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    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 215





    Vinyl Chloride






    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.



    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.


    World Health Organization
    Geneva, 1999

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
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    WHO Library Cataloguing in Publication Data

    Vinyl chloride.

         (Environmental health criteria ; 215)

         1.Vinyl chloride - analysis  2.Vinyl chloride - toxicity
         3.Vinyl chloride - adverse effects  4.Environmental exposure
         5.Occupational exposure I.International Programme on
         Chemical Safety  II.Series

         ISBN 92 4 157215 9  (NLM Classification: QV 633)
         ISSN 0250-863X

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    proprietary products are distinguished by initial capital letters.

    CONTENTS

        ENVIRONMENTAL HEALTH CRITERIA FOR VINYL CHLORIDE

    1. SUMMARY

        1.1. Identity, physical and chemical properties, and 
              analytical methods
        1.2. Sources of human and environmental exposure
        1.3. Environmental transport, distribution and transformation
        1.4. Environmental levels and human exposure
        1.5. Kinetics and metabolism in laboratory animals and 
              humans
        1.6. Effects on laboratory mammals and  in vitro test
              systems
        1.7. Effects on humans
        1.8. Effects on other organisms in the laboratory and
              field

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
        METHODS

        2.1. Identity
        2.2. Physical and chemical properties
        2.3. Conversion factors
        2.4. Analytical methods
              2.4.1. General analytical methods and
                        detection
              2.4.2. Sample preparation, extraction and analysis 
                        for different matrices
                        2.4.2.1   Air
                        2.4.2.2   Water
                        2.4.2.3   PVC resins and PVC products
                        2.4.2.4   Food, liquid drug and cosmetic
                                  products
                        2.4.2.5   Biological samples
                        2.4.2.6   Human monitoring
                        2.4.2.7   Workplace air monitoring

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

        3.1. Natural occurrence
        3.2. Anthropogenic sources
              3.2.1. Production levels and processes
                        3.2.1.1   Production of VC
                        3.2.1.2   Production of PVC from VC
                        3.2.1.3   PVC products
              3.2.2. Emissions from VC/PVC plants
                        3.2.2.1   Sources of emission during the
                                  production of VC
                        3.2.2.2   Emission of VC and dioxins from VC/PVC
                                  plants during production

              3.2.3. Accidental releases of VC
                        3.2.3.1   PVC plant and transport accidents
                        3.2.3.2   Leakage and discharge from VC/PVC
                                  plants
              3.2.4. VC residues in virgin PVC resin and products
                        3.2.4.1   VC residues in different PVC samples
                        3.2.4.2   VC residues in PVC products
                        3.2.4.3   VC formation as a result of heating PVC
              3.2.5. Other sources of VC
                        3.2.5.1   VC as a degradation product of
                                  chlorinated hydrocarbons
                        3.2.5.2   VC formation from tobacco
        3.3. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

        4.1. Transport and distribution between media
              4.1.1. Air
              4.1.2. Water and sediments
              4.1.3. Soil and sewage sludge
              4.1.4. Biota
        4.2. Transformation
              4.2.1. Microbial degradation
              4.2.2. Abiotic degradation
                        4.2.2.1   Photodegradation
                        4.2.2.2   Hydrolysis
              4.2.3. Other interactions
        4.3. Bioaccumulation
        4.4. Ultimate fate following use
              4.4.1. Waste disposal
              4.4.2. Fate of VC processed to PVC

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

        5.1. Environmental levels
              5.1.1. Air
                        5.1.1.1   Outdoor air
                        5.1.1.2   Indoor air
              5.1.2. Water and sediment
              5.1.3. Soil and sewage sludge
                        5.1.3.1   Soil
                        5.1.3.2   Sewage sludge
              5.1.4. Food, feed and other products
              5.1.5. Terrestrial and aquatic organisms
        5.2. General population exposure
              5.2.1. Estimations
              5.2.2. Monitoring data of human tissues
                        or fluids
        5.3. Occupational exposure

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

        6.1. Absorption
              6.1.1. Oral exposure
              6.1.2. Inhalation exposure
              6.1.3. Dermal exposure
        6.2. Distribution and retention
              6.2.1. Oral exposure
              6.2.2. Inhalation exposure
              6.2.3. Partition coefficients  in vitro
        6.3. Metabolic transformation
        6.4. Elimination and excretion
              6.4.1. Oral exposure
              6.4.2. Inhalation exposure
        6.5. Reaction with body components
              6.5.1. Formation of DNA adducts
              6.5.2. Alkylation of proteins
        6.6. Modelling of pharmacokinetic data for
              vinyl chloride

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

        7.1. Acute toxicity
        7.2. Short-term toxicity
              7.2.1. Oral exposure
              7.2.2. Inhalation exposure
              7.2.3. Dermal exposure
        7.3. Long-term toxicity - effects other than tumours
              7.3.1. Oral exposure
              7.3.2. Inhalation exposure
        7.4. Skin and eye irritation; sensitization
        7.5. Reproductive toxicity, embryotoxicity and
              teratogenicity
              7.5.1. Male reproductive toxicity
              7.5.2. Embryotoxicity and teratogenicity
        7.6. Special studies
              7.6.1. Neurotoxicity
              7.6.2. Immunotoxicity
              7.6.3. Cardiovascular effects
              7.6.4. Hepatotoxicity
        7.7. Carcinogenicity
              7.7.1. Oral exposure
              7.7.2. Inhalation exposure
                        7.7.2.1   Short-term exposure
                        7.7.2.2   Long-term exposure
              7.7.3. The effect of age on susceptibility to 
                        tumour induction
              7.7.4. The effect of gender on susceptibility to 
                        tumour induction
              7.7.5. Carcinogenicity of metabolites

        7.8. Genotoxicity
              7.8.1.  In vitro studies
              7.8.2.  In vivo studies
              7.8.3. Genotoxicity of VC metabolites
              7.8.4. Other toxic effects of VC metabolites
              7.8.5. Mutagenic and promutagenic properties of DNA
                        adducts formed by VC metabolites
              7.8.6. Mutations in VC-induced tumours
        7.9. Factors modifying toxicity
        7.10. Mechanisms of toxicity - mode of action
              7.10.1. Mechanisms of VC disease
              7.10.2. Mechanism of carcinogenesis

    8. EFFECTS ON HUMANS

        8.1. General population
        8.2. Controlled human studies
        8.3. Occupational exposure
              8.3.1. Overview
              8.3.2. Non-neoplastic effects
                        8.3.2.1   Acute toxicity
                        8.3.2.2   Effects of short- and long-term
                                  exposure
                        8.3.2.3   Organ effects
              8.3.3. Neoplastic effects
                        8.3.3.1   Liver and biliary tract cancers
                        8.3.3.2   Brain and central nervous
                                  system (CNS)
                        8.3.3.3   Respiratory tract
                        8.3.3.4   Lymphatic and haematopoietic
                                  cancers
                        8.3.3.5   Malignant melanoma
                        8.3.3.6   Breast cancer
                        8.3.3.7   Other cancer sites
        8.4. Genotoxicity studies
              8.4.1. Cytogenetic studies of VC-exposed
                        workers
              8.4.2. Mutations at the hypoxanthine guanine
                        phosphoribosyltransferase (hprt) locus
              8.4.3. Mutations in ASL from VC-exposed
                        workers
                        8.4.3.1   p53 gene
                        8.4.3.2   ras genes
        8.5. Studies on biological markers
              8.5.1. Excretion of metabolites
              8.5.2. Genetic assays
              8.5.3. Enzyme studies
              8.5.4. von Willebrand factor
              8.5.5.  p53 and  ras proteins
        8.6. Susceptible subpopulations
              8.6.1. Age susceptibility
              8.6.2. Immunological susceptibility
              8.6.3. Polymorphic genes in VC metabolism

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

        9.1. Laboratory experiments
              9.1.1. Microorganisms
                        9.1.1.1   Water
                        9.1.1.2   Soil
              9.1.2. Aquatic organisms
                        9.1.2.1   Invertebrates
                        9.1.2.2   Vertebrates
        9.2. Field observations
              9.2.1. Aquatic organisms

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE
         ENVIRONMENT

        10.1. Evaluation of human health effects
              10.1.1. Hazard identification
                        10.1.1.1  Non-neoplastic effects
                        10.1.1.2  Neoplastic effects
              10.1.2. Dose-response analysis
                        10.1.2.1  Non-neoplastic effects
                        10.1.2.2  Neoplastic effects
              10.1.3. Human exposure
                        10.1.3.1  General population
                        10.1.3.2  Occupational exposure
              10.1.4. Risk characterization
        10.2. Evaluation of effects on the environment

    11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH

        11.1. Public health
        11.2. Occupational health

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    ANNEX 1. REGULATIONS CONCERNING VINYL CHLORIDE

    ANNEX 2. PHYSIOLOGICAL MODELLING AND RECENT RISK ASSESSMENTS

    ANNEX 3. EXECUTIVE SUMMARY OF VINYL CHLORIDE PANEL REPORT

    RESUME

    RESUMEN
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication. In the interest of all users of the Environmental Health
    Criteria monographs, readers are requested to communicate any errors
    that may have occurred to the Director of the International Programme
    on Chemical Safety, World Health Organization, Geneva, Switzerland, in
    order that they may be included in corrigenda.


                             *   *   *


         A detailed data profile and a legal file can be obtained from the
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    Environmental Health Criteria

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    FIGURE 



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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR VINYL CHLORIDE

     Members

    Dr A. Barbin, International Agency for Research on Cancer, Lyon,
    France

    Professor V.J. Feron, TNO Nutrition and Food Research Institute, HE
    Zeist, Netherlands

    Ms P. Heikkilä, Uusimaa Regional Institute of Occupational Health,
    Helsinki, Finland

    Dr J. Kielhorn, Chemical Risk Assessment, Fraunhofer Institute for
    Toxicology and Aerosol Research, Hanover, Germany  (Co-Rapporteur)

    Professor M. Kogevinas, Respiratory and Environmental Health Research
    Unit, Municipal Institute of Medical Investigation (IMIM), Barcelona,
    Spain

    Mr H. Malcolm, Institute of Terrestrial Ecology, Monks Wood, Abbots
    Ripton, Huntingdon, Cambridgeshire, United Kingdom  (Co-Rapporteur)

    Dr W. Pepelko, National Center for Environmental Assessment, Office of
    Research and Development, US EPA, Washington DC, USA

    Dr A. Pintér, National Institute of Environmental Health, Budapest,
    Hungary  (Vice-Chairman)

    Dr L. Simonato, Department of Oncology, University of Padua, Venetian
    Tumours Registry, Padua, Italy

    Professor H. Vainio, Division of Health Risk Assessment, National
    Institute of Environmental Medicine, Karolinska Institute, Stockholm,
    Sweden  (Chairman)

    Dr E.M. Ward, Division of Surveillance Hazard, Evaluation and Field
    Studies, National Institute for Occupational Safety and Health
    (NIOSH), Robert Taft Laboratory, Cincinnati, Ohio, USA (Contact
    address: Environmental Cancer Epidemiology, International Agency for
    Research on Cancer, Lyon, France

    Dr J.M. Zielinski, Biostatistics and Research Coordination Division,
    Ottawa, Ontario, Canada

     Secretariat

    Dr A. Aitio, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland  (Secretary)

    Dr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer Institute for
    Toxicology and Aerosol Research, Hanover, Germany

    Dr C. Melber, Chemical Risk Assessment, Fraunhofer Institute for
    Toxicology and Aerosol Research, Hanover, Germany

    Dr U. Wahnschaffe, Chemical Risk Assessment, Fraunhofer Institute for
    Toxicology and Aerosol Research, Hanover, Germany

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR VINYL CHLORIDE

         A WHO Task Group on Environmental Health Criteria for Vinyl
    Chloride met at the Fraunhofer Institute for Toxicology and Aerosol
    Research, Hanover, Germany, from 25 to 29 January 1999. Professor H.
    Muhle welcomed the participants on behalf of the Institute and its
    Director, Professor U. Heinrich. Dr A. Aitio, IPCS, welcomed the
    participants on behalf of the Director, IPCS, and the three IPCS
    co-operating organisations (UNEP, ILO, and WHO). The Group reviewed
    and revised the draft and made an evaluation of the risks for human
    health and the environment from exposure to vinyl chloride.

         The first and second drafts of this monograph were prepared,
    under the co-ordination of Dr I. Mangelsdorf, by the authors
    Dr J. Kielhorn, Dr C. Melber and Dr U. Wahnschaffe. In the preparation
    of the second draft, the comments received from the IPCS contact
    points were carefully considered.

         Dr A. Aitio of the IPCS Central Unit was responsible for the
    scientific aspects of the monograph, and Dr P.G. Jenkins for the
    technical editing.

         The efforts of all who helped in the preparation and finalisation
    of the monograph are gratefully acknowledged.

                              *  *  *

         The Federal Ministry for the Environment, Nature Conservation and
    Nuclear Safety, Germany, contributed financially to the preparation of
    this Environmental Health Criteria monograph, and the meeting was
    organised by the Fraunhofer Institute for Toxicology and Aerosol
    Research.

    ABBREVIATIONS

    Epsilon A   1, N 6-ethenoadenine
    Epsilon C   3, N 4-ethenocytosine
    Epsilon dA  1, N 6-etheno-2'-deoxyadenosine
    Epsilon dC  3, N 4-etheno-2'-deoxycytidine
    Epsilon G   ethenoguanine
    7-OEG       7-(2'-oxoethyl)guanine
    ALAT        alanine aminotransferase
    ASAT        aspartate aminotransferase
    ASL         angiosarcoma of the liver
    BCF         bioconcentration factor
    CA          chromosomal aberration
    CAA         chloroacetaldehyde
    CEO         chloroethylene oxide
    CI          confidence interval (95% unless otherwise stated)
    CNS         central nervous system
    CYP2E1      cytochrome P-450 isozyme 2e1
    ECD         electron capture detection
    EDC         1,2-dichloroethane
    FDA         Food and Drug Administration (USA)
    FID         flame ionization detector
    GC          gas chromatography
    GST         glutathione S-transferase
    HCC         hepatocellular carcinoma
    HLA         human-leukocyte-associated antigen
    HPLC        high performance liquid chromatography
    HWD         hazardous waste dump
    IR          infrared
    LOAEL       lowest-observed-adverse-effect level
    MN          micronuclei
    MOR         morbidity odds ratio
    MS          mass spectrometry
    MSW         municipal solid waste
    NER         non-extractable residue
    NOAEC       no-observed-adverse-effect concentration
    NOAEL       no-observed-adverse-effect level
    NOEL        no-observed-effect level
    PCDD        polychlorinated dibenzodioxin
    PCDF        polychlorinated dibenzofuran
    PCE         tetrachloroethene (perchloroethene)
    PID         photoionization detector
    PVC         polyvinyl chloride
    SCE         sister chromatid exchange
    SIR         standardized incidence ratio
    SLRL        sex-linked recessive lethal
    SMR         standardized mortality ratio
    TCE         trichloroethene
    TEQ         toxic equivalent quantity
    UV          ultraviolet
    VC          vinyl chloride
    VOC         volatile organic compound

    1.  SUMMARY

         This monograph deals with vinyl chloride (VC) monomer itself and
    is not an evaluation of polyvinyl chloride (PVC), the polymer of VC.
    Exposures to VC in mixtures are not addressed.

    1.1  Identity, physical and chemical properties, and analytical
         methods

         Under ambient conditions, VC is a colourless, flammable gas with
    a slightly sweet odour. It has a high vapour pressure, a high value
    for Henry's Law constant and a relatively low water solubility. It is
    heavier than air and is soluble in almost all organic solvents. It is
    transported in liquid form under pressure.

         At ambient temperatures in the absence of air, dry purified VC is
    highly stable and non-corrosive but above 450°C, or in the presence of
    sodium or potassium hydroxide, partial decomposition can occur.
    Combustion of VC in air produces carbon dioxide and hydrogen chloride.
    With air and oxygen, very explosive peroxides can be formed,
    necessitating a continuous monitoring and limitation of the oxygen
    content, particularly in VC recovery plants. In the presence of water,
    hydrochloric acid is formed.

         Polymerization reactions to PVC are technically the most
    important reactions from an industrial view, but addition reactions
    with other halogens at the double bond, e.g., to yield
    1,1,2-trichloroethane or 1,1-dichloroethane, are also important.

         The concentration of VC in air can be monitored by trapping it on
    adsorbents and, after liquid or thermal desorption, analysis by gas
    chromatography. In ambient air measurements, several adsorbents in
    series or refrigerated traps may be needed to increase the efficiency
    of trapping. Peak concentrations at workplaces can be measured with
    direct-reading instruments based on, for instance, FID or PID. In
    continuous monitoring, IR and GC/FID analysers combined with data
    logging and processing have been used. In analysis of VC in liquids
    and solids, direct injection, extraction and more increasingly head
    space or purge-and-trap techniques are applied. Also in these samples,
    VC is analysed by GC fitted to, for instance, FID or MS detectors.

    1.2  Sources of human and environmental exposure

         VC is not known to occur naturally although it has been found in
    landfill gas and groundwater as a degradation product of chlorinated
    hydrocarbons deposited as solvent wastes in landfills or in the
    environment of workplaces using such solvents. VC is also present in
    cigarette smoke.

         VC is produced industrially by two main reactions: a) the
    hydrochlorination of acetylene; and b) thermal cracking (at about
    500°C) of 1,2-dichloroethane (EDC) produced by direct chlorination
    (ethylene and chlorine) or oxychlorination (ethylene, HCl and air/O2)
    of ethylene in the "balanced process". The latter process is the most
    usual nowadays.

         The world production of PVC (and therefore VC) in 1998 was about
    27 million tonnes. PVC accounts for 20% of plastics material usage and
    is used in most industrial sectors. About 95% of the world production
    of VC is used for the production of PVC. The remainder goes into the
    production of chlorinated solvents, primarily 1,1,1-trichloroethane
    (10 000 tonnes/year).

         Three main processes are used for the commercial production of
    PVC: suspension (providing 80% of world production), emulsion (12%)
    and mass or bulk (8%). Most of the case studies describing adverse
    effects of VC concern plants using the suspension (also called
    dispersion) process.

         There have been reports of VC release through accidents in PVC
    plants or during transportation. VC recovery has been introduced in
    many countries to recover residual non-converted VC from
    polymerization and other sources of the process such as in off-gas and
    water effluents. Where special precautions are not taken, VC can be
    detected in PVC resins and products.

         The level of residual VC in PVC has been regulated since the late
    1970s in many countries. Since then, release of VC from the thermal
    degradation of PVC is either not detectable or is at very low levels.

         Dioxins can be formed as contaminants in VC production. The
    levels of dioxins emitted into the environment are controversial.

    1.3  Environmental transport, distribution and transformation

         Owing to its high vapour pressure, VC released to the atmosphere
    is expected to exist almost entirely in the vapour phase. There are
    indications for wet deposition.

         VC has a relatively low solubility in water and has a low
    adsorption capacity to particulate matter and sediment. Volatilization
    of VC is the most rapid process for removal of VC introduced into
    surface waters. Half-lives reported for volatilization from surface
    waters range from about 1 to 40 h.

         Volatilization half-lives from soil were calculated to be 0.2-0.5
    days. Estimated losses of VC (after one year under a 1 m soil cover)
    ranged from 0.1-45%, depending on soil type. Soil sorption
    coefficients estimated from physicochemical data indicate a low
    sorption potential and therefore a high mobility in soil. Another
    important distribution route is leaching through the soil into
    groundwater where VC may persist for years.

         Laboratory experiments with aquatic organisms showed some
    bioaccumulation, but no biomagnification within the foodchain.

         With few exceptions, VC is not easily degraded by unadapted
    microbial consortia under environmental conditions. Maximum
    unacclimated biodegradation half-lives of VC were estimated to be in
    the order of several months or years. However, special enrichment or
    pure (e.g.,  Mycobacterium sp.) cultures are capable of degrading VC
    under optimal culture conditions. The main degradation products were
    glycolic acid or carbon dioxide after aerobic conversion and ethane,
    ethene, methane or chloromethane after anaerobic transformation.
    Frequently, the degradation reaction of VC proceeded faster with
    aerobes than with anaerobes.

         Reaction with photochemically produced OH radicals is the
    dominant atmospheric transformation process, resulting in calculated
    tropospheric half-lives of 1 to 4 days. Several critical compounds,
    such as chloroacetaldehyde, formaldehyde and formyl chloride, are
    generated during experimental photolysis reactions.

         Photolytic reactions as well as chemical hydrolysis are thought
    to be of minor importance in aqueous media. However, the presence of
    photosensitizers may enhance the transformation of VC.

         There are indications for reactions of VC with chlorine or
    chloride used for water disinfection, thus leading to
    chloroacetaldehyde and other undesirable compounds. Another
    possibility for interaction is with salts, many of which have the
    ability to form complexes with VC, perhaps resulting in increased
    solubility.

         Methods employed (with differing success) for removal of VC from
    contaminated waters include stripping, extraction, adsorption and
    oxidation. Some  in situ bioremediation techniques (for groundwater
    or soil) couple evaporative and other methods with microbial
    treatment. VC in waste gases can be recycled, incinerated or
    microbially degraded. Most of the VC produced industrially is bound in
    PVC articles. Their incineration involves a risk of formation of
    PCDDs/PCDFs and other unwanted chlorinated organic compounds.

    1.4  Environmental levels and human exposure

         There is very little exposure of the general population to VC.

         Atmospheric concentrations of VC in ambient air are low, usually
    less than 3 µg/m3. Exposure of the general population may be higher
    in situations where large amounts of VC are accidentally released to
    the environment, such as in a spill during transportation. However,
    such exposure is likely to be transient. Near VC/PVC industry and
    waste disposal sites, much higher concentrations (up to 8000 µg/m3
    and 100 µg/m3, respectively) have been recorded.

         Indoor air concentrations in houses adjacent to land fills
    reached maximal concentrations of 1000 µg/m3.

         The main route of occupational exposure is via inhalation and
    occurs primarily in VC/PVC plants. Occupational exposures to VC
    amounted to several thousands of mg/m3 in the 1940s and 1950s, and
    were several hundreds of mg/m3 in the 1960s and early 1970s. After
    the recognition of the carcinogenic hazards of VC, occupational
    exposure standards were set at approximately 13-26 mg/m3 (5-10 ppm)
    in most countries in the 1970s. Compliance with these guidelines has
    considerably lowered workplace VC concentrations, but even in the
    1990s higher concentrations have been reported and may still be
    encountered in some countries.

         VC has occasionally been detected in surface waters, sediment and
    sewage sludges, with maxima of 570 µg/litre, 580 µg/kg, and
    62 000 µg/litre, respectively. Soil samples near an abandoned chemical
    cleaning shop contained very high VC concentrations (up to 900 mg/kg).
    Maximal VC concentrations in groundwater or leachate from areas
    contaminated with chlorinated hydrocarbons amounted to 60 000 µg/litre
    (or more). High concentrations (up to 200 mg/litre) were detected in
    well water in the vicinity of a PVC plant 10 years after leakages.

         The few data available show that VC can be present in tissues of
    small aquatic invertebrates and fish.

         In the majority of drinking-water samples analysed, VC was not
    present at detectable concentrations. The maximum VC concentration
    reported in finished drinking-water was 10 µg/litre. There is a lack
    of recent data on VC concentrations in drinking-water, but these
    levels are expected to be below 10 µg/litre. If contaminated water is
    used as the source of drinking-water, higher exposures may occur. Some
    recent studies have identified VC in PVC-bottled drinking-water at
    levels below 1 µg/litre. The frequency of occurrence of VC in such
    water is expected to be higher than in tap water.

         Packaging with certain PVC materials can result in VC
    contamination of foodstuff, pharmaceutical or cosmetic products,
    including liquors (up to 20 mg/kg), vegetable oils (up to 18 mg/kg),
    vinegars (up to 9.8 mg/kg) and mouthwashes (up to 7.9 mg/kg). Owing to
    the legislative action of many countries, a significant reduction in
    VC levels and/or in the number of positive samples has been achieved
    since the early 1970s.

         Dietary exposure to VC from PVC packages used for food has been
    calculated by several agencies and, based upon estimated average
    intakes in the United Kingdom and USA, an exposure of < 0.0004 µg/kg
    per day was estimated for the late 1970s and early 1980s. An early
    study identified VC in tobacco smoke at the ng/cigarette range.

    1.5  Kinetics and metabolism in laboratory animals and humans

         VC is rapidly and well absorbed after inhalation or oral
    exposure. The primary route of exposure to VC is inhalation. In animal
    and human studies, under steady-state conditions, approximately 40% of
    inspired VC is absorbed after exposure by inhalation. Animal studies
    showed an absorption of more than 95% after oral exposure. Dermal
    absorption of VC in the gaseous state is not significant.

         Data from oral and inhalation studies on rats indicate rapid and
    widespread distribution of VC. Rapid metabolism and excretion limits
    accumulation of VC in the body. Placental transfer of VC occurs
    rapidly in rats. No studies on distribution after dermal exposure have
    been reported.

         The main route of metabolism of VC after inhalation or oral
    uptake involves oxidation by cytochrome P-450 (CYP2E1) to form
    chloroethylene oxide (CEO), a highly reactive, short-lived epoxide
    which rapidly rearranges to form chloroacetaldehyde (CAA). The primary
    detoxification reaction of these two reactive metabolites as well as
    chloroacetic acid, the dehydrogenation product of CAA, is conjugation
    with glutathione catalysed by glutathione  S-transferase. The
    conjugation products are further modified to substituted cysteine
    derivatives  (S-(2-hydroxyethyl)-cysteine,  N-acetyl- S-
    (2-hydroxyethyl)cysteine,  S-carboxymethyl cysteine and
    thiodiglycolic acid) and are excreted via urine. The metabolite
    carbon dioxide is exhaled in air.

         CYP2E1 and glutathione  S-transferase isoenzymes are known to
    have large inter-species and inter-individual variation in activity.

         After inhalative or oral exposure to low doses, VC is
    metabolically eliminated and non-volatile metabolites are excreted
    mainly in the urine. Comparative investigations of VC uptake via
    inhalation revealed a lower velocity of metabolic elimination in
    humans than in laboratory animals, on a body weight basis. However,
    when corrected on a body surface area basis, the metabolic clearance
    of VC in humans becomes comparable to that of other mammalian species.
    With increasing oral or inhalative exposure, the major route of
    excretion in animals is exhalation of unchanged VC, indicating
    saturation of metabolic pathways. Independently of applied dose, the
    excretion of metabolites via faeces is only a minor route. No studies
    were located that specifically investigated excretion via the bile.

         CEO is thought to be the most important metabolite  in vivo,
    concerning the mutagenic and carcinogenic effects of VC. CEO reacts
    with DNA to produce the major adduct 7-(2'-oxoethyl)guanine (7-OEG),
    and, at lower levels, the exocyclic etheno adducts,
    1, N6-ethenoadenine (Epsilon A), 3, N4-ethenocytosine (Epsilon C)
    and  N2,3-ethenoguanine (Epsilon G). The etheno DNA adducts exhibit
    pro-mutagenic properties, in contrast to the major adduct 7-OEG.
    7-OEG, Epsilon A, Epsilon C and Epsilon G have been measured in

    various tissues from rodents exposed to VC. Physiologically based
    toxicokinetic (PBTK) models have been developed to describe the
    relationship between target tissue dose and toxic end-points for VC.

    1.6  Effects on laboratory mammals and  in vitro test systems

         VC appears to be of low acute toxicity when administered to
    various species by inhalation. The 2-h LC50 for rat, mouse,
    guinea-pig and rabbit were reported to be 390 000, 293 000, 595 000
    and 295 000 mg/m3, respectively. No data are available on acute
    toxicity after oral or dermal application. VC has a narcotic effect
    after acute inhalation administration. In rats, mice and hamsters,
    death was preceded by increased motor activity, ataxia and
    convulsions, followed by respiratory failure. In dogs, severe cardiac
    arrythmias occurred under narcosis after inhalative exposure to
    260 000 mg/m3. After acute inhalation exposure to VC in rats,
    pathological findings included congestion of the internal organs,
    particularly lung, liver and kidney, as well as pulmonary oedema.

         No studies or relevant data are available for assessing effects
    of dermal exposure, skin irritation or sensitizing property of VC.

         Short-term oral exposure to VC for 13 weeks in rats resulted in a
    no-observed-effect level (NOEL), based on increase in liver weight, of
    30 mg/kg.

         In various species, the main target organ for short-term (up to
    6 months) inhalation exposure to VC was the liver. Increases in
    relative liver weights and hepatocellular changes were noted in rats
    at 26 mg/m3 (the lowest dose level tested); at higher levels
    (> 260 mg/m3) more pronounced liver changes occurred in a
    dose-related manner. Other target organs were the kidney, lung and
    testis. Rats, mice and rabbits seem to be more sensitive than
    guinea-pigs and dogs.

         Long-term exposure to VC by inhalation resulted in statistically
    significant increases in mortality in some strains of rats at a dose
    of as low as 260 mg/m3, in mice at 130 mg/m3 and in hamsters at
    520mg/m3 for various lengths of exposure. Rats exposed to
    130 mg/m3 showed reduced body weight and increased relative spleen
    weight, hepatocellular degeneration and proliferation of cells lining
    the liver sinusoids. Exposure to higher levels produced degenerative
    alteration in the testis, tubular nephrosis and focal degeneration of
    the myocardium in rats. For rats and mice exposed via inhalation, the
    no-observed-adverse-effect level (NOAEL) concerning non-neoplastic
    effects is below 130 mg/m3.

         Chronic feeding studies showed increased mortality, increased
    liver weights and morphological alteration of the liver.

         After oral exposure, liver cell polymorphism (variation in size
    and shape of hepatocytes and their nuclei) could be seen in rats at
    levels as low as 1.3 mg/kg body weight. The NOAEL was 0.13 mg/kg body
    weight.

         Long-term feeding studies in rats with VC in PVC granules yielded
    significantly increased tumour incidences of liver angiosarcoma (ASL)
    at 5.0 mg/kg body weight per day and neoplastic liver nodules
    (females) and hepatocellular carcinoma (HCC) (males) at 1.3 mg/kg body
    weight per day.

         In inhalation studies with VC in Sprague-Dawley rats, a clear
    dose-response relationship was observed for ASL and, at high
    concentrations, Zymbal gland carcinomas. No clear dose-dependency for
    hepatoma or extrahepatic angiosarcoma, nephroblastomas,
    neuroblastomas, or mammary malignant tumours was observed. In mice,
    the spectrum of tumours induced by long-term inhalation exposure is
    similar to that observed in rats but an increase in lung tumours was
    only observed in mice. In hamsters, an increased tumour incidence of
    ASL, mammary gland and acoustic duct tumours, melanomas, stomach and
    skin epithelial tumours was reported.

         The mutagenic and genotoxic effects of VC have been detected in a
    number of  in vitro test systems, predominantly after metabolic
    activation. VC is mutagenic in the Ames test in  S. typhimurium
    strains TA100, TA1530 and TA1535 but not in TA98, TA1537 and TA1538,
    indicating mutations as a result of base-pair substitutions
    (transversion and transition) rather than frameshift mutations. This
    is in agreement with the finding that etheno-DNA adducts formed by the
    reactive metabolites CEO and CAA convert to actual mutations by
    base-pair substitutions.

         Other gene mutation assays in bacteria, yeast cells and mammalian
    cells have revealed positive results exclusively in the presence of
    metabolic activation. Mutagenic effects were also reported in a human
    cell line containing cloned cytochrome P-450IIE1, which is capable of
    metabolizing VC. Gene mutation was also detected in plant
    ( Tradescantia ) cuttings exposed to VC. In gene conversion assays,
    positive results were reported with  Saccharomyces cerevisiae in the
    presence of a metabolic activation system. VC exposure induced
    unscheduled DNA synthesis in rat hepatocytes and increased
    sister-chromatid exchange (SCE) in human lymphocytes after addition of
    exogenic activation system. No growth inhibition was detected in DNA
    repair-deficient bacteria without metabolic activation. Cell
    transformation assays revealed positive results both with and without
    metabolic activation.

         VC exposure induced gene mutation and mitotic recombination in
     Drosophila melanogaster but not gene mutation in mammalian germ
    cells. VC showed clastogenic effects in rodents, increased SCE in
    hamsters and induced DNA breaks in mice. In host-mediated (rat)
    assays, VC induced gene conversion and forward mutations in yeast.

         CEO and CAA were found to be mutagenic in different test systems.
    CEO is a potent mutagen, whereas CAA is highly toxic. CEO and CAA were
    found to be carcinogenic in mice, CEO being much more active than CAA.

         Mutations of the  ras and  p53 genes were analysed in liver
    tumours induced by VC in Sprague-Dawley rats: base-pair substitutions
    were found in the Ha- ras gene in hepatocellular carcinoma (HCC) and
    in the  p53 gene in ASL. These mutations are in agreement with the
    observed formation and persistence of etheno adducts in liver DNA,
    following exposure of rats to VC, and with the known pro-mutagenic
    properties of etheno adducts.

         Studies into the mechanism of carcinogenicity of VC suggest that
    the reactive epoxide intermediate CEO interacts with DNA to form
    etheno adducts, which result in a base-pair substitution leading to
    neoplastic transformation.

    1.7  Effects on humans

         Concentrations of VC in the region of 2590 mg/m3 (1000 ppm),
    which were not unusual prior to 1974, over periods ranging from 1
    month to several years, have been reported to cause a specific
    pathological syndrome found in VC workers called the "vinyl chloride
    illness". Symptoms described were earache and headache, dizziness,
    unclear vision, fatigue and lack of appetite, nausea, sleeplessness,
    breathlessness, stomachache, pain in the liver/spleen area, pain and
    tingling sensation in the arms/legs, cold sensation at the
    extremities, loss of libido and weight loss. Clinical findings
    included scleroderma-like changes in the fingers with subsequent bony
    changes in the tips of the fingers described as acroosteolysis,
    peripheral circulatory changes identical with the classical picture of
    Raynaud's disease and enlargement of the liver and spleen with a
    specific histological appearance, and respiratory manifestations.

         Studies in humans have not been adequate to confirm effects on
    the reproductive system. A few morbidity studies have reported
    elevated incidence of circulatory diseases among vinyl chloride
    workers. However, large cohort studies have found lower cardiovascular
    disease mortality.

         There is strong and consistent evidence from epidemiological
    studies that VC exposure causes the rare tumour, angiosarcoma of the
    liver. Brain tumours and hepatocellular carcinoma of the liver may
    also be associated with VC, although the evidence cannot be considered
    definitive. Other cancer sites reported to be in excess, but less
    consistently, include lung, lymphatic and haematopoietic tissue, and
    skin.

         VC is mutagenic and clastogenic in humans. Frequencies of
    chromosomal aberrations (CA), micronuclei (MN) and SCE in the
    peripheral blood lymphocytes of workers exposed to high levels of VC
    have been shown to be raised compared to controls. Although in many

    studies the exposure concentrations and duration of exposure were only
    estimated, a dose-response relationship and a "normalization" of
    genotoxic effects with time after reduction of exposure can be seen.

         Point mutations have been detected in  p53 and  ras genes in
    tumours from highly exposed (before 1974) autoclave workers with liver
    angiosarcoma (ASL) and another VC worker with hepatocellular
    carcinoma.

         Biological markers that have been investigated as indicators for
    VC exposure or VC-induced effects include a) excretion of VC
    metabolites (e.g., thiodiglycolic acid), b) genetic assays (e.g.,
    chromosomal abnormalities or micronucleus assay), c) levels of enzymes
    (e.g., in liver function tests), d) serum oncoproteins (p21 and p53)
    and/or their antibodies as biomarkers of VC-induced effects.

