI 73-92);
NIOSH;                            (SMR) analyses and 95%          Cancer of lymphatic and          Quality score B
Mundt et al., 2000; Tabershaw     confidence intervals were       haematopoietic tissue: SMR
 t al., 1974, Cooper ,1972,       done with ProSMR (ProQuest      86 (95% CI 67-108);
Wong et al., 199133,34,36,37      database system). Cox’s         Stratified log rank analyses
                                  proportional hazards            identified
                                  models and stratified log rank  duration of exposure as the
                                  tests were                      strongest predictor
                                  used to further assess          of hazard (p<0.001,
                                  occupational factors            controlling for age and
                                                                  controlling for year of first
                                                                  exposure); 80 deaths from
                                                                  liver cancer, 41% due to
                                                                  angiosarcoma; All deaths due
                                                                  to cancer of connective and
                                                                  other soft tissue in workers
                                                                  first exposed before 1960
  etrospective cohort study;      No exposure measurement         Liver cancer: SMR 2.4 (53        Well-described study
  urope (Italy, Norway, Sweden,   data, quantitative estimates    obs, 95%CI 1.8-3.1); Thyroid     (sufficient number of
UK); VCM/PVC industry (19         per worker based on             cancer: SIR 2.21 (7 obs,         participants); no exposure
 lants); 1955-1996 (except for 2  interviews (smell threshold of  95%CI 0.89-4.55);                measurements; confounding
 lants in Italy (from 1972 and    400 or 500 ppm), air            Malignant melanoma: SMR          factors not taken into account;
 974) and 1 plant in Sweden       measurements since 1970s        1.6 (15 obs, 95%CI 0.9-2.65);    well-performed study
rom 1961), 80% of cohort has      and job history for 9,775       Among 71 cases of liver
 een traced ≥ 15 years); 12,700   participants resulting into     cancer were 37 angiosarcomas     Quality score B
 articipants (male workers,       categories: <1 ppm-years, 1-5   (for autoclave workers: 25
 mployed ≥ 1 year); control data  ppm-years and ≥5 ppm-years;     liver cancers, 16
rom WHO data base (age-,          Vital status and cause of death angiosarcomas); Risk for
 alendar period and country-      from death certificates, cancer angiosarcoma 200 times
 pecific);                        registry records, medical       greater than for reference
Ward et al., 2001; Simonato et    records, and listings of        population; Liver cancer
 l., 199129,30                    angiosarcoma cases from         correlates with time since first
                                  several registries; estimated   employment, duration of
                                  incidence angiosarcoma 0.1      employment, and cumulative
                                  per million population per      exposure. For liver
                                  year; Statistical analyses by   angiosarcoma strong relation
                                  internal Poisson regression,    with cumulative exposure and
                                  95% CIs calculated using a      duration of employment
                                  Poisson distribution            (≥21 y).
  8            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 69 =================================================================

<br><br>====================================================================== Pagina 70 ======================================================================

<pre>Meta-analysis of two multi center For details see studies       Meta-SMR for liver cancer     Well-documented meta-
 ohort studies (Italy/Sweden/     summarized in this table      increased (based on 2 multi   analysis of multiple
Norway/UK and US/Canada) and      individually; meta-analysis   center cohort studies): 2.96  previously published data.
  smaller studies (Former USSR,   based on random-effects       (133 cases, 95% CI 2.00-4.39) Well-performed analysis
  rance, Canada, Germany, China,  modeling, if heterogeneity ≥  and 1.35 (68 cases,
  aiwan); VC/PVC industry;        0.01. Meta-SMR values and     95% CI 1.04-1.77) if ASL is   Quality score B
 ariable follow-up, 1940 and      their 95% CI were calculated  excluded; Increased meta-
 997; 43,810 participants;                                      SMRs for brain cancer 1.26
  offetta et al., 2003;                                         (95% CI 0.98-1.62), soft
Ward et al., 2001; Mundt et al.,                                tissue sarcomas 2.52
 000; Smulevich et al., 1988,                                   (95% CI 1.56-4.07), non-
  aplanche et al., 1992;                                        Hodgkin lymphoma 1.23
  heriauld and Allard, 1981;                                    (95% CI 0.70-2.19)
Weber et al., 1981; Wong et al.,
 00230,34,38,57,65,67,69,70
  e-analysis of meta-analysis of  Meta-analysis using fixed     Based on all studies: meta-   Well-documented meta-
wo multi center cohort studies    effects modeling, when        SMR for liver cancer 4.95     analysis of previously
Italy/Sweden/Norway/UK and        heterogeneity p ≥0.01; using  (95% CI 2.32-10.65), without  published data.
US/Canada) and 6 smaller          random effects modeling,      ASL 2.37 (95% CI 1.27-4.44),  no exposure measurements.
 tudies (Former USSR, France,     when heterogeneity p ≤0.01    soft tissue sarcomas 2.52     Limited study (only
  anada, Germany, China,                                        (95% CI 1.66-3.82), skin      supportive)
  aiwan); VC/PVC industry;                                      cancer 1.20
 ariable, between 1939-1997;                                    (95% CI 0.86-1.68), brain     Quality score B
  waen and Duijts, 2005;                                        cancer 1.28
  offetta et al., 200338,66                                     (95% CI 1.01-1.61),
                                                                neoplasms of the lymphatic
                                                                and hematopoietic systems
                                                                1.61 (95% CI 0.96-2.70),
                                                                non-Hodgkin lymphoma 1.31
                                                                (95% CI 0.71-2.41), leukemia
                                                                1.43 (95% CI 0.67-3.02)
  etrospective cohort mortality   No exposure measurement       Hepatobiliary cancer          Well-described study
 tudy: New York plant             data available. Exposure was mortality was elevated among   Moderate number of
manufacturing rubber and plastic. estimated by duration of      workers ever exposed to VCM   participants. No exposure
  roduction of VCM and PVC        employment (yrs). Any         (11 observed deaths, of these measurements , only
rom 1946.                         worker assigned to the PVC, 5 were defined as ‘liver        estimated exposure
 ,874 participants employed at    VCM department prior 1995 primary’, 5 ase ‘liver
he plant between 1946 and 1994 was considered exposed. In       unspecified’, and 1 as        Quality score B
 nd 2006.                         addition employees in several ‘intrahepatic bile duct’).
  ontrol mortality data from US jobs assigned to other          Over all SMR=3.80;
 opulation rates.                 departments were also         (95% CI 1.89-6.80)
Carreon et al., 2014 update of considered exposed
  rince et al. 2000                                             No significant associations
‘NIOSH cohort’))43,82                                           between VCM and non-
                                                                Hodgkin lymphoma or
                                                                pancreatic cancer
                Human studies                                                                                            69
</pre>

====================================================================== Einde pagina 70 =================================================================

<br><br>====================================================================== Pagina 71 ======================================================================

<pre>0 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 71 =================================================================

<br><br>====================================================================== Pagina 72 ======================================================================

<pre>nnex F
     Animal experiments
     Quality criteria83:
     1: Reliable without restriction (This includes studies or data from the literature or reports which were
     carried out or generated according to generally valid and/or internationally accepted testing
     guidelines (preferably performed according to GLP) or in which the test parameters documented are
     based on a specific (national) testing guideline (preferably performed according to GLP) or in which
     all parameters described are closely related/comparable to a guideline method)
     2: Reliable with restriction (This includes studies or data from the literature, reports (mostly not
     performed according to GLP), in which the test parameters documented do not totally comply with
     the specific testing guideline, but are sufficient to accept the data or in which investigations are
     described which cannot be subsumed under a testing guideline, but which are nevertheless well
     documented and scientifically acceptable)
     3: Not reliable (This includes studies or data from the literature/reports in which there are
     interferences between the measuring system and the test substance or in which organisms/test
     systems were used which are not relevant in relation to the exposure (e.g., unphysiologic pathways of
     application) or which were carried out or generated according to a method which is not acceptable,
     the documentation of which is not sufficient for an assessment and which is not convincing for an
     expert judgment)
     Animal experiments                                                                                       71
</pre>

====================================================================== Einde pagina 72 =================================================================

<br><br>====================================================================== Pagina 73 ======================================================================