         Children living near landfill sites and other point sources may
    be at increased risk based on suggested evidence of early life
    sensitivity in animal studies. However, there is no direct evidence in
    humans.

         In epidemiological studies, a clear dose-response is only evident
    for ASL alone or in combination with other liver tumours. Only one
    epidemiological study has sufficient data for quantitative
    dose-response estimation.

    1.8  Effects on other organisms in the laboratory and field

         There is a lack of standard toxicity data on the survival and
    reproduction of aquatic organisms exposed to VC. Care must be taken
    when interpreting the data that are available, as most of it was
    generated from tests where the exposure concentration was not measured
    and therefore losses due to volatilization were not taken into
    account.

         The lowest concentration of VC that caused an effect in
    microorganisms was 40 mg/litre. This was an EC50 value based upon
    inhibition of respiration in anaerobic microorganisms in a batch assay
    over 3.5 days.

         The lowest concentration that caused an effect in higher
    organisms was 210 mg/litre (48-h LC50 for a freshwater fish); with a
    corresponding no-observed-adverse-effect concentration (NOAEC) of 128
    mg/litre. Effects due to VC have been reported at lower concentrations
    in other species, but the ecological significance of these effects was
    not verified.

         VC concentrations predicted to be non-hazardous to freshwater
    fish were calculated to range from 0.088 to 29 mg/litre.

         There is a paucity of data concerning the effects of VC on
    terrestrial organisms.
    

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

         This monograph deals with vinyl chloride (VC) monomer itself and
    is not an evaluation of polyvinyl chloride (PVC), the polymer of VC.

    2.1  Identity

    Chemical formula:             C2H3Cl

    Chemical structure:           H2C=CHCl

    Relative molecular mass:      62.5

    Common names:                 Vinyl chloride

    CAS chemical name:            Ethene, chloro-

    IUPAC name:                   Chloroethene

    CAS Registry                  75-01-4
    number:

    EC Number:                    602-023-007

    EINECS Number:                2008310

    Synonyms:                     vinyl chloride monomer,
                                  monochloroethene;
                                  monochloroethylene;
                                  1-chloroethylene, chloroethene,
                                  chloroethylene

    Purity                        99.9% (by weight); water: max.
                                  120 mg/kg; HCl: max. 1 mg/kg
                                  (BUA, 1989)
                                  Up to the 1960s the purity was not
                                  so high (Lester et al., 1963)

    Typical trace                 10-100 mg/kg range: chloromethane,
    components                    chloroethane; 1-10 mg/kg range:
                                  ethyne
                                  (acetylene), 1,3-butadiene, butene,
                                  1,2-dichloroethane, ethene,
                                  propadiene
                                  (allene), propene, 1-butyne-3-ene
                                  (vinyl acetylene) (BUA, 1989)

    2.2  Physical and chemical properties

         Some physical properties of VC are given in Table 1. Under
    ambient conditions, vinyl chloride is a colourless, flammable gas with
    a slightly sweet odour. It is heavier than air and has relatively low
    solubility. There are discrepancies in the literature with regard to
    Henry's Law constant (air-water partition coefficient, Hc). Whereas
    some authors give a value between 1 and 3 kPa.m3/mol, other sources
    quote a value two orders higher. Large uncertainties in the absolute
    aqueous solubility in older studies probably contribute most to these
    discrepancies (Ashworth et al., 1988). It is an azeotrope with water:
    0.1 parts water/100 parts vinyl chloride (Bönnighausen, 1986; Rossberg
    et al., 1986). VC is soluble in almost all organic solvents.

         Since it is a gas that is heavier than air, VC can spread over
    the ground creating an exposure long distances away from the original
    source and can form explosive mixtures. The odour threshold value is
    very subjective (see Table 1) and is far above the present accepted
    occupational safety threshold values (see Annex 1).

         VC is transported as a compressed liquid. As it does not tend to
    polymerize easily, liquid VC (in the absence of oxygen and water) can
    be stored and transported without polymerization inhibitors
    (Bönnighausen, 1986).

         At ambient temperatures in the absence of air, dry purified VC is
    highly stable and non-corrosive. Above 450°C, partial decomposition
    occurs yielding acetylene, hydrogen chloride and trace amounts of
    2-chloro-1,3-butadiene (chloroprene) (Rossberg et al., 1986). This
    reaction also occurs by lower temperatures (at 30°C and under) in the
    presence of sodium or potassium hydroxide (Bönnighausen, 1986).

         Combustion of VC in air produces carbon dioxide and hydrogen
    chloride. Under oxygen deficient conditions, traces of phosgene may be
    formed (Rossberg et al., 1986). In chlorine-atom-initiated oxidation
    of VC, the vinyl chloride peroxide formed decomposes to formaldehyde,
    hydrogen chloride and carbon monoxide (Bauer & Sabel, 1975; Sanhueza
    et al., 1976).

         With air and oxygen, very explosive peroxides can be formed
    (Rossberg et al., 1986). There are reports of explosions in vinyl
    chloride plants (Terwiesch, 1982). In VC recovery plants there is a
    higher chance of explosion, which necessitates continuous monitoring
    and limitation of the oxygen content.

        Table 1. Some physical and chemical properties of vinyl chloride
                                                                                 

    Melting point                    -153.8 °C               Bönnighausen (1986);
                                                             Dreher (1986)

    Boiling point                    -13.4 °C                Bönnighausen (1986);
    (at 101.3 kPa)                                           Dreher (1986)

    Flash point                      -78 °C                  Bönnighausen (1986);
    (open cup)                                               Dreher (1986)

    Autoignition                     472 °C                  Bönnighausen (1986);
    temperature                                              Dreher (1986)

    Critical temperature             156 °C                  Bönnighausen (1986);
                                                             Dreher (1986)

    Critical pressure                5600 kPa                Bönnighausen (1986);
                                                             Dreher (1986)

    Explosion limits in air          3.8-29.3 vol%           Bönnighausen (1986)
                                     in air (20 °C);
                                     4-22 vol%               Dreher (1986)

    Decomposition                    450 °C                  Bönnighausen (1986)
    temperature

    Density (20 °C)                  0.910 g/cm3             Bönnighausen (1986)

    Vapour pressure at -20 °C        78 kPa                  Dreher (1986)
                         0 °C        165 kPa
                        20 °C        333 kPa

    Solubility of VC in              0.95 wt% (9.5 g/litre)  DeLassus & Schmidt
    water; extrapolated              over temperature        (1981)
    from low pressure                range
    experiments                      1.1 g/litre             Euro Chlor (1999)
    over range 15-85 °C
    at 20 °C

    Solubility of water              0.02 ml (-20 °C)        Bönnighausen (1986)
    in 100 g VC                      0.08 ml (+20 °C)

    Henry's Law Constant             1.96 at 17.5 °C         Gossett (1987)
    (Hc) (kPa.m3/mol)                2.0-2.8 at 25 °C        Ashworth et al. (1988)
                                     18.8 at 20 °C           Euro Chlor (1999)

    Table 1. (cont'd)
                                                                                 

    Solubility in organic            soluble in most         Dreher (1986)
    solvents                         organic liquids and
                                     solvents;
                                     insoluble in lower      Bönnighausen (1986)
                                     polyalcohols

    log n-octanol/water              1.58 (measured;         BUA (1989)
    partition coefficient            22 °C)
    (log Kow)                        1.36 (calculated)       BUA (1989)
                                     1.52                    Gossett et al. (1983)

    Odour threshold value            26-52 mg/m3 by          Hori et al. (1972)
                                     some, but by all at
                                     2600 mg/m3
                                     650 mg/m3               Baretta et al. (1969)
                                     10 700 mg/m3            Patty (1963)
                                                                                 

         Polymerization reactions to form PVC are the most important
    reactions from an industrial view (see section 3.2.1.2).

         nH2C = CHCl -> (- H2C - CHCl -)n;   Delta HR = -71.2 kJ/mol

    The reaction is exothermic. Addition reactions with other halogens at
    the double bond, for instance, to yield 1,1,2-trichloroethane or
    1,1-dichloroethane, are also important. Catalytic halogen exchange by
    hydrogen fluoride gives vinyl fluoride (Rossberg et al., 1986). In the
    presence of water, hydrochloric acid is formed which attacks most
    metals and alloys. This hydrolysis probably proceeds via a peroxide
    intermediate (Lederer, 1959).

         Vinyl chlorine reacts with chlorine to form trichloroethane.
    1,1-Dichloroethane is formed from the exothermal reaction of VC with
    hydrogen chloride in the presence of iron compounds.

    2.3  Conversion factors

    1 ppm     = 2.59 mg/m3 at 20°C and 101.3 kPa
    1 mg/m3   = 0.386 ppm

    2.4  Analytical methods

    2.4.1  General analytical methods and detection

         Stringent regulations for the production, use and handling of
    carcinogenic VC have been made in several countries (see Annex 1)
    necessitating the usage of reliable methods to detect trace amounts of

    this compound in air, water and in PVC articles in such human contact
    applications as food packing, medical equipment and potable water
    transport.

         VC in air has been monitored by trapping it on different
    adsorbents, e.g., activated charcoal, molecular sieve and carbotrap.

         VC can be removed from adsorbents by liquid or thermal desorption
    and analysed by GC fitted with FID, PID or MS detection. In ambient
    air measurements, several adsorbents in sieves or refrigerated traps
    have been used to increase the efficiency of trapping. In continuous
    monitoring of workplace and ambient concentration, IR and GC/FID
    analysers can be used.

         Direct injection, extraction and more increasingly head space or
    purge and trap techniques have been applied for analysis of liquids
    and solids. VC can be detected by GC fitted to, for instance, FID,
    PID, MS or Hall detectors.

         A pre-concentration step and chemical derivatization may increase
    sensitivity.

         An overview of analytical methods for detecting VC in various
    matrices is given in Table 2.

    2.4.2  Sample preparation, extraction and analysis for different
           matrices

    2.4.2.1  Air

         Most methods are based on that of Hill et al. (1976a), using
    adsorption on activated charcoal, desorption with carbon disulfide and
    analysis by GC/FID. Kruschel et al. (1994) used a three-stage carbon
    molecular sieve adsorbent cartridge to collect a wide range of
    selected polar and non-polar VOCs. After purging with helium prior to
    analysis, levels of water and other interfering compounds were reduced
    sufficiently to allow cryogenic preconcentration and focusing of the
    sample onto the head of the analytical column. VC was detected at
    levels below the detection limit of former methods.

         Landfill gas monitoring has been carried out by trapping VC on a
    molecular sieve, and samples have been analysed using, for instance,
    GC/MS (Bruckmann & Mülder, 1982) or GC/ECD with prior conversion to
    the 1,2-dibromo derivative (Wittsiepe et al., 1996).


        Table 2. Analytical methodsa
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    Air

    Expired air    collected in 50 ml      GC                FID         50 ppb                                   Baretta et al. (1969)
                   pipettes; direct        (packed                       (130 µg/m3)
                   injection               column)

    Expired air    multistage cryogenic    GC                FID; MS     low ppb         low reproducibility;     Conkle et al. (1975)
                   trapping; thermal       (packed & cap.)                               long sampling time
                   desorption

    Expired air    500 ml charcoal tubes   GC                            0.3 mg/m3                                Krajewski & Dobecki
                                                                                                                  (1978, 1980)

    Expired air    1 litre canister;       capGC             MS          n.g.            for collecting           Pleil & Lindstrom
                   pressurized with                                                      alveolar samples; e.g.,  (1997)
                   neutral gas; cryogenic                                                16 and 25 µg/m3
                   concentration

    Air in car     charcoal tube, CS2      GC                FID         10 ppb                                   Going (1976); Hedley
    interior       desorption                                            (26 µg/m3)                               et al. (1976)

    Ambient air    activated charcoal/CS2  GC                FID         2.6 mg/m3                                Hill et al. (1976a)

    Ambient air    silica gel at -78°C,    GC                FID         2.6 mg/m3                                IARC (1978)
                   thermal desorption

    Ambient air    activated charcoal      GC                n.g.        0.5 ppb                                  Dimmick (1981)
                   column; 24-h sampling                                 (1.3 µg/m3)

    Ambient air    sampling (1 to 10       HRGC              MS          1 ng            VOCs                     Kruschel et al.
                   litre) on carbon trap;                    FID         (0.3 µg/m3)                              (1994)
                   thermal desorption

    Table 2. (cont'd)
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    Ambient air    solid phase sample      capGC             IMS         2 mg/m3         new method for           Simpson et al.
                   trap preconcentration                                                 field monitoring         (1996)

    Landfill gas   (20 litre) carbon       capGC             ECD         82 ng/m3                                 Wittsiepe et al.
                   molecular sieve; CS2                                                                           (1996)
                   desorption;
                   conversion to
                   1,2,-dibromo
                   derivative

    Tobacco        charcoal tube, CS2      GLC               ECD         15 pg per                                Hoffmann et al.
    smoke          extraction;                                           injection                                (1976)
                   conversion to
                   1,2,-dibromo
                   derivative

    Workplace      CS2 desorption          GC (packed        FID         0.04 µg         working range            NIOSH (1994)
    air                                    column)                       (5 litre        0.4 to 40 mg/m3          (based on Hill
                                                                         sample)                                  et al., 1976a)

    Workplace      charcoal sorbent        GC (packed        FID         5 mg/m3                                  Kollar et al.
    air            tube; extraction        column)                       (3 dm3 sample)                           (1988)
                   with
                   nitro-methane

    Workplace      carbon trap,            GC                FID         2.6 mg/m3                                Hung et al. (1996)
    air            thermal desorption

    Workplace      activated charcoal,     GC                FID         0.1 mg/m3       working range            HSE (1987);
    air            CS2 desorption                                                        0.07-25 mg/m3 for        ASTM (1993)
                                                                                         30-litre samples

    Workplace      continuous              process GC        FID         n.g.                                     Pau et al. (1988)
    air            sampling

    Table 2. (cont'd)
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    Workplace      continuous              pyrolysis         detection   1 mg/m3                                  Nakano et al.
    air            sampling                                  of HCl                                               (1996)

    Water

    Water          purge & trap            GC                MC          n.g.            in PVC pipes             Dressman &
                                                                                                                  McFarren (1978)

    Water          purge & trap            GC                MS          0.05 µg/litre                            Schlett &
                                                                                                                  Pfeifer (1993)

    Water          headspace               capGC             MS          1 µg/litre                               Gryder-Boutet &
                                                                                                                  Kennish (1988)

    Water          purge & trap            capGC             PID-ELCD    n.g.            modification of US       Driscoll et al.
                                                                                         EPA Methods 601          (1987)
                                                                                         & 602 for VOC

    Water          purge & trap            capGC             PID-ELCD    0.1 µg/litre    VOC                      Ho (1989)

    Water          purge & trap;           capGC             ECD         1.6 ng/litre                             Wittsiepe et al.
                   CS2 desorption;                                                                                (1990, 1993)
                   1,2-dibromo
                   derivatization

    Water                                  GC                PID and     n.g.            VCM loss during          Soule et al.
                                                             Hall                        laboratory holding       (1996)
                                                             detector                    time

    Water          purge & trap            GC                FID         n.g.            VOC                      Lopez-Avila et
                                                                                                                  al. (1987a)

    Table 2. (cont'd)
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    Water          CS2 desorption;         capGC             ECD         1.6 ng/litre                             Wittsiepe et al.
                   conversion to                                                                                  (1990, 1996)
                   1,2,-dibromo
                   derivative

    Bottled        headspace with          GC                MS          10 ng/litre                              Benfenati et al.
    drinking-      thermal desorption                                                                             (1991)
    water          cold-trap
                   injector (TCT)

    Water          solid phase             capGC             FID         n.g.                                     Shirey (1995)
                   micro-extraction                          MS

    Food, liquids, biological fluids and tissues

    Liquid         headspace               GC                FID         0.1 ppb                                  Watson et al.
    drugs;                                                                                                        (1979)
    cosmetics

    Food;          headspace               GLC               confirmation                10 ppb                   Williams (1976a)
    liquids                                                  with MS

    Liquids        derivatization to       GLC               ECD         15 µg/litre                              Williams (1976b)
                   1-chloro-1,2-                                         (vinegar);
                   dibromoethane                                         50 µg/litre oil

    Food           direct injection        GC                FID         2-5 µg/kg       detection limit          UK MAFF (1978)
                                                                                         depends on medium

    Food           headspace               GC                FID         1 µg/kg                                  IARC (1978)

    Table 2. (cont'd)
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    Oil                                    GC                FID         5 µg/litre                               Rösli et al.
                                                                                                                  (1975) based on
                                                                                                                  Williams & Miles
                                                                                                                  (1975)

    Food           headspace               GC                n.g.        2-5 µg/kg                                UK MAFF (1978)

    Intravenous    headspace               capGC             FID         1 µg/litre                               Arbin et al.
    solutions                                                                                                     (1983)

    Blood (rat)    headspace               GC                FID         5 µg/litre                               Zuccato et al.
                   ethanol-water                                                                                  (1979)
                   extraction

    Tissues        freezing,               GC                FID         30 µg/kg                                 Zuccato et al.
    (rat)          homogenization                                                                                 (1979)
                   then as above

    Urine          dry; dissolution        GC                MS          50 µg/litre     TDGA                     Müller et al.
                   in methanol;                                                                                   (1979)
                   methylation with
                   diazomethane

    Urine          extraction and          GC                FID         10 mg/litre     TDGA; standard:          Draminski &
                   silylation                                                            o-phthalic acid          Trojanowska
                                                                                                                  (1981)

    Urine          conversion to           GC                MS          < 0.5           TDGA; standard:          Pettit (1986)
                   dibutyl ester                                         µmol/litre      pimelic acid

    PVC

    PVC products   charcoal tube,          GC                FID         10 ppb                                   Going (1976)
                   CS2 desorption                                        (26 µg/m3)

    Table 2. (cont'd)
                                                                                                                                      

    Matrix         Sampling/preparation    Separation        Detector    Detection       Comments                 References
                                                                         limitb
                                                                                                                                      

    PVC            headspace               packed column                 5 ppb                                    ASTM (1985)
                                           GC

    PVC            headspace               capGC             FID                         update suggestion for    Wright et al.
                                                             FID-PID                     ASTM (1985)              (1992)

    PVC            extraction/headspace    GC                FID                         0.1 mg/kg                Puschmann (1975);
                                                                                                                  IARC (1978)

    PVC                                    HPLC                          < 1 ppm         for temperatures         Kontominas et al.
    packaging                                                                            simulating storage       (1985)
    of foods                                                                             conditions (8 to 27 °C)

    PVC            dynamic headspace       GC                FID         low ppb                                  Poy et al. (1987)
                   with a sparging and
                   focusing step
                   before thermal
                   desorption

    PVC film or                            GC                FID         2.2 ng                                   Gilbert et al.
    resin                                                                (5 ppb (w/w))                            (1975)

    Packaging                                                MS          8.7 pg
    materials

    PVC bags       purge/trap              GC                FID/ECD     0.3 ppb                                  Thomas & Ramstad
                   (Tenax/charcoal)                                                                               (1992)
                                                                                                                                      

    Table 2. (cont'd)

    a    Abbreviations: capGC = capillary gas chromatography; ECD = electron capture; ELCD = electrolytic conductivity detector;
       FID = flame ionization detector; GC = gas chromatography; GLC = gas-liquid chromatography; HRGL = high-resolution gas
       chromatography; IMS = ion mobility spectrometry; MC = microcoulometric titration detector; MS = mass spectrometry;
       PID = photoionization detector; SPME = solid-phase microextraction; TDGA = determination of the metabolite, thiodiglycolic
       acid; VOC = volatile organic chemical (a general method); n.g. = not given

    b    The % recovery was not given in most cases


    2.4.2.2  Water

         VC is first purged from the water and then collected for GC
    analysis by headspace/purge and trap. VC is highly volatile and has a
    low specific retention volume on Tenax-GC, the most commonly used
    trapping medium in purge/trap analysis. Combination traps such as
    Tenax/silica gel/charcoal (Ho, 1989) or Tenax/OV-1/silica (Lopez-Avila
    et al., 1987b) have been used. Another approach is to bypass the trap
    altogether by purging directly onto a cryocooled capillary column
    (Gryder-Boutet & Kennish, 1988; Pankow & Rosen, 1988; Cochran, 1988;
    Cochran & Henson, 1988), but here there are complications due to the
    need to remove water when stripping from an aqueous solution. A more
    recent adaptation of the headspace method uses solid-phase
    microextraction (SPME) in which a stationary phase, usually
    poly(dimethylsiloxane), coated on a fused-silica fibre is used to
    extract aqueous samples in completely filled sealed vials (Shirey,
    1995).

         It should be noted when measuring VC content in water or
    groundwater that samples should be analysed as soon as possible, as
    the VC content decreases with holding time (Soule et al., 1996).

    2.4.2.3  PVC resins and PVC products

         For the quantification of residual VC in PVC, a solid and a
    solution approach have been used. The former involves the
    equilibration of a solid polymer sample at 90°C in a sealed system,
    followed by headspace analysis with single or multiple extraction
    (Berens et al., 1975; Kolb, 1982). The solution approach involves the
    equilibration of a 10% solution of PVC in dimethylacetamide in a
    sealed system, followed by analysis of the headspace gas (Puschmann,
    1975). A automatic dynamic headspace method involving a sparging and a
    focusing step before desorption into the GC column has been developed
    to increase the sensitivity of the solution approach method (Poy et
    al., 1987).

    2.4.2.4  Food, liquid drug and cosmetic products

         For monitoring VC in foods in contact with PVC packaging,
    headspace GC is the usual method. Before the levels of VC allowed in
    PVC was regulated in the 1970s (see Annex I), many of the VC levels
    observed were high enough to be determined by direct injection
    methods. Limits of detection are given as 2, 5 and 5 µg/kg for
    aqueous, ethanolic, and oleaginous medium respectively using
    headspace-GC-FID (UK MAFF, 1978). Williams (1976a,b) reported a
    gas-liquid chromatographic method using subsequent GC-MS confirmation,
    and a further GC/ECD method requiring derivatization to
    1-chloro-1,2-dibromoethane for determination of VC content in liquid
    foods.

         Methods for VC levels in liquid drug and cosmetic preparations
    were described by Watson et al. (1979). A weighed aliquot of the
    commercial product in a tightly septum-sealed vial with accurately
    known headspace volume is heated to 50°C for 30 min. A portion of the
    warm headspace gas is then injected into a GC equipped with FID and a
    styrene-divinylbenzene porous polymer column.

    2.4.2.5  Biological samples

         There are few data on VC analysis in biological tissues. The only
    report available was on rat blood and tissues (Zuccato et al., 1979).

    2.4.2.6  Human monitoring

         Methods for measuring VC concentrations in exhaled air (breath)
    have been described (see Table 2) but, although useful for studying
    metabolism, they are not well suited for biological monitoring due to
    the short half times in the body and the saturable metabolism of VC.

         Metabolites of vinyl chloride have been identified in the urine
    of rats (Müller et al., 1976; Green & Hathway, 1977) and humans
    (Müller et al., 1979) using GC-MS. As there is a strong correlation
    between VC exposure in humans and increased excretion of
    thiodiglycolic acid (Müller et al. 1978), this metabolite has been
    using for monitoring purposes. It is, however, not specific for VC as
    certain drugs and other C2 compounds also have thiodiglycolic acid as
    a urinary metabolite (Müller et al., 1979). Since thiodiglycolic acid
    is also detected in unexposed subjects (Müller et al., 1979; van
    Sittert & de Jong, 1985) and even premature babies (Pettit, 1986),
    this approach can only be used to demonstrate high levels of exposure.
    A discussion of biological markers for VC exposures and VC-induced
    liver cancer is presented in section 8.5.

         Thiodiglycolic acid has been determined by dissolving the dried
    urine residue in methanol, methylating with diazomethane and analysing
    with GC-MS (Müller et al., 1979), analysing the metabolite as its
    dibutyl ester by GC-MS using selected ion monitoring (Pettit, 1986),
    and by using GC/FID (Draminski & Trojanowska, 1981). Care must be
    taken with methods which analyse for VC metabolites, as these
    metabolites are not specific to VC.

         A specific and sensitive new method has been reported for the
    quantification of the VC metabolite  N-acetyl- S-(2-hydroxyethyl)
    cysteine by exchange solid-phase extraction and isotope dilution
    HPLC-tandem mass spectrometry (Barr & Ashley, 1998). This method may
    prove useful for monitoring occupational VC exposure, as the detection
    limit of 0.68 µg/litre is low enough to detect this metabolite even in
    people with no overt exposure to VC, ethylene oxide or ethylene
    dibromide.

    2.4.2.7  Workplace air monitoring

         Before the 1960s, when it was established that VC was a
    carcinogenic substance, halogen detectors and explosimeters were used,
    non-specific for VC, with detection limits of 518-1295 mg/m3 (200-500
    ppm). Gradually more sophisticated techniques became available for
    detection of low ppm levels of VC, such as IR analysers, FID, PID
    (ECETOC, 1988) and more recently mass spectrometry. In order to check
    for leaks or for control measurements during cleaning and repair work,
    detector tubes or direct-reading instruments with FID or PID can be
    used, although they are not specific for VC and regular calibration is
    necessary (Depret & Bindelle, 1998).

         Continuous analyses based on, for instance, IR, GC/FID or HCl
    detection have been developed (IARC, 1978; Pau et al., 1988; Nakano et
    al., 1996). Analysers can be equipped for computerized data logging
    and processing. The detection limit of an IR analyser depends on, for
    instance, path length and is about 1.3 mg/m3 (IARC, 1978). The
    analyser detecting HCl from VC pyrolyzed in a quartz tube was reported
    to have a detection limit of 1 mg/m3 when the sampling time was 40
    seconds (Nakano et al., 1996).

         Breathing zone concentrations can be measured by sampling VC with
    portable pumps or diffusion on activated charcoal (Nelms et al., 1977;
    Heger et al., 1981; ASTM, 1993; NIOSH, 1994; Du et al., 1996). By
    using thermosorption tubes (carbotrap 110-400), detection limits can
    be decreased and the use of carbon disulfide in desorption avoided
    (Hung et al., 1996).

         Passive monitors for occupational personal monitoring of exposure
    to VC are commercially available.
    

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         VC is not known to occur naturally.

    3.2  Anthropogenic sources

         Anthropogenic sources of VC include the intentional manufacture
    of the compound for further processing, primarily to PVC, and
    unintentional formation of VC in, for instance, sanitary landfills, as
    a degradation product of chlorinated hydrocarbons such as those used
    as solvents, and the subsequent presence of VC in emitted gases and
    groundwater. VC is also found in tobacco smoke.

    3.2.1  Production levels and processes

         VC was first synthesized by Regnault in 1835. It was not until
    the 1930s that techniques were devised to polymerize VC into stable
    forms of PVC.

         VC production methods were altered in 1974 in many countries
    after the confirmation that VC was a human carcinogen. Manufacturers
    developed closed production methods to reduce exposure of the
    workforce.

         Annual total world production of VC, which is approximately equal
    to PVC production, was about 17 million tonnes in 1985 and over 26
    million tonnes in 1995 (see Table 3). More than half the world's
    capacity (64%) in 1985 was concentrated in Western Europe and the USA.
    Since that time many new VC/PVC plants have been opened or are under
    construction in SE Asia, Eastern Europe, the Indian subcontinent and
    developing and oil-producing countries. Thus there has been a
    geographical shift of VC/PVC production.

         The leading producers of PVC and therefore also of VC are the
    USA, Japan, Germany, France and SE Asian countries such as Taiwan and
    China (CHEM-FACTS, 1992). The capacity has only increased moderately
    in the USA and Western Europe in recent years. Significant increases
    in production have been reported for Japan and Taiwan. All the
    countries of Eastern Europe have PVC plants and have exported PVC to
    Western European countries. The PVC capacity and imports and exports
    for each country are given in CHEM-FACTS (1992).

         VC is produced in Western Europe by 14 companies. The plants are
    in Belgium (3 plants), France (3 plants), Germany (8 plants), Italy (4
    plants), the Netherlands (1 plant), Spain (2 plants), Sweden (2
    plants), United Kingdom (1 plant) (Euro Chlor, 1999).


        Table 3. World PVC (and therefore VC) production/capacity 1980-1998
                                                                                             

    Region                            Production/capacity in 1000 tonnes/year          

                                    1980a     1985a      1990a      1995b     1998c
                                                                                             

    World capacity                  16 000    17 000     20 700     26 400    approx. 27 000
    World production                11 750    14 200     18 300

    North America total             3200      3390       4700       6070
    Suspension and mass             2810      2990
    Vinyl acetate copolymer         200       210
    Emulsion                        190       190

    Western Europe total            3900      4330       4800       5750      approx. 5600
    Suspension and mass             33 350    3700
    Vinyl acetate copolymer         130       130
    Emulsion                        420       500

    Eastern Europe                  925       1100       1200       2700d
    Former Soviet Union             370       700        760

    China                           150       400        790
    Japan                           1400      1550       2070       8200e
    SE Asia                         330       600        900

    South America                   400       540        780
    Rest of the world               1075      1590       2300       3680
                                                                                             

    a  Allsopp & Vianello (1992)
    b  Rehm & Werner (1996)
    c  Although exact figures are not available, an increase in world production
       was seen in 1998 but no great increase in Western Europe (personal
       communication, European Council of Vinyl Manufacturers, 1999)
    d  Including former Soviet Republics
    e  Total Asia


         The manufacture of VC/PVC is one of the largest consumers of
    chlorine.

    3.2.1.1  Production of VC

         VC is produced industrially by two main reactions, the first is
    hydrochlorination of acetylene, which proceeds via the following
    reaction:

         C2H2 + HCl -> CH2=CHCl

    This route was used in the past when acetylene, produced via calcium
    carbide from coal, was one of the important basic feedstocks for the
    chemical industry (Rossberg et al., 1986). Today all USA and most
    Western European manufacturers use the "balanced process" described
    below. However, many Eastern European countries such as Poland and the
    countries of the former Soviet Union still use acetylene to
    manufacture VC because of relatively cheap raw materials such as
    calcium carbide and natural gas. Mercury has been used as a catalyst,
    although a new catalyst has now been developed in Russia, based on
    platinum metal salts instead of mercury, which has increased yields
    with acetylene conversion from 95 to 99% (Randall, 1994).

         The second major production process involves thermal cracking
    [reaction iii] (at about 500°C) of 1,2-dichloroethane (EDC), produced
    by direct chlorination [reaction i] of ethylene or oxychlorination
    [reaction ii] of ethylene in the "balanced process".

    [i]       CH2=CH2 + Cl2 -> Cl CH2-CH2 Cl

    [ii]      CH2=CH2 + 2 HCl + 5 O2 -> Cl CH2-CH2 Cl + H2O

    [iii]     Cl CH2-CH2 Cl -> CH2=CHCl + HCl

    After the cracking (pyrolysis), HCl and unconverted EDC are separated
    from VC by two steps of distillation and recycled. The VC is stored
    either under pressure at ambient temperature or refrigerated at
    approximately atmospheric pressure (European Council of Vinyl
    Manufacturers, 1994). More than 90% of the VC produced today is based
    on this route (Rossberg et al., 1986; Allsopp & Vianello, 1992).

         Other methods of industrial production include:

    a)   VC from crack gases, where unpurified acetylene and ethylene are
         chlorinated together, acetylene being first chlorinated to
         1,2-dichloroethane.

    b)   VC from ethane, which is readily available in some countries. The
         major drawback is that ethane must first be functionalized by
         substitution reactions giving rise to a variety of side chain
         reactions and therefore the reaction must be kinetically
         controlled to obtain maximal VC yield.

    3.2.1.2  Production of PVC from VC

         Many PVC plants are fully integrated beginning with ethylene and
    chlorine (or sodium chloride).

         VC is a gas at ambient temperatures but is handled as a
    compressed volatile liquid in all polymerization operations. PVC
    polymerization reactors are thick-walled jacketed steel vessels with a
    pressure rating of 1725 kPa. The polymerization of VC is strongly
    exothermic. The explosive limits of VC in air are 4-22 vol%, and the
    plant must be designed and operated with this in mind, particularly
    when handling unreacted VC in the recovery system (Allsopp & Vianello,
    1992).

         Three main processes are used for the commercial production of
    PVC: suspension (providing 80% of world production), emulsion (12%)
    and mass or bulk (8%). In Western Europe, the proportion of PVC
    produced by the different processes is: 80% suspension; 13% mass; 5%
    emulsion and 2% copolymers (Wrede, 1995).

         In the suspension (also called dispersion) process,
    polymerization takes place at 40-70°C (depending on the type of PVC
    being produced) in a reactor (autoclave) of 25-150 m3 capacity fitted
    with a jacket and/or condenser for heat removal, as the reaction is
    strongly exothermic. Precautions have to be taken in order to avoid
    explosive mixtures with air. Liquid VC under its autogenous vapour
    pressure is dispersed in water by vigorous stirring to form droplets
    of average diameter 30-40 µm. The polymerization takes place within
    these droplets and is started by addition of initiators dissolved in
    the monomer. Stabilizers are added to prevent the drops rejoining and
    to prevent the already polymerized PVC particles from agglomerating.
    The reaction conditions can be exactly controlled and the properties
    of the product, such as relative molecular mass, can be controlled
    exactly. Once polymerization has ended, the autoclave charge is
    emptied into degassing tanks, and the non-polymerized VC is degassed,
    compressed and stored for reuse (ECETOC, 1988; Allsopp & Vianello,
    1992).

         During the polymerization process, the PVC is dispersed in the
    aqueous phase and it cannot be prevented that a film of PVC forms on
    the inside wall of the reactor. This film interferes with the transfer
    of heat between the reactor and contents, and the process has to be
    interrupted periodically to allow the reactor to be cleaned. The
    autoclave, after being emptied, is opened, rinsed and washed either
    with solvents or more usually by means of automatic high-pressure jets
    (ECETOC, 1988). The latest development in this area is the use of
    proprietary build-up suppressants, which are applied before every PVC
    batch. After each batch, low pressure rinse with water can remove
    loose polymers and the batch cycle is ready to restart. The reactor
    needs then to be opened for a thorough cleaning only after 500 or more
    batches (Randall, 1994).

         Before awareness of the toxicity of VC, it was the autoclave
    cleaning personnel who were primarily highly exposed to the compound.
    In the past autoclaves were cleaned manually; the inside had to be
    scraped with a spatula, or sometimes hammer and chisel to remove the
    encrusted polymer adhering to the walls of the vessel and mixing
    devices. Lumps of polymer often released monomer when broken,
    resulting in high concentrations of VC in the autoclave. Before about
    1970, it was usual to check that the level was below 1036 mg/m3 (400
    ppm), i.e. two orders of magnitude below the lower explosion limit of
    VC. Occupational exposure limits are now 18 mg/m3 (7 ppm) or less
    (see Annex I). Further details of workplaces with a former high
    exposure to VC are given in section 5.3 and Jones (1981).

         Once polymerization has ended, the polymerization batch is
    transferred to the stripping unit and then to the slurry tank. The
    slurry is a suspension of PVC in water that has to be permanently
    stirred; it is then dewatered in a centrifuge decanter and dried. The
    resulting dried powder is either stored in silos or bagged. PVC is
    then further processed into ready-to-use resins (Depret & Bindelle,
    1998).

    3.2.1.3  PVC products

         PVC is a polymer of VC with 700-1500 monomeric units. It is
    relatively inexpensive and is used in a wide range of applications.
    PVC is a generic name. Each producer makes a range of PVC polymers,
    which vary in morphology and in molecular mass according to the
    intended use. PVC resins are rarely used alone but can be mixed with
    heat stabilizers, e.g., lead, zinc and tin compounds (Allsopp &
    Vianello, 1992), lubricants, plasticizers (e.g., diethylhexyl
    phthalate) fillers and other additives, all of which can
    influence its physical and mechanical properties (Williamson &
    Kavanagh, 1987; Allsopp & Vianello, 1992). Such additives may
    constitute up to 60% of the total weight in some finished PVC plastics
    (Froneberg et al., 1982). These plastics are formed into a multitude
    of consumer products by extrusion, thermoprocessing and rotational
    moulding, and into rigid or flexible film by extrusion or calendering.

         PVC accounts for 20% of plastic material usage and is used in
    most industrial sectors (ECETOC, 1988; European Council of Vinyl
    Manufacturers, 1994).

    *    Packaging

         *    bottles (produced by blow-moulding) for containing liquid
              foods, beverages, cooking oils, vinegar, etc.

         *    rigid film (calendered or extruded) which is converted into
              tubes and shaped containers by subsequent vacuum or
              pressure-forming for packaging of various foodstuffs

         *    flexible film (made by blowing or calendering) for wrapping
              solid foods such as cheese, meat, vegetables, fresh fruit,
              etc.

         *    coatings in metal cans

    *    Building - floor coverings, wall coverings, windows, roller
         shutters, piping; 58% of the water supply network and 80% of the
         waste water disposal systems in Europe use pipes and fittings
         made from PVC.

    *    Electrical appliances - wires and cables insulation

    *    Medical care - equipment such as blood bags and gloves;
         pharmaceutical and cosmetic packaging. Worldwide, more than 25%
         of all plastic-based medical devices used in hospitals are made
         from PVC (Hansen, 1991)

    *    Agriculture - piping; drainage; tubing in dairy industry

    *    Automobiles - car dash boards and lateral trimming

    *    Toys

         At present, the largest use of PVC is in the building sector
    (Rehm & Werner, 1996).

    3.2.2  Emissions from VC/PVC plants

    3.2.2.1  Sources of emission during the production of VC

         Process waste, by-products and unreacted material from a balanced
    process and from a PVC plant include (Randall, 1994): a) light/heavy
    ends from EDC purification (from direct chlorination and
    oxychlorination reactors); b) heavy ends from VC purification (from
    pyrolysis reactor); c) pyrolysis coke/tars (from thermal reactions in
    the pyrolysis reactor); d) spent catalyst (from direct chlorination,
    oxychlorination); e) recovery of unreacted VC (from PVC reactor); f)
    offspec batches (from PVC reactor); g) aqueous streams (from EDC
    washing, vent scrubbing, oxychlorination water; from centrifuge, VC
    stripping, slurry tanks); h) vent gases (from distillation columns,
    flash drums, reactor vents, storage tanks, vessel openings; from VC
    recovery systems, dryer stacks, centrifuge vent, blending, storage
    facilities); i) spills and leaks (sampling, pumps, flanges, pipes,
    loading/unloading, valves; bag filling, agitator seals); and j)
    equipment cleaning (tanks, towers, heat exchangers, piping; PVC
    reactor, product dryer, recovery system).

    a)  Strategies for minimizing emissions

         During the sixties, some control of exposure levels was
    introduced resulting in an important decrease of estimated ambient
    levels of VC.

         In the 1970s, efforts were focused on controlling emissions at
    the most significant emission points: reactors, filters and storage
    tanks. Elementary modifications of equipment, room and local
    ventilation by fans, provisional operation procedures, etc., enabled
    the reduction of exposure levels in working areas.

         Technical developments have achieved further reductions:

    *    removal of residual VC from the PVC suspension by stripping
         between polymerization and drying with a flow of steam or in
         closed-loop systems;

    *    appropriate collection of residual vents to thermal oxidizers or
         other abatement systems;

    *    reduction of all sources of fugitive emission by maintenance and
         upgraded equipment;

    *    high pressure internal cleaning of the autoclaves to remove PVC
         crusts;

    *    intensive removal of VC before opening or a closed process
         design.

         Appropriate working procedures, personnel awareness and high
    standard equipment, associated with good maintenance practices, are
    the recommended ways to reduce fugitive emission to very low levels
    (Depret & Bindelle, 1998).

    b)  Disposal of by-products

         The main waste streams of EDC/VC production process in Europe are
    light ends (gases: VC, EDC, HCl, ethylene, dioxins; aqueous effluents:
    EDC, copper, dioxins) and heavy ends (viscous tars). According to the
    PVC Information Council the total amount produced is approximately
    0.03 tonnes of by-products per tonne of VC produced (European Council
    of Vinyl Manufacturers, 1994). The fractions are either used as
    feedstocks for other processes or combusted under controlled
    conditions (> 900°C) or by catalytic oxidation to produce CO2, CO,
    HCl and water which can be recycled (see above). Exit gases should be
    treated using HCl absorbers and gas scrubbers. Spent catalyst, metal
    sludges and coke from EDC cracking should be disposed of in controlled
    hazardous waste dumps (HWD) or incinerated under controlled
    conditions. Sludges from effluent purification should be either
    combusted under controlled conditions or deposited in HWD (European
    Council of Vinyl Manufacturers, 1994).

    3.2.2.2  Emission of VC and dioxins from VC/PVC plants during
             production

    a)  VC

         An estimated 550 tonnes of VC was released into air, 451 kg to
    water and 1554 kg to soil from manufacturing and processing facilities
    in the USA in 1992, although this was not an exhaustive list (ATSDR,
    1997). From a VC capacity of 6 200 000 tonnes, an average emission of
    80 g/tonne can be calculated (Depret & Bindelle, 1998).

         Euro Chlor (1999) reported emissions of VC from suspension PVC
    plants in Europe to be 448 tonnes/year, 22 tonnes/year being released
    in waste water. An estimated emission value of 300 tonnes VC/year was
    provided by German producers (BUA, 1989), i.e., about 55 g VC/tonne
    PVC. Total VC emissions in England and Wales were reported to be
    3800 tonnes in 1993 and 18 990 tonnes in 1994 (HMIP, 1996).

         An estimated 200 000 tonnes of VC was released into the worldwide
    atmosphere during 1982 (based on a worldwide PVC production of
    17 million tonnes), i.e., 12 kg/tonne of PVC produced (Hartmans et
    al., 1985). In 1974, a VC emission of 0.5 kg/tonne PVC was estimated
    (Kopetz et al., 1986).

    b)  Dioxins

         PCDDs/PCDFs, some of which are classified as human carcinogens
    (IARC, 1997), are formed during EDC/VC production. Concentrations in
    VC distillation residues (PU4043) (probably "heavy ends") for two
    production factories were 3192 and 5602 ng ITEQ (international toxic
    equivalent)/kg, which was estimated to be 12 to 30 g of dioxin/year at
    a production level of 200 000 tonnes VC/year in heavy ends (Stringer
    et al., 1995). However, the VC/PVC industry argues that, although
    dioxins may be found in production wastes, these are incinerated and
    are not ultimately emitted to the environment (Fairley, 1997), at
    least in those countries where waste streams are regulated (not all
    countries possess such high standards of waste incineration). Some
    companies do not incinerate their waste products but dispose of them
    in other ways, e.g., deep-well injection (Stringer et al., 1995).

         Wastewater from VC production can also be contaminated with
    PCDDs/PCDFs, in particular if they contain suspended solids.
    Installation of filtration devices should lower solid levels and
    subsequently PCDD/PCDF emissions (Stringer et al., 1995). Using such
    filtration devices, PCDD/PCDF concentrations in wastewater from
    EDC/VC/PVC facilities in the USA ranged from not detectable to 6.7
    pg/litre TEQ (Carroll et al., 1996).

         Annual global emission of dioxins into the environment from
    EDC/VC manufacture has been estimated to be 0.002-0.09 kg TEQ by the
    European PVC industry but 1.8 kg by Greenpeace (Miller, 1993).

         Virgin suspension PVC resin from 11 major production sites in
    Europe was found not to contain any process-generated PCDDs/PCDFs at
    concentrations above the limits of quantification (2 ppt) (Wagenaar et
    al., 1998).

    3.2.3  Accidental releases of VC

    3.2.3.1  PVC plant and transport accidents

         An explosion occurred at a VC recovery plant in 1978 in Germany,
    which was set off by vinyl chloride peroxides (Terwiesch, 1982; see
    also section 2.2).

         A freight train with 12 tank cars of VC was derailed in McGregor,
    Manitoba, Canada in March, 1980 under near-blizzard conditions and
    -20°C and two of the tanks released VC (Charlton et al., 1983). One
    car lost 47 500 litres in the first hour and the other car lost
    23 100 litres at an initial rate of 1400 litres/hour, decreasing to
    45 litres/hour after 31 h. In the first 15 min, 5680 litres of VC
    vapourized by free surface evaporation; thereafter only 2.5% of the
    discharging liquid evaporated rapidly. The remaining liquid in the
    snow bank was assumed to have evaporated at a rate of 15% per hour,
    leaving about 900 litres of VC in the snow bank after 36 h. Although
    there was an explosion hazard, no fire occurred.

         Two incidences, in 1988 and 1996, occurred in Germany involving
    accidental release of VC due to derailment of trains transporting the
    liquid substance (Neuhoff, 1988; Anon, 1996). Both accidents were
    followed by explosion and fire. Derailment of a goods train occurred
    1 km from Schönebeck (near Magdeburg in Germany) and the subsequent
    explosion and fire produced a 600- to 800-m black column of smoke. In
    all, 1044 tonnes of VC were involved of which 261 tonnes burnt and
    350 tonnes could be reclaimed after the fire; 153 tonnes of HCl were
    released. Median measurements of the numerous air samples taken at the
    place of accident or surroundings did not exceed the German technical
    guidance level of 5 vol ppm, although these were not taken until 14 h
    after the fire. Maximum concentrations of VC measured were 78 mg/m3
    (30 ppm) near the train and 26 mg/m3 (10 ppm) at a distance of 200 m
    from the centre of the fire (Hahn et al., 1998). Levels in nearby
    industrial sewage pipes were up to 1250 ppm (Anon, 1996). A cytogenic
    analysis was carried out on some of the general population exposed to
    VC from this accident (Hüttner & Nikolova, 1998; see section 8.1 and
    Table 42).

    3.2.3.2  Leakage and discharge from VC/PVC plants

         Leakage from a waste liquor basin of a VC/PVC plant in Finland
    caused high concentrations of VC and dichloroethene in groundwater in
    1974. Concentrations of up to 484 mg/litre of the chlorocarbons were
    measured in groundwater in the mid-1980s (Nystén, 1988).

         It should be noted that in the 1960s and before, when the
    toxicity of VC was not known, large amounts of PVC production sludges
    containing VC were dumped onto landfills (and possibly still are in
    countries where there are no adequate restrictions).

    3.2.4  VC residues in virgin PVC resin and products

    3.2.4.1  VC residues in different PVC samples

         VC is not soluble in PVC nor is it absorbed or adsorbed in the
    resin particle. It is entrapped and can escape to the ambient air
    (Wheeler, 1981). PVC in a bulk-container loses its residual monomer at
    a rate of 25 to 50% per month. Heating tends to accelerate this step,
    but when the residual monomer has disappeared PVC is not a significant
    source of VC.

         Since the 1970s when VC was confirmed as a human carcinogen, it
    has been mandatory in many countries to "degas" PVC after
    polymerization (see section 3.3.1) and before further processing.
    There are limit values for VC content in PVC (see Annex I). For
    example, in 1974 raw PVC usually contained more than 1000 ppm of
    residual VC. This was subsequently reduced to 10 ppm by regulation
    (German Environmental Office, 1978). In a survey of 45 samples of raw
    PVC from various countries carried out in 1976-1977, over a third had
    VC residues of > 1 ppm, but a third had residues of over 50 ppm, with
    4 samples over 200 ppm. The samples with the highest residue level
    came from Hungary, Rumania, Italy and the USA (German Environmental
    Office, 1978).

    3.2.4.2  VC residues in PVC products

         In a survey of PVC products carried out in 1976-1977, the
    following indoor articles had a VC content of > 0.05 ppm: bathroom
    tiles, piping, plastic bottle for table oil, and kitchen film. The
    highest concentrations were found in music records, those bought
    recently having a VC content of up to 210 ppm and one record 10 years
    old having a content of 970 ppm. In record shops and other rooms
    containing many records, this could have been an important source of
    VC. In contrast, the VC content of toys, kitchen utensils, food
    wrappings, wallpaper and car interiors was < 0.05 ppm (German
    Environmental Office, 1978).

         Whereas in 1974 the typical level of residual VC in PVC bottles
    was 50 mg/kg, introduction of improved manufacturing practices at the
    polymer resin processing stage reduced this to 3 mg/kg by 1975. In a
    1978 survey, 22 out of 24 PVC bottles contained VC at less than
    0.4 mg/kg (UK MAFF, 1978).

         In a more recent survey, VC residues in various PVC samples were
    given as follows: rigid water bottle (850 ppb); thin plasticized food
    film (3 ppb); monopolymer powder (10 ppb); copolymer film (15 ppb)

    (Poy et al., 1987). PVC film is still used widely for food packaging.
    For example, in Denmark, in 1990, 129/239 samples of cling-film used
    for cheese wrapping were of PVC (Svensson, 1994).

         Residual VC could not be detected (< 0.1 ppm) in two PVC
    products from Thailand (Smerasta et al., 1991) or in PVC and products
    from it in Poland (Stareczek, 1988). PVC medical devices are regulated
    in the USA and have to meet certain requirements (a maximum of 5 ppb
    residual monomer for flexible compounds and a 10 ppb ceiling for rigid
    compounds (Rakus et al., 1991)).

         Levels of VC found in food and pharmaceutical articles are given
    in section 5.1.4. Annex I gives current regulations for VC content in
    various PVC products.

    3.2.4.3  VC formation as a result of heating PVC

    a)  Thermal degradation of PVC

         PVC is thermally stable below 225°C. Between 225°C and its
    ignition temperature of 475°C, thermal degradation results in the
    release of about 50 compounds (Boettner et al. 1969). PVC does not
    degrade back to VC. Thermal degradation of two types of bulk PVC
    samples at 148-232°C resulted in the release of long-chain aliphatic
    alcohols, toluene, benzene, various chlorinated species, and a major
    peak of HCl. The main components released at 260°C-315°C were aromatic
    hydrocarbons such as benzene, phenol and adipates, along with various
    aliphatic alcohols, alkenes, anhydrides, some of them chlorinated, and
    carbon monoxide (Froneberg et al., 1982). When 1 kg of PVC is heated
    to 300°C, it releases about 13 g HCl and 5 g CO.

    b)  Release of VC from heating PVC

         Various PVC resins from different producers were tested for VC
    evolution over the 130 to 500°C range using a heating rate of
    10°C/min. A consistently low level of VC, amounting to 15-30 ppm
    (based on resin), was found in the volatile decomposition products
    from all of the samples tested, regardless of resin type or
    manufacturing source (USA) (Wakeman & Johnson, 1978). A 100-mg sample
    was programmed for heating from 200 to 450°C at 3°C/min; this resulted
    in the formation of a total of 23.2 ppm VC, the major portion being
    generated in the 275-350°C region. Dehydrochlorination occurred most
    rapidly between 250 and 275°C. During this period only 2.3 ppm of VC
    was formed. The VC evolved by heating PVC is the VC monomer entrapped
    in the PVC resin.

         At temperatures required for thermoforming PVC for food packaging
    applications (90-120°C for a few seconds), no detectable VC was formed
    in up to 1 h of exposure at 130°C (detection limit of analysis in air
    - 1 ppb). Temperatures for calendering and extrusion operations are
    175-210°C. Maximum VC levels determined at 210°C were 0.5 ppm (resin
    basis) after 5 min and 1.2 ppm after 30 min (Wakeman & Johnson, 1978).

         In more recent studies into VC formation during the thermal
    welding of plasticized PVC sheeting (about 225°C), in normal field
    situations such as piping in sewers, VC concentrations were usually
    not above the detection limit of 0.05 ppm. Only where there was poor
    ventilation were higher levels detected (0.2 ppm VC; 1.0-3.5 ppm HCl)
    (Williamson & Kavanagh, 1987).

    3.2.5  Other sources of VC

    3.2.5.1  VC as a degradation product of chlorinated hydrocarbons

         VC as a gas, in leachate and groundwater (see Table 4), has been
    found in landfills and surroundings where there were no VC/PVC
    production facilities in the vicinity. It was found that VC can be
    formed, under anaerobic conditions, from the reductive halogenation of
    the more highly chlorinated chloroethenes: tetrachloroethylene (PCE),
    trichloroethene (TCE), and the dichloroethene isomers ( cis-1,2-DCE,
     trans-1,2-DCE, and 1,1-DCE) (Parsons et al., 1984; Vogel & McCarty,
    1985; McCarty, 1996, 1997, see Fig. 1). PCE and TCE are widely used as
    industrial solvents in particular for degreasing and cleaning metal
    parts and electronic components, and in dry cleaning. Production
    levels for 1984 were 260 and 200 thousand tonnes for PCE and TCE,
    respectively (Wolf et al., 1987). Careless handling, storage and
    disposal, as well as the high chemical stability of these compounds,
    have made them, and consequently VC, some of the most frequently
    encountered groundwater contaminants (Arneth et al., 1988). Although
    VC may be further degraded to less chlorinated and non-chlorinated
    ethenes, and possibly finally to carbon dioxide and ethane, this
    proceeds only at a slow rate under highly reducing conditions
    (Freedman & Gossett, 1989; DiStefano et al., 1991; De Bruin et al.,
    1992; see also section 4.2). As a consequence, VC can be detected in
    landfill sites in and surrounding areas through spreading. Reports
    from several countries show high levels of VC contamination of soil
    and groundwater, aquifers and wells (see Table 4 and section 5.1).

         There have recently been several field studies in
    PCE/TCE-contaminated landfill sites and aquifers (Major et al., 1991,
    1995; Fiorenza et al., 1994; Lee et al., 1995, see Table 5). These
    have shown that under anaerobic conditions, PCE and TCE can be
    intrinsically biodegraded to ethene by indigenous methanogenic,
    acetogenic and sulfate-reducing bacteria. Furthermore, under aerobic
    conditions there is a potential for direct or co-metabolic oxidation
    of DCE and VC. Therefore, an efficient bioremediation of chlorinated
    ethene-contaminated aquifers may occur in contaminant plumes
    characterized by upgradient anaerobic and downgradient aerobic zones,
    such as where anaerobic, chlorinated ethene plumes discharge to
    aerobic surface water bodies. However, this depends on the ability of
    the stream-bed microbial community to degrade efficiently and
    completely DCE and VC over a range of contaminant concentrations (Cox
    et al., 1995; Bradley & Chapelle, 1998a). It should be noted that this
    bioremediation occurs under specific conditions. The biodegradation
    studies listed in chapter 4 give conflicting results.

    FIGURE 1



        Table 4.  Vinyl chloride found in landfill/waste disposal sites as a gas, in leachate and in groundwater
    formed probably from degradation of higher chloroethenes
                                                                                                                         

    Sample           Place (year) of sampling               Valuea         Concentrations        Reference
                                                                                                                         

    Landfill gas     2 landfills USA                        max            230 mg/m3             Lipsky & Jacot (1985)
                                                            average        34 mg/m3
    Landfill gas     landfill, UK                           max            11 mg/m3              Ward et al. (1996)
                     plume, 100 m from boundary                            40 mg/m3
                     due to subsurface migration (1991)

    Landfill gas     landfill, Braunschweig, Germany        mean           9 mg/m3               Henning & Richter (1985)

    Gas effluents    garbage dump, Berlin, Germany                         0.27 mg/m3            Höfler et al. (1986)

    Gas              Germany,                               average                              Janson (1989)
                     industrial waste disposal site                        41 mg/m3
                     municipal waste disposal site                         10 mg/m3

    Gas              Germany, waste disposal site           range          0.03-0.3 mg/m3        Bruckmann & Mülder (1982)

    Landfill gas     UK, 7 waste disposal sites             range          < 0.1-87 mg/m3        Allen et al. (1997)
    Soil air         Germany, solvent waste sites           3 max out      128 mg/m3,            Köster (1989)
                                                            of 200         47 mg/m3,
                                                                           5 mg/m3

    Leachate         MSW, Wisconsin, USA (1982)             range          61 µg/litre           Sabel & Clark (1984)
    Leachate         USA sites established before 1980      range          8-61 µg/litre         Chilton & Chilton (1992)
                     (6 chosen sites)
    Leachate or      industrial landfill                    range          140-32 500,           Brown & Donnelly (1988)
    groundwater      municipal landfill                                    20-61 000
    plume                                                                  µg/litre

    Groundwater,     Germany, contaminated water            range          < 5-460 µg/litre      Brauch et al. (1987)
    Wells                                                   range          15-1000 µg/litre
    Groundwater      Germany, solvent waste site            3 max          1000 µg/litre,        Köster (1989)
                                                            samples/200    500 µg/litre,
                                                                           200 µg/litre

    Table 4. (cont'd)
                                                                                                                         

    Sample           Place (year) of sampling               Valuea         Concentrations        Reference
                                                                                                                         

    Groundwater      Germany                                max            120 µg/litre          Milde et al. (1988)
    Groundwater      Santa Clara Valley, USA (near          range          50-500 µg/litre       Wolf et al. (1987)
                     plants manufacturing electronic
                     equipment which use
                     significant amounts of
                     chlorinated solvents)

    Groundwater      Germany: 136 samples from              max            12 000 µg/litre       Dieter & Kerndorff (1993)
                     down-gradient wells of 100 waste       mean           1694 µg/litre
                     disposal sites

    Groundwater      sand aquifer near industrial           max            > 5 µg/litre          Semprini et al. (1995)
                     site, Michigan, USA. Concentration                    at 10 m;
                     increased with depth consistent                       56 400 µg/litre
                     with methane                                          at 23 m

    Outwash aquifer  Gloucester landfill, Canada (1988)     range          < 1-40 µg/litre       Lesage et al. (1990)
                                                                                                                         

    a  This column indicates whether the concentration is a maximum (max), average or range value


         Each landfill site has individual conditions (e.g., presence of
    other solvents such as acetone and methanol), so that the degradation
    rates cannot be directly compared. The most extensively studied site
    of intrinsic chlorinated solvent biodegradation is the St Joseph
    (Michigan, USA) Superfund site where groundwater concentrations of TCE
    as high as 100 mg/litre have been found, with extensive transformation
    to  cis-DCE, VC and ethene. Conversion of TCE to ethene was most
    complete where methane production was highest and where removal of
    nitrate and sulfate by reduction was most complete (McCarty, 1996;
    Weaver et al., 1996). At another site in the USA (Dover Air Force
    Base), half-lives of 1 to 2 years have been estimated for each stage
    in the reaction chain (e.g., DCE to VC; VC to ethene) (Ellis et al.,
    1996). The degradability of chlorinated aliphatic compounds was
    studied under methanogenic conditions in batch reactors with leachate
    from eight landfill sites in Denmark. PCE and TCE were found to be
    degraded in only three of the eight leachates, with significantly
    different conversion rates. In one leachate, complete conversion of
    chlorinated ethenes, including conversion of VC, was observed within
    40 days, while another leachate showed only 50% conversion of PCE
    (Kromann et al., 1998).

         No known microorganism can aerobically destroy PCE. Laboratory
    studies have shown that some anaerobic bacteria (e.g.,  Dehalobacter
     restrictus ) use chlorinated solvents for respiration
    (halorespiration), breaking them down in the process to form
     cis-dichloroethene, although restricted diet conditions are
    necessary (Sharma & McCarty, 1996). Recently, a coccoid bacterium has
    been isolated (provisionally named  Dehalococcoides ethenogenes
    strain 195) which, together with extracts from mixed microbial
    cultures, can dechlorinate PCE, removing further chlorine atoms to
    form vinyl chloride and finally ethene (Maymó-Gatell et al., 1997).

         Escape of landfill gas from the disposal site can take place via
    the surface (emission) or into the ambient soil (migration). VC is
    emitted from the landfill surface into the ambient air (Wittsiepe et
    al., 1996). Awareness of this problem has encouraged the development
    of  in situ bioremediation of chlorinated solvents and VC using
    anaerobic or aerobic co-metabolic processes (Dolan & McCarty, 1995b;
    Jain & Criddle, 1995; Semprini, 1995; see section 4.2).

         The estimated emission of vinyl chloride from landfill sites in
    the USA is 60-33 000 tonnes/annum (Lahl et al., 1991).

    3.2.5.2  VC formation from tobacco

         VC was identified in the smoke of all 13 cigarettes tested
    (1.3-16 ng/cigarette) and in both small cigars tested (14-27
    ng/cigar). The level correlates directly with the chloride content of
    the tobacco. Filter tips with charcoal reduce selectively the VC
    content of cigarette smoke (Hoffmann et al., 1976).



        Table 5.  Some examples of formation of VC through biodegradation of tetrachloroethene
    in landfill sites (concentrations in mg/litre unless stated otherwise)a
                                                                                                                                

    Site                Sample               PCE         TCE          cis-DCE      VC             Ethene     Reference
                                                                                                                                

    Chemical transfer   groundwater          4.4         1.7          5.8          0.22           0.01       Major et al.
    factory facility,   downgradient well    n.d.        none         76           9.7            0.42       (1991)
    North Toronto,
    Canada

    Carpet backing      groundwater          n.d.                     56           4.2            0.076      Fiorenza et al.
    manufacturing       downgradient from    n.d.                     4.5          5.2            low        (1994)
    plant, Ontario,     lagoon
    Canada

    Refuse landfills                         7.15        5.09         not          5.6                       McCarty &
    (average of 8)                           (ppmv)      (ppmv)       measured     (ppmv)                    Reinhard (1993)

    Landfill            groundwater          0.54        2.6          2.2          2.7            33         Lee et al. (1995)
                        well                 3.4         14           44           54             43
                                             15          270          140          48             14

    Heavily polluted    groundwater          20          70           20           2                         Middeldorp et
    site (solvent                                                                                            al. (1998)
    distributor) in
    Netherlands
                                                                                                                                

    a  PCE = tetrachloroethene; TCE = trichloroethene; DCE = dichloroethene; n.d. = not detected


    3.3  Uses

         About 95% of the world production of VC is used for the
    production of PVC. The remainder is used for the production of
    chlorinated solvents, primarily 1,1,1-trichloroethane (10 000 tonnes
    per year; European Council of Vinyl Manufacturers, 1994), via the more
    toxic 1,1,2-trichloroethane and 1,1-dichloroethane.

         VC was previously used as a refrigerant (Danziger, 1960) and as a
    propellant in aerosol sprays for a variety of products, such as
    pesticides, drugs and cosmetics (Wolf et al., 1987). These uses have
    been banned since 1974 in the USA and in other countries.
    

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         Depending on the sources, VC can enter the environment via air,
    water or soil. The most critical matrices are probably air and
    groundwater. Euro Chlor (1999) calculated the partitioning of VC into
    environmental compartments, based upon the Mackay Level 1 model, to be
    99.99% air, 0.01% water, < 0.01% soil and < 0.01% sediment.

    4.1.1  Air

         Owing to its high vapour pressure (saturation vapour pressure
    P0 > 10-4 mmHg; see also section 2), VC released to the
    atmosphere is expected, based on calculations of Eisenreich et al.
    (1981), to exist almost entirely in the vapour phase. The atmospheric
    life-time of VC is limited by its reaction with photochemically
    produced OH radicals (see section 4.2.2).

         VC is volatilized to the atmosphere from area sources such as
    landfill sites. Models have been developed to predict such short-range
    dispersion. These models were validated by VC concentrations ranging
    from < 5 to 31 µg/m3 (< 2 to 12 ppb) measured in the vicinity of a
    landfill in Los Angeles 3 years after it last received any waste
    containing VC (Chitgopekar et al., 1990).

         No data are available on wet deposition.

         In order to model distribution processes, liquid : air partition
    coefficients have been determined (Gargas et al., 1989). Coefficients
    of 0.43 and of 24.4 were obtained for 0.9% saline : air and for olive
    oil : air, respectively.

    4.1.2  Water and sediments

         VC has a relatively low solubility in water (see section 2), and
    the solubility can be increased by the presence of salts (see section
    4.2.3).

         Experimental data on adsorption to particulate matter in the
    water column or to sediment are not available. A partition constant
    (unitless) of 8.2 for a sediment-water system was calculated (from a
    Kow value of 17) by Mabey et al. (1982), indicating a low adsorption
    capacity. A high input of VC into water may lead to low-level
    long-term storage in the associated sediment (Hill et al., 1976b).

         Volatilization of VC acts as a significant transport mechanism.
    It is considered to be the most rapid route for removal of VC from
    surface water, but to be an unlikely pathway for disappearance from
    groundwater that is not directly exposed to air (Smith & Dragun,
    1984). Volatilization parameters such as vapour pressure and Henry's
    Law constants indicate that VC is highly volatile. Another factor, the
    reaeration rate ratio (rate constant for loss of VC from aqueous

    solution divided by the rate constant for oxygen uptake by the same
    solution), was reported to be 0.675 at 25°C (theoretical calculation
    by Mabey et al., 1982) and approximately 2 (experimental measurement
    by Hill et al., 1976b). The results of measurements or calculations of
    volatilization half-lives of VC from water bodies are given in Table
    6; they range from < 1 h to 5 h (measured in models for disturbed or
    quiescent water) and from 2.5 to 43 h (calculated for natural water
    bodies). In groundwater, however, VC may remain for months or years
    (ATSDR, 1990).

         More or less complex models have been developed to describe the
    stability of VC in aquatic ecosystems (Hill et al., 1976b; Miller,
    1992).

    4.1.3  Soil and sewage sludge

         Owing to its high vapour pressure, VC can be expected to
    volatilize rapidly, especially from dry soil surfaces. No experimental
    data are available. However, volatilization of VC from soil can be
    predicted based upon its physicochemical properties. The amount of VC
    volatilized from a soil depth of 1 m in 1 year was reported to range
    from 16 to 45% in a sandy soil and 0.1 to 0.7% in a clay soil. These
    calculations were based upon a Henry's Law constant of 0.44 and a
    degradation half-life of between 30 and 180 days (Jury et al., 1992).

         It has been observed at landfill sites that subsurface migration
    of VC is a significant transport mechanism (Hodgson et al., 1992;
    Little et al., 1992; Ward et al., 1996). Quantitative experimental
    data on the potential of VC for gaseous subsurface migration (see
    section 5.1.1) were not found.

         Because of its solubility in water, VC can be leached through the
    soil to groundwater. Additionally, the high solubility of VC in many
    organic solvents may increase its mobility at special locations, e.g.,
    landfills or waste disposal sites. Standard experimental studies on
    soil sorption of VC are lacking. The soil adsorption coefficients of
    VC were estimated from its water solubility, octanol/water partition
    coefficient and from the molecular topology and quantitative
    structure-activity relationship analysis method according to equations
    given by Chiou et al. (1979), Kenaga & Goring (1980), Lyman et al.
    (1982, 1990) and Sabljic (1984). The Koc values obtained ranged from
    14 to 240, indicating a low adsorption tendency and therefore a high
    mobility of VC introduced into soil (US EPA , 1985a; Stephens et al.,
    1986; ATSDR, 1997).

         A field study performed to determine non-extractable (bound)
    residues (NER) of highly volatile chlorinated hydrocarbons gave a low
    value of 2.4% for VC, as measured in a lysimeter after one growth
    period in the upper (10 cm) soil layer (Klein et al., 1989).

         VC was assumed not to appear frequently in sewage sludge due to
    its low adsorption potential (log Kow < 2.0) and its high
    volatilization tendency (Wild & Jones, 1992).


        Table 6.  Half-lives reported for volatilization of VC from water
                                                                                                                        

    Source               Method          Conditions                          Half-life          Reference
                                                                                                                        

    Dilute aqueous       experimental    22-25°C,                                               Dilling et al. (1975);
    solution (200 ml)    (laboratory)    rapid continuous                    25.8 min           Dilling (1977);
    stored in an                         stirring
    open container                       continuous stirring (200 rpm)       26-27.6 min        Callahan et al. (1979)
                                         discontinuous stirring              approx. 80-90
                                         (5% of time)                        min
                                         quiescent, no stirring              290 min

    Flowing channel      experimental    water input: 35 litre/second        0.9 h              Scherb (1978)
                         (field)         flow velocity: < 0.50 m/second
                                         depth: 30 cm

    Stream               calculation     based on Hc = 243 kPa.m3/mol        2.5 h              Lyman et al. (1990)
                                         depth: 1 m
                                         flow velocity: 1 m/second
                                         wind current: 3 m/second

                         calculation     based on reaeration rate ratio of                      US EPA (1985a)
                                         2; assumed oxygen reaeration ratesa:
    Pond                                 0.008 h-1                           43.3 h
    River                                0.04 h-1                            8.7 h
    Lake                                 0.01 h-1                            34.7 h
                                                                                                                        

    a  According to Tsivoglou (1967); Lyman et al. (1990)


    4.1.4  Biota

         VC has been identified in environmental samples of fish tissue
    (see section 5.1.5) and in several species of aquatic laboratory
    animals (molluscs, crustaceans, insects and vertebrates) and algae
    experimentally exposed to VC-containing water (see section 4.3).
    Reports on the presence of VC in terrestrial plants and animals have
    not been found in the literature.

         Further experimental data, e.g., in what way and to what extent
    VC is capable of entering the biota, are lacking. However, a few
    estimations have been made on the basis of the physicochemical
    properties of VC. They refer to uptake of VC by terrestrial plants and
    animals. Plant uptake was considered to be unlikely (Ryan et al.,
    1988; Shimp et al., 1993) because, at an assumed half-life of
    < 10 days (Ryan et al., 1988), VC should be lost from the system
    rather than be taken up by the plant. Another study (Wild & Jones,
    1992) screened organic contaminants for possible transfers into plants
    and animals by summarizing approach data. Within the three categories
    used (high, moderate, low potential) VC was classified in the
    following way:

    *    retention by root surface: low;
    *    uptake and translocation: moderate;
    *    foliar uptake: high;
    *    transfer to animal tissues by soil ingestion: low;
    *    transfer to animal tissues by foliage ingestion: moderate.

    4.2  Transformation

    4.2.1  Microbial degradation

         There have been many studies on the biodegradation of VC under
    various simulated environmental conditions and these are listed in
    Tables 8 to 10. The biodegradation studies have given contradictory
    results, with no evidence of degradation under some aerobic conditions
    such as surface water (Hill et al., 1976b) and sewage (Helfgott et
    al., 1977) and under anaerobic conditions such as groundwater
    (Barrio-Lage et al., 1990). Unacclimated biodegradation half-lives of
    VC were generally estimated to be of the order of several months or
    years (Howard et al., 1991). However, other studies reported complete
    degradation in 3 months in simulated aerobic groundwater (Davis &
    Carpenter, 1990). Where degradation is reported care must be taken to
    ensure that the loss of VC is due to degradation and not from other
    losses such as volatilization from the test system. Phelps et al.
    (1991b) reported that > 99% of VC was lost from a bioactive reactor
    compared to 60% from the control reactor.

         Significant microbial degradation of VC under aerobic and
    anaerobic conditions has been detected in studies using enrichment or
    pure cultures isolated mostly from sites contaminated with different
    organic chemicals (Tables 8 to 10). Vinyl chloride cannot be used by
    most microorganisms as sole carbon source, but it can be

    degraded/metabolized in the presence of propane, methanol,
    3-chloropropanol, propylene, isopropene and glucose. However, in some
    cases VC can even serve as sole substrate, as is seen with
     Mycobacterium sp. (Table 9). The main degradation products include
    glycolic acid or CO2 after aerobic conversion (Tables 7 to 9) and
    ethane, ethene, methane or chloromethane after anaerobic
    transformation (Table 10). Anaerobic mineralization of VC to CO2 has
    been demonstrated (Table 10) and may occur under special conditions
    (Bradley & Chapelle, 1998b).