<pre>              4: Not assignable (This includes studies or data from the literature, which do not give sufficient
              experimental details and which are only listed in short abstracts or secondary literature (books,
              reviews, etc.)
  tudy design and animal        Data on exposure and effect           Results                                Remarks
 pecies                         endpoints
  reliminary repeated dose      Inhalation; 0, 1, 10, 100 ppm         Pulmonary tumours: found only at Limited study (only
 tudy; CD1 mice (male);         (corresponds to appr. 0, 2,6, 26,     40 weeks after exposure; 0/10, 1/9, supportive).
 0/group; 30/ control group;    260 mg/m3); 5 hr/day, 5 days/         2/9 and 5/9; 1, 1, 2 and 4 mice (at 0,
  uzuki, 198184                 week, 4 weeks; 0 (10/group),          1, 10 and 100 ppm, resp.) found        Klimisch score 4
                                12 (10 animals found dead/group)      dead during observation time.
                                or 40 weeks (survivors); gross
                                pathology; no statistical analyses
  epeated dose study; CD1       Inhalation; 0, 1, 10, 100, 300, 600   Alveologenic tumours; no tumours       Limited study (only
mice (male); 30/ all groups     ppm (corresponds to appr. 0, 2,6,     directly after exposure, first tumour  supportive).
 xcept 600 ppm, 40/ 600 ppm; 26, 260, 767, 1,534 mg/m3);              10 weeks post exposure, after 12
 0 controls/ group; Suzuki,     6 hr/ day, 5 days/ week, 4 weeks;     weeks tumour incidence 8/9 and         Klimisch score 4
 983; Suzuki, 198184,85         sacrifice at 0 (10/ dose, 20 of       6/9 at 600 and 300 ppm, resp., after
                                control group), 12 (6-9/dose, 18 of   40/41 weeks: 6/7, 5/7, 6/9, 3/9,
                                control group), 40-41 (7-9/ dose,     1/9for 600, 300, 100, 10 and 1 ppm,
                                17 of control group) or over 41       resp. (0/17 in controls; m ortality
                                weeks after exposure (4 at 600 ppm    due to Vinyl chloride cannot be
                                and 2 control); Histopathology and    deduced from data; dose-related
                                electron microscopy of tumours; no    increased incidence of pulmonary
                                statistical analyses                  (alveologenic) tumours, inverse
                                                                      relation dose to latency period; size
                                                                      of tumours related to dose; no
                                                                      metastases into other organs
  epeated dose study; NMRI      Inhalation; 0, 50 or 500 ppm          Alveologenic adenoma: none in          Well-documented
mice (male and female);         (corresponds to appr. 0, 130 or       controls; 13/24 at 50 ppm, first       study.
 2/sex/group;                   1,300 mg/m3); 6 hr/day, 5 days/       26 weeks after start exposure;
Holmberg et al., 197686         week; 26 weeks (0, 500 ppm),          24/24 at 500 ppm;                      Klimisch score 2
                                52 weeks (0, 50 ppm, except 4/sex/ Haemangiosarcoma: none in
                                group killed at 26 weeks); gross      controls; 15/24 at 50 ppm
                                pathology and histopathology;         (subperitoneal, subcutaneous
                                no statistical analyses               and/or lungs); 8/24 at 500 ppm
                                                                      (subperitoneal, liver); Mammary
                                                                      carcinoma: none in controls;
                                                                      1/24 at 50 ppm; 4 at 500 ppm;
                                                                      Overall tumour incidence 3/48,
                                                                      18/24 and 24/24 for 0, 50 and
                                                                      500 ppm resp
  2           Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 73 =================================================================

<br><br>====================================================================== Pagina 74 ======================================================================

<pre> epeated dose study; NMRI      Inhalation; 0, 50 and 500 ppm        After 6 months:                      Limited study (only
mice (male and female);        (corresponds to 0, 130 and 1,300     Lung adenoma: 0/8, 2/8 and 8/8; no   supportive).
 2/sex/group; 24 controls/sex; mg/m3); 6 hours/ day, 5 days/ week,  haemangiosarcoma found;
Winell et al., 1976;           52 weeks (50 ppm) or 26 weeks        After 12 months:                     Klimisch score 4
Holmberg et al., 197686,87     (500 ppm); life time observation;    Lung adenoma: 0/24, 13/24
                               histopathology; no statistical       and 24/24;
                               analyses                             Haemangiosarcoma (subperitoneal,
                                                                    subcutaneous, pulmonary, hepatic
                                                                    and renal): 0/24, 14/24 and 8/24;
                                                                    mean time of death: 46 and 35
                                                                    weeks resp. at 50 and 500 ppm
                                                                    (no further data on mortality)
 epeated dose study; A/J       Inhalation; 0, 50 and 500 ppm        Pulmonary tumours; no sex-           well-performed study.
mice (male and female);        (corresponds to 0, 130 and 1,300     difference observed; 50/140,
 0-72 sex/group;               mg/m3); 6 hr/day, 5 d/week, 6        115/142 and 140/140 (average         Klimisch score 2
 0 controls/sex;               months; mice killed at end of        male/female, for 0, 50 and 500 ppm
Adkins et al., 198688          exposure; lung histopathology;       resp.); mortality at 500 ppm higher
                               one-way analysis of variance of      (43% vs 1 and 3% in other groups);
                               Kruskal-Wallis test, Duncan’s new male mice had significantly more
                               multiple-range test                  tumours at 50 ppm than females
                                                                    (p<0.001)
 epeated dose study; A/J       Inhalation; 0, 50 and 200 ppm        Pulmonary tumours: 8/30, 26/30,      well-performed study
mice (female); 30/group;       (corresponds to 0, 130 and           30/30; no substance-related
 0 controls;                   520 mg/m3); 6 hr/day, 5 d/week,      mortality                            Klimisch score 2
Adkins et al., 198688          6 months; mice killed at end of
                               exposure; lung histopathology;
                               one-way analysis of variance of
                               Kruskal-Wallis test, Duncan’s new
                               multiple-range test
Repeated dose study;           Inhalation; 0 or 100 ppm             As incidence of tumours was          well-performed study.
 ischer-344 rats (female);     (corresponds to 0 or 260 mg/m3); higher if exposure started earlier in
 6-76/group; 112 controls;     6 hr/ day, 5 days/ week, exposed for life, only results with start of     Klimisch score 2
Drew et al., 198373            6 (starting at t=0, 6, 12 or 18      exposure at t=0 are given:
                               months), 12 (starting at t=0, 6 or   0, 100 ppm (0-6, 0-12, 0-18, 0-24
                               12 months), 18 or 24 months; up to months):
                               24 months observation time; gross haemangiosarcoma (liver), 1/112
                               pathology and histopathology;        (4/76, 11/55, 13/55, 19/55);
                               statistical analyses by life table   haemangiosarcoma (all sites),
                               analyses and contingency tables      2/112 (4/76, 12/56, 15/55, 24/55);
                                                                    mammary gland adenocarcinoma
                                                                    5/112 (6/76, 11/56, 9/55, 5/55),
                                                                    hepatocellular carcinoma 1/112
                                                                    (3/75, 4/56, 8/54, 9/55), all p<0.01
               Animal experiments                                                                                            73
</pre>

====================================================================== Einde pagina 74 =================================================================

<br><br>====================================================================== Pagina 75 ======================================================================

<pre> epeated dose study; Golden Inhalation; 0 or 200 ppm                As incidence of tumours was           well-performed study
 yrian hamster (female);       (corresponds to 0 or 130 mg/m3);     higher if exposure started earlier in
 6/group; Drew et al., 198373 6 hr/ day, 5 days/ week, exposed for  life, only results with start of      Klimisch score 2
                               6 (starting at t=0, 6, 12 or 18      exposure at t=0 are given:
                               months), 12 (starting at t=0, 6 or   0, 200 ppm (0-6, 0-12, 0-18
                               12 months), 18 or 24 months; 24      months):
                               months observation time; gross       haemangiosarcoma (all sites) 0/143
                               pathology and histopathology;        (13/88, 4/52 (both p<0.01), 2/103);
                               statistical analyses by life table   mammary gland carcinoma 0/143
                               analyses and contingency tables      (28/87, 31/52, 47/102; all p<0.01);
                                                                    stomach adenoma 5/138 (23/88,
                                                                    3/50, 20/101; all p<0.01);
                                                                    Skin carcinoma 0/133 (2/80, 9/48
                                                                    (p<0.01), 3/90)
 epeated dose study; B6C3F1 Inhalation; 0 or 50 ppm                 As incidence of tumours was           well-performed study
 nd CD-1 mice (female);        (corresponds to 0 or 520 mg/m3); higher if exposure started earlier in
 4/group; Drew et al., 198373 6 hr/ day, 5 days/ week, exposed for life, only results with start of       Klimisch score 2
                               6 (starting at t=0, 6, 12 or 18      exposure at t=0 are given:
                               months), 12 (starting at t=0, 6 or   0, 50 ppm (0-6, 0-12, 0-18),
                               12 months), 18 or 24 months;         CD-1 mice:
                               24 months observation time; gross Haemangiosarcoma (all sites)
                               pathology and histopathology;        1/71 (29/67, 30/47, 20/45),
                               statistical analyses by life table   mammary gland carcinoma 2/71
                               analyses and contingency tables      (33/67, 22/047, 22/45), lung
                                                                    carcinoma 9/71 (18/65, 15/47,
                                                                    11/45), all p<0.01;
                                                                    0, 50 ppm (0-6, 0-12), B6C3F1
                                                                    mice: Haemangiosarcoma (all
                                                                    sites) 4/69 (46/67, 69/90),
                                                                    mammary gland carcinoma 3/69
                                                                    (29/67, 37/90), all p<0.01
 epeated dose study; Sprague Inhalation; 0, 50, 250, 500, 2500, 0 (50, 250, 500, 2500, 6,000,             Well-performed study.
Dawley rats (males and         6,000, 10,000 ppm (corresponds       10,000 ppm): Liver angiosarcoma
emales); 30/sex/group;         to 0, 130, 650, 1,300, 6,500, 15,600 0/58 (1/60, 3/59, 6/60, 13/60,        Klimisch score 2
 8 controls; Maltoni et al and or 26,000 mg/m3); 4 hours/day,       13/59, 7/60); Extra-liver
 efemine, 1974;                5 days/ week, 52 weeks; total        angiosarcoma 0/58 (1/60, 2/59,
Maltoni et al., 198174,75      experimental time 135 weeks;         1/60, 3/60, 3/59, 3/60);
                               complete histopathology; no          Nephroblastoma 0/58 (1/60, 5/59,
                               statistical analyses                 6/60, 6/60, 5/59, 5/60);
                                                                    Neuroblastoma 0/58 (0/60, 0/59,
                                                                    0/60, 4/60, 3/59, 7/60); Zymbal
                                                                    gland carcinoma 0/58 (0/60, 0/59,
                                                                    4/60, 2/60, 7/59, 16/60); Skin
                                                                    epithelioma 1/58 (1/60, 2/59, 1/60,
                                                                    1/60, 2/59, 3/60); Mammary
                                                                    tumour 0/58 (2/60, 2/59, 1/60, 2/60,
                                                                    0/59, 3/60)
 4            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 75 =================================================================

<br><br>====================================================================== Pagina 76 ======================================================================

<pre>  epeated dose study; Sprague Inhalation; 0, 100, 150 or 200 ppm   0 (100, 150, 200 ppm): Liver          Well-performed study.
Dawley rats (males and        (corresponds to 0, 260, 390 or 520   angiosarcoma 0/185 (1/120, 6/119,
emales); 119-120/group;       mg/m3); 4 hours/day, 5 days/ week,   12/120); Hepatoma 0/185 (3/120        Klimisch score 2
 85 controls;                 52 weeks; total experimental time    (only 200 ppm); Nephroblastoma
Maltoni et al., 198174        143 weeks; complete                  0/120 (10/120, 11/119, 7/120);
                              histopathology; no statistical       Zymbal gland carcinoma 2/185
                              analyses                             (1/120, 4/119, 4/120); Skin
                                                                   epithelioma 2/185 (1/120, 4/119,
                                                                   5/120); Mammary tumour 2/185
                                                                   (4/120, 6/119, 6/120)
  epeated dose study; Sprague Inhalation; 0, 50, 250, 500, 2,500,  0 (50, 250, 500, 2,500, 6,000,        Well-performed study.
Dawley rats (males and        6,000, 10,000 ppm (corresponds to    10,000 ppm): Liver angiosarcoma
emales); 58-60/ group,        0, 130, 650, 1,300, 6,500, 15,600    0/190 (1/60, for 500, 2500 and        Klimisch score 2
 90 controls; Maltoni and     or 26,000 mg/m3); 4 hours/day,       6000 ppm only); Hepatoma 0/190
  efemine, 1974;              5 days/ week, 17 weeks; total        (0/58, 0/59, 0/60, 2/60, 1/60, 1/58);
Maltoni et al., 198174,75     experimental time 156 weeks;         Nephroblastoma 0/190 (3/58, 6/59,
                              complete histopathology; no          0/60, 2/60, 1/60, 1/58);
                              statistical analyses                 Neuroblastoma 0/190 (0/58, 0/59,
                                                                   0/60, 5/60, 12/60, 9/58); Zymbal
                                                                   gland carcinoma 2/190 (0/58,
                                                                   1/59, 1/60, 7/60, 9/60, 9/58); Skin
                                                                   epithelioma 1/190 (1/58, 0/59,
                                                                   0/60, 2/60, 5/60, 5/58)
Repeated dose study; Sprague  Inhalation; 0, 50, 250, 500, 2,500,  0 (50, 250, 500, 2,500, 6,000,        Well-performed study.
Dawley rats (males and        6,000, 10,000 ppm (corresponds to    10,000 ppm): Liver angiosarcoma
 emales); 56-60/group;        0, 130, 650, 1,300, 6,500, 15,600 or 0/150 (1/60, 18/60, 14/60, 16/59,     Klimisch score 2
 50 controls; Maltoni and     26,000 mg/m3); 4 hours/day, 5        13/60, 10/56); Extra-liver
  efemine, 1974;              days/ week, 30 weeks; total          angiosarcoma 1/150 (1/60, 3/60,
Maltoni et al., 198174,75     experimental time 81 weeks;          7/60, 8/59, 1/60, 1/56); Lung
                              complete histopathology; no          tumour 15/150 (6/60, 41/60, 50/60,
                              statistical analyses                 40/59, 47/60, 46/56); Mammary
                                                                   carcinoma 1/150 (12/60, 12/60,
                                                                   8/60, 8/59, 8/60, 13/56); Skin
                                                                   epithelioma 2/150 (0/60, 2/60,
                                                                   4/59, 7/60, 4/56).
  epeated dose study; Wistar  Inhalation; 0, 50, 250, 500, 2,500,  0 (50, 250, 500, 2,500, 6,000,        Well-performed study.
ats (males); 25-28/group;     6,000, 10,000 ppm (corresponds to    10,000 ppm): Liver angiosarcoma
 8 controls;                  0, 130, 650, 1,300, 6,500, 15,600    0/38 (0/28, 1/27, 3/28, 3/25, 3/26,   Klimisch score 2
Maltoni et al., 198174        or 26,000 mg/m3); 4 hours/day,       8/27); Hepatomas 1/25 and 2/26 at
                              5 days/ week, 52 weeks; total        2,500 and 6,000 ppm only;
                              experimental time 165 weeks;         Nephroblastoma 0/28 (1/28, 0/27,
                              complete histopathology; no          2/28, 0/25, 2/26, 1/27);
                              statistical analyses                 Neuroblastoma 1/25, 1/26 and 3/27
                                                                   at 2,500, 6,000, 10,000 ppm only;
                                                                   Zymbal gland carcinoma 2/26, 2/27
                                                                   at 6,000 and 10,000 ppm only
              Animal experiments                                                                                            75
</pre>

====================================================================== Einde pagina 76 =================================================================

<br><br>====================================================================== Pagina 77 ======================================================================

<pre>  epeated dose study; Golden  Inhalation; 0, 50, 250, 500, 2,500,  0 (50, 250, 500, 2,500, 6,000,        Well-performed study.
 amsters (males); 30/group;   6,000 or 10,000 ppm (corresponds     10,000 ppm): Liver angiosarcoma
 0 controls;                  to 0, 130, 650, 1,300, 6,500, 15,600 0/60 (2/30, 1/30 and 1/30 for 2,500,  Klimisch score 2
Maltoni et al., 198174        or 26,000 mg/m3); 4 hours/day,       6,000 and 10,000 ppm); Cholangio
                              5 days/ week, 30 weeks; total        carcinoma 0/60 (2/30 for 6,000 and
                              experimental time 109 weeks;         10,000 ppm); Acoustic Duct
                              complete histopathology; no          Epithelioma 3/30, 1/30, 2/30 and
                              statistical analyses                 1/30 for 500, 2,500, 6,000 and
                                                                   10,000 ppm); Skin epithelioma
                                                                   3/60 (9/30, 3/30, 7/30, 3/30, 1/30,
                                                                   7/30); Melanomas 0/60 (1/30, 1/30,
                                                                   0/30, 1/30, 2/30, 1/30);
                                                                   Forestomach papilloma and
                                                                   acanthoma 3/60 (3/30, 4/30, 9/30,
                                                                   17/30, 10/30, 10/30); Hepatomas
                                                                   1/25 and 2/26 at 2,500 and 6,000
                                                                   ppm only; Nephroblastoma 0/28
                                                                   (1/28, 0/27, 2/28, 0/25, 2/26, 1/27);
                                                                   Neuroblastoma 1/25, 1/26 and 3/27
                                                                   at 2,500, 6,000, 10,000 ppm only;
                                                                   Zymbal gland carcinoma 2/26, 2/27
                                                                   at 6,000 and 10,000 ppm only
Repeated dose study; Sprague Inhalation; 0 or 50 ppm               0, 50 ppm: Liver angiosarcoma         Well-performed study.
Dawley rats (male and         (corresponds to 0 or 130 mg/m3); 0/98, 14/294; Liver angioma 0/98,
 emale); 294/group;           4 hours/day, 5 days/ week,           8/294; Extra-liver angiosarcoma       Klimisch score 2
 8 controls;                  52 weeks; total experimental time 0/98, 11/294; Zymbal gland
Maltoni et al., 198174        142 weeks; complete                  carcinoma 0/98, 9/294; Skin
                              histopathology; no statistical       epithelioma 0/98, 3/294; Mammary
                              analyses                             gland malignant tumour 10/98,
                                                                   62/294
  epeated dose study; Sprague Inhalation; 0, 1, 5, 10 or 25 ppm    0 (1, 5, 10 or 25 ppm): Liver         Well-performed study.
Dawley rats (male and         (corresponds to 0, 2,6, 13, 26 or    angiosarcoma 1/119, 5/120 at
 emale); 120/group;           65 mg/m3); 4 hours/day, 5 days/      10 and 25 ppm ; Extra-liver           Klimisch score 2
 20 controls;                 week, 52 weeks; total experimental angiosarcoma 2/119 at 10 ppm;
Maltoni et al., 198174        time 147 weeks; complete             Zymbal gland carcinoma 2/120
                              histopathology; no statistical       (1/118, 1/119, 2/119, 4/120);
                              analyses                             Mammary gland malignant tumour
                                                                   7/120 (15/118, 22/119, 21/119,
                                                                   17/120)
  epeated dose study; Wistar Inhalation; 0 or 1 ppm (corresponds 0, 1 ppm: Extra-liver angiosarcoma      Well-performed study.
ats (male and female);        to 0 or 2,6 mg/m3); 4 hours/day,     0/94, 3/99; Hepatomas 0/99, 1/99
 4/group; 99 controls;        5 days/ week, 52 weeks; total                                              Klimisch score 2
Maltoni et al., 198174        experimental time 134 weeks;
                              complete histopathology; no
                              statistical analyses
  6           Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 77 =================================================================