         A complete mass balance was given by degradation studies with
    radiolabelled VC, for example, in aerobic resting cell suspensions of
     Rhodococcus sp. A starting concentration of 1 mg [1,2-14C] VC
    produced more than 66% 14CO2 and 20% 14C aqueous phase products, and
    10% was incorporated into the biomass (Malachowsky et al., 1994).
    Aerobic cultures of  Mycobacterium aurum growing on a special filter
    material were reported to mineralize VC quantitatively according to
    the following equation:

       VC + microorganisms -> biomass + HCl + CO2 + H2O (Meier, 1994).

         The underlying reaction mechanisms for the aerobic and anaerobic
    degradation of VC have been postulated to be oxidative and reductive
    dehalogenations, respectively, involving a variety of pathways (Vogel
    et al., 1987; Barrio-Lage et al., 1990; Ensley, 1991; Castro et al.,
    1992a; Leisinger, 1992; Castro, 1993; Meier, 1994; Hartmans, 1995;
    Jain & Criddle, 1995).

         Frequently, the degradation reaction of VC proceeds more readily
    with aerobes than with anaerobes (Tables 7 to 10). The reverse occurs
    (Freedman & Gossett, 1989; Semprini et al., 1995) with PCE, an
    important precursor of VC in the environment (see chapter 3). Thus,
    two-stage treatment systems consisting of anaerobic (first stage) and
    aerobic (second stage) cultures have been proposed to achieve the
    complete degradation of a range of alkenes having different degrees of
    chlorination (Leisinger, 1992; Murray & Richardson, 1993; Nelson &
    Jewell, 1993). Recently, a chlorobenzoate-enriched biofilm reactor
    using  Desulfomonile tiedjei DCB-1 was developed which degraded PCE
    under anaerobic conditions without any detectable VC remaining
    (Fathepure & Tiedje, 1994).

         There have been many efforts to use the VC-degrading capacities
    of microorganisms in practical applications such as the purification
    of waste gases (Meier, 1994) or of municipal waste waters (Narayanan
    et al., 1995) and the remediation of landfill leachates (Lesage et
    al., 1993), groundwaters (McCarty, 1993; Holliger, 1995) and
    contaminated soils (Schulz-Berendt, 1993). Possible limitations arise
    from physical (temperature, accessibility of substrate), chemical (pH,
    redox state, concentration of VC and other contaminants, presence of
    additional secondary substrates, salinity) and biological (presence of
    predators, competition phenomena, adsorption of microbes to surfaces)
    factors (Van der Meer et al., 1992).


        Table 7.  Aerobic degradation of vinyl chloride by mixed microbial consortia from different sites
                                                                                                                                     

    Inoculum             Test design/        Measured   Initial             Duration     Efficiency of         Reference
                         conditionsa         parameter  concentration                    degradation
                                                                                                                                     

    Surface water        room                VC         20 ml/2.9 ml        41 h         no degradation        Hill et al. (1976b)
    samples              temperature

    Mixed consortium     21°C;               VC         20-120 mg/litre     several      no degradaion         Hill et al. (1976b)
    from natural         + / - nutrients                                    weeks
    aquatic systems

    Mixed consortium     20°C                oxygen                         25 days      no degradation        Helfgott et al.
    from domestic        + nutrients         demand                                                            (1977)
    sewage

    Mixed consortium     25°C;               14CO2      0.05 mg/litre       5 days       21.5% degradation     Freitag et al.
    from activated       + nutrients                                                                           (1982, 1985)
    municipal sewage
    sludge

    Naturally            simulated           14CO2,     1 mg/kg             108 days     > 99% degradation     Davis &
    occurring            aquifers:           VC         soil-water                       65% mineralization    Carpenter
    consortium from      soil-water                                                      (CO2)                 (1990)
    groundwater          microcosms                     0.1 mg/kg           109 days     50% mineralization
                         (prepared with                 soil-water                       (CO2)
                         sub-surface soil
                         and groundwater
                         (20°C)

    Consortium           aquifer sediment    14CO2,     17 µmol/litre       84 h         22-39%                Bradley &
    indigenous to        microcosms          VC                                          mineralization        Chapelle (1996)
    anaerobic aquifer                                                                    (CO2)
    systems
    (contaminated
    with CHs)

    Table 7. (cont'd)
                                                                                                                                     

    Inoculum             Test design/        Measured   Initial             Duration     Efficiency of         Reference
                         conditionsa         parameter  concentration                    degradation
                                                                                                                                     

    Consortium           creek bed sediment  14CO2,     0.2-57 µmol/litre   24 h         6.2-58%               Bradley &
    indigenous to        microcosms          VC                                          mineralization        Chapelle (1998a)
    creek sediment                                                                       (CO2)
    (contaminated
    with DCE)

    Consortium from      soil microcosms     VC         5.3 mg/litre        95 h         little change         Dolan & McCarty
    aquifer material                                                                     in VC                 (1995a)
    (from a                                                                              concentration
    VC-contaminated
    site)
                                                                                                                                     

    a  CH = chlorinated hydrocarbons; DCE = dichloroethene

    Table 8.  Elimination of vinyl chloride in aerobic tests with mixed microbial consortia utilizing special substratesa
                                                                                                                                     

    Inoculum         Additional   Test             Efficiency of             Remarks                     Reference
                     substrate                     degradation
                                                                                                                                     

    Mixed            methane      laboratory       removal of up             inhibition by               Fogel et al. (1986,
    methanotrophs                 studies          to 100% within            methane and 1,1-DCE         1987); Strandberg et al.
                                                   4 h-30 days               possible; toxic             (1989); Uchiyama et al.
                                                                             effects of VC and VC        (1989); Nelson & Jewell
                                                                             products possible           (1993); Dolan & McCarty
                                                                                                         (1995a); Chang & Alvarez-Cohen
                                                                                                         (1996)

                     methane      field study      about 95%                 inhibition by               Semprini et al. (1990, 1991)
                                  (groundwater)    in-situ                   methane possible
                                                   transformation
                                                   i.c. =
                                                   0.03 mg/litre

    Mixed            propane      laboratory       > 99% loss after          > 60% loss in               Phelps et al. (1991b);
    microbial                     study            30 days                   control                     Lackey et al. (1994)
    consortia                                      i.c. =
                                                   4-20 mg/litre

                     methane      laboratory       82 to > 99%                                           Phelps et al. (1991b);
                     plus         study            loss after 10-21                                      Lackey et al. (1994)
                     propane                       days; i.c. =
                                                   1-20 mg/litre

    Mixed            methane      laboratory       2.3 µmol VC per           relative TCs from           Dolan & McCarty (1995a)
    methanotrophs    plus         study            mg of cells during        highest to lowest:
                     formate                       26 h i.c. =               trans-DCE;
                                                   14.8 mg/litre             cis-DCE; VC;
                                                                             TCE; 1.1-DCE

    Table 8.  (cont'd)
                                                                                                                                     

    Inoculum         Additional   Test             Efficiency of             Remarks                     Reference
                     substrate                     degradation
                                                                                                                                     

    Mixed            methane      laboratory       removal of up to                                      Deipser (1998)
    consortia                     study            > 99% within 15
                                                   days i.c. =
                                                   0.55 mg/litre
                                                                                                                                     

    a  i.c.= Initial concentration; DCE = dichloroethene; TCE = trichloroethene;
       TC = transformation capacity

    Table 9.  Survey on isolated bacterial cultures capable of degrading vinyl chloride under aerobic conditions
                                                                                                                                 

    Inoculum                       Additional             Major degradation    Remarks               Reference
                                   substrate              producta
                                                                                                                                 

    Mixed culture                  n. sp.                 CO2 (> 67%)                                Malachowsky et al. (1991)
    consisting of
    Rhodococcus rhodochrous
    and 2 bacteria of the
    order Actinomycetales

    Bacterium of the order         propane,               CO2 (> 67%)                                Phelps et al. (1991a)
    Actinomycetales                glucose or
                                   acetate

    Alcaligenes denitrificans      isoprene               n. sp.                                     Ewers et al. (1990)
    ssp. Xylosoxidans

    Methylosinus trichosporium     methane                n. sp.               inactivation          Tsien et al. (1989); Chang
    OB3b                                                                       possible              & Alvarez-Cohen (1996)
                                   methane                glycolic                                   Castro et al. (1992a)
                                                          acid (44%;
                                                          determined at
                                                          68% conversion)

    Mycobacterium sp. ;            no                     CO2 ; initially:     VC as primary         Hartmans et al. (1985, 1992);
    M. aurum                                              chlorooxirane        substrate;            Hartmans & DeBont (1992);
                                                          (epoxide)            inhibition            Meier (1994)
                                                                               possible

    Mycobacterium                  no                     CO2, HCl             maximum growth        Hauschild et al. (1994)
    aurum L1                                                                   rates at
                                                                               1 mmol
                                                                               VC/litre

    Mycobacterium vaccae           propane                n. sp.                                     Wackett et al. (1989)
    (JOB 5)

    Table 9. (cont'd)
                                                                                                                                 

    Inoculum                       Additional             Major degradation    Remarks               Reference
                                   substrate              producta
                                                                                                                                 

    Nitrosomonas europaea          ammonia                n. sp.                                     Vannelli et al. (1990)

    Pseudomonas sp.                3-chloro-propanol      glycolic acid                              Castro et al. (1992b)
                                                          (71%; determined
                                                          at 25%
                                                          conversion)

    Rhodococcus sp.                propane                CO2 (> 66%)                                Malachowsky et al. (1994)

    Rhodococcus                    isoprene               n. sp.                                     Ewers et al. (1990)
    erythropolis

    Xanthobacter                   propylene              n. sp.                                     Ensign et al. (1992)
    (strain Py 2)
                                                                                                                                 

    a  The degradation efficiency is given in parentheses; n. sp. = not specified

    Table 10.  Survey on anaerobic microbial degradation of vinyl chloridea
                                                                                                                                     

    Inoculum              Test design/ Conditions   Major degradation   Efficiency of             Remarks             Reference
                                                    products            degradation
                                                                                                                                     

    Mixed methanogenic    liquid cultures           n. sp.              i.c. = 400 µg/litre                           Brauch et al.
    consortium (from      (20°C) groundwater                                                                          (1987)
    PCE-, TCE-,           with sterile sand                             approx. 50% (100%)
    VC-contaminated                                                     after 4 (11) weeks
    groundwater)
                          without sterile sand                          approx. 20% (55%)
                                                                        after 4 (11) weeks

    Mixed consortium      incubation of             n.sp.               94% within 16 days                            Nerger &
    (from                 groundwater plus                              i.c. = 18 µg/litre                            Mergler-Völkl
    TCE-contaminated      waste water                                                                                 (1988)
    water)                (9 : 1)( 21°C)

    Mixed consortium      digesters filled          n.sp.               low degradation                               Deipser (1998)
    (from compost)        with mature sieved                            (0.2 mg/m3 compost/h)
                          compost from private
                          households

    Mixed consortium      soil-groundwater          (< 1% CO2)          no degradation in 5                           Barrio-Lage et
    (from natural         microcosms (25°C)                             months                                        al. (1990)
    sites)                                                              i.c. = 2 mg/litre

    Mixed consortium      flow-through column       methane plus        89% degradation           traces of           Barrio-Lage et
    (from natural         packed with soil,         ethene (82%),       (in 9-15 days)            chloromethane       al. (1990)
    sites)                a. s.: mixture of         CO2 (7%)
                          phenol, citrate,
                          ammonium
                          dihydrogenphosphate,
                          methanol and methane

    Table 10. (cont'd)
                                                                                                                                     

    Inoculum              Test design/ Conditions   Major degradation   Efficiency of             Remarks             Reference
                                                    products            degradation
                                                                                                                                     

    Consortium            aquifer sediment          CO2                 15-34% mineralization                         Bradley &
    indigenous            microcosms, anaerobic                         in 84 h (versus 3-5%                          Chapelle (1996)
    to anaerobic          conditions plus                               without Fe-EDTA
    aquifer systems       Fe(III) as Fe-EDTA                            amendment)
    (contaminated                                                       i.c. = 17 µmol/litre
    with CHs)

    Mixed                 varying conditions        chloroethane        slow degradation                              Baek et al.
    methanogenic or       15-30°C                   or ethene                                                         (1990); Carter &
    methanol-enriched                               (plus ethane)                                                     Jewell (1993);
    consortia                                                                                                         Skeen et al.
                                                                                                                      (1995)

    Enriched PCE- and     batch cultures            ethene              partial to nearly         inhibition by       Freedman &
    TCE-degrading         (35°C)                                        complete degradation      PCE possible        Gossett (1989);
    consortia                                                                                                         DiStefano et al.
                                                                                                                      (1991); Tandoi
                                                                                                                      et al. (1994)

    Mixed anaerobic       fixed-bed columnb         ethene plus         almost complete                               De Bruin et al.
    consortia from        24°C a.s.:                ethane              conversion of                                 (1992)
    river sediment        lactate                                       PCE (95-98%)
    and wastewater                                                      via VC
    sludge

    Methanobacterium      resting cell                                  no degradation                                Castro et al.
    thermoautotrophicum   suspensions (60°C)                            i.c. = 10-3                                   (1994)
                                                                        mol/litre

    Table 10. (cont'd)
                                                                                                                                     

    Inoculum              Test design/ Conditions   Major degradation   Efficiency of             Remarks             Reference
                                                    products            degradation
                                                                                                                                     

    "Dehalococcoides      anaerobic H2-PCEb         ethene              90% conversion            decay in rate       Maymó-Gatell
    ethenogenes strain    enrichment culture                            of PCE via VC             of VC               et al. (1995,
    195"c + mixed                                                                                 conversion          1997)
    microbial consortia
                                                                                                                                     

    a  a.s. = additional substrate; i.c. = initial concentration; n.sp. = not specified; CH = chlorinated hydrocarbons;
         PCE = tetrachloroethene; TCE = trichloroethene
    b  starting material PCE
    c  preliminary name


    4.2.2  Abiotic degradation

    4.2.2.1  Photodegradation

         Studies on the photodegradation of VC are summarized in Table 11.
    They include direct and indirect photolysis.

         VC in the vapour phase or in water does not absorb wavelengths
    above 220 nm or 218 nm, respectively (Hill et al., 1976b). However,
    solar radiation reaching the troposphere lacks wavelengths below about
    290 nm due to the stratospheric ozone shield. So, direct photolysis of
    VC is expected to be insignificant under environmental conditions,
    because there is no overlap between the absorption spectrum of VC and
    the sunlight radiation spectrum (Callahan et al., 1979). Consistently,
    no photodegradation was observed with pure VC in the gas phase or in
    water at wavelengths above 220 nm. After irradiation at 185 nm, VC was
    photolysed (Table 11).

         In the environment, indirect photolysis occurs and includes
    reactions of VC in the presence of photosensitizers and those
    (Table 12) with photochemically produced reactive particles.

         A variety of photolytic products was formed after irradiation of
    VC under several experimental conditions (Table 11). Some
    intermediates, e.g., chloroacetaldehyde, were of considerable
    photochemical stability. Therefore, the photooxidation is unsuitable
    as a means of removing VC from waste gases (Gürtler et al., 1994). On
    the other hand, treatment of  water  contaminated  with VC and other
    halogenated organic compounds by means of UV-enhanced oxidation
    (UV/ozone or UV/hydrogen peroxide) was reported to be successful (Zeff
    & Barich, 1992).

         The atmospheric fate of VC depends on its reaction with reactive
    particles such as free OH and NO3 radicals, Cl atoms, ozone and
    singlet oxygen. As can be seen from Table 12, the reaction with OH
    radicals is the dominant transformation process, showing calculated
    tropospheric half-lives of 1-2 days or more. Factors influencing
    indirectly (via OH radical concentration) the lifetime of VC are the
    degree of air pollution and solar radiation, leading to spatial,
    diurnal and seasonal variations (e.g., Hesstvedt et al., 1976).
    Reaction products include formaldehyde (HCHO) and formyl chloride
    (HCOCl), the latter being a stable potential toxicant (Tuazon et al.,
    1988; Pitts, 1993).

         Rate constants for the photodegradation of VC in aqueous
    solutions have been reported to range from 6.99 × 109 mol-1 second-1
    (Grosjean & Williams, 1992) to 7.1 × 109 mol-1 second-1 (Klöpffer et
    al., 1985). Mabey et al. (1982) reported that photolysis of VC was not
    an environmentally relevant process. They reported oxidation rate
    constants of < 108 mol -1h -1 and 3 mol -1h -1 for reactions with
    singlet oxygen (1O2) and peroxy radicals (RO2), respectively. On
    the basis of an average OH radical concentration of 10-17 mol in


        Table 11.  Survey on vinyl chloride photolysis studies
                                                                                                                                      

    Medium                Irradiation            Photolytic degradation         Photolytic productsa             Reference
                          (Duration)
                                                                                                                                      

    VC in a high-vacuum   medium pressure        yes                            primary products: radicals       Fujimoto et al. (1970)
    system                arc                                                   (C2H3, Cl); C2H2, HCl

    VC in air             sunlight (outdoors)    yes                            n.sp.                            Pearson & McConnell
                                                 (half-life = 11 weeks ± 50%)                                    (1975)
                          xenon arc (> 290 nm)   yes                            CO (90%); HCl

    VC in air             high pressure          yes (> 99% within 15 min)      chloroacetaldehyde,              Kagiya et al. (1975)
                          mercury lamp                                          HCl, CO2

                          outdoors               yes (55% within 2 days)

    VC in air (dry)       > 230 nm (4 h)         yes                            chloroacetaldehyde (primary      Müller & Korte (1977)
                                                                                product), HCl, CO, formyl
                                                                                chloride

    VC in air             < 400 nm (45 min)      yes                            CO2, CO, H2O, HCl, HCOOH,        Woldbaek & Klaboe
                                                                                C2H2                             (1978)
                          sunshine (3-45 h)      very slow

    VC (adsorbed on       > 290 nm (n.sp.)       yes                            n.sp.                            Freitag et al. (1985)
    silica gel)                                  (15.3% of applied amount)

    VC in an oxygen       185 nm (up to 50 min)  yes                            formyl chloride,                 Gürtler et al. (1994)
    atmosphereb                                  (quantum yield: 2-3)           monochloroacetaldehyde,
                                                                                acetylene, CO, CO2,
                                                                                monochloroacetyl chloride,
                                                                                HClc, formic acidc
                          254 nm (up to 6 h)     no

    VC in air             xenon lamp             yes                            n.sp.                            Haag et al. (1996)
                                                 (initial k: 0.09 second-1)

    Table 11. (cont'd)
                                                                                                                                      

    Medium                Irradiation            Photolytic degradation         Photolytic productsa             Reference
                          (Duration)
                                                                                                                                      

    VC in air plus        UV (> 290 nm)          yes                            formic acid, HCl, CO,            Cox et al. (1974);
    nitrogen oxides       (up to 22 h)          (half-life = 1-7 h, + NO        formaldehyde, ozone,             Dilling et al. (1976);
                                                 half-life = 18 h, - NO)        (other minor products)           Gay et al. (1976);
                                                                                                                 Carassiti et al.
                          xenon lamp             yes                            formaldehyde, Hcl                (1977) Kanno et al.
                          (0-120 min)                                                                            (1977)

                          < 400 nm (25 min)      yes                            at low NO2 conc.: the same       Woldbaek & Klaboe
                                                (increase in reaction rate      products as observed in air      (1978)
                                                 as compared to NO2/NO          (see above);
                                                 being absent)                  at high NO2 conc.:
                                                                                additionally nitrosyl
                                                                                chloride, N2O

    VC in air plus        xenon lamp             yes                            n.sp.                            Haag et al. (1996)
    1,1-DCE                                      (initial k: 0.15 second-1)

    VC in pure water      > 300 nm               no                                                              Hill et al. (1976b)
    (10 mg/litre)         (90 h)

    VC in natural water   > 300 nm               no
    samples               (20 h)
    (10 mg/litre)

    VC in water plus      > 300 nm               yes (rapid)                    various products
    photosensitizers

    VC in PVC plant       > 300 nm               yes (half-life = 40 h)         n.sp.
    effluent              sunlight (25 h)        very little
                                                                                                                                      

    a n.sp. = not specified; DCE = dichloroethene
    b direct photolysis
    c in the presence of water vapour

    Table 12.  Rate constants and half-lives for gas-phase reactions of vinyl chloride with OH radicals and other reactive particles
                                                                                                                                      

    VC reaction   Rate constant             Temperature         Assumed atmospheric         Calculated           Reference
    with a        (in units of              (°C) c              concentration of the        half-life c,d
                  cm3/molecule-sec) b                           reactive particle c
                                                                                                                                      

    * OH          5.6 × 10-12               27                  1 × 106 molecules/cm3       1.4 days             Cox et al. (1974);
                  (measured)                                                                                     US EPA (1985a)

    * OH          4.5 × 10-12               23 (296 K)          1 × 106 molecules/cm3       1.8 days             Howard (1976); US
                  (measured)                                                                                     EPA (1985a)

    * OH          6.60 × 10-12              26 (299 K)          n.sp.                       n.sp.                Perry et al. (1977)
                  5.01 × 10-12              85 (358 K)
                  3.95 × 10-12              149 (423K)
                  (measured)

    * OH          6.60 × 10-12              26                  1 × 106 molecules/cm3       1.2 days             US EPA (1985a)
                  (Perry et al., 1977)

    * OH          6.60 × 10-12              room temperature    1 × 106 molecules/cm3       (3.5 days)           Atkinson et al.
                  (Perry et al., 1977)      (298 ± 2 K)         (12-h daytime average,                           (1979, 1987);
                                                                Crutzen, 1982)                                   Atkinson (1985)

    * OH          6.60 × 10-12              room temperature    n.sp.                       n.sp.                Atkinson (1987)
                  (measured)
                  5.3 × 10-12
                  (calculated)

    * OH          6.60 × 10-12              25 ± 2              5 × 105 molecules/cm3       (approx 3 days)      Tuazon et al. (1988)
                  (Perry et al., 1977)      (298 ± 2 K)

    * OH          6.60 × 10-12              26                  5 × 105 molecules/cm3       2.2-2.7 days         BUA (1989)
                  (Perry et al., 1977)                          (Crutzen, 1982)

    * OH          6.8 × 10-12               27 (300 K)          5 × 105 molecules/cm3       approx 2.4 days      BUA (1989)
                  (Becker et al., 1984)                         (Crutzen, 1982)

    Table 12. (cont'd)
                                                                                                                                      

    VC reaction   Rate constant             Temperature         Assumed atmospheric         Calculated           Reference
    with a        (in units of              (°C) c              concentration of the        half-life c,d
                  cm3/molecule-sec) b                           reactive particle c
                                                                                                                                      

    * OH          6.60 × 10-12              26                  8 × 105 molecules/cm3       1.5 days             Howard (1989)
                  (Perry et al., 1977)

    * OH          4.0 × 10-12               26 (299 K)          n.sp.                       n.sp.                Kirchner et al.
                  cm3/mol-sec                                                                                    (1990)
                  (measured)

    * OH          10.6 ×  10-12             n.sp.               n.sp.                       n.sp.                Klamt (1993)
                  (calculated)

    * OH          n.sp.                     n.sp.               1 × 106 molecules/cm3       (42 h)               Pitts (1993)
                                                                (24-h average)

    * OH          6.60 × 10-12              n.sp.               6.5 × 105 molecules/cm3     (2.7 days)           Helmig et al.
                  (Perry et al., 1977)                          (estimated global mean;                          (1996)
                                                                Tie et al., 1992)

    * OH          6.60 × 10-12              26                  7.5 × 105 molecules/cm3     1.6 days             Palm (1997)
                  (Perry et al., 1977)                          (24-h average, BUA, 1993)                        personal
                                                                                                                 communication

    * NO3         2.3 × 10-16               room temperature    2.4 × 109 molecules/cm3     (42 days)            Atkinson et al.
                  (measured)                (298 ± 2 K)         (12-h nighttime average,                         (1987)
                                                                Platt et al., 1984)

    * NO3         1.4 × 10-16               23 (296 ± 1 K)      n.sp.                       n.sp.                Andersson &
                  (measured)                                                                                     Ljungström (1989)

    Cl            12.7 × 10-11              25 (298 ± 2 K)      n.sp.                       n.sp.                Atkinson & Aschmann
                  (measured)                                                                                     (1987); Grosjean &
                                                                                                                 Williams (1992)

    Table 12. (cont'd)
                                                                                                                                      

    VC reaction   Rate constant             Temperature         Assumed atmospheric         Calculated           Reference
    with a        (in units of              (°C) c              concentration of the        half-life c,d
                  cm3/molecule-sec) b                           reactive particle c
                                                                                                                                      

    O3            1.9 × 10-19               25                  n.sp.                       n.sp.                Gay et al. (1976);
                                                                                                                 Singh et al. (1984)

    O3            2.0 × 10-18               n.sp.               n.sp.                       4 days               Hendry & Kenley
                                                                                                                 (1979);
                                                                                                                 ECETOC (1983)

    O3            2.45 (± 0.45) × 10-19     room temperature    n.sp.                       n.sp.                Zhang et al. (1983)
                                            (approx. 25)

    O3            2.5 × 10-19               25                  7 × 1011 molecules/cm3      (66 days)            Atkinson & Carter
                  (Zhang et al., 1983)                          (Singh et al., 1978)                             (1984); Atkinson et
                                                                                                                 al. (1987)

    O3            2.45 × 10-19              25                  1 × 1012 molecules/cm3      33 days              US EPA (1985a)
                  (Zhang et al., 1983)

    O3            1.2 × 106                 27                  1.6 × 1012 molecules/cm3    4.2 days             Lyman et al. (1982,
                  cm3/mole-sec                                                                                   1990); US EPA (1985a)

    O3            1.7 × 10-19               22                  7 × 1011 molecules/cm3      67 days              Klöpffer et al.
                                                                                                                 (1988)

    O3            2.5 × 10-19 (calculated   n.sp.               n.sp.                       n.sp.                Meylan & Howard
                  according to AOP)                                                                              (1993)

                  19 × 10-19 (calculated    n.sp.               n.sp.                       n.sp.
                  according to FAP)

    O (3P)        8.6 × 10 -13              25                  2.5 × 104 molecules/cm3     373 days             Sanhueza & Heicklen
                                                                                                                 (1975); US EPA
                                                                                                                 (1985a)

    Table 12. (cont'd)
                                                                                                                                      

    VC reaction   Rate constant             Temperature         Assumed atmospheric         Calculated           Reference
    with a        (in units of              (°C) c              concentration of the        half-life c,d
                  cm3/molecule-sec) b                           reactive particle c
                                                                                                                                      

    O (3P)        5.98 × 10 -13             25                  2.5 × 104 molecules/cm3     532 days             Atkinson & Pitts
                                                                                                                 (1977); US EPA
                                                                                                                 (1985a)
                                                                                                                                      

    a  O(3P) = oxygen atom
    b  AOP = Atmospheric Oxidation Program (currently used by US EPA); FAP = Fate of Atmospheric Pollutants (part of US EPA's Graphical
       Exposure Modeling system, GEMS)
    c  n.sp. = not specified
    d  Values in parentheses reported as 'lifetime'


    natural water, the kOH rate constant resulted in a half-life of
    approximately 110 days (US EPA, 1985a). Both of the other reactions
    appeared to be negligible.

    4.2.2.2  Hydrolysis

         Observations on chemical hydrolysis of VC derive from experiments
    with effluent water from a VC plant (pH = 4.3-9.4; 50°C; 57 h;
    Callahan et al., 1979), water of different pH values (85°C; 27 h; Hill
    et al., 1976b; Mabey et al., 1982), water saturated with O2 (85°C;
    12 h; Hill et al., 1976b), water plus ethanol (120°C; Rappoport & Gal,
    1969) and two natural water samples (pH = 6.1/4.2 for river/swamp
    water, both at room temperature and at 85°C; 41 h; Hill et al.,
    1976b). In all cases, no or only slow hydrolysis occurred. The
    hydrolytic half-life was estimated to be < 10 years at 25°C (Hill et
    al., 1976b). Hydrolysis experiments under strongly alkaline, high
    temperature (and therefore environmentally irrelevant) conditions
    resulted in a polymerization of VC (Jeffers & Wolfe, 1996).

    4.2.3  Other interactions

         Under experimental conditions, VC and chlorine in water form
    chloroacetaldehyde, chloroacetic acid and other unidentified compounds
    (Ando & Sayato, 1984).

         Many salts have the ability to form complexes with VC, thus
    possibly leading to an increase in its solubility (Callahan et al.,
    1979).

    4.3  Bioaccumulation

         Owing to its high vapour pressure and low octanol/water partition
    coefficient, VC is expected to have little tendency for
    bioaccumulation (BUA, 1989). Theoretical calculations resulted in
    bioconcentration factors (BCFs) of 2.8 (based on a log Kow of
    approximately 0.9) and around 7 (based on a water solubility of
    2763 mg/litre) in aquatic organisms (US EPA, 1985a). A BCF of 5.7
    (based on log Kow = 1.23) was calculated by Mabey et al. (1982) for
    aquatic microorganisms.

         Experiments performed with 14C-VC (initial concentration:
    250 µg/litre) in a closed laboratory model aquatic ecosystem gave the
    following results: after 3 days at 26.7°C 34% of the 14C was found in
    the water and 65% in the air. The organisms from different trophic
    levels contained 14C residues (in VC equivalents, µg/kg) of 1307
    (alga,  Oedogonium cardiacum), 621 (waterflea,  Daphnia magna), 123
    (snail,  Physa sp.), 1196 (mosquito larva,  Culex pipiens
     quinquefasciatus) and 312 (fish,  Gambusia affinis) (Lu et al.,
    1977). These values led to BCFs ranging from 3 to 31 when compared to
    the VC water concentration of 42 µg/litre, indicating some
    bioaccumulation, but no biomagnification within the food chain.

         Another study determined BCFs for green algae  (Chlorella fusca)
    after a 24-h exposure to 0.05 mg VC/litre and for fish (golden ide,
     Leuciscus idus melanotus) exposed to a constant average
    concentration of 0.05 mg VC/litre over 3 days. BCFs of 40 and < 10,
    respectively, were found (Freitag et al., 1985).

         After 5 days of incubation of 0.05 mg VC/litre in activated
    sewage sludge, an accumulation factor of 1100 (based on the
    distribution of VC between sludge, dry weight and water) was observed
    (Freitag et al., 1985).

    4.4  Ultimate fate following use

    4.4.1  Waste disposal

         Several methods have been employed for removal of VC from waste
    water: stripping with air, steam or inert gas (Nathan, 1978;
    Cocciarini & Campaña, 1992; Hwang et al., 1992), extraction (Nathan,
    1978) or adsorption onto activated charcoal or adsorbent resin
    (Nathan, 1978; Dummer & Schmidhammer, 1983, 1984).

         Like VC waste gases produced during other processes (see
    chapter 3), the recovered VC can be recycled or incinerated (US EPA,
    1982; BUA, 1989). Special biological filters have been developed for
    degrading VC in waste emissions (Meier, 1994, 1996; see also section
    4.2.1).

         Incineration leading to the total destruction of VC requires
    temperatures ranging from 450°C to 1600°C and residence times of
    seconds for gases and liquids, or hours for solids (HSDB, 1995).

         Photochemical oxidations (Topudurti, 1992; Zeff & Barich, 1992;
    Berman & Dong, 1994; see also section 4.2.2) are further methods of VC
    elimination. UV-enhanced oxidation (oxidants used: ozone, hydrogen
    peroxide) was applied for purification of polluted waters, (e.g.,
    waste, leachate, groundwater) (Zeff & Barich, 1992). Treatment with
    sodium dichromate in concentrated sulfuric acid was recommended for
    the destruction of small quantities of VC, for instance, from
    experimental laboratories (HSDB, 1995).

         Chlorinated volatile organic compounds (VOCs) can be removed from
    drinking-water/groundwater by treatment with activated charcoal
    (Schippert, 1987), air stripping (after water is pumped to the
    surface) (Boyden et al., 1992) or by air sparging (applied  in situ)
    (Pankow et al., 1993). Recently, on-site and  in situ bioremediation
    techniques, which couple evaporative or other methods with microbial
    treatment, have been developed for restoration of groundwater systems
    (Roberts et al., 1989; Portier et al., 1992, 1993; Fredrickson et al.,
    1993; McCarty, 1993; Lackey et al., 1994) or soils (Schulz-Berendt,
    1993) contaminated with VC and other VOCs.

    4.4.2  Fate of VC processed to PVC

         Most of the VC produced is used for the manufacture of PVC (see
    section 3) and will therefore be connected with the fate of PVC. PVC
    and articles made from it can be disposed of in landfills,
    incineration or feedstock recycling. While rigid PVC is an extremely
    persistent material, flexible PVC may be less recalcitrant to
    disintegration (Harris & Sarvadi, 1994). At incineration, PVC plastics
    do not depolymerize to form VC (Harris & Sarvadi, 1994), but produce
    volatile aliphatic hydrocarbons and volatile chlorinated organic
    compounds (Nishikawa et al., 1992; see also section 3.2.4). There is
    evidence for formation of PCDFs/PCDDs (Theisen et al., 1989, 1991;
    IPCS, 1989).
    

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

         There is very little exposure of the general population to VC.

         Concentrations of VC in ambient air are low, usually less than
    3 µg/m3. Exposure of the general population may be higher in
    situations where large amounts of VC are accidentally released to the
    environment, such as a spill during transportation. However, such
    exposure is likely to be transient. Near VC/PVC industry and waste
    disposal sites, relatively much higher concentrations, up to
    8000 µg/m3 and 100 µg/m3, respectively, have been observed. VC has
    only rarely been detected in surface waters, sediment or sewage
    sludges. Maximal VC concentrations in groundwater or leachate from
    areas contaminated with chlorinated hydrocarbons amount to 60 000
    µg/litre.

    5.1.1  Air

    5.1.1.1  Outdoor air

         Atmospheric air levels of VC in rural/remote and suburban/urban
    areas range from not detectable to 24 µg/m3 (Table 13). Higher values
    were recorded in industrial areas, with maxima in the vicinity of
    VC/PVC producing or processing plants, even at distances of 5 km. Peak
    concentrations were as high as 86 mg/m3 (33 ppm) and 17 mg/m3 (7
    ppm), measured, respectively, in 1974 in the USA and 1983 in China
    (Table 13). In many countries, VC concentrations near plants have
    decreased with time due to regulatory measures (Table 13).

         In more recent years attention has been paid to the occurrence of
    VC near waste disposal sites, where levels of up to 0.18 mg/m3
    (70 ppb) have been detected (Table 13). This is much less than the
    significant amounts of VC found in undiluted landfill gas (see
    section 3). Bruckmann & Mülder (1982) assumed that gas discharges of
    landfills are diluted by a factor of 104 when entering the
    atmosphere.

         VC emissions of < 0.5 µg/m3 (remote from VC plants) or of a few
    µg/m3 (near VC plants) in Germany and the Netherlands were derived
    from a computer model (Besemer et al., 1984; WHO, 1987; LAI, 1992).
    Ambient air concentrations in three geographical areas of the USA were
    computed to range from trace to about 3 µg/m3 (Pellizzari et al.,
    1979).

        Table 13. Vinyl chloride measured in ambient (atmospheric) aira
                                                                                            

    Country; site and         Valueb             Concentrations          Reference
    year of sampling                             (µg/m3)
                                                                                            

    Rural/remote areas        single             0.1                     Kruschel et
    Canada: pine forest                                                  al. (1994)
    near Barrie, Ontario
    year n. sp.