<br><br>====================================================================== Pagina 78 ======================================================================

<pre> epeated dose study; CD1       Inhalation; exposure 0, 50, 250, or   Bronchiolo-alveolar adenoma, liver   Animal numbers
mice (male and female);        1,000 ppm (corresponds to 0, 130,     haemangiosarcoma and mammary         limited due to interim
 6/sex/group; 36 controls/sex; 650 or 2,600 mg/m3); 6 hr/day,        gland tumours (females only)         sacrifices; limited
 ee et al., 1977/197889,90     5 days/week; 4/sex/group              increased at all exposure levels;    study (supportive
                               sacrificed at 1, 2, 3, 6, 9 and       first incidences of bronchiolo-      only).
                               12 months; gross and                  alveolar adenoma in second month
                               histopathological examinations;       of exposure, haemangiosarcoma        Klimisch score 4
                               no statistical analyses               and mammary gland tumour
                                                                     incidence started 6th month;
                                                                     dose-related increase in mortality
                                                                     (females more susceptible; most
                                                                     mice died in month 7-9);
                                                                     dose-related increase in tumour
                                                                     incidence
 epeated dose study; CD rats   Inhalation; exposure 0, 50, 250, or   Mainly hepatic and/or pulmonary      Animal numbers
male and female); 36/sex/      1,000 ppm (corresponds to 0, 130,     haemangiosarcoma in rats at all      limited due to interim
 roup; 36 controls/sex/group;  650 or 2600 mg/m3); 6 hr/day, 5       concentrations; dose-related         sacrifices
 ee et al., 1977/197889,90     days/week; 1, 2, 3, 6, 9 and 12       increase in mortality (females more
                               months; gross and                     susceptible; most died month         Klimisch score 4
                               histopathological examinations; no    8-12); dose-related increase in
                               statistical analyses                  tumour incidence (first incidences
                                                                     in month 6 at 250 and 1,000 ppm)
 epeated dose study; CD1       Inhalation; 0, 50, 250 or 1,000 ppm   Cumulative incidence (no sex-        All exposure periods
mice (male and female);        (corresponds to 0, 130, 650 or        related difference): Hepatic         together sufficient
 -16/sex/group;                2,600 mg/m3); 6 hr/ day, 5d/ week,    haemangiosarcoma: 1/120, 2/80,       animals;
 6-28 controls/sex/group;      for 1, 3 or 6 months; sacrifice 12    13/40, 18/76; Bronchioloalveolar     well-performed study.
Hong et al., 198172            months after exposure; gross and      sarcoma: 16/120, 18/80, 52/84,
                               histopathological examinations;       50/76; Mammary gland                 Klimisch score 2
                               one-tailed Fisher exact probability   adenocarcinoma/ carcinoma
                               test (compare tumour incidence)       (females): 4/60, 10/40, 13/40, 6/38;
                               and Armitage test for linear trends   mortality increased dose-
                               in proportions                        dependently
 epeated dose study; CD rats Inhalation; 0, 50, 250 or 1,000 ppm     Cumulative incidence (no sex-        All exposure periods
male and female); 4-16/sex/ (corresponds to 0, 130, 650 or           related difference): Neoplastic      together sufficient
 roup; 4-16 controls/sex/      2,600 mg/m3); 6 hr/ day, 5d/week,     nodules: 0/72, 0/66, 10/68, 2/36;    animals;
 roup; Hong et al.,198172      for 1, 3, 6 or 10 months; sacrifice   Hepatocellular carcinoma: 1/72,      well-performed study.
                               12 months after exposure; gross       0/72, 2/68, 7/72;
                               and histopathological                 Hepatic haemangiosarcoma: 0/72,      Klimisch score 2
                               examinations; one-tailed Fisher       0/66, 5/68, 14/72;
                               exact probability test (compare       Bronchioloalveolar tumour: 0/72,
                               tumour incidence) and Armitage        0/66, 2/68, 4/72;
                               test for linear trends in proportions Pulmonary haemangiosarcoma:
                                                                     0/72, 0/66, 2/68, 7/72;
                                                                     Malignant lymphoma: 0/72, 0/66,
                                                                     1/68, 4/36; other tumour incidence
                                                                     comparable to control/no dose-
                                                                     relationship;
                                                                     mortality increase dependent on
                                                                     dose and time of exposure
              Animal experiments                                                                                               77
</pre>

====================================================================== Einde pagina 78 =================================================================

<br><br>====================================================================== Pagina 79 ======================================================================

<pre>Acute study; ICR mice (both   Inhalation; 0, 50, 500, 5,000 and      8 and 18 months combined:            Well-performed study
 exes); 90 /sex/group;        50,000 ppm (corresponds to 0, 130,     Bronchio-alveolar adenoma:
  82 controls/sex;            1,300, 13,000 and 130,000 mg/m3);      12/120, 14/139, 18/139, 24/143       Klimisch score 2
Hehir et al., 198191          1 hour; 8 or 18 months observation;    and 45/137;
                              clinical signs, weight,                Bronchio-alveolar carcinoma:
                              (histo-)pathology; no statistical      0/120, 0/139, 1/139, 1/143 and
                              analyses                               3/137; no substance-related
                                                                     mortality; pneumonitis in all mice
                                                                     at 500 ppm and above
  epeated dose study;         Inhalation; 0, 50 and 500 ppm          For 0 and 100 x 50 ppm, and for      Well-performed study;
A/J mice (both sexes);        (corresponds to 0, 130 and 1,300       0 and 10 x 500 ppm (8, 16 and        A similar experiment
 0 /sex/group;                mg/m3); 1 hour/ day for 10 days        20 month sacrifices combined):       with rats were
 0-50 controls/sex;           (500 ppm) or 100 days (50 ppm);        Pulmonary adenoma: 29/84,            mentioned, but results/
Hehir et al., 198191          8, 16 or 20 months observation;        65/158 (not significant), and 31/90, group were not
                              (histo-) pathology, electron           124/166 (p≈0.001); Pulmonary         mentioned; mice were
                              microscopy; Z test                     carcinomas:2/84, 7/158 (not          stated to be more
                                                                     significant), and 3/90, 22/166       sensitive to vinyl
                                                                     (p≈0.001)                            chloride.
                                                                                                          Klimisch score 2
Repeated dose study; Wistar   Inhalation; 0, 500, 2,000, 5,000,      Skin squamous cell carcinoma:        Limited described
 ats (male and female); 150/  10,000 and 20,000 ppm                  0/200, 3/150 (p< 0,01), 0/200,       study; no mortality
 roup (20,000, 500 ppm        (corresponds to approx. 0, 1,300,      20/200, 34/200 and 67/150;           data; limited study
 roups) or 200/ group (other  5,200, 13,000, 26,000, and 52,000      Liver angiosarcoma: 0/200, 4/150     (only supportive).
 roups); 200/ control group;  mg/m3); 4 hr/ day, 5 days/ week,       (p< 0,01), 10/200, 12/200, 16/200
 o data on sex distribution   1 year; tumours/ animal; Χ2 test       and 18/150 (p < 0.0005);             Klimisch score 4
within groups; Caputo et al   versus control                         Lung adenocarcinoma:
 974; Viola et al., 197192,93                                        0/200, 0/150, 8/200, 4/200
                                                                     (p<0.0005), 14/200 and 21/150;
                                                                     Liver cholangioma: 13/150 at
                                                                     20,000 ppm; no data on mortality
  epeated dose study;         Inhalation; 0 or 600 ppm               Liver angiosarcoma: 0/80, 2/80;      Limitedly described
  prague-Dawley rats (male);  (corresponds to appr. 0 and            Skin fibroma: 0/80, 1/80; 13         study (only
 0/group; 80/ control group;  1,560 mg/m3); 4hr/ day,                exposed rats died (8 control rats)   supportive).
  adike et al., 197794        5 days/ week, for 1 year; 8 weeks
                              observation; Histology of 6 vinyl                                           Klimisch score 4
                              chloride rats; no statistical analyses
  8            Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 79 =================================================================