    Germany: Westerland,      mean values        6.6-24                  Bauer
    Schwarzwald,                                                         (1981)
    Lüneburger Heide,
    Bayer Wald; prior to
    1977

    Germany: Taunus;          mean value         0.1                     Dulson
    1975                      (n = 4)                                    (1978)

    USA: rural Northwest      (n = n. sp.)       n.d. (< 0.013)          Grimsrud &
    USA (Pullman,                                                        Rasmussen
    Washington);                                                         (1975)
    1974-1975

    USA: over ocean           (n = n. sp.)       n.d. (< 26)             Lillian et
    Sandy Hook, NJ                                                       al. (1975)
    (3 miles offshore);
    1974

    Suburban/urban areas

    Canada: urban (22)        meanc              0.06                    Dann &
    and rural (1) sites;      (n = 1370; 4%                              Wang (1992)
    1989-1990                 > detection)

    Germany: Berlin           range (n=78)       n.d. (n.sp.) - 3.5      Dulson
    (3 sites); 1977           means              0.3-0.4                 (1978);
                                                                         Lahmann
                                                                         (1980)

    Germany: Frankfurt/M.     n = 1              2.6                     Bergert &
    (city); 1974                                                         Betz (1976)

    Germany: Frankfurt/M.     mean (n = 16)      21.1                    Arendt et
    (suburban); 1975                                                     al. (1977)

    Germany: Merkenich        annual mean        3.6                     German Expert
    (North-Rhine                                                         Group on the
    Westfalia); 1980                                                     Environment
                                                                         (1988)

    Table 13. (cont'd)
                                                                                            

    Country; site and         Valueb             Concentrations          Reference
    year of sampling                             (µg/m3)
                                                                                            

    Germany: Cologne          means              0.5-15.3                Anon (1981);
    (3 stations);             (n = n.sp.)                                BUA (1989)
    1979-1986

    Germany: several          mean values        0.2-11                  Bouscaren
    sites; year n. sp.                                                   et al. (1987)

    Germany: Hamburg          annual means       2.4-9.0 (including      Bruckmann
    (12 sites in the city);   (n = 300)          1-butene)               et al. (1988)
    1986-1987

    USA: New Jersey           geom. mean         1981: 0                 Harkov et
    (3 urban sites:           (3/113)d and       1982: 0                 al. (1983,
    Newark, Elizabeth,        (0/105)d           (detection limit:       1984)
    Camden); 1981-1982                           0.013)

    USA (eastern): urban      daily mean         0.62                    Dann &
    sites; 1989               (n=397; 2%                                 Wang (1992)
                              > detection)

    Industrial sites

    Canada: Shawinigan        range              n.d. - 117              Thériault
    (vicinity of VC                                                      et al. (1983)
    polymerization
    plant); year n. sp.

    China: dormitories for    n = 16×3                                   Zhao et al.
    workers (50, 100 and      (4 h/day for                               (1994)
    1000 m from a VC          4 days at
    polymerization plant)     3 stations)

          1983                maxima             17 400 / 5900 / 1500
                              daily means        4810 / 1080 / 580
          1984                maxima             7800 / 2500 / 1400
                              daily means        4080 / 720 / 500
          1986                maxima             6600 / 2000 / 1100
                              daily means        3120 / 820 / 520
          1988                maxima             12 700 / 1000 / 300
                              daily means        4430 / 320 / 200
          1989                maxima             3100 / 700 / 300
                              daily means        760 / 220 / 170

    Table 13. (cont'd)
                                                                                            

    Country; site and         Valueb             Concentrations          Reference
    year of sampling                             (µg/m3)
                                                                                            

    Finland: 1.2 km from                                                 Kinnunen
    a PVC plant                                                          (1996)
          1993                range of           0.1-1.3
                              monthly means
          1994                range of           0.1-0.8
                              monthly means
          1995                range of           < 0.1-0.1
                              monthly means
                              range of single    0.1-11
                              measurements
                              (n approx. 4000)
          1996                range of           0.1-0.4                 Kinnunen
                              monthly means                              (1997)
                              range of single    0.1-13
                              measurements
                              (n approx. 7000)

    Germany: n.sp.;           maximum            252                     Bouscaren
    prior to 1980                                                        et al. (1987)

    Germany: Ruhrgebiet       99th percentile    69                      BUA (1989)
    West; year n. sp.

    Germany: 1978-1982        max. (n = n.sp.)   113                     Bauer (1981)

    Germany: Marl (80 m       mean (n = 24)      213                     Rohrschneider
    and 500 m above           mean (n = 9)       108                     et al. (1971)
    chemical plant);1970

    Germany: Frankfurt/M.     n.sp.              4.5                     Atri (1985)
    (industrial area);
    year n.sp.

    Netherlands: > 600 m      maximum            ca. 600                 Besemer
    from VC plant;            mean               210                     et al.
    1976-1977                                                            (1984)

    0-500 m distant           range (n = 200)    < 21-504
    500 m distant; 1978       range (n = 100)    13-55
                              mean               18

    Netherlands:              range              7.8-181                 Guicherit &
    VC/PVC plants;            (n = n.sp.)                                Schulting
    1980                                                                 (1985)

    Table 13. (cont'd)
                                                                                            

    Country; site and         Valueb             Concentrations          Reference
    year of sampling                             (µg/m3)
                                                                                            

    UK: 5 VC plants;          overall means      < 13-228                Turner et al.
    1984 (April-July)         daily means        23-218                  (1984)
                              (ranges related
                              to the 5 plants,
                              total n = 440)

    Plant VI (7 stations,     max. (n = 28);     20 202 (0 km),
    0-4.8 km distant)                            880 (0.8 km)

    Plant IX (15 stations,    means (n = 180);   311-1373
    0.8-5 km distant)         maximum            8806 (5 km)

    USA: 1974-1975; VC        (n = 708)                                  US EPA
    plant (Narco)             means              3.4-262                 (1975);
    (4 stations,              geom. means        0-28                    Dimmick
    < 250 - > 1000 m          maximum            27 045 (< 250 m)        (1981)
    distant)

    PVC plant (Aberdeen)      (n = 438)
    (4 stations,              means              11.6-958
    < 250 - > 1000 m          geom. means        3.7-372
    distant)                  maximum            23 430 (300 m)

    PVC plant (Louisville)    (n = 712)
    (4 stations,              means              11.4-101
    < 250 - > 1000 m          geom. means        5-30
    distant)                  maximum            814 (250-400 m)

    USA: residential areas    range (n = 30)     n.d. - 104              US EPA
    near chemical plants                                                 (1975)
    (n = 15); 1974

    USA: Houston, Texas;      range (n = 18.)    8-3238                  Gordon &
    1974                                                                 Meeks
                                                                         (1977)

    USA: residential          max. (n = n.sp.)   > 2560                  Fishbein
    areas in the vicinity     mean (n = n.sp.)   44                      (1979)
    of VC/PVC plants;
    prior to 1975

    USA: vicinity of          max.               34                      McMurry &
    VC/PVC plants (Texas,                                                Tarr (1978)
    7 stations); 1977

    Table 13. (cont'd)
                                                                                            

    Country; site and         Valueb             Concentrations          Reference
    year of sampling                             (µg/m3)
                                                                                            

    Areas in the vicinity
    of waste sites

    Belgium: Mellery; prior   no details         19                      Lakhanisky
    to 1990                                                              et al. (1993)

    Germany: surroundings     no details         < 3                     Pudill (1993)
    of a hazardous waste
    site; about 1988

    Germany: 2 landfills      range              < 0.082-0.65            Wittsiepe
    near Bochum; 1990-1991    (n = 16)                                   et al. (1996)

    USA: West Covina,         range (24-h av;    26-104                  Camarena &
    California; 1981-1984     n = 32) max        130                     Coy (1984)

    USA: West Covina,         24-h averages      13-31 (n = 5 days)      Baker &
    California; 1984          5-day average      23                      MacKay
    site A (200 m distant     24-h averages      5.7-18                  (1985)
    from landfill)            5-day average      10.4 (n = 5 days)
    site B (20 m distant
    from landfill)

    USA: southern             max.               18                      Stephens
    California, 1981          range              5-18                    et al. (1986)
    after 1981                (6 stations)

    USA: California;          max.               30                      Little et
    prior to 1990                                                        al. (1992)

    USA: New York             range              n.d. (5.4) - 16         Lipsky &
    (2 sites) 1982                                                       Jacot
                                                                         (1985)
    Miscellaneous

    USA: all outdoor site     mean               8.5                     Shah &
    types; prior to 1988      (n = 574)                                  Singh
                                                                         (1988)
                                                                                            

    a n.d. = not detected (detection limit in parentheses, if specified);
      n.sp. = not specified
    b This column indicates whether the concentration is a maximum (max),
      average or range value
    c Values below detection set to 0.5 method detection limit (0.1 µg/m3)
    d Values in parentheses = no. detected / no. sampled

    5.1.1.2  Indoor air

         Indoor air concentrations of VC in houses near landfills in the
    USA reached concentrations of up to 1 mg/m3 air (Little et al., 1992:
    2 landfills, maxima of 0.13 and 0.3 mg/m3; Stephens et al., 1986:
    1 landfill, maximum of 1 mg/m3), thus exceeding the maximum outdoor
    levels reported in Table 13 for areas adjacent to landfills. Moreover,
    the Californian monitoring programme, collecting a total of 500 air
    samples at two outdoor and four indoor sites downwind of a landfill,
    revealed that the 120 samples containing the most VC
    (> 0.025 mg/m3; 10 ppb) were taken inside homes (Little et al.,
    1992). It is assumed that in addition to atmospheric transport,
    subsurface migration of VC accounts for the elevated indoor air levels
    of VC (Wood & Porter, 1987; Hodgson et al., 1992; Little et al.,
    1992).

         A room being painted with a red latex paint based on a terpolymer
    of vinyl chloride, vinyl acetate and ethylene showed VC levels of
    75 and 10 µg/m3 (29 and 4 ppb), respectively, during and some time
    (less than one day) after painting (Going, 1976).

         In the early 1970s it was investigated whether VC was present in
    car interiors as a result of volatization from PVC. Measurements of VC
    concentrations in the interior of seven different new 1975 automobiles
    gave positive results for two of them. Levels of 1036 to 3108 µg/m3
    (0.4 to 1.2 ppm) were detected (detection limit: 130 µg/m3; 0.05 ppm)
    (Hedley et al., 1976). Another study (Going, 1976) did not find VC in
    the interior ambient air of 16 new and used cars and 4 mobile homes
    (detection limit: 26 µg/m3; 10 ppb). It should be noted that since
    this time the levels of VC in PVC resins have been drastically reduced
    (see section 3.2.4).

    5.1.2  Water and sediment

         Owing to its high volatility, VC has rarely been detected in
    surface waters. The concentrations measured generally do not exceed
    10 µg/litre, with a maximum of 570 µg/litre from contaminated sites
    (Table 14).

         Much higher levels of up to 56 000 µg/litre have been found in
    groundwater samples from contaminated sites (Table 15).

         The levels in drinking-water supplies ranged from not detected to
    2 µg/litre in samples collected in 100 German cities in 1977. In a
    state-wide USA study performed in 1981-1982, random samples (taken
    from randomly selected water systems) had concentration ranges of n.d.
    to 1.1 µg/litre, and non-random samples (taken from systems that were
    likely to be contaminated with VOCs) varied from n.d. to 8 µg/litre.
    Prior to 1980 single maximum values of up to 380 µg/litre were
    reported from the USA (Table 16).


        Table 14.  Vinyl chloride concentrations measured in surface watera
                                                                                                                                      

    Country, source          Year of sampling    Valueb              Concentrations      Remarks           Reference
                                                                     (µg/litre)
                                                                                                                                      

    Germany

    River Rhine              (prior to) 1978     typical conc.       1                                     Anna & Alberti (1978)
                                                 (n = many)

    River Rhine              1982                                    < 0.2                                 Malle (1984)

    River Rhine              1990                range (n = 78)      < 0.01-0.031                          Wittsiepe (1990)

    Tributaries of Rhine     (prior to) 1978     typical conc.       < 1-5                                 Anna & Alberti (1978)
    (Northrhine-Westfalia)                       (n = many)

    Surface water from       n.sp.               range               < 0.0004-0.4        > 150 samples     Wittsiepe et al. (1990)
    unspecified sites                            (n = n.sp.)
    in former FRG

    River Main               1990                range (n = 22)      < 0.004-0.008                         Wittsiepe (1990)

    River Lippe              1989                range (n = 54)      0.12-0.4            receiving         Wittsiepe (1990)
                                                                                         wastewater from
                                                                                         VC/PVC plants

    River Ruhr (plus         1990                range (n = 60)      < 0.0004-0.005                        Wittsiepe (1990)
    artificial lake)                                                 (lake: up to
                                                                     0.06)

    River Wupper             1989                range (n = 36)      up to 0.069                           Wittsiepe (1990)

    River Saale              1990                range (n = 4)       up to 69            receiving         Wittsiepe (1990)
                                                                                         wastewater from
                                                                                         an industrial
                                                                                         area of the
                                                                                         former GDR

    Table 14. (cont'd)
                                                                                                                                      

    Country, source          Year of sampling    Valueb              Concentrations      Remarks           Reference
                                                                     (µg/litre)
                                                                                                                                      

    Japan

    Rivers in Osaka          1995                range (n = 28)      up to 1.2           (3/28)c           Yamamoto et
                                                                                                           al. (1997)

    USA

    Delaware River           1976-1977           (n = 11)            n. d.                                 Sheldon & Hites
                                                                                                           (1978)

    Surface water from       1977-1979           maximum             566                 (21/606)c         Page (1981)
    different sites                              (n = 606)
    in New Jersey                                median              0

    Surface water from       n.sp.               maximum             9.8                                   Burmaster (1982);
    9 states                                     (n = n.sp.)                                               Dyksen & Hess (1982)

    Final effluent from a    1980-1981           mean                6.2                                   Gossett et al. (1983)
    waste-water treatment                        (n = 5)
    plant in Los Angeles

    Surface waters           prior to 1984       median              < 5                 (63/1048)c        Staples et al. (1985)
                                                 (n = 1048)

    Indian River Lagoon      n.sp.               (n = n.sp.)         n.d. (< 1.0)                          Wang et al. (1985)
    (near water discharge
    of VC), several
    stations

    Surface water near       1985-1990           (n = n.sp.)         n.d.                                  Hallbourg et al. (1992)
    3 landfills in
    Florida

    Table 14. (cont'd)
                                                                                                                                      

    Country, source          Year of sampling    Valueb              Concentrations      Remarks           Reference
                                                                     (µg/litre)
                                                                                                                                      

    Surface water at a       1989-1990           range               0.23                                  Chen & Zoltek (1995)
    landfill in Florida      1992-1993           (n = 5)             n.d.
    (Orange County)
                                                                                                                                      

    a  n.d = not detected (detection limit in parentheses, if specified); n.sp. = not specified;
       GDR = German Democratic Republic
    b  This column indicates whether the concentration is a maximum (max), average or range
       value
    c  Values in parentheses = no. detected / no. sampled


         One reason for the occurrence of VC in drinking-water may be that
    residual VC can migrate from PVC pipes used in some water distribution
    systems into the water flowing through them. This has been found out
    by field (Dressman & McFarren, 1978) and experimental (Banzer, 1979;
    Nakamura & Mimura, 1979; Ando & Sayato, 1984) studies. The extent of
    leaching depended on the VC concentration in the pipe material. In the
    field study the highest VC concentrations (1.4 µg/litre) consistently
    occurred in water from new pipes, whereas the lowest level (0.03
    µg/litre) was found in the oldest (9 years of age) distribution
    system. VC concentrations in landfill leachate samples amounted to up
    to 61 mg/litre (Table 17). A gross analysis of water (no
    specification) available for the USA and based on 5553 observations
    reported maximum and median concentrations of VC as high as
    202.6 mg/litre and 107 µg/litre, respectively (US EPA, 1985a).

         No VC was detected in urban stormwater run-off from 15 cities in
    the USA (n = 86) during a monitoring project concerning priority
    pollutants (Cole et al., 1984).

         Generally, a time trend cannot be derived from the water analysis
    data available.

         Most sediment samples contain very low VC concentrations, even at
    rather contaminated sites. Sediment was monitored for VC during
    1981-1982 in Florida (USA) at several stations (n = 8) of the Indian
    River Lagoon and a conveying canal. Although the latter received
    discharged water having VC concentrations of 34-135 µg/litre, no VC
    was detected in the sediment samples (3 from each station, collected
    monthly over a year), the detection limit being 2 ng/g (Wang et al.,
    1985). The same was true for surface water (Table 14) and oyster
    (section 5.1.5) samples from this site. Sediment samples (n = 2) taken
    near the discharge zone of a wastewater treatment plant in Los Angeles
    County (California, USA) contained < 0.5 µg VC/kg dry weight. The
    corresponding water concentration of VC was 6.2 µg/litre (Gossett et
    al., 1983). A survey of 343 sediment samples from the USA gave a
    median VC concentration of < 0.5 µg/kg dry weight (Staples et al.,
    1985). However, higher VC concentrations were also reported. According
    to US EPA (1985a), VC was detected in sediment samples (no further
    details given) in the USA at levels ranging from 0-580 µg/kg (n = 649;
    median = 23 µg/kg).

    5.1.3  Soil and sewage sludge

    5.1.3.1  Soil

         Subsurface soil samples near the waste pit of an abandoned
    chemical cleaning shop in southern Finland showed VC concentrations as
    high as 900 mg/kg (Salkinoja-Salonen et al., 1995). After an
    accidental spillage of VC into snow in 1980, VC levels as high as
    500 mg/kg were measured in the soil at up to 2 m depth (Charlton
    et al., 1983).

    5.1.3.2  Sewage sludge

         VC has been detected in municipal sewage sludges in the USA. The
    concentrations ranged from 3 to 110 mg/kg dry weight (corresponding to
    145 to 3292 µg/litre), being detected in 3 of 13 samples, with a
    median concentration of 5.7 mg/kg dry weight (corresponding to
    250 µg/litre) (Naylor & Loehr, 1982). Another study reported a mean
    concentration of 35.4 mg/kg dry weight for 6 of 44 samples (Fricke
    et al., 1985). A range of 8-62 000 µg/litre was found in 35 of 435 raw
    sludge samples (Burns & Roe, 1982).

    5.1.4  Food, feed and other products

         VC is not a general contaminant of foodstuff and pharmaceutical
    or cosmetic products, but it can be detected after contact of these
    products with PVC packaging materials. The use of PVC as packaging
    material for food, drink and drugs began in the early sixties (chapter
    3), whereas legislative action for safeguarding consumers from
    exposure to VC did not begin until the early seventies (starting with
    a ban on the use of PVC containers for packaging alcoholic beverages
    in the USA; Anon, 1973). Current EC and US FDA regulations on the
    level of VC in PVC materials intended to come into contact with
    foodstuffs are listed in Annex 1.

         VC concentrations measured in PVC-packed food and drink of
    several countries are compiled in Table 18. A maximum value of
    20 mg/kg was found in liquors. Other positive samples included
    vegetable oils (up to 18 mg/kg), vinegars (up to 9.8 mg/kg),
    margarines (up to 0.25 mg/kg), fruit drinks (> 0.2 mg/kg) and bottled
    water (< 0.6 µg/litre).

         Retail surveys of foods showed a significant reduction in VC
    levels and/or in the number of positive samples since 1974 (UK MAFF,
    1978, 1984; van Lierop, 1979; Codex Committee, 1984).

         The latest data were from the 1990s (Table 18) and refer to
    bottled drinking-water. In addition to small amounts of VC, there were
    also indications for the presence of possible reaction products of VC
    with chlorine (Fayad et al., 1997).

         Pharmaceutical and cosmetic products were less frequently
    monitored. The highest concentration, amounting to 7.9 mg/kg, was
    detected in mouthwashes (Table 19).

         Reports on analyses of animal feed were not available.

         The potential for leaching of residual VC from PVC packaging into
    the contents has been demonstrated by a variety of product analyses
    (Tables 18 and 19) and by experimental studies using food or food
    simulants (Daniels & Proctor, 1975; Hocking, 1975; Tester, 1976;
    Diachenko et al., 1977; Pfab & Mücke, 1977; UK MAFF, 1978; Chan et
    al., 1978; vom Bruck et al., 1979; van Lierop, 1979; Benfenati et al.,
    1991; Thomas & Ramstad, 1992). Altogether, the results indicated that


        Table 15.  Vinyl chloride concentrations measured in groundwatera
                                                                                                                                      

    Country; source                Year of      Valueb                 Concentrations          Remarks              Reference
    of groundwater                 sampling                            (µg/litre)
                                                                                                                                      

    Canada

    from a VC spill site           1980         maximum; 10 weeks      10 000                                       Charlton et al.
                                                after the spill        < 20                                         (1983)

    beneath a landfill             1988         range (n = 37)         < 1-40                  (5/37)c              Lesage et al.
    near Ottawa                                                                                                     (1990)

    Finland

    from village wells             mid-1980     range                  5-200 mg/litre                               Nystén (1988);
    (contaminated by leakage of                                        (including DCE)                              Salkinoja-Salonen
    a waste liquor basin of                                                                                         et al. (1995)
    VC/PVC industry - detected
    in 1974)

    Germany

    from different sites                        mean values            n.d. (< 5) - 460                             Brauch et al.
    (4 sites)                                                                                                       (1987)

    from different wells                        mean values            15-1040
    of a large surface
    contamination (5 wells)
    from a catchment area of                    range (n = 30)         < 1-120                                      Milde et al.
    a water-works                                                                                                   (1988); Nerger &
    (TCE / PCE-contaminated)                                                                                        Mergler-Völkl
                                                                                                                    (1988)

    contaminated by waste          until 1988   range (n = 113)        < 1-12 000              (14/113)c            Schleyer et al.
    disposal sites (92                          mean                   2700                                         (1988)
    sites)                                      median                 475

    Table 15. (cont'd)
                                                                                                                                      

    Country; source                Year of      Valueb                 Concentrations          Remarks              Reference
    of groundwater                 sampling                            (µg/litre)
                                                                                                                                      

    from a site contaminated       n.sp.        (n = 3)                                        corresponding air    Köster (1989)
    with chlorinated                                                                           pockets in soil
    hydrocarbons                                                       1000                    128 000 µg/m3
                                                                       500                     47 000 µg/m3
                                                                       200                     5000 µg/m3

    from a site contaminated       ca. 1989     max.  (n = 5)          110                                          Leschber et
    with chlorinated                                                                                                al. (1990)
    hydrocarbons (in Berlin)

    from a contaminated site       n.sp.        range (n = 3)          710-1670                                     Kästner (1991)
    (in Braunschweig)

    of a catchment area of a       1989         (n = n.sp.)            up to 0.130                                  Wittsiepe et al.
    waterworks                                                                                                      (1990)

    Contaminated by accidental     1989         (n = n.sp.)            up to 3
    spillage of TCE and PCE

    Contaminated by waste          n.sp.        mean (n = 136)         1693                    18% positive         Dieter &
    disposal sites (approx.                     max.                   12 000                                       Kerndorff (1993)
    100 sites)

    USA

    from different sites in        1977-1979    max. (n = 1060)        9.5                     (4/1060)c            Page (1981)
    New Jersey

    from 9 states                               max.                   380                     7% positive          Dyksen & Hess
                                                                                                                    (1982)

    monitoring wells near          n.sp.        max.                   635                     present in           Stuart (1983)
    industrial waste sites in                                                                  3 out of 9 wells
    Connecticut

    Table 15. (cont'd)
                                                                                                                                      

    Country; source                Year of      Valueb                 Concentrations          Remarks              Reference
    of groundwater                 sampling                            (µg/litre)
                                                                                                                                      

    from Nassau County,            1980         range (n = >100)       1.6-2.5                                      Connor (1984)
    Long Island

    from Miami, Florida            n.sp.        mean (n = 3)           6.8                                          Parsons et al.
                                                                                                                    (1984)

    from a TCE spill site in       n.sp.        mean (n = 3)           82                                           Parsons et al.
    Vero Beach, Florida                                                                                             (1984)

    monitoring wells near MSW                   n.sp.                  present (in                                  Sabel & Clark
    landfills in Minnesota                                             5/20 sites),                                 (1984)
                                                                       but not quantified

    near 3 plants manufacturing    n.sp.        range (n = 3)          50-500                  chlorinated          White Paper
    electronics equipment                                                                      solvents stored in   (1984) cited in
    (Santa Clara Valley)                                                                       underground tanks    Wolf et al.
                                                                                                                    (1987)

    near solvent recovery                       range (n = 4)                                                       Cline & Viste
    facilities                                                                                                      (1985)
    Connecticut                    1980                                n.d. (< 10) - 2700
    Wisconsin                      1983                                n.d. (< 10) - 210

    from a residential area        1983         maximum                2800                    contamination        Andreoli
    in Long Island, New York                                                                   from dry-cleaning    (1985)
    (several wells)                                                                            shop

    near a landfill in             (about       max.                   692                                          Shechter (1985)
    New Jersey                     1981)        (n = approx. 100)

    monitoring wells around        1985         max.                   2600                    seasonal, spatial    Stephens et al.
    hazardous waste landfill                                                                   and analytical       (1986)
    in S. California                                                                           variations

    Table 15. (cont'd)
                                                                                                                                      

    Country; source                Year of      Valueb                 Concentrations          Remarks              Reference
    of groundwater                 sampling                            (µg/litre)
                                                                                                                                      

    monitoring wells near          1990         range (n = 64)         n.d. (1-2) - 12         (5/64)c              EMO (1992)
    an airforce base in Ohio

    near 3 landfills in Florida    1985-1990    mean values            < 0.22-26.5                                  Hallbourg et al.
    (10 locations)                                                                                                  (1992)

    monitoring wells at a          1989-1990    range (n = 3)          n.d. - 0.23             increase of VC       Chen & Zoltek
    landfill in central            1992-1993                           4.8-48.4                with time, decrease  (1995)
    Florida (Orange County)                                                                    in total VOC

    from an industrial site;                    (n = n.sp.)            51-146                                       Topudurti (1992)
    recycling operations
    (1940-1987); California

    near a former waste disposal                (n = n.sp.)                                                         US EPA (1992)
    facility in Wisconsin:
    on-property                                 max.                   77
    off-property                                max.                   5

    Contaminated by                1991         maxima                 < 5-56 400                                   Semprini et al.
    TCE > 10 years before                       minima                 < 5-321                                      (1995)
    (17 sites)

    near Plattburg, New York       n.sp.        (n = 2)                8 and 384                                    Bradley & Chapelle
    (2 locations)                                                                                                   (1996)
                                                                                                                                      

    a  n.d. = not detected (detection limit in parentheses, if specified); n.sp. = not specified; TCE = trichloroethene;
       PCE = tetrachloroethene; VOC = volatile organic compounds;  max. =  maximum; MSW = municipal solid waste
    b  This column indicates whether the concentration is a maximum (max), average or range value
    c  Values in parentheses = no. detected / no. sampled

    Table 16.  Vinyl chloride measured in drinking-water suppliesa
                                                                                                                                

    Country; source              Year of sampling     Valueb             Concentration       Remarks         Reference
                                                                         (µg/litre)
                                                                                                                                

    Germany

    drinking-water supplies      1977                 range              n.d. - 1.7                          Bauer (1981)
    of 100 cities

    drinking-water               n.sp.                (n = n.sp.)        ca. 1.6 ng/litre                    Wittsiepe et al.
    (no details)                                                                                             (1993)

    USA

    finished drinking-water      (prior to) 1975      max. (n = n.sp.)   10                                  Fishbein (1979)

    water supplies from          (prior to) 1975      max. (n = n.sp.)   5.6 & 0.27
    Florida and Philadelphia

    raw drinking-water           1975-1979            2 positives        2.2 & 9.4           (2/13)c         CEQ (1981)
    (13 cities)

    finished drinking-water                           1 positive         9.4                 (1/25)c
    (25 cities)

    drinking-water wells         (prior to) 1980      max. (n = n.sp.)   50                                  CEQ (1981);
    (state New York)                                                                                         Burmaster (1982);
                                                                                                             Craun (1984)

    drinking-water of            (prior to) 1981      range              0.05-0.18                           Kraybill (1983)
    113 cities                                        mean               0.052

    drinking-water               1977-1981            range of           trace - 380         (82/1288)c      Cotruvo et al.
    supplies (166)                                    positives                                              (1986)

    Table 16. (cont'd)
                                                                                                                                

    Country; source              Year of sampling     Valueb             Concentration       Remarks         Reference
                                                                         (µg/litre)
                                                                                                                                
    finished water supplies      1981-1982            max.:                                                  Westrick et al.
    (using groundwater                                random samples:    1.1                 (1/466)c        (1984)
    sources) from 51 states                           (n = 466)
    in the USA                                        non-random         8.4                 (6/479)c
                                                      samples:
                                                      (n = 479)

    private wells in             1982                 max.               4.5                 (1/63)c         Goodenkauf &
    Nebraska  (n = 63)                                                                                       Atkinson (1986)
                                                                                                                                

    a  n.d. = not detected (detection limit in parentheses, if specified); n.sp. = not specified
    b  This column indicates whether the concentration is a maximum (max), average or range value
    c  Values in parentheses = no. detected / no. sampled

    Table 17.  Vinyl chloride concentrations measured in leachatea
                                                                                                                                 

    Country; source          Year of sampling    Valueb          Concentrations        Remarks           Reference
                                                                 (µg/litre)
                                                                                                                                 

    Canada

    MSW landfill leachate    1988                n.sp.           14                                      Lesage et al. (1993)
    from Guelph (Ontario)    1989                n.sp.           23

    USA

    landfill leachates       n.sp.               (n = 6)         not quantified        present in 1/6    Sabel & Clark (1984)
    from Minnesota                                                                     samples

    landfill leachates       prior to 1982       max. (n = 4)    61                    (1/4)c
    from Wisconsin

    landfill leachates       prior to 1985       range (n = 5)   n.d.                                    Cline & Viste (1985)
    (municipal and                                               (< 10) - 120
    industrial)

    landfill leachates:      prior to 1988       range                                 total number of   Brown & Donnelly
                                                 (n = n.sp.)                           landfills: 58     (1988)
    municipal                                                    20-61 000
    industrial                                                   140-32 500

    MSW leachates (several   (prior to) 1988     range           8-61
    states in the USA)                           (n = n.sp.)
                                                 median          40                    (6/?)c            Chilton & Chilton
                                                                                                         (1992)
                                                                                                                                 

    a  n.d. = not detected (detection limit in parentheses, if specified); n.sp. = not specified;
       MSW = municipal solid waste
    b  This column indicates whether the concentration is a maximum (max), average or range value
    c  Values in parentheses = no. detected / no. sampled


    the amount of VC migrating into food or solvent was proportional to
    the VC concentration in the PVC packaging, to storage time and to
    increasing temperature.

         Until 1974 the use of VC as a propellant in aerosol sprays was
    allowed in the USA (chapter 3). Realistic application of such aerosol
    products (hairspray, deodorant, insecticide, disinfectant, furniture
    polish or window cleaner) resulted in high (ppm range) indoor air
    concentrations of VC (Gay et al., 1975).

         There have been no reports on VC levels found in food,
    pharmaceutical or cosmetic products in recent years. This may be due
    to regulatory measures for PVC packaging in several countries (see
    Annex 1).

    5.1.5  Terrestrial and aquatic organisms

         Oysters ( Crassostrea virginica) from the Indian River Lagoon in
    Florida (USA) contained no detectable levels of VC (detection limit:
    0.4 ng/g). The samples were collected weekly (1981) and monthly (1982)
    at three sites (Wang et al., 1985). VC was also not detected in the
    corresponding water and sediment samples (section 5.1.2).

         Another study (Gossett et al., 1983) did find low concentrations
    of VC (< 0.3 µg/kg wet weight) in a sample of small invertebrates
    from just above the bottom sediments (n = 1), in a muscle sample of
    shrimp (n = 1) and in liver samples of several fish species (n = 4).
    The animals were collected in 1981 in final effluent waters from a
    wastewater treatment plant in Los Angeles County (Palos Verdes,
    California, USA) that had VC concentrations of 6.2 µg/litre (section
    5.1.2).

         Data on fish tissue (no further details given) available from the
    US EPA STORET database were reported by US EPA (1985a). VC levels
    ranged from 0-250 mg/kg (n = 530; median: 6 mg/kg).

    5.2  General population exposure

         Exposure of the general population to VC is possible by several
    routes. They include inhalation of air polluted with VC (section
    5.1.1), mainly in the vicinity of VC/PVC plants or waste disposal
    sites, intake of contaminated drinking-water (sections 5.1.2 and
    5.1.4), ingestion of food, beverages and medicines packed in PVC
    (section 5.1.4), and absorption through skin from PVC-wrapped
    cosmetics (section 5.1.4).

         Normally, the general population is exposed to only small amounts
    of VC, if at all. However, the exposure varies according to the
    countries' regulatory measures, the occurrence of accidents or the
    spread of precursor substances.


        Table 18.  Levels of vinyl chloride in food and drink packaged, stored or transported in PVC articles
                                                                                                                                

    Country          Yeara            Product                    No.a,b        Concentrationsc          Reference
                                                                               (µg/kg)
                                                                                                                                

    Canada           n.sp.            alcoholic beverages        22            < 25-1600                Williams & Miles
                                      vinegars                   28            n.d. (10) - 8400         (1975)
                                      peanut oil                 10            300-3300

    Canada           n.sp.            alcoholic beverages        10            n.d. (10) - 2100         Williams (1976a)
                                      vinegars                   10            300-7800
                                      vinegars                   9             14-9800                  Williams (1976b)
                                      sherry                     3             500-2400
                                      peanut oil                 3             3800-18 000

    Canada           n.sp.            oil                        5             80-2100                  Page & O'Grady (1977)
                                      vinegars                   5             10-5700

    Canada           1981-1982        vinegars                   n.sp.         27-43                    Codex Committee (1984)
                                      other foods                n.sp.         < 10

    Italy            n.sp.            drinking-water             10            0.013-0.083              Benfenati et al. (1991)
                                      (PVC-bottled)

    Netherlands      1975             oil samples                8             > 50                     Van Lierop (1979)
                                      salad dressing             1             250
                                      margarine                  4             60-250
                                      ready-made salads          n.sp.         > 50
                                                                 (whole
                                                                 batch)
                                      wine                       n.sp.         760

    Netherlands      1976             margarine                  1             60                       Van Lierop (1979)
                                      fish                       1             90
                                      biscuit                    3             20-130

    Table 18. (cont'd)
                                                                                                                                

    Country          Yeara            Product                    No.a,b        Concentrationsc          Reference
                                                                               (µg/kg)
                                                                                                                                

                     1977             peanut butter              1             4100                     Van Lierop (1979)
                                      (very small
                                      individually wrapped
                                      portions)

                     1978             various foods:             67 (3 +)      n.d. (0.1) - 2           Van Lierop (1979)
                                      soya oil                   1             0.3
                                      vinegar                    1             0.6
                                      salmon salad               1             2

    Norway           1975             butter/margarine           16            n.d. (2)                 Ehtesham-Ud Din
                                      salad                      14            2-15                     et al. (1977)
                                      juices                     8             6-25
                                      vinegar                    27            6-2790
                                      mustard                    5             9-14

    Saudi Arabia     n.sp.            drinking-water             9 × 48d       < 0.6                    Fayad et al. (1997)
                                      (PVC-bottled)

    Sweden           1974             edible fats                127           n.d. (2) - 127           Fuchs et al. (1975)

    Sweden           1975-1976        various foods              104           n.d. (2) - 600           Albanus et al. (1979)
                                      (edible fats and oils,                   (mostly: < 10)
                                      ketchup, vinegar, lime
                                      juice, fruit syrup)

    Switzerland      1973-1975        edible oils                41            n.d. (5) - 1750          Rösli et al. (1975)

    United Kingdom   n.sp.            spirits                    n.sp.         0-250                    Davies & Perry (1975)

    Table 18. (cont'd)
                                                                                                                                

    Country          Yeara            Product                    No.a,b        Concentrationsc          Reference
                                                                               (µg/kg)
                                                                                                                                

    United Kingdom   1974             fruit drinks               25            10 - > 200               UK MAFF (1978)
                     1977                                        13            < 10
                     1974             cooking oil                23            10 - > 200
                     1977                                        7             < 2
                     1975             butter, soft margarine     51            < 2 - 200
                     1977                                        9             < 2

    USA              1971             vegetable oil              1             7000                     Breder et al. (1975)
                     1974                                        3             700

    USA              1973             spirits                    n.sp.         up to 20 000             Anon (1973);
                                                                                                        US FDA (1973)

    USA              1973-1975        alcoholic beverages        n.sp.         11 000-25 000            Codex Committee (1984)
                                                                                                                                

    a  n.sp. = not specified
    b  + = number of samples positive
    c  n.d. = not detected (detection limit in parentheses, if specified)
    d  9 brands (locally produced and imported)

    Table 19. Vinyl chloride detected in pharmaceutical and cosmetic
    products packaged in PVC materials
                                                                                          

    Product                     No.a        Concentrationb           Reference
                                            (µg/kg or µg/litre)
                                                                                          

    Blood coagulant             30          n.d. (15)                Breder et al.
    solutions                                                        (1975)

    Mouthwashes                 11          n.d. (20-30) - 7900

    Several capsules, tablets   11          n.d. (10-30)             Watson et al.
    and mouthwashes                                                  (1977)

    Large volume                5           n.d. (0.1) - < 1         Watson et al.
    parenterals                                                      (1979)

    Mouthwashes                 5           7-120

    Shampoos                    4           9-17

    Body oils                   4           n.d. (0.1) - 41

    Intravenous solutions       n.sp.       n.d. (1)                 Arbin et al.
                                (many)                               (1983)

    Cefmetazole sodium          4           n.d. (0.3) - <1          Thomas &
    (Zefazone(R) sterile                                              Ramstad
    powder)                                                           (1992)
                                                                                          

    a  n.sp. = not specified
    b  n.d. = not detected (detection limit in parentheses, if specified)


    5.2.1  Estimations

         Estimations of the respiratory intake of VC reported for the USA
    ranged from 0 to 48.3 mg per person per day, based on exposure values
    of 0 to 2.1 mg/m3 and assuming that 23 m3 of air are inhaled per day
    (US EPA, 1985b). According to Seiber (1996) over 100 000 Californians,
    particularly those living near landfills, may be exposed to VC levels
    of 2.59 µg/m3 (1 ppb) or more.

         A European study (Besemer et al., 1984) evaluating the exposure
    of the Dutch population to VC in ambient air assumed an average
    exposure of about 0.2 µg/m3, which resulted in a calculated daily
    intake of 4 µg VC per person. Small fractions of the population were
    concluded to be exposed to higher average levels: 0.01% (> 8.5
    millions) to > 5 µg/m3, 0.04% to 4-5 µg/m3, and 0.05% to
    3-4 µg/m3. The corresponding estimated daily intakes of VC were
    > 100 µg, 80 µg and 60 µg, respectively.

         Intake via drinking-water from public water supplies in the USA
    was estimated to exceed 1 µg/litre for 0.9% of the population,
    5 µg/litre for 0.3% and 10 µg/litre for 0.1% of the population. These
    would result in daily VC intakes (assuming a 70-kg man and 2 litres of
    water/day) of > 2, 10, and 20 µg/day. Maximal values were estimated
    to be approximately 120 µg/day (US EPA, 1985b).

         Another study (Benfenati et al., 1991) estimated the daily intake
    of VC from PVC-bottled drinking-water bought in Italian supermarkets.
    Based on the analytical results (Table 18) and assuming a consumption
    of 2 litres of water per person per day and a storage time of 2 months
    for the PVC bottles, the authors calculated that the oral intake could
    exceed 100 ng VC per person per day.

         Evaluation of the results of food surveillance programmes from
    the United Kingdom led to a calculated maximum likely VC intake of
    1.3 µg/day per person in 1974, of 0.1 µg/day per person in 1976, and
    less than 0.02 µg/day per person by 1978 (UK MAFF, 1978, 1984). These
    calculations were based on the typical daily consumption of fruit
    drink, cooking oil and soft margarine.

         Evaluating and summing up possible maximum user intakes of VC
    from PVC-bottled liquor, wine and oil, and food packaged in PVC
    materials, the US FDA calculated a maximum lifetime-averaged exposure
    of 25 ng/person per day (US FDA, 1986). An earlier review reported an
    estimated dietary intake of VC of 40 ng/day per person in the USA
    (Codex Committee, 1984).

         The intake by food and drinking-water in the Netherlands was
    estimated (without specifying details) to be about 0.1 µg/day per
    person or less (Besemer et al., 1984). Estimates (no details given) of
    the average human intake for Switzerland were reported to be 3 ng/kg
    body weight per day (Lutz & Schlatter, 1993).

    5.2.2  Monitoring data of human tissues or fluids

         Monitoring human tissues or fluids as an indirect measure of
    exposure to VC has not frequently been applied. As with workers in the
    plastics industry (section 5.3), the urine of premature babies was
    found to contain large amounts of thiodiglycolic acid (thiodiacetic
    acid), a metabolite of VC (chapter 6), but the relationship to
    possible VC exposure was questionable (Pettit, 1986).

    5.3  Occupational exposure

         The main route of occupational exposure to VC is via inhalation
    (Sittig, 1985), while dermal absorption is considered to be negligible
    (ECETOC, 1988).

         Industrial environments associated with VC exposure include VC
    production plants, VC polymerization (PVC production) plants and PVC
    processing factories. Estimates of numbers of workers exposed to VC
    were, for example, in the USA (1981-1983) in the range of 80 000
    (ATSDR, 1997) or in Sweden (1975-1980) more than 5000 (Holm et al.,
    1982). Since, at the onset of VC/PVC production in the USA and Western
    Europe, VC was not recognized as a toxic compound, no precautions
    against contact were provided for nor was regular workplace monitoring
    performed. Therefore, only sporadic measurements or retrospective
    estimates (Table 20) of exposures are available for the period prior
    to 1975. Published data from various countries on VC contamination of
    workplace air throughout the early and later periods are compiled in
    Table 21 and 22. Highest exposures occurred in the VC/PVC production
    plants, with peak concentrations of several thousand ppm whereas much
    lower exposure levels were measured in processing plants. Owing to
    standard-setting and legislative regulations by national authorities
    and technical improvements, levels dropped markedly to values of a few
    ppm in many countries. Official exposure limits can serve as an
    additional indication of approximate VC concentrations occurring in
    plants in many countries. These limits have declined gradually (IARC,
    1979). Generally, standards require that exposures do not exceed 13 to
    26 mg/m3 (5 to 10 ppm) (Torkelson, 1994; Rippen, 1995; ACGIH, 1999).

         However, even in the 1990s the standards were not always realized
    in all countries (Table 21).

         Whereas in industrialized countries factories that could not
    satisfy the rigorous regulations of the early 1970s to reduce VC
    emissions were forced to close down, in the countries of eastern
    Europe and developing countries this was not possible for
    socioeconomic reasons and large plants with old-fashioned technologies
    continued to function (Hozo et al., 1996).

        Table 20. Retrospective estimates of daily occupational
    exposures to vinyl chloride prior to 1975a
                                                                              

    Country          Period             VC exposure     Reference
                                        (mg/m3)
                                                                              

    Germany          "first years"      > 2600          Szadkowski & Lehnert
                     prior to 1971      1300            (1982)
                     1971               260
                     1974               5.2-7.8

    Norway           1950-1954          5200            Hansteen et al. (1978);
                     1955-1959          2600            Heldaas et al. (1984)
                     1960-1967          1300
                     1968-1972          260
                     1973-1974          207

    Sweden           1945-1954          1300            Holm et al. (1982)
                     1955-1964          780
                     1965-1969          520
                     1970-1974          130

    United Kingdom   1945-1955          2600            Barnes (1976);
                     1955-1960          1040-1300       Anderson et al. (1980);
                     1960-1970          780-1040        Purchase et al. (1987)
                     mid 1973           390
                     1975               13
                     1940-1955          1300-2070       Jones et al. (1988)
                     1956-1974          390-1300

    USA              1945-1955          2600             Wu et al. (1989)
                     1955-1970          780-1300
                     1970-1974          260-520
                     1975               < 2.6-13
                                                                              

    a  Exposure levels during autoclave cleaning may have been as high as
       7800 mg/m3 (Barnes, 1976)


        Table 21.  Levels of vinyl chloride reported for workplace air samples in VC/PVC production plants
                                                                                                                       

    Country            Workplace                Yearc         Concentrations reported         Reference
                                                              (mg/m3)c
                                                                                                                       

    China              PVC production plant     n.sp.         30-210                          Bao et al. (1982)

    Croatia            plastics industry        n.sp.         mean = 13                       Fucic et al. (1990a)
                                                              5200 (occasional peak)

    Croatia            VC/PVC plant             1949-1987     mean = 543                      Hozo et al. (1996,
                                                              up to 1300 (occasional peak)    1997)

    Former             n.sp.                    n.sp.         2-41                            Hrivnak et al. (1990)
    Czechoslovakia

    Egypt              VC/PVC plant             n.sp.         0.05-18 (8-h TWA)               Rashad et al. (1994)

    Finland            PVC production plant,                  n.d.              range
                       breathing zone           1981-1985     1.6             < 0.3-57        Viinanen (1993)
                       concentrations (TWA)     1986-1989     1.6             < 0.3-46
                                                1993          0.3             < 0.3-26

    France             PVC production plant     1977-1978     2.3-7.3 (range of monthly       Haguenoer et al.
                                                              means)                          (1979)

    Germany            PVC production           1974          < 65-181                        Fleig & Thiess (1974)
                       department

                       PVC production plant     1977          1.3-91                          German Environmental Office (1978)

                       PVC production plant     1979          12 (12-h TWA; stationary);      Heger et al. (1981)
                                                              15.5 (12-h TWA; personal)

    Germany            24 plants                1981-1984     3% of 33 samples: > 5           Coenen (1986);
                                                              (90 percentile: < 1);           BIA (1996)
                                                              (shift means)

    Table 21. (cont'd)
                                                                                                                       

    Country            Workplace                Yearc         Concentrations reported         Reference
                                                              (mg/m3)c
                                                                                                                       

                       46 plants                1989-1992     all of 117 samples: < 5
                                                              (90 percentile: < 0.1);
                                                              (shift means)

    Italy              VC/PVC plants            1950-1985     < 13- > 1300                    Pirastu et al. (1991)

    The Netherlands    PVC plant                1976-1977     2.6-26 (8-h TWA)                De Jong et al. (1988)

    Norway             PVC plant                1974          65                              Hansteen et al.
                                                                                              (1978)

    Poland             VC/PVC plant             1974          (30-600)a                       Studniarek et al.
                       (several departments)    1975          (30-270)a                       (1989)
                                                1976          (15-60)a
                                                1977          (6-150)a
                                                1978          (1-30)a
                                                1979          (1-15)a
                                                1981          (0.1-36)a
                                                1982          (0.1-12)a
                       (autoclave cleaners)     1974          (990)a
                                                1982          (9-180)a
                       breathing zone of VC     1986          21.3                            Dobecki &
                       synthesis mechanic       1987          66.9                            Romaniwicz (1993)
                                                1988          43.7
                                                1989          0.7
                                                1990          0.2

    Romania            PVC production plant     1965-1967     112-554                         Anghelescu et al.
                                                                                              (1969)

    Russia             VC/PVC plant                                                           Gáliková et al. (1994)
                       16 probes (whole plant)  1990-1993     1-9 (range of annual means)
                       under the reactor        1990-1993     up to 200 (range of annual
                                                              means)

    Table 21. (cont'd)
                                                                                                                       

    Country            Workplace                Yearc         Concentrations reported         Reference
                                                              (mg/m3)c
                                                                                                                       

                       in compressor room       1990-1993     up to 400 (range of annual
                                                              mean)

    Singapore          PVC production plant     1976
                                                after 1983    2.6-54 (15.3)a                  Ho et al. (1991)
                                                              up to 26 (short-term) (3.9)a

    Sweden             PVC production plant     1974-1981     0.26-114 (8-h TWA)              Holm et al. (1982)
                       PVC production plant     1974-1980     0.26-5.7 (6-h TWA)

    Taiwan             PVC plants (n = 5):      n.sp.                                         Du et al. (1996)
                       15 different operation                 range (n=114): n.d.
                       units (e.g. outside                    (0.13) - 1009 range (n=4):
                       reaction tank)b                        6-1009 (mean: 296; median: 86)
                       15 different job titles                range of TWA (n=85):
                       (e.g. tank supplier)b                  n.d. - 3680 range (n=9):
                                                              5.7-3680 (mean: 660; median:
                                                              23.7)

    United Kingdom     PVC production plant     "early days"  7800                            Barnes (1976)
                       (full-time autoclave
                       cleaner)

    USA                PVC plant                1950-1959     up to 10 400; 13-2140           Ott et al. (1975)
                                                              (8-h TWA)
                                                1960-1963     up to 1300; 13-620 (8-h TWA)
                       PVC plant                n.sp.         up to 650 (weekly TWA)          Baretta et al. (1969)

    USA                VC/PVC plants            1973          up to 390 (TWA); peaks          Rowe (1975)
                                                              2600-10 400

    Table 21. (cont'd)
                                                                                                                       

    Country            Workplace                Yearc         Concentrations reported         Reference
                                                              (mg/m3)c
                                                                                                                       

    Former USSR        VC/PVC plants            early 1950s   100-800                         Smulevich et al.
                                                                                              (1988)
                       PVC producing plant                    50-800                          Filatova &
                                                              (occasionally 87 300)           Gronsberg (1957)

    Former             PVC production plant     1974          > 195                           Orusev et al. (1976)
    Yugoslavia
                                                                                                                       

    a  Concentrations in parentheses designate geometric means
    b  Showing highest mean VC concentration
    c  n.sp.= not specified; TWA = time-weighted average; n.d. = not detected

    Table 22.  Levels of vinyl chloride reported for workplace air samples in PVC processing plants
                                                                                                                               

    Country           Workplace                       Year             Concentrations reported       Reference
                                                                       (mg/m3)
                                                                                                                               

    China             PVC processing plant            n.sp.            > 30                          Bao et al. (1982)

    Germany           PVC processing department       1974             < 2.6-67                      Fleig & Thiess (1974)

    Germany           polymer extrusion (17 plants)   1989-1992        all of 33 samples:            BIA (1996)
                                                                       < 8 (90 percentile:
                                                                       < 0.15) (shift means)

    Sweden            PVC processing plant            1974             < 0.26-0.8                    Holm et al. (1982)

    Sweden            PVC processing plant            prior to 1975    >13 - > 26 (8-h TWA)          Lundberg et al.
                                                                                                     (1993)

    Russia            PVC processing plant            prior to 1990    0.007-1.26                    Solionova et al.
                      (rubber footwear plant)                                                        (1992)

    Russia            PVC processing plant            prior to 1966    < 113.6                       Bol'shakov (1969)
                      (synthetic leather plant)

    United Kingdom    PVC processing plants           n.sp.            0.4-0.9                       Murdoch & Hammond
                      (cable factories)                                                              (1977)

    USA               automotive assembly plant(s)    1970s            0.13-7.8                      Nelson et al. (1993)
                                                                       (2 personal samples)
                                                                                                                               


         Autoclave cleaners in Croatia were exposed to extremely high
    concentrations of VC (between 1295 and 3885 mg/m3; 500 and 1500 ppm).
    A retrospective investigation of exposure to VC has been conducted
    with 37 autoclave workers (emptying and cleaning) in Split, Croatia,
    who were exposed to VC in a suspension polymerization plant. The
    investigation covered the period from 1969 to 1987, when the factory
    was closed because of its VC emissions. At the beginning, measurements
    were done by simple means (Draeger's tubes) and later, from 1980 on,
    by infra-red spectroscopy. The 37 workers were exposed to average VC
    concentrations of 1412 mg/m3 (543 ppm) (Hozo et al., 1996; Hozo,
    1998).
    

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption

         Animal and human studies have shown that VC is readily and
    rapidly absorbed. The primary route of exposure to VC is inhalation.
    However, the net uptake after exposure by inhalation is only 30-40% of
    inspired VC. This is due to the fact that VC is taken up rapidly until
    it reaches a blood concentration in equilibrium with that based upon
    inspired concentration and the blood-to-air partition coefficient.
    Uptake then decreases to an amount sufficient to replace that
    metabolized. The importance of metabolism was shown by Bolt et al.
    (1977) who showed that uptake of VC ceased once equilibrium was
    reached.

         While uptake by the oral route is near 100%, any VC not
    metabolized during first pass through the liver will be expired. Thus,
    the net dose may be less than the uptake, especially at high doses
    resulting in saturation of metabolizing enzymes.

    6.1.1  Oral exposure

         In a study reported by Watanabe & Gehring (1976) and Watanabe et
    al. (1976a), male rats received a single dose by gavage of 0.05, 1.0,
    20 or 100 mg/kg body weight and 14C-labelled VC and the excreted
    radioactivity was determined for 72 h. As only 2.4, 2.2, 1.0 and 0.5%,
    respectively, of the administered radioactivity (Table 23) was
    recovered in the faeces (total recovery 91, 89, 81 and 82%,
    respectively), it can be assumed that there is nearly complete
    absorption of VC in the gastrointestinal tract. Likewise, oral
    administration of 0.25 or 450 mg/kg body weight 14C-VC to male rats
    resulted in excretion of only 4.6 or 0.7%, respectively (Table 23), of
    the applied radioactivity via faeces 0-72 h after application (Green &
    Hathway, 1975).

         Similar results were obtained by Feron et al. (1981), who fed
    rats with different amounts of VC monomer in PVC powder via the diet.
    The average amount of VC detected in faeces was 8, 10 and 17% for oral
    intakes of 2.3, 7.0 and 21.2 mg/kg body weight per day, respectively.
    Since the VC excreted in the faeces was considered by the authors to
    be still enclosed in PVC granules and was not bioavailable, it was
    concluded that the available VC was nearly completely absorbed in the
    gastrointestinal tract.

         Studies conducted by Withey (1976) have shown the rapid
    absorption of VC from the gastrointestinal tract in male rats after a
    single gavage application of 44 to 92 mg/kg body weight in aqueous
    solution. Highest blood levels were always measured within 10 min
    after administration. After an oral dose of 10 mg VC/kg body weight,
    peak levels in brain, liver, kidney and lung were measured 5 min after
    dosing, indicating rapid absorption from gastrointestinal tract
    (Zuccato et al., 1979).


        Table 23. Excretion of radioactivity in rats (in % of applied dose) 72 h after a single oral dose of VCa
                                                                                                                                    

    Dose in mg/kg     VC in           CO2 in        Urine      Faeces     Carcass and   Total recovery   Reference
    body weight       exhaled air     exhaled air                         tissues
                                                                                                                                    

    0.05              1.4             9.0           68.3       2.4        10.1          91.2             Watanabe et al. (1976a)
    0.25              3.7             13.5          75.1       4.6        n.g.          n.g.             Green & Hathway (1975)
    1.0               2.1             13.3          59.3       2.2        11.1          88.8             Watanabe et al. (1976a)
    20                41.6            4.8           22.6       1.0        11.0          81.0             Watanabe & Gehring (1976)
    100               66.6            2.5           10.8       0.5        1.8           82.3             Watanabe et al. (1976a)
    450               91.9            0.7           5.4        0.7        n.g.          n.g.             Green & Hathway (1975)
                                                                                                                                    

    a  n.g. = not given


    6.1.2  Inhalation exposure

         Bolt et al. (1977) blocked the metabolism of VC in male rats by
    i.p. injection of 6-nitro-1,2,3-benzothiadiazole (50 mg/kg body
    weight), a compound that inhibits most microsomal monooxygenases. The
    rats were exposed to approximately 1.2 mg/m3 14C-labelled VC in a
    closed system 30 min after the injection. VC was taken up by the
    animals until equilibrium was reached between VC in the atmosphere and
    in the organism after 15 min, suggesting a rapid uptake of VC.
    Similarly, equilibrium blood levels were observed by Withey (1976) in
    male rats 30 min after the start of exposure to 18 200 mg VC/m3 (head
    only).

         Bolt et al. (1976) measured the decline of 14C-VC in a closed
    system due to uptake by 3 male rats using an initial concentration of
    130 mg/m3. The radioactivity in the air of the exposure system
    decreased with a half-life of 1.13 h. Calculation of the clearance of
    VC revealed an absorption of inspired VC of about 40%. These results
    are in accordance with the data of Hefner et al. (1975a), who reported
    in kinetic studies on male rats a similar decline at the same exposure
    concentration.

         Krajewski et al. (1980) measured the retention of VC in the lungs
    of five human male volunteers exposed for 6 h to 7.5, 15, 30 or
    60 mg/m3 through a gas mask. The percentage of retention (mean 42%)
    was independent of the VC concentration and reached the highest level
    of 46% in the first 15 min of exposure.

         Buchter et al. (1978) reported toxicokinetic experiments on
    themselves. In an open system, about 3-5 min after the start of
    inhalation of 6.5 mg VC/m3 in the exposure atmosphere, an equilibrium
    was reached between VC inspired and VC expired; 26% (person A) and 28%
    (person B) of the VC inspired were removed by the body, probably by
    absorption and subsequent metabolism. Metabolism started within the
    first minutes of exposure, suggesting fast absorption of VC.

         Breath samples were measured of volunteers who had showered in
    VC-contaminated well water (Pleil & Lindstrom, 1997). For a brief
    10-min shower exposure of 25 µg/m3 (inhalation) and 4 µg/litre
    (dermal contact in water), 0.9 µg absorbed dose of VC and a blood
    concentration of 0.01 µg/litre was calculated.

    6.1.3  Dermal exposure

         Hefner et al. (1975b) exposed the whole body (excluding the head)
    of male rhesus monkeys to 2080 (2.5 h) or 18 200 mg/m3 (2.0 h)
    14C-labelled VC. Very little VC was absorbed through the skin.
    Although minuscule, the quantity absorbed appeared
    concentration-dependent. The major portion of the VC absorbed was
    eliminated by the lungs. The authors argued that no significant
    percutaneous absorption would be expected under occupational exposure
    conditions.

    6.2  Distribution and retention

         Data from inhalation and oral studies on rats indicate rapid and
    widespread distribution of VC. Rapid distribution of VC was also
    reported in humans after inhalation exposure. Rapid metabolism and
    excretion limit accumulation of VC in the body. Data on distribution
    after oral exposure showed similar results. No studies are available
    concerning distribution after dermal exposure. Under conditions of
    blocked VC metabolism, VC has been found to accumulate in adipose
    tissue.

    6.2.1  Oral exposure

         Green & Hathway (1975) investigated the distribution in the
    tissues of young rats 0.25, 2 and 4 h after oral administration of
    30 mg/kg body weight [14C]-VC using whole-animal autoradiography. At
    15 min after gavage, most radioactivity was detected in the liver,
    followed by the gut (no data about the stomach), and there were small
    amounts in the lung and kidney. After 2 h, label was observed in the
    liver, kidney, small intestine, stomach, skin, para-auricular region
    (probably Zymbal glands), and there were small amounts in lung and
    heart. A similar distribution was determined after 4 h, with
    additional label in the thymus, salivary gland and Harders gland, but
    no radioactivity in the stomach lumen.

         The distribution of VC and VC metabolites remaining in the body
    (11.1% of recovered radioactivity) 72 h after a single oral
    administration via gavage of 1 mg/kg body weight 14C-VC was described
    as follows (expressed as % of administered radioactivity per gram
    tissue): liver 0.182, skin 0.076, carcass 0.046, plasma 0.053, muscle
    0.031, lung 0.061, fat 0.045 (no data about amount in the kidney). A
    similar distribution pattern was observed using doses of 0.05 or
    100 mg/kg body weight (Watanabe et al., 1976a).

    6.2.2  Inhalation exposure

         Whole body autoradiograms of male rats showed radioactivity in
    the liver, bile duct, digestive lumen and kidneys when animals were
    exposed for 5 min to 52 g/m3 14C-labelled VC and sacrificed 10 min
    after the end of the exposure period. Animals sacrificed 2-3 h after
    the exposure period showed a wider distribution of radioactivity, with
    most of the labelled substances being observed in the liver, urinary
    system, digestive lumen, lacrimal glands, skin and thymus (Duprat et
    al., 1977).

         Buchter et al. (1977) pretreated male rats i.p. with 50 mg/kg
    body weight 6-nitro-1,2,3-benzothiadiazole (to block VC metabolism)
    and exposed the rats in a closed system for 5 h to VC concentrations
    of between 65 and 26 000 mg/m3. Authors observed an equilibrium
    between 14C-labelled VC in the gas phase and the exposed organism.
    The distribution of VC was independent of the exposure concentration.

    The following distribution of VC (labelled and unlabelled) in
    different organs (expressed as mol VC in 1 g tissue per mol VC in 1 ml
    air) was reported immediately after the exposure period: blood 0.65,
    liver 0.62, spleen 0.59, kidney 0.59, muscle 0.68 and adipose tissue
    8.3. These results indicated that unmetabolized VC is accumulated in
    adipose tissue due to its lipophilicity. In contrast, without blockage
    of VC metabolism, most radioactivity was detected in kidney and liver
    (5 h, 260 mg/m3).

         In similar studies Bolt et al. (1976) measured radioactivity
    (representing mostly VC metabolites) in different organs immediately
    after exposure of male rats to 14C-VC (initial concentration 130
    mg/m3) for 5 h. Highest levels were detected in the kidney (2.13%;
    expressed as % of incorporated VC per g tissue) and liver (1.86%),
    followed by spleen (0.73%), muscle (0.32%), adipose tissue (0.22%) and
    brain (0.17%).

         Distribution pattern changed with longer post-exposure
    observation periods. Watanabe et al. (1976b) reported the following
    percentages of 14C activity (mostly VC metabolites) in rats per gram
    tissue 72 h after inhalation exposure to 26 or 2600 mg/m3
    14C-labelled VC, respectively, for 6 h: liver (0.139; 0.145), kidney
    (0.079; 0.057), skin (0.072; 0.115); carcass (0.048; 0.049), plasma
    (0.051; not detected), muscle (0.052; 0.038), lung (0.065; 0.046), fat
    (0.026; not detected). There was no significant difference between low
    and high dose. 72 h after the exposure period most of radioactivity
    had been excreted; 13.8% (low dose), 14.5% (high dose) of total
    recovered radioactivity remained in carcass and tissues (Table 25). A
    similar distribution pattern were presented by Watanabe et al. (1978b)
    using the same experimental design but rats exposed once or repeatedly
    to 13 000 mg/m3. Furthermore, the authors detected no significant
    difference between single and repeated exposure.

         Ungváry et al. (1978) presented evidence for the permeability of
    the placenta to VC. After exposure of pregnant rats to 5500, 18 000 or
    33 000 mg VC/m3 for 2.5 h on day 18 of gestation, VC was detected in
    fetal (13, 23 and 31 µg/ml, respectively) and maternal blood (19, 32
    and 49 µg/ml), as well as in amniotic fluid (4, 5 and 14 µg/ml).

         Toxicokinetic experiments on humans (self-experiments) were
    reported by Buchter et al. (1978). Using an open system with a
    concentration of 6.5 mg VC/m3 inspired air, the concentration in the
    expired air reached a constant concentration after about 5 min
    exposure in subject A and 7 min in subject B, indicating the end of
    the distribution phase.

    6.2.3  Partition coefficients in vitro

          In vitro studies using the vial equilibration method (3 h
    incubation, blood and tissue homogenates from male Sprague-Dawley
    rats) revealed the following VC partition coefficients for male rats:
    blood/air 2.4; fat/blood 10.0; muscle/blood 0.4; liver/blood 0.7; and
    kidney/blood 0.7 (Barton et al., 1995). In similar experiments
    tissue/air partition coefficients were obtained for different rodent
    species (Gargas et al., 1989; Clement International Corporation, 1990;
    Table 24). These data suggested that the concentration of VC in
    adipose tissue is higher than in other tissues. Furthermore, in all
    species in which both sexes were tested, partition coefficients for
    fat/air were greater in females than in males (Table 24).

    6.3  Metabolic transformation

         The main route of metabolism of VC in the liver into non-volatile
    compounds after inhalative or oral uptake involves 3 steps: a) the
    oxidation by cytochrome P-450 to form chloroethylene oxide (CEO, also
    known as 2-chlorooxirane), a highly reactive, short-lived epoxide that
    rapidly rearranges to form chloroacetaldehyde (CAA); b) the
    detoxification of these two reactive metabolites as well as
    chloroacetic acid, the dehydrogenation product of CAA, through
    conjugation with glutathione catalysed by glutathione  S-transferase;
    c) the modification of the conjugation products to substituted
    cysteine derivatives, which are excreted via urine. The main metabolic
    pathways are shown in Fig. 2. At high dose levels the metabolism of VC
    is saturable.

         The first step in VC metabolism requires microsomal
    mixed-function oxidases (cytochrome P-450 enzymes) together with
    oxygen and NADPH as cofactors. This was confirmed by studies  in vitro
    (Barbin et al., 1975; Guengerich et al., 1979) and  in vivo
    (Reynolds et al., 1975a,b; Guengerich & Watanabe, 1979; Bartsch et
    al., 1979; Guengerich et al., 1981). The major catalyst of the
    oxidation is CYP2E1 in humans. This has been demonstrated by  in vitro
    systems using purified human CYP2E1 or by inhibition of catalytic
    activity in human liver microsomes with rabbit anti-human CYP2E1. In
    liver microsomes from  uninduced rats, VC is activated solely by
    CYP2E1, at concentrations ranging from 1 to 106 ppm in the gas phase,
    according to Michaelis-Menten kinetics (El Ghissassi et al., 1998).
    The following kinetic constants were determined:

         Km      = 7.42 ± 0.37 µmol/litre;
         Vmax    = 4674 ± 46 nmol.mg protein -1 min-1.

    Comparison of the Vmax obtained in this study to the Vmax determined
     in vivo in rats (Gehring et al., 1978; Filser & Bolt, 1979) shows
    that virtually all the metabolic activation of VC  in vivo occurs in
    the liver.

        Table 24. Tissue/air VC partition coefficients for rodent tissuesa
                                                                           

    Species; strain    Sex         Blood/     Liver/     Muscle/     Fat/
                                   air        air        air         air
                                                                           

    Rat; F344          male        1.60       1.99       2.06        11.8
                       female      1.55       2.05       2.39        21.1

    Rat; CDBR          male        1.79       3.0        2.18        14.6
                       female      2.12       1.66       1.28        19.2

    Rat; Wistar        male        2.10       2.69       2.72        10.2
                       female      1.62       1.48       1.06        22.3

    Mouse; B6C3F1      male        2.83       n.g.       n.g.        n.g.
                       female      2.56       n.g.       n.g.        n.g.

    Mouse; CD-1        male        2.27       n.g.       n.g.        n.g.
                       female      2.37       n.g.       n.g.        n.g.

    Hamster;           male        2.74       3.38       2.56        14.3
    Syrian golden      female      2.21       1.31       1.96        21.1
                                                                           

    a Data from Clement International Corporation (1990); vial
      equilibration method (Gargas et al., 1989), blood or tissue
      homogenates incubated for 1-4 h until equilibrium was achieved,
      as indicated by two consecutive time points without significant
      difference; n.g. = not given

    Table 25. Percentage of 14C activity eliminated during 72 h following
    inhalation exposure to [14C]-vinyl chloride for 6 h in male ratsa
                                                                              

    Exposure groups             26 mg/m3        2600 mg/m3        13 000 mg/m3
    (number of animals)         (4)             (4)               (2)
                                                                              

    Expired as unchanged VC     1.6             12.3              54.5
    Expired as CO2              12.1            12.3              8.0
    Urine                       68.0            56.3              27.1
    Faeces                      4.4             4.2               3.2
    Carcass and tissues         13.8            14.5              7.3
                                                                              

    a  Expressed as percentage of the total 14C activity recovered
       (similar experimental design; Watanabe & Gehring, 1976;
       Watanabe et al., 1976b, 1978b)

    FIGURE 2

         Applying the pharmacokinetic model developed by Andersen et al.
    (1987) to describe the metabolism of inhaled gases and vapours, the
    uptake of VC by rats  in vivo, as determined by Gehring et al. (1978)
    and by Filser & Bolt (1979), could be accurately predicted.

         Using S9 extracts from human liver samples, Sabadie et al. (1980)
    observed a great interindividual variability in the capacity to
    activate VC into mutagenic metabolites. This is in agreement with the
    observation of Guengerich et al. (1991) who found that levels of
    CYP2E1 varied considerably among individual humans. Sabadie et al.
    (1980) noted that the average activity of human samples is similar to
    that of rat samples.

         Chloroethylene oxide (CEO) has a half-life of only 1.6 min at pH
    7.4 and 37°C (Malaveille et al., 1975). It can spontaneously rearrange
    to CAA (Barbin et al., 1975) or hydrolyse to glycolaldehyde
    (Guengerich et al., 1979; Guengerich, 1992). The latter reaction can
    also be catalysed by epoxide hydrolase (Fig. 2).

         Evidence for the detoxification of reactive VC metabolites
    through conjugation with hepatic glutathione catalysed by glutathione
     S-transferase (GST) has been shown by measuring the decrease of the
    hepatic non-protein sulfhydryl content (primarily glutathione) and the
    excretion of thiodiglycolic acid via urine in rats after inhalative
    exposure to high levels (> 260 mg/m3) of VC (Watanabe & Gehring,
    1976; Watanabe et al., 1976c, 1978a; Jedrychowski et al., 1984).

         The conjugation products  S-carboxymethyl glutathione and
     S-formylmethyl glutathione are excreted in the urine of animals as
    substituted cysteine derivatives [ N-acetyl- S-(2-
    hydroxyethyl)cysteine,  S-carboxymethyl cysteine and thiodiglycolic
    acid] and the metabolite CO2 in exhaled air (Green & Hathway, 1975,
    1977; Watanabe et al., 1976a,b; Müller et al., 1976; Bolt et al.,
    1980). Thiodiglycolic acid has been detected in the urine of workers
    occupationally exposed to 0.36-18.2 mg/m3 (Müller et al., 1978).

         An alternative pathway has been suggested from inhibition studies
    of VC metabolism with ethanol (Hefner et al., 1975c). Pretreatment of
    rats with ethanol (5 ml/kg body weight) significantly reduced the
    depression of the concentration of non-protein sulfhydryl in the liver
    caused by exposure to 2780 mg VC/m3 for 105 min. This inhibition was
    less pronounced in rats exposed to < 260 mg/m3. It is postulated
    that at low concentrations, a sequential oxidation to 2-chloroethanol,
    2-chloroacetaldehyde and 2-chloroacetic acid, involving alcohol
    dehydrogenase, takes place. It is speculated that ethanol inhibits
    specific P-450 enzymes. However, this hypothesis has not been
    substantiated by further experimental data and this pathway has not
    been recognized as a direct pathway in recent physiologically based
    pharmacokinetic (PBPK) models and risk assessments based on them
    (sections 6.6 and 10).