<br><br>====================================================================== Pagina 80 ======================================================================

<pre> epeated dose study;           Inhalation; 0 and 948 ppm            Results for interim sacrifices are   Limitedly described
 prague-Dawley rats (male      (corresponds to appr. 0 or 2,465     considered less relevant and not     study (only supportive)
 nd female; 6, 18, 32 and      mg/m3); 7 hr/day, 5 days/week,       presented here. Angiosarcomas
 2 weeks old groups);          for 24,5 weeks (mean); sacrifice at  (liver, spleen, lung) in final       Klimisch score 4
 10-128/sex/group; 110-128     3, 6, 9 months and 43 weeks; gross   sacrifice group: 2 (female)/75 for
 ontrols/sex/group;            pathology and microscopical          6 week-old, 7 (female)/91 for 18
Groth et al., 198195           examination; statistical analyses by week-old, 26/94 for 32 week-old
                               Fisher’s exact test (compare age     and 24/109 for 52 week-old
                               groups) or method of weighted        compared to one (subcutaneous) in
                               least squares regression (determine  all the control groups; incidence of
                               effect of age on angiosarcoma        other tumours comparable to
                               incidence)                           control rats; mean survival was
                                                                    comparable between age groups,
                                                                    age-related response, in older mice
                                                                    tumours appeared earlier and with
                                                                    increased frequency compared to
                                                                    younger mice
 epeated dose study            Inhalation; 0 or 2,500 ppm           Malignant tumours in 52/54 (2,500    Well-performed study
chronic); Sprague-Dawley       (corresponds to appr. 0 or           ppm) and 9/60 (controls);
ats (female); 54 exposed       6,500 mg/m3); 4hr/day (up to week    Neuroblastoma 32/54,                 Klimisch 2
 nd 60 controls;               7), 7hr/day (week 8-69),             hepatocarcinoma 5/54,
Maltoni & Cotti, 198896        5 days/week, lifetime observation;   angiosarcoma 27/54 (2500 ppm),
                               Full necropsy and histopathology     all 0/60 (controls)
 epeated dose study            Inhalation; 0 or 2,500 ppm           Malignant tumours in 122/127         Well-performed study
including pre-natal            (corresponds to appr. 0 or 6,500     (2,500 ppm) and 53/307 (controls);
 xposure); Sprague-Dawley mg/m3); 4hr/day (up to week 7),           Neuroblastoma 58/127,                Klimisch 2
ats (male and female, at start 7hr/day (week 8-69), 5 days/week;    hepatocarcinoma 65/127,
 xposure 12-day embryo’s); lifetime observation; Full necropsy      angiosarcoma 82/127 (2,500 ppm),
 3 (M) and 64 (F) exposed      and histopathology                   for controls 0/307, 1/307
 nd 158 ( M) and 149 (F)                                            and 0/307 resp
 ontrols;
Maltoni & Cotti, 198896
 epeated dose study            Inhalation; 0 or 2,500 ppm           Malignant tumours in 114/120         Well-performed study
including pre-natal            (corresponds to appr. 0 or 6,500     (2,500 ppm) and 53/307 (controls);
 xposure); Sprague-Dawley mg/m3); 4hr/day (up to week 7),           Neuroblastoma 18/120,                Klimisch 2
ats (male and female, at start 7hr/day (following 8 weeks),         hepatocarcinoma 84/120,
 xposure 12-day embryo’s); 5 days/week, lifetime observation;       angiosarcoma 52/120
 0/ sex exposed and 158 ( M) Full necropsy and histopathology       (2,500 ppm), for controls 0/307,
 nd 149 (F) controls;                                               1/307 and 0/307 resp
Maltoni & Cotti, 198896
               Animal experiments                                                                                            79
</pre>

====================================================================== Einde pagina 80 =================================================================

<br><br>====================================================================== Pagina 81 ======================================================================

<pre>  epeated dose study; mice    Inhalation; 0, 2,500 and 6,000 ppm   tumours; proliferation and            Study with focus on
male); 3/2500 ppm,            (corresponds to appr. 0, 6,500 and   hypertrophy of bronchiolar            histopathology of
 / 6,000 ppm; 4/ control      15,600 mg/m3); 5 hr/day,             epithelium noted in exposed           pulmonary tumours,
 roup; Suzuki, 198184         5 days/week, 5 months ; 6 days;      animals (preneoplastic), pulmonary    limited data on other
                              gross pathology, histopathology      tumours in all exposed mice (none     parameters. Low
                              (light and electron microscopy);     in controls), no metastasis           number of animals; no
                              no statistical analyses              observed, no parenchymal fibrosis     guideline followed,
                                                                   nor fibrotic adhesions of the pleura, performed before GLP
                                                                   no data on mortality                  principles were in
                                                                                                         place; relevant
                                                                                                         exposure route;
                                                                                                         observed effects
                                                                                                         relevant for humans;
                                                                                                         limited study (only
                                                                                                         supportive).
                                                                                                         Klimisch score 2
  epeated dose study; mice    Inhalation; 0, 2500 and 6,000 ppm    tumours; proliferation and            Study with focus on
male); 14/2500 ppm,           (corresponds to appr. 0, 6,500 and   hypertrophy of bronchiolar            histopathology of
 / 6,000 ppm; 7/control       15,600 mg/m3); 5 hr/day,             epithelium noted in exposed           pulmonary tumours,
 roup; Suzuki, 198184         5 days/week, 6 months ;              animals (preneoplastic), chronic      limited data on other
                              2 or 37 days; gross pathology,       inflammatory changes particularly     parameters. Adequate
                              histopathology (light and electron   after 40 weeks observation,           number of animals; no
                              microscopy); no statistical analyses pulmonary tumours in all exposed      guideline followed,
                                                                   mice, except 1 at 6000 ppm            performed before GLP
                                                                   (none in controls), no metastasis     principles were in
                                                                   observed, no parenchymal fibrosis     place; relevant
                                                                   nor fibrotic adhesions of the pleura, exposure route;
                                                                   no data on mortality                  observed effects
                                                                                                         relevant for humans;
                                                                                                         limited study (only
                                                                                                         supportive).
                                                                                                         Klimisch score 2
  epeated dose study; Wistar  Inhalation; 0 and 5,000 ppm          No tumours were found after           Limitedly described
ats (males and females); 62/  (corresponds to 0 and                4-26 weeks;                           study(only
ex/group; 62 controls/sex;    13,000 mg/m3); 7 hr/day,             Liver angiosarcoma: 3/9 males and     supportive).
 eron et al., 197997          5 days/week, for 52 weeks;           6/10 females after 52 weeks;
                              10/sex/group sacrificed at 4, 13, 26 Hepatocellular carcinoma:             Klimisch score 4
                              or 52 week; liver effects: light and 1/9 males and 1/10 females after
                              electron microscopy; no statistical  52 weeks; no data on final sacrifice
                              analyses
  epeated dose study;         Inhalation; 0, 30,000 ppm            Tumours; all rats showed              High level of
Wistar rats (male); 26/group; (corresponds to 0 and                parenchymal lesions, degeneration     exposure; oral intake
 5/ control group;            78,000 g/m3); 4 hr/ day,             of cerebellum, severe chronic         may be significant due
  iola et al., 197192         5 days/ week, 12 months; clinical    hepatitis, interstitial pneumonia,    to licking of fur.
                              signs, mortality, histopathology;    adverse kidney effects,
                              no statistical analyses              17 developed skin tumours near the    Klimisch score 4
                                                                   submaxillary and parotid glands,
                                                                   6 had lung tumours, 5 had bone
                                                                   tumours (none of these effects in
                                                                   controls)
 0              Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 81 =================================================================

<br><br>====================================================================== Pagina 82 ======================================================================