         VC exposure does not result in enzyme induction but, on the
    contrary, causes destruction of the cytochrome P-450 protein
    responsible for its biotransformation (Pessayre et al., 1979; Du et
    al., 1982). The impaired rate of oxidative metabolism associated with
    P-450 destruction may partly explain the phenomenon of saturation of
    the VC metabolism already at relatively low dosage levels and on the
    other hand explain the tolerance to liver damage in experimental
    animals subjected to continuous intermittent exposure to high VC
    concentrations (73 000 mg/m3, 7 h/day, 5 days/week for 6 weeks).

         Enzymes metabolizing VC were shown to be saturated in rats at a
    concentration of 650 mg/m3 (rats exposed in a closed system; Bolt et
    al., 1977; Filser & Bolt, 1979). In rhesus monkeys saturation of
    metabolic elimination of VC was observed at atmospheric concentrations
    greater than 520 mg/m3 (closed system; Buchter et al., 1980).
    Saturation of metabolism occurred in rats at a single oral dose of
    20 mg/kg body weight by gavage (Watanabe & Gehring, 1976; Table 23).
    Saturation conditions were not reached in humans at an inhalation
    exposure to 60 mg/m3 for 6 h (Krajewski et al., 1980).

         In closed systems, after the initial absorption of VC until
    equilibrium between atmosphere and organism, the continued absorption
    is attributed to metabolism (Bolt et al., 1977). Rats exposed to VC
    concentrations that did not exceed the above-mentioned threshold of
    saturation metabolized VC in accordance with first-order kinetics with
    a half-time of 86 min. At concentrations above saturation, the
    elimination followed zero-order kinetics (Hefner et al., 1975a,c;
    Filser & Bolt, 1979).

         Although VC is primarily metabolized in the hepatocyte
    (Ottenwälder & Bolt, 1980), the primary target cell for
    carcinogenicity in the liver is the sinusoidal cell, as can be seen
    from the incidence of ASL in both animals and humans. Non-parenchymal
    cells have only 12% of the activity of hepatocytes in transforming VC
    into reactive, alkylating metabolites (Ottenwälder & Bolt, 1980). VC
    does not induce DNA damage in isolated non-parenchymal liver cells, as
    measured by an alkaline comet assay (Kuchenmeister et al., 1996),
    whereas it does in isolated hepatocytes. However, the majority of the
    DNA adduct studies have been conducted or related to the hepatocyte.
    It can be postulated that the majority of reactive metabolites can
    leave the intact hepatocyte to produce tumours in the sinusoidal cells
    (Laib & Bolt, 1980). The greater susceptibility of the sinusoidal
    cells to the carcinogenic effects of VC may also result from the
    inability of the sinusoidal cells to repair one or more of the DNA
    adducts produced by VC as efficiently as the hepatocyte.

    6.4  Elimination and excretion

         After low doses, VC is metabolically eliminated and non-volatile
    metabolites excreted mainly in the urine. At doses that saturate the
    metabolism, the major route of excretion is exhalation of unchanged

    VC. Independent of applied dose, the excretion of metabolites via
    faeces is only a minor route. The metabolic clearance of VC is slower
    in humans than in experimental animals, on a body weight basis.
    However, it is comparable in several mammalian species, including
    humans, when calculated on a body surface area basis.

    6.4.1  Oral exposure

         Male rats were gavaged with different doses of 14C-labelled VC,
    and the radioactivity excreted was determined during the following
    72 h (Green & Hathway, 1975; Watanabe & Gehring, 1976; Watanabe et
    al., 1976a). Results are presented in Table 23. With low doses
    radioactivity was mainly excreted as conjugated metabolites via the
    urine or exhaled as 14C-labelled CO2 (section 6.3), but with doses
    of 20 mg/kg body weight or more the main elimination route was
    exhalation of unchanged VC (Table 23), suggesting saturated
    metabolism. A minor route of excretion at all doses tested is via the
    faeces.

         Measuring the elimination of radioactivity in the urine as a
    function of time revealed biphasic elimination at dose levels up to
    100 mg/kg body weight with a half-life of approximately 4.6 h in the
    initial rapid phase (first-order kinetics) (Watanabe et al., 1976a).

         At low doses (1 mg/kg body weight) pulmonary elimination (as
    CO2) during the first 4 h was monophasic with a half-life of 58 min,
    but with a dose of 100 mg/kg body weight elimination of mainly
    unchanged VC was biphasic with an initial rapid phase (half-life
    14.4 min) followed by a slow phase (half-life 41 min) (Watanabe et
    al., 1976a).

         Most of the radioactivity excreted via urine or exhaled as the
    metabolite CO2 was eliminated during the first 24 h after gavaging of
    0.25 or 450 mg/kg body weight, whereas elimination of unchanged VC via
    the lung was complete within 3-4 h (Green & Hathway, 1975).

         Pretreatment of rats with unlabelled VC (up to 300 mg/kg body
    weight per day orally for 60 days) had no effect on the rate of
    elimination of a single oral dose of 14C-VC (oral application on
    day 1 and 60) (Green & Hathway, 1975), suggesting that VC did not
    induce its metabolism.

    6.4.2  Inhalation exposure

         Metabolic elimination of VC has been investigated in different
    species, measuring the decline of VC in the gas phase of a closed
    system into which VC was initially injected (Buchter et al., 1978;
    Filser & Bolt, 1979; Buchter et al., 1980). Using VC concentrations
    that did not exceed the saturation threshold (section 6.3), the
    following first-order metabolic clearance rates for VC (expressed in
    litre/h per kg body weight; initial concentration in mg/m3 in
    parentheses) were determined: rat 11.0 (< 650), mouse 25.6 (130),

    gerbil 12.48 (130), rabbit 2.74 (130), rhesus monkey 3.55 (< 520),
    humans 2.08 (26). Because the metabolism of VC is perfusion-limited
    (Filser & Bolt, 1979), comparison of clearance rates should be made on
    a body surface area basis rather than a body weight basis. In this
    case, these six mammalian species exhibit similar clearance rates.
    With exposure concentrations above the "saturation point"
    (> 650 mg/m3), the maximum velocity of metabolic elimination in rats
    was 110 µmol/h per kg body weight (Filser & Bolt, 1979) or 3.6 mg/h
    per kg body weight (Barton et al., 1995).

         Elimination and excretion of 14C in rats within 72 h after a 6-h
    exposure to 26, 2600 or 13 000 mg/m3 14C-labelled VC is shown in
    Table 25 (similar experimental design; Watanabe et al., 1976b, 1978b;
    Watanabe & Gehring, 1976). The amount of expired VC increased with the
    exposure concentration, whereas the relative urinary excretion of
    metabolites decreased, indicating a saturation of metabolism. Minor
    decreases were seen in the proportion excreted via the faeces or
    expired as CO2.

         Measuring the time course of expiration in these experiments, the
    pattern of pulmonary elimination of unchanged VC was similar at all
    exposure concentrations, following first-order kinetics with
    half-lives of 20.4, 22.4 (Watanabe et al., 1976b) and 30 min (Watanabe
    et al., 1978b), respectively. After a 6-h exposure to 26 and
    2600 mg/m3, elimination of the 14C-label via urine as a function of
    time revealed a biphasic excretion of radioactivity with estimated
    half-lives for the first (rapid) phase of 4.6 and 4.1 h (Watanabe et
    al., 1976b). Because of extremely variable excretion curves in the
    second phase, no attempts were made to estimate the half-lives of the
    slow phase, which accounted for less than 3% of the radioactivity
    excreted in the urine. Similar results were presented by Bolt et al.
    (1976). Rats exposed for 5 h to 130 mg/m3 14C-VC excreted 70% of
    incorporated radioactivity during the first 24 h after exposure in
    urine and less than 3% in the following 3 days.

         The rate of elimination of a single inhalative exposure to
    14C-VC is not influenced by prior repeated exposure to the same
    concentration (13 000 mg/m3) of unlabelled VC 6 h/day, 5 days/week
    for 7 weeks (Watanabe et al., 1978b).

         In human volunteers, the mean concentration of VC in the expired
    air up to 30 min after a 6-h exposure to 7.5-60 mg/m3 reached no more
    than 5% of the inhaled concentration (Krajewski et al., 1980).

         When male volunteers were exposed to 130 (n=6), 650 (n=4) or
    1300 mg/m3 (n=4) for 7.5 h, the VC concentration in expired air was
    2.6, 23 or 52 mg/m3, respectively, 1 h after exposure (Baretta et
    al., 1969).

    6.5  Reaction with body components

    6.5.1  Formation of DNA adducts

          In vitro, both CEO and CAA can form etheno adducts with nucleic
    acid bases (Fig. 3; Bolt, 1986; Bartsch et al., 1994; Barbin, 1998),
    but the former exhibits greater reactivity (Guengerich, 1992). In
    addition, 7-OEG has been characterized as a major reaction product of
    CEO with guanine (Scherer et al., 1981), whereas CAA does not yield
    this adduct (Oesch & Doerjer, 1982). 1, N6-Ethenoadenosine and
    3, N4-ethenocytidine were characterized as reaction products of VC
    with ribonucleosides in the presence of a microsomal activation system
    (Barbin et al., 1975; Laib & Bolt, 1978). Analysis of DNA incubated
     in  vitro with rat liver microsomes, an NADPH-regenerating system
    and [14C]-VC revealed the formation of 7-OEG, the major DNA adduct,
    and of 1, N6-etheno-2'-deoxyadenosine (Epsilon dA) and
    3, N4-etheno-2'-deoxycytidine (Epsilon dC) (Laib et al., 1981).
    More recently, Müller et al. (1997) quantified six adducts in DNA
    treated with CEO, including 7-OEG, the four ethenobases and
    5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazo[1,2-alpha]purine. The
    reactivity of CAA towards double-stranded B-DNA is very low
    (Guengerich, 1992). CAA reacts with unpaired A and C bases to yield
    Epsilon A and Epsilon C, respectively. Treatment of DNA with CAA has
    also been reported to result in the formation of  N2,3-Epsilon G and
    1, N2-Epsilon G moieties (Oesch & Doerjer, 1982; Kusmierek & Singer,
    1992; Guengerich, 1992).

         The formation of Epsilon dC and tentatively of Epsilon dA in
    liver DNA from rats exposed to VC in their drinking-water for 2 years
    was reported by Green & Hathway (1978). In subsequent studies, Epsilon
    A and Epsilon C were found in the nucleotides in hydrolysates of rat
    liver RNA and 7-OEG but not Epsilon A or Epsilon C in DNA after
    exposure to [14C]-VC (Laib & Bolt, 1977, 1978; Laib et al., 1981).
    Similar results were found in mice (Osterman-Golkar et al., 1977).
    More recent studies, using analytical methods (HPLC and fluorescence
    spectrophotometry, monoclonal antibodies and negative-ion chemical
    ionization with mass spectrometry using electrophore labelling; Fedtke
    et al., 1989, 1990a; Eberle et al., 1989) or experimental designs with
    greater sensitivity (young rats, short delay between exposure and
    analysis), have led to conclusive demonstration of Epsilon dA and
    Epsilon dC as DNA adducts in different rat organs after inhalation
    exposure to VC (Table 26). The concentration of DNA adducts was 3- to
    8-fold higher in the liver than in the lung and kidney, reflecting the
    higher capacity of the liver for metabolic activation of VC (Fedtke et
    al., 1990b; Swenberg et al., 1992). Both etheno bases (Epsilon C and
    Epsilon A) accumulated in rat liver DNA during intermittent exposure
    to VC (1300 mg/m3). Only Epsilon C accumulated in rat lung and
    kidney, Epsilon A appearing to accumulate principally in the target
    organ, the liver (Guichard et al., 1996). Subsequently, analysis of
    further tissues showed increased levels of Epsilon A in the testis,
    but not in the brain and spleen of rats exposed intermittently for 8
    weeks; levels of Epsilon C increased in the testis and spleen but not
    in the brain (Barbin, in press).

    FIGURE 3


         The rate of reaction of CAA with nucleic bases is slower than
    with CEO (Zajdela et al., 1980). In  in vitro studies, CEO but not
    CAA was shown to be the main entity giving rise to etheno adducts
    (Guengerich, 1992). Furthermore, as discussed in section 7.8, CEO but
    not CAA show similar toxicity/mutagenic profiles to VC in a
    metabolically competent human B-lymphoblastoid line (Chiang et al.,
    1997). These findings seem to corroborate the original suggestion that
    it is CEO rather than CAA that is the main source of etheno adducts
    (Van Duuren, 1975; Guengerich et al., 1981; Gwinner et al., 1983).

         In pre-weanling rats exposed to VC, 7-OEG had a half-life of
    approx. 62 h, while the etheno adducts are highly persistent with a
    half-life for Epsilon G of approx. 30 days (Swenberg et al., 1992).
    Studies on the persistence of Epsilon A and Epsilon C in the liver of
    adult rats have shown that there is no significant decrease in adduct
    levels 2 months after termination of VC exposure (Guichard et al.,
    1996). This is in contrast with the known repair of etheno adducts  in
     vitro (Dosanjh et al., 1994). The rat and human 3-methyladenine DNA
    glycosylases can excise Epsilon A from DNA (Saparbaev et al., 1995).
    Epsilon C can be released by the human mismatch-specific thymine-DNA
    glycosylase (Saparbaev & Laval, 1998).

         DNA adduct formation seems to be age-dependent; about 5- to
    6-fold more DNA adducts were determined in young animals compared to
    adults (Laib et al., 1989). Similar results were presented by Fedtke
    et al. (1990b) who exposed adult and 10-day-old Sprague-Dawley rats
    (Table 26). Ciroussel et al. (1990) exposed 7-day-old and 13-week-old
    rats (strain BD IV) for 2 weeks to VC and detected 6 times more DNA
    adducts in the liver of young rats compared to adults (Table 26).

         It should be noted that background levels of etheno bases have
    been found in various tissues in unexposed rodents (Guichard et al.,
    1996; Fernando et al., 1996; Barbin, in press) and humans (Nair et
    al., 1995, 1997). Lipid peroxidation products have been shown to react
    with nucleic acid bases yielding etheno adducts (El Ghissassi et al.,
    1995a; Chung et al., 1996; Bartsch et al., 1997). The role of lipid
    peroxidation products in the endogenous formation of background levels
    of etheno bases is further supported by the finding of elevated levels
    of Epsilon dA and Epsilon dC in the liver from Long Evans Cinnamon
    rats (Nair et al., 1996) and from patients with Wilson's disease or
    with primary haemochromatosis (Nair et al., 1998).

         Etheno adducts are also formed via substituted oxiranes formed
    from other vinyl monomers, e.g., vinyl bromide (Bolt, 1994) and vinyl
    and ethyl carbamate (urethane) (Park et al., 1993).

    6.5.2  Alkylation of proteins

         Bolt et al. (1980) studied covalent binding of radiolabel to
    proteins in rats exposed to 14C-labelled VC. The target of alkylation
    is the free sulfhydryl group of proteins. The liver always showed the
    highest binding rate. The fraction of VC that was irreversibly bound

    to proteins was independent of the VC dose applied, indicating no
    threshold effect even at low doses.  In vivo studies on rats
    (Guengerich & Watanabe, 1979) have shown that the amount of total VC
    metabolites bound in the liver to proteins is twice that bound to DNA,
    RNA and lipids. Osterman-Golkar et al. (1977) reported the alkylation
    of cysteine  (S-(2-hydroxyethyl)cysteine) and histidine ( (N-1-and
     N-3) hydroxyethylhistidine) of the globin precipitate of haemoglobin
    and small amounts of the alkylated histidines in proteins from testis
    in mice exposed to 1,2-14C-vinyl chloride.

          In vitro studies have shown that incubation of rat liver
    microsomes with 14C-labelled VC results in NADPH-dependent microsomal
    uptake and covalent binding to microsomal proteins (Kappus et al.,
    1975, 1976; Baker & Ronnenberg, 1993). It has been suggested that VC
    metabolites might be involved in the destruction of the haem moiety of
    cytochrome P-450 in the liver (Guengerich & Strickland, 1977).

    6.6  Modelling of pharmacokinetic data for vinyl chloride

         There has been progress in recent years in the development of
    physiologically based toxicokinetic (PBTK) models describing the
    toxicokinetics of chemicals. These theoretical models permit
    predictions of the dose of active metabolites reaching target tissues
    in different species, including humans, and, therefore, have improved
    the toxicokinetic extrapolation in cancer risk assessments. PBTK
    models have also been used as a tool to examine the behaviour of VC in
    mammalian systems. The description of PBTK models for VC is presented
    in Annex 2.

        Table 26.  Detection of DNA adducts in vivo after VC inhalation in ratsa
                                                                                                                                       

    Strain; sex;       Treatment;             Investigated     Alkylated bases in                 Comments                  References
    age                post-exposure          organs           DNA (max. concentration
                       survival time                           in pmol/µmol unmodified
                                                               base in specified organs)
                                                                                                                                       

    BD IV; male &      1300 mg/m3, 7 h/day,   liver, lung,     epsilon-dA (0.131, 0.105,          higher sensitivity of     Ciroussel
    female; 7 days     7 days/week for        brain, kidney    0.06, b.d.l.); epsilon-dC          young rats compared       et al.(1990)
                       2 weeks; none                           (0.492, 0.246, 0.216,              with adults
                                                               b.d.l.)                            (see section 7.7.4)

    BD IV; male;       1300 mg/m3, 7 h/day,   liver            epsilon-dA (0.019);                                          Ciroussel
    13 weeks           7 days/week for                         epsilon-dC (0.080)                                           et al. (1990)
                       2 weeks; none

    S.-D.; male &      1560 mg/m3, 4 h/day    liver, lung,     7-OEG (162, 20, 29, <10,           higher sensitivity of     Fedtke et
    female; 10 days    for 5 days;            kidney,          <10); N2,3-epsilon-G (1.81,        young rats compared       al. (1990b)
                       0, 3, 7, 14 days       brain, spleen    0.21, 0.31, <0.12, <0.12);         with adults (see
                                                               measured immediately a.e.          section 7.7.4)
                                                                                                  concerning liver
                                                                                                  adducts

    S.-D.; female;     1560 mg/m3, 4 h/day    liver, lung,     7-OEG (43, 20, n.g.);              DNA adduct formation      Fedtke et
    adult              for 5 days;            kidney           N2,3-epsilon-G (0.47,              max. at the end of        al. (1990b)
                       0, 3, 7, 14  days                       0.27, <0.12); measured             exposure; most DNA
                                                               immediately a.e.                   adducts in the liver

    S.-D.; male &      5200 mg/m3, 7 h/day    liver, lung      epsilon-dA (0.05, 0.13)            more DNA adducts in the   Eberle et
    female; 11 days    on days 1-9 and 24 h                    epsilon-dC (0.16, 0.33)            lung than in the liver    al. (1989)
                       on day 10; none

    S.-D.;  male &     1560 mg/m3, 4 h/day    liver, lung,     7-OEG (162, 20, 29);               DNA adduct                Swenberg
    female; 10 days    for 5 days;            kidney           N2,3-epsilon-G  (1.81, 0.21,       max. at the end           et al.
                       0, 3, 7, 14 days                        0.31); epsilon-dC (0.98, 0.30,     exposure; most DNA        (1992)
                                                               0.29); epsilon-dA (0.21, 0.065,    adducts in the liver
                                                               0.04); measured immediately a.e.

    Table 26. (cont'd)
                                                                                                                                       

    Strain; sex;       Treatment;             Investigated     Alkylated bases in                 Comments                  References
    age                post-exposure          organs           DNA (max. concentration
                       survival time                           in pmol/µmol unmodified
                                                               base in specified organs)
                                                                                                                                       

    S.-D.; male;       1300 mg/m3, 4 h/day,   liver, lung,     epsilon-dA (liver: background      exposure-time-dependent   Guichard
    6 weeks            5 days/week for 1,     kidney,          0.0004, a.e. up to 0.045;          increase of adducts in    et al. (1996)
                       2, 4, 8 weeks; none    lymphocytes      background lung and kidney up to   liver (ca. 100-fold);
                                                               0.033, no increase a.e.);          no (lymphocytes) or
                                                               epsilon-dC (liver: background      slight increase (ca.
                                                               0.0007, a.e. up to 0.08; kidney:   2-fold in kidney, ca.
                                                               background 0.086, a.e. up to       5-fold in lung) of
                                                               0.16; lung: background 0.072,      adducts in other
                                                               a.e. up to 0.38)                   organs but higher
                                                                                                  background levels

                       8 weeks                brain, testis,   epsilon-dA (increase in testis,                              Barbin
                                              spleen           not in brain or spleen)                                      (in press)
                                                               epsilon-dC (increase in testis
                                                               and spleen, but not in brain)
                                                                                                                                       

    a  a.e. = after exposure; b.d.l. = below detection limit; n.g. = not given; S.-D. = Sprague-Dawley; epsilon-dA = 1,N6-ethenodeoxyadenosine;
       epsilon-dC = 3,N4-ethenodeoxycytidine; 7-OEG = 7-(2-oxoethyl)guanine; epsilon-G = ethenoguanine
        

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Acute toxicity

         VC appears to be of low acute toxicity when administered to
    various species by inhalation. A summary of acute toxicity is given in
    Table 27. No data are available on acute toxicity after dermal
    application.

         VC has a narcotic effect (see also section 7.6) after inhalative
    administration of high doses. In rats, mice and hamsters, death was
    preceded by increased motor activity, twitching of extremities,
    tremor, ataxia, tonic-clonic convulsions and accelerated respiration
    (Patty et al., 1930; Mastromatteo et al., 1960; Prodan et al., 1975).
    In dogs, severe cardiac arrhythmias occurred under narcosis after
    inhalative exposure to 260 000 mg VC/m3 (Oster et al., 1947). Similar
    results were reported by Carr et al. (1949). Pneumonitis was more
    frequent in experimental mice than in controls 8 and 18 months after a
    single 1-h exposure to 1000, 3000, 13 000 or 130 000 mg/m3 (Hehir et
    al., 1981).

         After acute inhalative exposure to VC, pathological findings in
    the rat included congestion of the internal organs, particularly lung,
    liver and kidney as well as pulmonary oedema (Patty et al., 1930;
    Mastromatteo et al., 1960; Lester et al., 1963; Prodan et al., 1975).

         Exposure to VC (3900 mg/m3) for 24 h did not cause pathological
    changes in male and female rats or female New Zealand rabbits. In
    mice, exposure to the same concentration for 4 and 8 h resulted in
    circulatory changes, while longer exposure (12 and 24 h) caused
    vasomotor paralysis followed by characteristic shock with subsequent
    alterations in the liver and lungs (Tátrai & Ungváry, 1981).

    7.2  Short-term toxicity

    7.2.1  Oral exposure

         Groups of 15 male and 15 female weanling Wistar rats were gavaged
    with VC dissolved in soya-bean oil (0, 30, 100 and 300 mg/kg body
    weight, once daily, 6 days/week for 13 weeks). The treatment caused no
    noticeable changes in appearance or behaviour, body weight gain or
    food intake. The total number of white blood cells and the sugar
    content of the blood were slightly decreased by the intermediate and
    high dose levels. The activities of serum ASAT and ALAT and of urinary
    ASAT were decreased in males given the top dose. There were no other
    significant changes in the haematological or biochemical indices and
    no treatment-related alterations were observed in the microscopic
    constituents of the urine. The relative weight of the liver in males
    and females showed a tendency to increase with increasing doses of VC
    but the difference from the controls was statistically significant
    only at the highest dose level. The NOEL was given as 30 mg/kg body
    weight (Feron et al., 1975). In contrast, in another study, all male

    and female Wistar rats (presumably a total of 15 rats) receiving once
    daily 300 mg VC/kg body weight in peroxide-free corn oil by gavage
    died within 60 days of treatment (Knight & Gibbons, 1987).

    7.2.2  Inhalation exposure

         A summary of the non-neoplastic effects of VC after short-term
    inhalation is presented in Table 28. Information on carcinogenic
    effects after short-term inhalation are presented in section 7.7 and
    Table 30.

         In various species, the main target of VC toxicity is the liver.
    A dose-related significant increase in relative liver weight was found
    in male rats at exposure levels of 26, 260 and 7800 mg/m3 (Bi et al.,
    1985). Degenerative effects on liver parenchyma were reported in
    rabbits at a dose level of 520 mg/m3 (Torkelson et al., 1961), in
    rats at 1300 mg/m3 (Torkelson et al., 1961; Wisniewska-Knypl et al.,
    1980), and in mice at 2600 mg/m3 (Lee et al., 1977). Bi et al. (1985)
    reported a decreased relative testis weight in rats at exposure levels
    of 260 and 7800 mg/m3; however, the effect was not dose-related.
    These authors also reported a higher incidence and severity of damage
    to the testicular seminiferous tubules at all dose levels tested (26,
    260 and 7000 mg/m3), the differences with the controls being
    statistically significant only at the two highest dose levels.
    However, the severity of the testicular damage was clearly
    dose-related (correlation coefficient 0.993;  P < 0.01) suggesting
    an adverse effect of VC on the testes already at 26 mg/m3. Effects on
    relative liver weight were detected in rats at 26 mg/m3 (Bi et al.,
    1985) (see also Table 28 and section 7.5.1). Effects on the kidney
    (Lee et al., 1977; Feron et al., 1979a,b; Himeno et al., 1983) and the
    lung (Suzuki, 1980) were observed in rats and/or mice at higher doses
    (Table 28). For mice a LOEL of 130 mg/m3 was given (decreased
    survival; Hong et al., 1981). Rats, mice and rabbits seem to be more
    sensitive than guinea-pigs and dogs (Torkelson et al., 1961; Hong et
    al., 1981).

    7.2.3  Dermal exposure

         No studies were available on short-term dermal exposure.

    7.3  Long-term toxicity - effects other than tumours

    7.3.1  Oral exposure

         Studies on effects induced by long-term oral application of VC in
    rats are presented in detail in Table 29. Studies on other species are
    not available.

         Long-term feeding studies in male and female rats showed
    increased mortality in males at doses > 5.0 mg/kg body weight per
    day (Feron et al., 1981) and in females at doses of > 1.3 mg/kg

        Table 27. Toxicity of VC after acute inhalation exposurea
                                                                                       

    Species        Duration of     Parameter            Value        References
                   exposure                             in g/m3
                                                                                       

    Rat            2 h             LC50                 390          Prodan et
                                   LC100                525          al. (1975)

    Rat            30 min          LC100                780          Mastromatteo
                                                                     et al. (1960)

    Rat            1 h             ataxia,              130          Hehir et al.
                                   hyperventilation                  (1981)

    Mouse          2 h             LC50                 293          Prodan et al.
                                   LC100                375          (1975)

    Mouse          30 min          LC100                780          Mastromatteo
                                                                     et al. (1960)

    Guinea-pig     2 h             LC50                 595          Prodan et al.
                                   LC100                700          (1975)

    Guinea-pig     30 min          death,               780          Mastromatteo
                                   threshold dose                    et al. (1960)

    Guinea-pig     2-6 h           deep narcosis,       260          Patty et al.
                                   no death                          (1930)

    Guinea-pig     18-55 min       death,               390-650      Patty et al.
                                   threshold dose                    (1930)

    Guinea-pig     90 min          narcosis,            65-130       Patty et al.
                                   threshold dose                    (1930)

    Rabbit         2 h             LC50                 295          Prodan et al.
                                   LC100                700          (1975)
                                                                                       

    a  Cited studies not conducted according to present-day standards


        Table 28.  Toxicity of vinyl chloride in animals after short-term inhalation exposures - non-neoplastic effectsa
                                                                                                                                              

    Species, strain;     Doses in       Exposure duration;       Significant effects                                      References
    number of animals    mg/m3          frequency;
    per dose per                        post-exposure
    exposure period                     observation period
                                                                                                                                              

    Rat, Wistar; 8       0, 26, 260,    3 or 6 mo;               26 mg/m3: relative spleen and heart weight               Bi et al.
    (3 mo) or 30         7800           6 d/week, 6 h/d;         * (6 mo); incidence of testicular seminiferous           (1985)
    (6 mo)  m rats                      none                     tubule damage * ! (exposure period not specified)
                                                                 > 26 mg/m3: relative liver weight * (6 mo) 260 mg/m3:
                                                                 relative heart weight * (3 mo) > 260 mg/m3: relative
                                                                 testis weight ** (6 mo); incidence of testicular
                                                                 tubule damage * 7800 mg/m3: relative kidney and
                                                                 spleen weight * (3 mo)

    Rat; n.g.; at high   0, 130, 260,   4.5 (high dose)          130 mg/m3: NOEL (body and organ weight,                  Torkelson
    dose 10 f &          520, 1300      or 6 mo;                 survival, haematology, clinical chemistry, urine         et al.
    10 m (control                       5 d/week,                analysis, histopathology) 260 mg/m3: relative liver      (1961)
    5 f & 5 m); other                   7 h/d; none              weight * (m+f) 1300 mg/m3: granular degeneration
    groups 20-24 m                                               in centrilobular liver parenchyma #;
    & 24 f                                                       liver weight * (m)

    Rat, Wistar;         0, 130,        1, 3, 6 mo;              130 mg/m3: slight changes such as proliferation          Wisniewska-Knypl
    8-10 m               1300,          5 d/week, 5 h/d;         of hepatocellular SER (3-6 mo)#                          et al.
                         52 000         none                     > 1300 mg/m3: liver weight * (1-6 mo), ultrastructural   (1980)
                                                                 hepatocellular changes (swollen mitochondria, lipid
                                                                 droplets *) after 3 and 6 mo #

    Rat,                 0, 2465        24.5 weeks;              2465 mg/m3: mortality *# (m+f), haematology and          Groth et
    Sprague-Dawley;                     7 h/d, 5 d/week;         clinical chemistry <->                                   al. (1981)
    110-128 rats                        up to 19 weeks
    per sex

    Rat, Wistar;         0, 13 000      4, 13, 26 weeks;         13 000 mg/m3, > 4 weeks: body weight **,                 Feron et al.
    10 f & 10 m                         5 d/week, 7 h/d;         blood clotting time ** > 13 weeks: liver function        (1979a,b)
                                        none                     (BSB-retention test) **; liver and kidney
                                                                 weight * (m+f)

    Table 28. (cont'd)
                                                                                                                                              

    Species, strain;     Doses in       Exposure duration;       Significant effects                                      References
    number of animals    mg/m3          frequency;
    per dose per                        post-exposure
    exposure period                     observation period
                                                                                                                                              

                                                                 26 weeks: spleen weight * (m+f); clear cell foci         Feron &
                                                                 and basophilic foci in the liver * (m+f)#                Kroes (1979)

    Rat, Sherman;        0, 52 000      92 d; 5 d/week,          52 000 mg/m3: relative liver weight * and                Lester et al.
    12-15 rats/sex                      8 h/d;  none             spleen weight ** (m+f); white blood cell counts **;      (1963)
                                                                 swelling of hepatocytes with vacuolization,
                                                                 compression of sinusoids #

    Mouse, CD-1;         0, 130, 650,   1, 3, 6 mo;              > 130 mg/m3: survival after 6 mo exposure ** # (low      Hong et al.
    8-28 mice/sex        2600           5 d/week, 6 h/d;         dose: m, 1/8 versus 22/28 in control; f, 0/8 versus      (1981)
                                        12 mo                    23/28; tumour incidences no differences)

    Mouse, CD-1;         0, 2600        3-9 exposures;           2600 mg/m3: early deaths (2 m + 1 f)!; pathological      Lee et al.
    36 mice/sex                         5 d/week, 6 h/d;         changes in dead animals: acute toxic hepatitis           (1977)
                                        none                     (congestion, diffused necrosis), tubular necrosis
                                                                 in renal cortex

    Mouse, n.g.;         6500           1 or 6 mo;               6500 mg/m3: hyperplastic nodules and dilatated           Schaffner
    5 m (1 mo) or        (no control)   5 d/week, 5 h/d;         sinusoids in liver parenchyma after 6 mo                 (1979)
    14 m (6 mo)                         none                     exposure #

    Mouse, CD-1;         0, 6500,       5-6 mo;                  > 6500 mg/m3: proliferation and hypertrophy of           Suzuki
    3-16 m               15 600         5 d/week, 5 h/d;         bronchiolar cells, hypersecretion of bronchial           (1980)
                                        2-37 d                   and bronchiolar epithelium, hyperplasia of
                                                                 alveolar epithelium, bronchiolar inflammation #
                                                                 (only pulmonary effects recorded; effects not
                                                                 dose related)

    Mouse, CD-1;         13 000         10 weeks;                13 000 mg/m3: focal lung hyperplasia, proliferation      Himeno et
    10 m                 (no control)   5 d/week, 4 h/d;         of sinusoidal cells of the liver, proliferative          al. (1983)
                                        none                     effects in renal glomeruli, giant cells in testis #

    Table 28. (cont'd)
                                                                                                                                              

    Species, strain;     Doses in       Exposure duration;       Significant effects                                      References
    number of animals    mg/m3          frequency;
    per dose per                        post-exposure
    exposure period                     observation period
                                                                                                                                              

    Mouse, ICR;          a) 0, 13 000,  a) 5 to 6 d,             basophilic stippled erythrocytes * (#) in a) and b),     Kudo et
    n.g.                 26 000;        b) 62 d; a) 4 h/d,       related effect not dose                                  al. (1990)
                         b) 78 to 104   b) continuously;
                                        none

    Hamster,             0, 520         6 mo; 5 d/week,          520 mg/m3: survival **                                   Drew et
    golden Syrian;                      6 h/d;  life span                                                                 al. (1983)
    56 f

    Guinea-pig,          0, 130,        6 mo; 5 d/week,          520 mg/m3: NOEL (body and organ weight,                  Torkelson
    n.g.; 10-12 m        260, 520       7 h/d;  none             survival,  clinical chemistry, histopathology)           et al. (1961)
    & 8-12 f

    Rabbit, n.g.;        0, 130,        6 mo; 5 d/week,          260 mg/m3: NOEL (body and organ weight,                  Torkelson
    3 rabbits/sex        260, 520       7 h/d; none              survival,  clinical chemistry, histopathology)           et al. (1961)

                                                                 520 mg/m3: degeneration of centrilobular
                                                                 liver parenchyma (m+f) with periportal cellular
                                                                 infiltration (f) #

    Dog; n.g.;           0, 130,        6 mo; 5 d/week,          130-520 mg/m3: no effects recorded (body and             Torkelson
    1 dog/sex            260, 520       7 h/d; none              organ weight, survival, haematology, clinical            et al. (1961)
                                                                 chemistry, urine analysis, histopathology) #
                                                                                                                                              

    a  d = day; mo = month, m = male; f = female; n.g. = not given;  ! = increase not significant; # = no data about significance;
       * = increased; ** = decreased; <-> = no change


    body weight per day (Feron et al., 1981; Til et al., 1983, 1991). At
    14.1 mg/kg body weight per day, blood clotting time was decreased and
    alpha-fetoprotein levels in blood serum were increased (Feron et al.,
    1981). Skin fibrosis was observed at 30 mg/kg body weight per day
    administered by gavage (Knight & Gibbons, 1987).

         As for short-term exposure, the primary target organ of VC in
    rats after long-term oral exposure is the liver. Female rats appeared
    to be more sensitive than males to the hepatotoxicity of VC
    (section 7.7.4). Increased relative liver weights were found at
    14.1 mg/kg body weight per day after feeding periods of 6 or 12 months
    (Feron et al., 1981). Morphological alterations of the liver included
    extensive hepatocellular necrosis at doses > 5 mg/kg body weight
    per day, foci of haematopoiesis at 14.1 mg/kg body weight per day, and
    cysts and liver cell polymorphism (variation in size and shape of
    hepatocytes and their nuclei) at doses > 1.3 mg/kg body weight per
    day (Feron et al., 1981; Til et al., 1983, 1991). Foci of
    hepatocellular alteration (clear cell, mixed cell, eosinophilic and
    basophilic foci) were common findings. Clear cell, mixed cell and
    eosinophilic foci occurred at doses > 1.3 mg/kg body weight per day
    and basophilic foci at doses > 0.014 mg/kg body weight per day (Til
    et al., 1983, 1991).