<pre> epeated dose study; Wistar     Oral (via feed); 0, 0.46, 4.6 and    Hepatocellular carcinomas: 0/99,    Well-performed study;
at (male and female);           46 ppm (actual intake 0, 0.013,      0/99, 0/99 and 3/49 (males,         only liver tumours
 00/sex/group except highest    0.13 and 1.3 mg/kg bw/day;           p<0,05), 1/98, 0/100, 1/96 and 3/49 tabulated.
 ose: 50/sex/group; 100         = oral intake minus faecal Vinyl     (females);
ontrols/sex; Til et al., 199198 chloride which was considered to     Liver angiosarcoma: 0/99, 0/99,     Klimisch score 2
                                be still enclosed in the PVC         0/99 and 1/49 (males), 0/98, 0/100,
                                granules); lifetime exposure 150     0/96 and 2/49 (females)
                                weeks; microscopic examination of
                                liver, all visible tumours in the
                                abdominal cavity, Zymbal and
                                mammary glands and glutathione
                                level in liver; Fisher’s exact
                                probability test, one-tailed
 epeated dose study;            Oral (gavage); 0, 0.03, 0.3, 1 mg/kg 0 (0.03, 0.3, 1 mg/kg bw/day):      Well-performed study.
 prague-Dawley rats (male       bw/day; 59 weeks; total              Liver angiosarcoma 0/150 (0/150,
nd female); 150/group;          experimental time 136 weeks;         1/148, 3/149); Zymbal gland         Klimisch score 2
 50 controls;                   complete histopathology; no          carcinoma 1/150 (0/150, 0/150,
Maltoni et al., 198174          statistical analyses                 5/149); Mammary gland malignant
                                                                     tumour 7/150 (14/150; 4/14;
                                                                     12/149)
 epeated dose study;            Oral (gavage); 0, 3.3, 16.65,        0 (3.3, 16.65, 50 mg/kg bw/day):    Well-performed study.
 prague-Dawley rats (male       50 mg/kg bw/day; 52 weeks; total     Liver angiosarcoma 0/80 (0/80,
nd female); 80/group;           experimental time 136 weeks;         10/80, 17/80); Extra-liver          Klimisch score 2
 0 controls;                    complete histopathology; no          angiosarcoma 0/80 (1/80, 0/80,
Maltoni et al., 198174          statistical analyses                 2/80); Nephroblastoma 0/80
                                                                     (0/80, 3/80, 2/80); Forestomach
                                                                     papilloma and acanthoma 0/80
                                                                     (0/80, 1/80, 2/80)
              Animal experiments                                                                                            81
</pre>

====================================================================== Einde pagina 82 =================================================================

<br><br>====================================================================== Pagina 83 ======================================================================

<pre>2 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 83 =================================================================

<br><br>====================================================================== Pagina 84 ======================================================================

<pre>nnex G
     Evaluation of the Subcommittee on
     the Classification of carcinogenic
     substances
     Existing evaluations
     IARC (2012), U.S. NTP Report on Carcinogens (2006), and U.S. ATSDR (2014)
     evaluated the carcinogenic potential of vinyl chloride monomer (VCM). The
     Subcommittee did not identify human data of a more recent date.1-3
     In the present evaluation (September 2015) the DECOS Subcommittee on the
     Classification of Carcinogenic Substances evaluated the existing and new
     information regarding human, animal, and in vitro studies on carcinogenicity and
     genotoxicity of VCM based on the reports by IARC (2012), U.S. NTP Report on
     Carcinogens (2014), and U.S. ATSDR (2006).1-3
     Classification and labelling as a carcinogenic substance
     IARC classified VCM as carcinogenic to humans (Group 1) in 1974, 1979, 1987,
     2008 and 2012.1,4-7
     The European Union has classified VCM in carcinogenicity category 1A,
     (substance known to have carcinogenic potential for humans), as listed under
     index number # 602-023-00-7 in Annex VI of Regulation (EC) No 1272/2008
     (CLP Regulation).8
     Evaluation of the Subcommittee on the Classification of carcinogenic substances  83
</pre>

====================================================================== Einde pagina 84 =================================================================

<br><br>====================================================================== Pagina 85 ======================================================================

<pre>  VCM is listed in the Dutch SZW-list of carcinogenic substances.9
  In 1986 a committee of the Health Council of the Netherlands concluded that
  VCM should be considered a genotoxic carcinogen in humans.10
  Human studies
  A considerable number of case reports and epidemiological studies concerning
  carcinogenicity of VCM is available in the literature and has repeatedly been
  reviewed by national and international agencies.1-3 All agencies concluded that
  there was sufficient evidence from epidemiological studies that VCM is a human
  carcinogen.
  The main epidemiological evidence for the carcinogenicity of VCM comes from
  two large multicentre cohort studies from Europe and North America.
  The most recent publication on the European multicentre cohort study is from
  Ward et al.11 A total of 71 deaths from liver cancer (primary liver cancer,
  including 37 angiosarcomas, 10 hepatocellular carcinomas, and 24 liver cancers
  of other and unknown histology were observed. A strong positive trend for time
  since first employment, duration of employment, and cumulative exposure was
  found with relative risks for all liver cancers combined, angiosarcoma, and
  hepatocellular carcinoma. The highest relative risks were observed for
  angiosarcoma of the liver, even though workers in the reference group already
  experienced an estimated 200-fold higher risk of angiosarcoma than the general
  population (based on 4 cases among approximately 200,000 person-years in the
  reference group). No other type of cancer was found in excess.
  The most recent and complete publication on the North American multicentre
  cohort study is from Mundt et al.12 895 cancer deaths were reported. While total
  cancer mortality was not elevated, mortality from cancers of the liver and biliary
  tract was significantly increased. Modest excesses of brain cancer and cancer of
  connective and soft tissue were also observed. Hazard rates from proportional
  hazard analyses supported associations with age at first exposure, duration of
  exposure, and year of first exposure for cancers of the liver and soft tissues, but
  not the brain. Hazard rates for ‘all known angiosarcomas’ (n=48) were associated
  with duration of exposure, though not with age at first exposure or year of first
  exposure.
4 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 85 =================================================================

<br><br>====================================================================== Pagina 86 ======================================================================

<pre>Results from the European and North American multicentre studies were
combined with six independent studies of cancer among VCM workers (from
former USSR, France, Canada, Germany, China, Taiwan) in a meta-analysis by
Boffetta et al.13. Together these studies include 43,810 vinyl chloride/
polyvinylchloride workers with variable follow-up ranging between 1940 and
1997. With SMR values ranging from 1.63 to 57.1, all six studies for which these
ratios could be obtained suggested an increased risk of liver cancer, though these
results were deemed too heterogeneous to be included in a meta-analysis. A
significantly increased meta-SMR was also reported for liver cancers other than
ASL (based on the 2 multicentre studies) and for soft-tissue sarcoma, however,
these results may have been influenced by the under diagnosis of true ASL. A
meta-analysis for ASL was not conducted as relevant SMR values were difficult
to estimate due to the extreme rarity of the disease in the general population.
The epidemiological literature indicates a strong association between exposure to
VCM and liver cancer incidence and mortality. The elevated risk for liver cancer
appears to be primarily driven by ASL. However, studying the association
between exposure to VCM and ASL is statistically challenging because this form
of liver cancer is extremely rare. Studying the association between exposure to
VCM and liver cancer excluding ASL is also difficult because of the risk of
misdiagnosis of true ASL. Several other forms of cancer have been associated
with exposure to VCM in individual studies, but these associations are not
consistent across studies.
Animal studies
The carcinogenicity of VCM has been studied extensively in mice, rats, and
hamsters. These studies have been reviewed in depth by U.S. ATSDR, IARC,
and U.S. NTP.1-3 All agencies concluded that there was sufficient evidence from
animal studies that VCM is an animal carcinogen. The studies consistently
showed hepatic and extrahepatic angiosarcomas in mice and rats. Various other
malignant neoplasms also occurred at several anatomical sites. However, the
reporting of the results has often been incomplete.5 While studies have assessed
the effects of exposure via inhalation, skin, and ingestion, exposure via
inhalation is likely the most relevant exposure route for humans. Three large
inhalation studies are described below.
Hong et al.14 reported on an experiment in which rats and mice were exposed to
0, 130, 650 or 2,600 mg/m3 VCM via inhalation for 6 hours/day, 5 days/week
Evaluation of the Subcommittee on the Classification of carcinogenic substances    85
</pre>

====================================================================== Einde pagina 86 =================================================================

<br><br>====================================================================== Pagina 87 ======================================================================

<pre>  during 1, 3 or 6 months and describe the development and incidence of
  neoplastic changes and other effects during a 12 month post-exposure follow-up
  period. Unscheduled mortality increased in both species in a dose-related way,
  and occurred at earlier time points at higher concentrations. There was no
  significant sex-related difference in the number of unscheduled deaths (or
  sacrifices). In mice, cumulative incidence of hepatic haemangiosarcoma during
  recovery period was increased at higher VCM concentration. The tumour was
  mostly multiple in site distribution and varied greatly in size. Overall, the
  incidence of this tumour rose as the concentration and duration of VCM
  exposure increased. Also the incidence of bronchioloalveolar tumours were
  greater in mice exposed to increasing levels of VCM and for longer exposure
  periods. In female mice mammary gland adenocarcinoma/carcinoma was
  observed. Metastatic adenocarcinoma originating from the mammary gland was
  also seen in lungs of mice exposed to VCM, but not in lungs of control mice.
      Drew et al.15 observed induced haemangiosarcomas and mammary gland
  carcinomas in two strains of mice and lung carcinomas in Swiss mice after six
  months of exposure to 130 mg/m3 VCM. Longer exposure had no significant
  effect on tumour incidence, while incidence was higher when exposure started
  earlier in life. In rats, mainly haemangiosarcomas of the liver, mammary
  neoplasms and hepatocellular carcinoma were found after 6 months of exposure.
  The incidence of haemangiosarcomas was a function of the duration of the
  exposure. If the exposure took place early in life, a higher incidence of
  haemangiosarcomas was noted. In hamsters, haemangiosarcomas, mammary
  gland carcinomas, stomach adenomas, and skin carcinomas were produced by
  exposure to 520 mg/m3 VCM. The highest incidence was seen in animals
  exposed early in life.
      A large series of experiments was performed by Maltoni et al. using rats
  (Sprague-Dawley and Wistar), mice, and hamsters.16,17 In one group of studies,
  Maltoni et al. exposed Sprague-Dawley rats to VCM for 52 weeks at
  concentrations ranging from 1 to 30,000 ppm. Animals were examined at the
  time of their spontaneous death. Statistically significant increases were noted in
  the incidence of mammary gland carcinomas, Zymbal gland carcinomas,
  nephroblastoma, and liver angiosarcoma. Exposure of Swiss mice to 50 ppm
  VCM for 4 hours/day, 5 days/week for 30 weeks also appeared to increase the
  incidence of liver angiosarcoma and angioma. Some variation in the target
  organs that developed tumours was observed when different species were
  exposed to VCM.16,17 Whereas angiosarcomas of the liver were reported to occur
  in rats, mice, and hamsters, mammary gland carcinomas were found only in rats
  and mice; Zymbal gland carcinomas, neuroblastomas, and nephroblastomas were
6 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 87 =================================================================

<br><br>====================================================================== Pagina 88 ======================================================================

<pre>found only in rats; lung tumours were found only in mice; and melanomas,
acoustical duct epithelial tumours, and leukemias were found only in hamsters.3
In their review of the Maltoni study, ATSDR noted that limited histopathological
data were presented and cancer incidences were presented only in summary
tables. Also, survival of control animals was poor in some of the experiments.
Furthermore, statistical analyses, where present, appear to be based on a
compilation of data from several individual studies.3
    Based on the available data it can be concluded that tumour incidence
(number of rats with a tumour) and multiplicity (number of tumours/ rat)
following VCM in rats is clearly related to exposure concentration and duration.
The effects of VCM in laboratory animals indicate that the effects in animals and
in humans are comparable.
Mechanism of genotoxicity
Evidence for the genotoxic properties of VCM has been reviewed by IARC,
ATSDR, and NTP The three agencies concluded that VCM is a mutagen.1-3
VCM caused genetic damage in many test systems, including bacteria, yeast,
insects, cultured human and other mammalian cells, rodents, and in humans. The
genetic damage included mutations and chromosomal aberrations. Tables 6 and 7
include an overview of the in vivo and in vitro evidence for the genotoxicity of
VCM.
Table 6 Genotoxicity of VCM in vivo.a
Species(test system)              Endpoint                          # studies
Mouse                             Dominant lethal                    0 positive / 1 negative
                                  Micronuclei                        1 positive / 0 negative
Rat                               Dominant lethal                    0 positive / 3 negative
                                  Chromosomal aberration             1 positive / 0 negative
Hamster                           Chromosomal aberration             1 positive / 0 negative
Human lymphocyte                  Sister chromatid exchange          8 positive / 1 negative
                                  DNA damage                         2 positive / 0 negative
                                  Micronuclei                        4 positive / 0 negative
                                  Chromosomal aberration            21 positive / 1 negative
Rat                               DNA alkylation                     7 positive / 0 negative
Mouse                             DNA alkylation                     1 positive / 0 negative
                                  DNA damage                         1 positive / 0 negative
Rat                               DNA adduct                         6 positive / 0 negative
a Table modified from Table 3-3 in the toxicological profile for VCM by the U.S. ATSDR3, where
  references for all studies can be found.
Evaluation of the Subcommittee on the Classification of carcinogenic substances                87
</pre>

====================================================================== Einde pagina 88 =================================================================

<br><br>====================================================================== Pagina 89 ======================================================================

<pre> able 7 Genotoxicity of VCM in vitro.a
 pecies                               End point                 # studies with activation         # studies without activation
 almonella typhimurium                Reverse mutation          9 positive / 0 negative           7 positive / 2 negative
 A100, TA1535                         Base-pair substitution    2 positive / 0 negative           1 positive / 0 negative
 A98, TA1537, TA1538                  Frameshift mutation       0 positive / 1 negative           0 positive / 1 negative
 scherichia coli                      Frameshift mutation       0 positive / 0 negative           1 positive / 0 negative
 accharomyces cerevisiae              Frameshift mutation       0 positive / 0 negative           0 positive / 1 negative
                                      Gene conversion           1 positive / 0 negative           0 positive / 0 negative
 chizosaccharomyces pombe             Forward mutation          2 positive / 0 negative           0 positive / 1 negative
D7RAD yeast                           Gene conversion           1 positive / 0 negative           0 positive / 1 negative
 hinese hamster ovary cells           Gene conversion           2 positive / 0 negative           1 positive / 1 negative
 acillus subtillis                    Rec-repair                0 positive / 0 negative           0 positive / 1 negative
 at liver microsomes                  RNA alkylation            0 positive / 0 negative           1 positive / 0 negative
QT6 (avian cells)                     Inhibition of DNA         0 positive / 0 negative           1 positive / 0 negative
                                      synthesis
  Table modified from Table 3-4 in the toxicological profile for VCM by the U.S. ATSDR3, where references for all studies can
  be found.
             Conclusion
             Based on a review of the literature and existing evaluations by IARC, ATSDR,
             and NTP, the Subcommittee concludes that VCM induces cancer in humans and
             experimental animals (rodents) via a mutagenic mode-of-action. Consequently,
             DECOS Subcommittee reconfirms the decision by the Health Council of the
             Netherlands in 1986 that a stochastic genotoxic mechanism underlies the
             carcinogenicity of VCM. The Subcommittee follows the classification of VCM
             in category 1A (substance known to have carcinogenic potential for humans) by
             the European Union (Annex H).
             References (for Annex G)
             International Agency for Research on Cancer (IARC). Chemical Agents and Related Occupations.
             IARC Monogr Eval Carcinog Risk Chem Man 100F. 2012.
             NTP (National Toxicology Program). Report on Carcinogens, Thirteenth Edition. Research Triangle
             Park, NC: U.S. Department of Health and Human Services, Public Health Service.; 2014. Internet:
             http://ntp.niehs.nih.gov/pubhealth/roc/roc13/. Consulted: 03-11-2016.
             U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for
             Toxic Substances and Disease Registry. Toxicological profile for vinyl chloride. 2006.
             International Agency for Research on Cancer (IARC). Some anti-thyroid and related substances,
             nitrofurans and industrial chemical. IARC MonogrEval Carcinog Risk Chem Man 7, 1-326. 1974.
 8           Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 89 =================================================================

<br><br>====================================================================== Pagina 90 ======================================================================

<pre>  International Agency for Research on Cancer (IARC). Some monomers, plastics and synthetic
  elastomers, and acrolein. IARC MonogrEval Carcinog Risk Chem Man 19. 1979.
  International Agency for Research on Cancer (IARC). Summaries & Evaluations. 1987:
  Supplement 7.
  International Agency for Research on Cancer (IARC). 1,3-Butadiene, ethylene oxide and vinyl
  halides (vinyl fluoride, vinyl chloride and vinyl bromide). IARC MonogrEval Carcinog Risk Chem
  Man 97. 2008.
  European Parliament and Council. REGULATION (EC) No 1272/2008 OF THE EUROPEAN
  PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on classification, labelling and
  packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and
  1999/45/EC, and amending Regulation (EC) No 1907/2006. 2008.
  Ministerie van Sociale Zaken en Werkgelegenheid. SZW-lijst van kankerverwekkende stoffen en
  processen. 2016: 43.
0 Health Council of the Netherlands. Advies inzake vinylchloride. Toetsing van een criteriadocument
  en voorstel risico-evaluatie. The Hague, Netherlands: 22-5-1986.
1 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.
2 Mundt KA, Dell LD, Austin RP, Luippold RS, Noess R, Bigelow C. Historical cohort study of
  10,109 men in the North American vinyl chloride industry, 1942-72: update of cancer mortality
  to 31 December 1995. Occup Environ Med 2000; 57(11): 774-781.
3 Boffetta P, Matisane L, Mundt K, Dell L. Meta-analysis of studies of occupational exposure to vinyl
  chloride in relation to cancer mortality. Scand J Work Environ Health 2003; 29(3): 220-229.
4 Hong CB, Winston JM, Thornburg LP, Lee CC, Woods JS. Follow-up study on the carcinogenicity of
  vinyl chloride and vinylidene chloride in rats and mice: tumour incidence and mortality subsequent to
  exposure. J Toxicol Environ Health 1981; 7(6): 909-924.
5 Drew R, Boorman G, Haseman J, McConnell E, Busey W, Moore J. The effect of age and exposure
  duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol Appl
  Pharmacol 1983; 68 (1): 120-130.
6 Maltoni C, Lefemine G, Ciliberti A, Cotti G, Carretti D. Carcinogenicity bioassays of vinyl chloride
  monomer: a model of risk assessment on an experimental basis. Environ Health Perspect 1981;
  41: 3-29.
7 Maltoni C, Lefemine G, Chieco P, Carretti D. Vinyl chloride carcinogenesis: current results and
  perspectives. Med Lav 1974; 65(11-12): 421-444.
  Evaluation of the Subcommittee on the Classification of carcinogenic substances                       89
</pre>

====================================================================== Einde pagina 90 =================================================================

<br><br>====================================================================== Pagina 91 ======================================================================

<pre>0 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 91 =================================================================

<br><br>====================================================================== Pagina 92 ======================================================================

<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
                                                                                (before               (as from
                                                                                16 December 2008)     16 December 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 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.99
             Carcinogenic classification of substances by the Committee                                                 91
</pre>

====================================================================== Einde pagina 92 =================================================================

<br><br>====================================================================== Pagina 93 ======================================================================

<pre>2 Vinyl chloride monomer</pre>

====================================================================== Einde pagina 93 =================================================================

<br><br>====================================================================== Pagina 94 ======================================================================

<pre>nnex I
     Calculation of the HBC-OCRV based
     on animal data (Maltoni et al., 1981)
     The Committee is of the opinion that the epidemiological studies on VCM
     provide a reliable starting point for quantitative risk assessment. There is
     sufficient epidemiological evidence that VCM is carcinogenic for humans; the
     majority of the studies shows increased cancer risks. Based on the currently
     available human data a reliable calculation can be made. In addition however, for
     comparison the Committee calculated risk values based on animal data.
     The Committee considers the data from the long term inhalatory exposure
     experiments in rats, as reported by Maltoni et al. (1981) as experiments BT1,
     BT2 and BT15 (see also paragraph 3.2), suitable for the estimation of cancer risk
     values.74 The exposure in experiment BT1 ranged from 0 to 10,000 ppm, in BT2
     from 0 to 200 ppm and in BT 15 from 0 to 25 ppm. The Committee decides to
     perform a quantitative risk assessment based on angiosarcomas of the liver
     (ASL).
     The Committee derives a bench mark dose (BMD10) after applying the EPA
     software (2.6) to establish a dose-response on the data from the three respective
     experiments. As a rule, a series of quantitative models (gamma multi-hit,
     logistic. loglogistic, probit, logprobit, multistage, Weibull, quantal-linear) is used
     to fit the dose-response on the data from each experiment. Then, the statistical
     acceptability is established for each model applied. From all accepted models the
     Calculation of the HBC-OCRV based on animal data (Maltoni et al., 1981)                93
</pre>

====================================================================== Einde pagina 94 =================================================================

<br><br>====================================================================== Pagina 95 ======================================================================

<pre>          Committee uses the model with the lowest BMD10 value as point of departure
          for further risk calculation.2
          The Committee observes that the animal data from experiment BT2 and BT15
          allow reliable modelling of a dose-response relationship over the whole dose
          range (see Table 1 and Figures 2 and 3). The BMD modelling on the data from
          the BT1 experiment was reliable up to 500 ppm (=1,300 mg/m3) exposure (see
          Table 1 and Figure 1).
          The BMD10 derived from the BT1 experiment (up to 500 ppm, gamma multi hit
          model) was used below as a point of departure for further calculation of cancer
          risk values. First, the incidence per unit concentration (mg/m3) was calculated
          (Iconc).
                                                              BMR
conc =                                                                                                             =
       BMD x (Xpo/L) x (Xpe/L) x (exposure hrs per day/24) x (exposure days per week/7)
                                                0.1
     =                                                                                   = 1.95 x 10-3 [g/m3]-1
       (1,255 mg/m3) x (364/1000) x (945/1000) x (4/24) x (5/7)
          Where:
          •    Iconc is the carcinogenic activity that may be ascribed to exposure to the compound per
               unit of air concentration, expressed in mg per m3
          •    BMR, the bench mark response, expressed as 10 % increase in tumour incidence
          •    Xpo and Xpe are the exposure and experimental periods, respectively
          •    L is the standard lifespan for the animals in question (L rat is assumed to be 1000 days).
          Subsequently the extra cancer risk per unit concentration (HBC-OCRV) was
          calculated for humans occupationally exposed during a working life.
                             40 years          48 weeks           5 days           10 m3
HBC-OCRV = Iconc x                         x                 x                x               = 3.79 x 10-4 [mg/m3]-1
                             75 years          52 weeks           7 days           18 m3
 4        Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 95 =================================================================

<br><br>====================================================================== Pagina 96 ======================================================================

<pre>Where it is assumed:
•   that biological availability of VCM is 100% after inhalatory dosing
•   that no difference exists between rats and man with respect to toxicokinetics, mechanism of
    tumour induction, target, susceptibility etc., unless specific information is available which
    justifies a different approach
•   that the average man lives 75 years, weighs 70 kg and is exposed 24 hours per day, 7 days per
    week, 52 weeks per year for lifetime
•   that the average man is occupationally exposed for 40 years, 48 weeks per year, 5 days per week,
    8 hours per day, and inhales 10 m3 air per 8-hour-working day.
The Committee estimated that the concentration of VCM in the air, which
corresponds to an excess cancer risk of
• 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 10.55
    mg/m3
• and 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
    0.11 mg/m3.
Similar calculations were performed on the data from the two other experiments
(see Table 8 and Figures 1, 2 and 3). For experiments BT2 and BT15 a BMD10
was derived of 511 and 82 mg/m3 respectively using a logistic model. For data
from experiment BT2 this resulted in VCM concentrations of 4.54 and 0.05 mg/
m3 at risk levels of 4 per 1,000 and 4 per 100,000. For experiment BT15 the
respective results were 0.75 and 0.01 mg/m3.
Although the calculated values differ per experiment, they are of the same order
of magnitude nonetheless. The results from the animal data are slightly more
conservative than the results from the epidemiological study (65.5 and 0.65
mg/m3 at 4 per 1,000 and 4 per 100,000). The Committee is of the opinion that
the risk assessment based on the human data should be preferred, and that the
animal data may be considered supportive to the risk numbers established on
human data.
Calculation of the HBC-OCRV based on animal data (Maltoni et al., 1981)                              95
</pre>

====================================================================== Einde pagina 96 =================================================================

<br><br>====================================================================== Pagina 97 ======================================================================

<pre> able 8 Quantitative risk assessment based on the study by Maltoni et al. (1981).
 xposure       Rats         Number of Number of BMD10 BMDL10 Iconc                    HBC-OCRVExposure Exposure
4 h per day, 5 (Strain/Sex) ASL cases animals in                                                 at risk of  at risk of
 ays per                               group                                                     4 per 1,000 4 per 100,000
week,
or 1 yr)
mg/m3 (ppm)                 n          n            mg/m3     mg/m3         [mg/m3]-1 [ mg/m3]-1 mg/m3       mg/m3
                                                    (ppm)     (ppm)
 xperiment BT1 (Maltoni)
 (0)           Sprague-       0          58
               Dawley/
               M&F
 30            Sprague-       1          60
50)            Dawley/
               M&F
 50            Sprague-       3          59
250)           Dawley/
               M&F
 ,300          Sprague-       6          60         1,255     778           1.95x10-3 3.79x10-4  10.55       0.11
500)           Dawley/                              (482)     (299)
               M&F
 xperiment BT2 (Maltoni)
  (0)          Sprague-       0        185
               Dawley/
               M&F
260)100        Sprague-       1        120
               Dawley/
               M&F
 90 (150)      Sprague-       6        119
               Dawley/
               M&F
 20 (200)      Sprague-     12         120          511(196) 471            4.51x10-3 8.8x10-4   4.54        0.05
               Dawley/                                        (181)
               M&F
 xperiment BT15(Maltoni)
 (0)           Sprague-       0        120
               Dawley/
               M&F
 6 (10)        Sprague-       1        119
               Dawley/
               M&F
 2,5(25)       Sprague-       5        120          82(32)    68(26)        2.73x10-2 5.33x10-3  0.75        0.01
               Dawley/
               M&F
 6           Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 97 =================================================================

<br><br>====================================================================== Pagina 98 ======================================================================

<pre>Figure 1 BMD analysis on data from experiment BT1 (0 - 50 - 250 - 500 ppm), Maltoni et al. (1981).
Figure 2 BMD analysis on data from experiment BT2 (0 - 100 - 150 - 200 ppm), Maltoni et al. (1981).
 Calculation of the HBC-OCRV based on animal data (Maltoni et al., 1981)                            97
</pre>

====================================================================== Einde pagina 98 =================================================================

<br><br>====================================================================== Pagina 99 ======================================================================

<pre>  Figure 3 BMD analysis on data from experiment BT15 (0 - 10 - 25 ppm), Maltoni et al. (1981).
8 Vinyl chloride monomer
</pre>

====================================================================== Einde pagina 99 =================================================================

<br><br>====================================================================== Pagina 100 ======================================================================

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

====================================================================== Einde pagina 100 =================================================================

<br><br>