    7.3.2  Inhalation exposure

         A summary of non-neoplastic and neoplastic effects after
    long-term intermittent inhalation of VC is presented in Table 32 with
    details of exposure regime (see also section 7.7). Long-term exposure
    to VC by inhalation resulted in increased mortality in rats exposed to
    a dose of 260 mg/m3 for 12, 18 and 24 months, in mice exposed to
    130 mg/m3 for 6, 12 and 18 months and in hamsters exposed to
    520 mg/m3 for 6, 12 and 18 months (Drew et al., 1983). Maltoni et al.
    (1984) reported increased mortality in rats (BT15) and hamsters (BT8)
    at lower dose levels (2.6 and 130 mg/m3, respectively), but no
    statistical evaluation was performed. Rats exposed to 130 mg/m3
    showed reduced body weight and increased relative spleen weight (Sokal
    et al., 1980; see below). At this dose morphological alterations were
    reported in rat liver, such as hepatocellular lipid accumulation and
    mitochondrial swellings (Wisniewska-Knypl et al., 1980) as well as
    proliferation of cells lining the liver sinusoids (Sokal et al.,
    1980). Exposure to higher doses revealed degenerative alteration in
    the testis (1300 mg/m3; Sokal et al., 1980) and tubular nephrosis and
    focal degeneration of the myocardium (13 000 mg/m3; Feron & Kroes,
    1979) in rats.

         Male Wistar rats (42-80 per group) exposed to 0, 130, 1300 and
    52 000 mg VC/m3, 5 days/week, 5 h daily, for 10 months, showed
    significantly reduced body weight in all treatment groups; general
    condition and behaviour were not altered. Relative organ weights of
    spleen and heart (except at the mid dose) were significantly elevated
    at > 130 mg/m3, as well as liver and kidney weights at mid- and

    high-dose levels and testis weights at the high-dose level. X-ray
    analysis did not show any skeletal alterations. Histopathology
    revealed statistically significantly increased incidences of nuclear
    polymorphism (nuclei of variable size and irregular shape) of
    hepatocytes and proliferation of reticuloendothelial cells lining
    liver sinusoids at the two highest dose levels. Fatty degeneration of
    hepatocytes was found at all exposure levels. Ultrastructural changes
    in hepatocytes seen at all exposure levels, but not in controls,
    included swollen and giant mitochondria with broken cristae,
    proliferation and dilatation of smooth endoplasmic reticulum, nuclear
    membrane invaginations, areas of cytoplasmic degradation and increased
    numbers of small lipid droplets (Sokal et al., 1980; Wisniewska-Knypl
    et al., 1980). In addition, Sokal et al. (1980) reported necrotic foci
    of the spermatogenic epithelium and disorders of spermatogenesis
    accompanied by large multinuclear syncytial cells in the testis
    predominantly at 1300 mg/m3. Haematology, urine analysis and clinical
    chemistry did not reveal differences of toxicological significance.

         Thus NOEL for rats or mice concerning non-neoplastic effects
    could not be derived, since effects were observed at the lowest levels
    studied (130 mg/m3).

    7.4  Skin and eye irritation; sensitization

         No relevant data on skin irritation were identified. No studies
    were available on sensitizing effects of VC in animals. Erythema and
    second-degree burns were reported in a worker after accidental
    exposure to liquid VC (see section 8.3.2.1). Dryness of eyes and nose
    was reported by volunteers exposed to 1300 mg/m3 (see section 8.2).

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    7.5.1  Male reproductive toxicity

         Inhalation studies on rats showed some evidence of reduced
    fertility and morphological alterations of the testis. It should be
    noted that none of the studies cited were conducted according to
    current guidelines (OECD, 1983a,b).

         In dominant lethal studies on mice no reduction in fertility was
    observed (Anderson et al., 1976; Table 35). However, reduced fertility
    was noted in male CD rats (12 per group) mated once on week 11 of
    exposure (0, 130, 650 or 2600 mg/m3; 6 h/day, 5 days per week). VC
    treatment decreased dose-dependently the ratio of pregnant to mated
    females; this was significant at mid- and high-dose level (Short et
    al., 1977; see also section 7.8.2).

         Bi et al. (1985; for details see Table 28 and section 7.2.2)
    observed decreased relative testis weight at 260 mg/m3 and
    morphological alterations in the testis of rats even at the lowest
    dose of 26 mg/m3. Morphological alterations in the testis of rats
    were also reported by Sokal et al. (1980, see section 7.3.2).

         VC was administered to adult female CD rats at 0, 24, 260 and
    2860 mg/m3, 6 h/day, 5 days/week for at least 10 weeks prior to
    mating until day 4 of lactation (94 + days) in a two-generation study.
    Alterations in reproductive performance and fertility were not
    detected at any dose level tested. Centrilobular hypertrophy in the
    liver and increased relative liver weights, however, were noted at all
    dose levels tested in a dose-related manner (Shah, 1998).

    7.5.2  Embryotoxicity and teratogenicity

         Although the available studies did not follow guideline
    standards, the information leads to the conclusion that there is
    embryotoxicity or fetal toxicity, including increased numbers of
    resorptions, decreased numbers of live fetuses and delayed development
    at dose levels producing maternal toxicity. VC treatment did not
    induce gross malformations. There is evidence for the permeability of
    the placenta to VC (Ungváry et al., 1978; see section 6.2.2).

         John et al. (1977, 1981) investigated mice, rats and rabbits for
    teratogenic effects of inhaled VC. In all three species a similar
    experimental design was used. Pregnant CF-1 mice were exposed 7 h/day
    to 0, 130 or 1300 mg VC/m3 on day 6-15 of gestation. For both
    concentrations tested, concurrent control groups were sham-exposed.
    Animals were observed daily and maternal body weight recorded at
    several intervals (no further data). The mice were sacrificed on day
    18 of gestation. After determination of external anomalies, one-third
    of each litter (19-26 litters per group) was examined for soft tissue
    anomalies and the other mice for skeletal anomalies. Exposure to
    1300 mg/m3 led to deaths (5 of 29 bred females,  P < 0.05), reduced
    maternal body weight gain  (P < 0.05) and food consumption
     (P< 0.05). No maternal toxicity was apparent in females exposed to
    130 mg/m3. The number of live fetuses per litter and fetal body
    weight were significantly decreased and the number of resorptions
    significantly increased at 1300 mg/m3, but these values were within
    the range observed for the second concurrent control group or for
    historical controls. No soft tissue or external anomalies were
    detected. Significantly increased incidences of three skeletal
    variants (delayed skull and sternebrae ossification, unfused
    sternebrae) in the high-dose group were indicative of delayed skeletal
    development. No developmental toxicity was observed at 130 mg/m3.

         Sprague-Dawley rats were exposed to 0, 1300 or 6500 mg/m3 on
    gestation day 6-15 and dams were sacrificed on day 21 of gestation.
    Low-dose exposure resulted in reduced maternal weight gain
     (P< 0.05). At the high-dose level further maternal effects like
    reduced food consumption and increased liver weight were observed
     (P< 0.05), and one out of 17 pregnant rats died (no further
    information). Examination of 16-31 litters per group revealed
    significantly decreased fetal weight in the low-dose but not in the
    high-dose group. Significantly increased incidences in dilated ureter
    were observed at 6500 mg/m3.

         Rabbits were exposed on gestation day 6-18 to 0, 1300 or
    6500 mg/m3 and sacrificed on gestation day 29. Except for reduced
    food consumption in the low-dose group and 1 death in 7 bred females
    of the high-dose group, no further evidence of maternal toxicity was
    observed. In the high-dose group only 5 litters were examined, but in
    other groups 11-19 litters. Compared to the concurrent control, litter
    size was significantly reduced in the low-dose group (but not at
    6500 mg/m3). However, there was an increase in litter size in this
    treatment group compared to controls concurrent to the high-dose
    group. The incidence of delayed ossification of the sternebrae was
    increased at 1300 mg/m3, but not in the high-dose group (John et al.,
    1977, 1981).

         Ungváry et al. (1978) exposed pregnant CFY rats continuously to 0
    or 4000 mg VC/m3 during the first, second or last third of pregnancy
    (gestation day 0-8, 7-13 or 13-20). Dams were sacrificed on gestation
    day 20 and living, dead or resorbed fetuses were recorded. Placenta
    and fetuses were weighed and fetuses macroscopically investigated. One
    half of each litter was examined for soft tissue anomalies including
    histopathology of organs with abnormalities and the other half was
    processed for investigation of the skeletal system. Maternal weight
    gain was significantly reduced in pregnant rats exposed during the
    last third of pregnancy. Increased relative liver weight was observed
    in dams exposed during the first or second third, but histopathology
    revealed no pathological changes in the liver of any VC-treated rat.
    No further signs of maternal toxicity were reported. Examination of 13
    to 28 litters per group revealed increased fetal loss in per cent of
    total implantation sites after exposure during gestation day 0-8
    compared with the concurrent control. However, this value was not
    significant compared with other control groups (e.g., control exposed
    gestation day 13-20) of the same study. None of the soft tissue or
    skeletal anomalies were attributed to VC treatment.

         Exposure of 40 pregnant white Wistar rats to VC (mean level of
    6.15 mg/m3 during whole gestation) resulted in elevated embryonic
    mortality, lowered fetal weight, and induction of external and
    internal anomalies in the development of the fetus (Mirkova et al.,
    1978).

    7.6  Special studies

    7.6.1  Neurotoxicity

         Profound narcosis was reported in guinea-pigs exposed to
    65 000 mg VC/m3 for 90 min (Patty et al., 1930). Ataxia was observed
    at this dose level after 5 min of exposure. The anaesthetic action of
    VC was also observed in dogs (Oster et al., 1947) and mice (Peoples &
    Leake, 1933). Mastromatteo et al. (1960) reported deep narcosis in
    rats and mice exposed to 260 000 mg/m3 for 30 min. The narcotic
    effect was preceded by increased motor activity after 5 min of

    exposure, twitching of extremities (after 10 min), ataxia (after
    15 min) and tremor (after 15 min). Rats exposed to 130 000 mg/m3 for
    60 min showed ataxia preceded by hyperactivity but no narcotic effect
    (Hehir et al., 1981).

         Neuropathological alterations were observed in rats exposed to
    78 000 mg/m3 (4 h/day, 5 days/week) for 12 months (Viola, 1970; Viola
    et al., 1971). During the exposure period, the rats were slightly
    soporific. Histopathology revealed diffuse degeneration in the gray
    and white matter of the brain and at the level of the white matter
    zones of reactive gliosis. In the cerebellum, atrophy of the granular
    layer and degeneration of Purkinje cells were most prominent. In
    addition, peripheral nerve bundles were often surrounded and invaded
    by fibrotic processes.

         Reports on neurotoxicity in humans occupationally exposed to VC
    are given in section 8.3.2.3.

    7.6.2  Immunotoxicity

         Sharma & Gehring (1979) investigated mitogen-stimulated
    transformation in splenic lymphocytes isolated from mice exposed to
    26, 260 or 2600 mg/m3 for 2, 4 or 8 weeks (6 h/day, 5 days/week). The
    treatment produced no effects on body or organ weight, except
    increased spleen weight in high-dose groups, no effects on
    haematological parameters and no pathological alterations at necropsy.
    VC exposure caused stimulation of spontaneous lymphocyte
    transformation in lymphocyte cultures prepared from mice exposed for 2
    weeks to the high dose and from mice exposed for 4 weeks at all dose
    levels, but this was not dose-dependent. The response of lymphocytes
    to phytomitogens was increased at 2600 mg/m3 after exposure for
    2 weeks and at all dose levels after exposure for 4 or 8 weeks, with
    more pronounced effects at the mid-dose level. Stimulation of
    lymphocyte transformation was not observed in lymphocytes from
    unexposed mice cultured in the presence of VC, indicating that
    metabolites of VC formed  in vivo may be responsible for this effect.

         Exposure of mice to 26 mg/m3 for 6 months (Bi et al., 1985;
    Table 28) or rats to 130 mg/m3 for 10 months (Sokal et al., 1980;
    section 7.3.2) induced increased relative spleen weight, whereas much
    higher doses (52 000 mg/m3 for 92 days) produced decreased spleen
    weight and reduced white blood cell counts (Lester et al., 1963; see
    Table 28).

         Reports on immunological and lymphoreticular effects in humans
    occupationally exposed to VC are given in section 8.3.2.

    7.6.3  Cardiovascular effects

         Viola (1970) demonstrated thickening of the walls of small
    arterial vessels (in some vessels blockage of lumen) due to
    endothelial fibrosis and proliferation of endothelial cells in rats

    exposed to 78 000 mg/m3 (4 h/day, 5 days/week) for 12 months.
    Exposure of rats to 13 000 mg/m3 for 12 months (Feron & Kroes, 1979;
    see Table 32) resulted in thickened walls of arteries and focal
    degenerations of the myocardia.

         Oster et al. (1947) observed cardiac arrhythmias (e.g.,
    ventricular extrasystoles and fibrillation, auriculoventricular block)
    in dogs at a dose level of 260 000 mg/m3.

         Bi et al. (1985) reported increased relative heart weight in rats
    exposed for 6 months to 26 mg/m3 or for 3 months to 260 mg/m3 (Table
    28).

         Impaired peripheral circulation as well as other cardiovascular
    effects in occupational exposed humans are described in section 8.3.2.

    7.6.4  Hepatotoxicity

         Data on hepatotoxicity are presented in sections 7.2 and 7.3.

    7.7  Carcinogenicity

         VC causes a wide spectrum of tumours in animals and this spectrum
    is similar in a number of different species (see Table 33). For
    example in rats, the following tumours have been described after VC
    inhalation exposure: liver and other angiosarcomas, other liver
    tumours, mammary gland carcinoma, nephroblastoma, neuroblastoma,
    stomach tumours and Zymbal gland tumours. The lowest dose at which an
    increase in tumour incidences was observed when rats were exposed by
    inhalation was 130 mg/m3 for liver angiosarcoma (ASL) and 13 mg/m3
    for mammary tumours. There is evidence that animals are more
    susceptible to tumour induction early in life. There is also evidence
    that liver tumours are induced in female rats at lower doses than in
    males.

         VC is also carcinogenic in animals after oral application. The
    spectrum of tumours is similar to that observed after inhalation
    exposure. The lowest observed dose producing a carcinogenic effect
    (ASL) in rats was 1.3 mg/kg body weight per day.

    7.7.1  Oral exposure

         Details of studies on the carcinogenicity of VC in rats after
    oral administration are tabulated in Table 29. There are three gavage
    studies: two studies with 52 or 59 weeks gavage and a 32- or 18-week
    follow-up and a 2-year lifetime gavage study with small numbers of
    animals and high mortality at high doses (Maltoni et al., 1981 [BT11
    and BT27] and Knight & Gibbons, 1987). The two feeding studies used
    PVC powder containing VC incorporated into the diet; the numbers of
    animals were large, and the administration comprised the whole
    lifetime of the animals (Feron et al., 1981; Til et al., 1983, 1991).


        Table 29.  Long-term toxicity/carcinogenicity of vinyl chloride in experimental animals after oral administrationa
                                                                                                                                

    Species; strain;      Dose;                     1) Effects other than tumours (dose in mg/kg bw/d);            Reference
    initial number of     route of exposure;        2) number of animals for histopathological evaluation of
    animals per dose;     exposure period;             neoplastic effects;
    vehicle               frequency of treatment;   3) type of tumour: number of animals with this tumour/dose
                          post-exposure                group (unless otherwise given)
                          observation period
                                                                                                                                

    Rat; Wistar;          0, 1.7, 5.0, 14.1         1) > 1.7 mg/kg: haematology, biochemistry, urine analyis,      Feron
    60-80 rats/sex;       mg/kg bw./d,              organ function, body weight and food consumption <->          et al.
    PVC powder            bioavailable d (oral      mortality !* (f); liver clear cell foci (f+m), basophilic      (1981) e
    (vehicle)             intake 0, 1.8, 5.6,       foci (f), eosinophilic foci (m+f) !*; liver-cell
    containing VC         17.0 mg/kg bw/day);       polymorphism !* (m); liver cysts !* (f);> 5.0 mg/kg: general
    incorporated          oral feed; lifespan       condition ¡ (m+f, at mo 18); mortality !* (f+m); liver
    into the diet         study, terminated         basophilic foci !* (m); extensive liver necrosis !* (f);
                          at week 135 (m)           14.1 mg/kg: extensive liver necrosis and liver cysts !* (m); focal
                          and 144 (f); diet         haematopoiesis in liver !* (m); liver weight !* (f+m at mo
                          provided 4 h/d;           6, f at mo 12, interim sacrifice); blood clotting time at mo
                          none                      6 and alpha-fetoprotein at mo 12 ¡* (f+m);
                                                    2) 55, 58, 56, 59 m and 57, 58, 59, 57 f;
                                                    3) ASL in m: 0, 0, 6*, 27* and in f: 0, 0, 2, 9*;neoplastic liver
                                                    nodules in m: 0, 1, 7*, 23* and in f : 2, 26*, 39*, 44*;
                                                    hepatocellular carcinoma in m: 0, 1, 2, 8* and in f: 0, 4, 19*,
                                                    29*; lung angiosarcoma in m: 0, 0, 4*, 19* and in f: 0, 0, 1, 5*

    Rat; Wistar; 100      0, 0.014, 0.13, 1.3       1) > 0.014 mg/kg: bw. and  food consumption <-> (m+f); liver   Til et al.
    rats/sex except       mg/kg bw./d,              basophilic foci !* (f); 1.3 mg/kg: mortality  !* (f; at        (1983,
    high dose (50         bioavailable d (oral      week 149); liver glutathione level at week 40 or 80 <->        1991) f
    per sex); PVC         intake 0, 0.018,          (satellite groups); liver clear cell (m+f), basophilic (m),
    powder (vehicle)      0.17, 1.7 mg/kg           eosinophilic (f), and mixed cell foci (f) !*; liver cysts !*
    containing VC         bw./day); oral feed;      (f ); moderate to severe liver-cell polymorphism !* (m+f );
    incorporated into     lifespan study,           2) 99, 99, 99, 49 m and 98, 100, 96, 49 f;3) ASL in m: 0, 0,
    the diet              terminated at week        0, 1 and  0, 0, 0, 2 in f; neoplastic liver nodules in m 0,
                          149 (m) and 150 (f);      0, 0, 3 and 0, 1, 1, 10* in f; hepatocellular carcinoma in
                          diet provided 4 h/d;      m 0, 0, 0, 3* and 1, 0, 1, 3 in f
                          none

    Table 29. (cont'd)
                                                                                                                                

    Species; strain;      Dose;                     1) Effects other than tumours (dose in mg/kg bw/d);            Reference
    initial number of     route of exposure;        2) number of animals for histopathological evaluation of
    animals per dose;     exposure period;             neoplastic effects;
    vehicle               frequency of treatment;   3) type of tumour: number of animals with this tumour/dose
                          post-exposure                group (unless otherwise given)
                          observation period
                                                                                                                                

    Rat;                  0, 3.33, 16.6, 50         1) > 16.6 mg/kg: survival ¡# (m);  3.33 & 50: bw ¡# (m);       Maltoni
    Sprague-Dawley;       mg/kg bw./d;              2) 40 f and 40 m per group;                                    et al.
    40 rats/sex; pure     gavage; 52 weeks;         3) ASL in m: 0, 0, 4, 8* and in f:  0, 0, 6*, 9*;              (1981,
    virgin olive oil      once daily,               Zymbal gland carcinoma in m: 0, 0, 1, 1 and in f: 1, 0,        1984)
                          4-5 d/week; up to         1, 0; extrahepatic angiosarcoma in m: 0 in all groups and      [BT 11] b
                          84 weeks c                in f: 0, 2, 0, 2; nephroblastoma in m: 0, 0, 2, 1 and in
                                                    f: 0, 0, 1, 1;

    Rat;                  0, 0.03, 0.3, 1.0         1) > 0.03 mg/kg: survival and bw <->#;                         Maltoni
    Sprague-Dawley; 75    mg/kg bw./d;              2) 75, 75, 73, 75 m and 75, 75, 73, 75 f;                      et al.
    rats/sex; pure        gavage; 59 weeks;         3) ASL in m: 0, 0, 0, 1 and in f: 0, 0, 1, 2;                  (1981,
    virgin olive oil      once daily,               Zymbal gland carcinoma in m: 0, 0, 0, 2 and in f: 1, 0,        1984)
                          4-5 d/week; up to         0, 3; extrahepatic angiosarcoma in m: 0 in all groups and      [BT 27] b
                          77 weeks c                in f: 0, 0, 0, 1; nephroblastoma 0 in all groups


    Rat; Wistar;          0, 3, 30, 300 mg/kg       1) 3 mg/kg: bw <-> , rat skin composition <->, mortality       Knight &
    10-20 rats/sex;       bw./d; gavage;            1/16 (control n.g.) 30 mg/kg: bw <->, mortality 5/15;          Gibbons
    peroxide-free         95-125 weeks;             biochemical parameters for skin fibrosis !* 300 mg/kg:         (1987)
    corn oil              once daily; none          mortality 15/15 within first 60 days of treatment;
                                                    2) 20, 16, 15, 10;
                                                    3) Liver tumors (predominantly angiosarcomas):
                                                    0, 1, 11, 10 #
                                                                                                                                

    a In all studies vehicle-treated controls; analysis of VC concentration in vehicle in all studies except Knight & Gibbons (1987);
      bw. = body weight; d = day; f = females; m = males; mo = months; n.g. = not given; * = effect significant at P < 0.05;
      # = no statistical evaluation; <-> = unchanged; ¡ = decreased; ! = increased
    b Study number in experiments done by Maltoni and coworkers

    c Animals were kept until spontaneous death or sacrificed at the end of given post exposure observation period
    d Bioavailability studied in an ancillary study
    e Study comparable to OECD guidelines 451 with acceptable restrictions (OECD, 1981a,b)
    f Study comparable to OECD guidelines 453 (OECD, 1981a,b)


         A statistically significant increase in the incidence of ASL was
    seen in Sprague-Dawley rats at a dose level of 16.6 mg VC/kg body
    weight per day (gavage; study BT 11), and some similar tumours were
    also observed at dose levels of 0.3 and 1.0 mg/kg body weight per day
    (Maltoni et al., 1981). Hepatic angiosarcomas were also observed in
    gavage studies in Wistar rats (Knight & Gibbons, 1987). This tumour
    type is very rare in untreated rats (4 in several thousand rats of the
    colony used by Maltoni et al., 1981). Because of short dosage and
    follow-up in the first study, and small number of animals due to early
    mortality in the third, these studies probably did not reflect the
    total carcinogenic potential of VC.

         The results of the two feeding studies carried out by another
    working group (Feron et al., 1981; Til et al., 1983, 1991) confirmed
    the findings presented by Maltoni et al. (1981) concerning ASL
    (induction at 1.3 mg/kg body weight per day, significant at 5.0 mg
    VC/kg body weight per day). Furthermore these feeding studies
    presented evidence for significantly increased tumour incidences of
    neoplastic liver nodules (females) and of hepatocellular carcinoma
    (HCC) (males) at 1.3 mg/kg body weight per day (Til et al., 1991).

    7.7.2  Inhalation exposure

         After the first reports of the carcinogenicity of VC in rats
    (Viola, 1970; Viola et al., 1971), Maltoni and coworkers intensively
    investigated the effects of inhalation exposure to VC in different
    laboratory animals.a Study results were published in Maltoni et al.
    (1974), Maltoni & Lefemine (1975) and Maltoni et al. (1979), and the
    final report in Maltoni et al. (1981, 1984). Detailed information on
    these inhalation studies as well as pertinent studies from other
    working groups is tabulated in Table 30 (short-term studies) and Table
    32 (long-term studies). A summary of tumour types induced by long-term
    inhalation exposure to vinyl chloride in different species is given in
    Table 33. Further studies on inhalative carcinogenicity of VC not
    discussed in this section, but leading to similar results to the
    studies tabulated below, were performed on rats (short-term: Hong et
    al., 1981; long-term: Viola et al., 1971; Maltoni et al., 1974; Lee et
    al., 1977; Maltoni et al., 1981, 1983, 1984; Bi et al., 1985; Maltoni
    & Cotti, 1988; Froment et al., 1994) and mice (short-term: Suzuki,
    1978, 1981; Schaffner, 1979; Hehir et al., 1981; Himeno et al., 1983;
    Adkins et al., 1986; long-term: Keplinger et al., 1975; Lee et al.,
    1977; Holmberg et al., 1979; Drew et al., 1983).

    7.7.2.1 Short-term exposure

         Several carcinogenicity studies have been performed where animals
    were exposed by inhalation for rather short periods (up to 6 months)
    and kept for different post-exposure periods up to lifetime
    (Table 30). The tumour spectrum in rats and mice is very similar to

                 
    a Studies performed at Beautivoglio (BT) Laboratories; studies
          numerated BT1-BT27

        Table 30.  Short-term inhalation studies on carcinogenicity of vinyl chloride in experimental animalsa
                                                                                                                    

    Species; strain;          Doses in mg/m3;          1) Number of animals for histopathological        References
    age at start of           exposure period;            evaluation;
    experiment; initial       frequency of             2) type of tumour: number of animals with
    number of animals per     treatment;                  this tumour/dose group (unless otherwise
    dose per exposure         post-exposure               given); other observations
    period; type of           observation period
    control;
                                                                                                                    
    Rat;                      0, 15 600, 26 000;       1) 227, 120, 118;                                 Maltoni
    Sprague-Dawley;           5 weeks; 4 h/d,          2) (#) ASL: 0, 0, 1; extrahepatic                 et al.
    11 weeks; 120             5 d/week;                   angiosarcoma: 0, 0, 0; Zymbal gland            (1981)
    (control 240)             149 weeksc                  carcinoma: 0, 9, 9; hepatoma: 0, 0, 1;         [BT 10]b
    f & m; untreated                                      nephroblastoma: 0, 1, 0;
    control                                               neuroblastoma: 0, 1, 0

    Rat;                      0, 15 600, 26 000;       1) 227, 118, 119;                                 Maltoni
    Sprague-Dawley;           25 weeks; 1 h/d,         2) (#) ASL: 0, 3, 1; extrahepatic angiosarcoma:   et al.
    11 weeks; 120             4 d/week;                   0, 2, 0; Zymbal gland carcinoma: 0, 5, 9       (1981)
    (control 240)             129 weeksc                                                                 [BT 10]b
    f & m; untreated
    control

    Rat;                      15 600, 26 000;          1) 18 m and 24 f at low dose, 24 m and            Maltoni
    Sprague-Dawley;           5 weeks; 4 h/d,             20 f at high dose;                             et al.
    1-day-old;                5 d/week; 119c           2) ASL in m: 5, 6 and in f:12, 9;                 (1981)
    see number of                                         extrahepatic angiosarcoma in m: 5, 6           [BT 14]b
    animals for                                           and inf: 12, 9; hepatoma in m: 9, 13
    evaluation; no control;                               and in f: 11, 7

    Rat;                      0 or 2465;               1) 84-128 rats per sex per age group;             Groth
    Sprague-Dawley;           24.5 weeks; 7 h/d,       2) angiosarcomas (mostly in liver) in the 4       et al.
    6, 18, 32, or 52 weeks;   5 d/week; scheduled         age groups in exposed m: 1.2, 2.2, 7.4,        (1981)
    110-128 rats/sex          sacrifice at 3, 6 and       18% and in exposed f: 2.3, 7.2, 28, 13%;
    per age group;            9 months,                   only 1 subcutaneous angiosarcoma (m) in
    treated control           termination at              all control groups (739 mice) #; older
                              week 43                     adults more susceptible to
                                                          angiosarcoma-inducing effect

    Table 30. (cont'd)
                                                                                                                    

    Species; strain;          Doses in mg/m3;          1) Number of animals for histopathological        References
    age at start of           exposure period;            evaluation;
    experiment; initial       frequency of             2) type of tumour: number of animals with
    number of animals per     treatment;                  this tumour/dose group (unless otherwise
    dose per exposure         post-exposure               given); other observations
    period; type of           observation period
    control;
                                                                                                                    

    Rat; Wistar or            0, 6.5, 13, 26, 52,      1) 2-27 rats of each sex per dose per strain;     Laib
    Sprague-Dawley;           104, 208; 3 weeks;       2) dose dependent increase in ATPase-deficient    et al.
    3 days; 2-27 rats         8 h/d, 5 d/week;            liver foci (preneoplastic lesion),             (1985a)
    per sex per strain;       10 weeks                    presumably significant at > 52 mg/m3
    treated control                                       ( m Sprague-Dawley rats at > 104 mg/m3);
                                                          f more susceptable than m in both strains

    Rat; Wistar;              0 or 5200;               1) 2-10 rats of each sex per dose per exposure    Laib
    age-dependency            5-83 days, see 2);          period;                                        et al.
    studied early in life,    8 h/d, 7 d/week; rats    2) age dependent increase in  ATPase-deficient    (1985b)
    see 2); 4-10 rats         sacrificed at the age       liver foci lesion) (preneoplastic studied,
    per sex;                  of 4 months                 rats exposed a) during gestation or at
    treated control                                       postnatal day 1-5 (b), 1-11 (c), 1-17 (d),
                                                          1-47 (e), 1-83 (f), 7-28 (g), or 21-49 (h);
                                                          no effect in a & b, foci area steeply
                                                          increased in c and d but not further
                                                          enhanced in e and f, foci area not lowered
                                                          in g but only a few foci in h

    Mouse; CD1;               0, 2.6, 26, 260, 780,    1) see 2);                                        Suzuki
    5-6 weeks;                1560; 4 weeks;           2) pulmonary tumour incidences (#):week 0         (1983)
    30-60 m; treated          6 h/d, 5 d/week;            post-exposure: no tumour week 12:  0/18,
    control                   0, 12, 40 weeks             0/10, 0/9, 0/6, 6/9, 8/9 week 40: 0/17, 1/9,
                                                          3/9, 6/9, 5/7, 6/7; study focused on lung
                                                          tumours (no details on other tumours);
                                                          tumours derived from type II alveolar cells

    Table 30. (cont'd)
                                                                                                                    

    Species; strain;          Doses in mg/m3;          1) Number of animals for histopathological        References
    age at start of           exposure period;            evaluation;
    experiment; initial       frequency of             2) type of tumour: number of animals with
    number of animals per     treatment;                  this tumour/dose group (unless otherwise
    dose per exposure         post-exposure               given); other observations
    period; type of           observation period
    control;
                                                                                                                    

    Mouse; CD-1;              0, 130, 650, 2600;       1) 60, 40, 44, 38 m and 60, 40, 40, 38 f          Hong et al.
    2 months;                 1, 3, 6 months;             for cumulative effects;                        (1981)
    8-28 mice/sex;            6 h/d, 5 d/week;         2) cumulative (f+m); ASL: 1, 2, 13*, 18*;
    treated control           12 months                   extrahepatic angiosarcoma 0, 2, 6*, 2;
                                                          bronchioloalveolar tumor 16, 18, 52*, 50*;
                                                          cumulative (f): metastatic lung
                                                          adenocarcinoma 0, 4*, 2, 6*; mammary
                                                          carcinoma 4, 10*, 13*, 6; tumours at
                                                          different organ sites in f and m
                                                          increased in proportion to dose or duration
                                                          of exposure at higher dose levels
                                                                                                                    

    a d = day; f = females; m = males; n.g. = not given; # = no statistical evaluation; * = significant at P < 0.05
    b Study number in experiments done by Maltoni and coworkers
    c Animals were kept until spontaneous death or sacrificed at the end of given post-exposure observation period


    that observed in long-term inhalation studies (compare with Table 32).
    Hehir et al. (1981) presented evidence that even one single high dose
    (> 13 000 mg/m3) resulted in a dose-related increase of pulmonary
    tumours in mice. This effect was also demonstrated by repeated
    administration to mice at lower dose levels with exposure periods
    varying between 1 and 6 months (Hong et al., 1981; Suzuki, 1983).
    Incidences of ASL, extrahepatic angiosarcoma and mammary gland
    carcinoma were elevated in mice with increasing exposure periods at
    doses of 130 or 650 mg/m3 (Hong et al., 1981). Also in rats,
    angiosarcomas, predominantly in the liver, were induced by VC
    inhalation for 25 weeks (15 600 mg/m3, 1 h/day, Maltoni et al., 1981;
    2465 mg/m3, 7 h/day, Groth et al., 1981). Short-term exposure led to
    increased incidences of carcinoma of the Zymbal gland, a sebaceous
    gland of the ear canal in rats, at high doses (> 15 600 mg/m3;
    Maltoni et al., 1981, BT10).

         Short-term exposure studies on the effect of age on
    susceptibility to tumour induction are discussed in section 7.7.3.

    7.7.2.2  Long-term exposure

    a)  Rats

         Although differences in experimental design, notably in the
    duration of follow-up, and the low overall frequency of tumours tend
    to confuse the picture, a dose-response relationship could be observed
    in studies BT1, BT2, BT9 and BT15 on Sprague-Dawley rats for ASL
    (Table 31, Fig. 4 and chapter 10) and Zymbal gland carcinomas, while
    it was less clear for nephroblastomas, neuroblastomas and mammary
    malignant tumours.

         Lee et al. (1978) and Drew et al. (1983) reported similar
    findings on the incidence of ASL. Female rats seem to be more
    susceptible to ASL tumours than males (Lee et al., 1978; Maltoni et
    al., 1981). ASL was detected at 26 mg/m3 and the incidence was
    statistically significant at 130 mg/m3, which was at a lower level
    than other tumour types with the exception of mammary gland tumours
    (13 mg/m3; see Table 33) (Maltoni et al., 1981). VC exposure also
    caused angiosarcomas at extrahepatic sites (Maltoni et al., 1981, BT14
    see Table 30; Lee et al., 1978; Drew et al., 1983).

         Increased incidences of other tumour types than those reported by
    Maltoni et al. (1981) in Sprague-Dawley rats were shown by Drew et al.
    (1983) in Fischer-344 rats (neoplastic liver nodules and
    hepatocellular carcinoma) and by Feron & Kroes (1979) in Wistar rats
    (tumour of the nasal cavity). These were single dose experiments.

         Drew et al. (1983; see Table 32) studied the effect of exposure
    duration (6, 12, 18 or 24 months) on tumour incidences and
    demonstrated that longer exposure periods, and thus greater cumulative
    exposures, led to an increase in tumorigenic responses concerning
    liver angiosarcoma, angiosarcoma at all sites, and hepatocellular


        Table 31. Incidence of angiosarcomas of the liver (ASL) and mammary
    tumours observed in Sprague-Dawley ratsa
                                                                                                         

          Exposure       Concentration      ASL             ASL            ASL             Mammary
            (ppm)           (mg/m3)       (males)        (females)      (males +       adenocarcinomas
                                                                        females)
                                                                                                         

             0                0         0/173           0/239          0/412             12/239
             1              2.6          0/58            0/60          0/118              12/60
             5               13          0/59            0/60          0/119              22/60
            10               26          0/59            1/60          1/119              11/60
            25               65          1/60            4/60          5/120              15/60
            50              130         2/174          13/180         15/354             61/180
           100              260          0/60            1/60          1/120               3/60
           150              390          1/60            5/60          6/120               6/60
           200              520          7/60            5/60         12/120               5/60
           250              650          1/29            2/30           3/59               2/30
           500             1300          0/30            6/30           6/60               1/30
          2500             6500          6/30            7/30          13/60               2/30
          6000           15 600          3/29           10/30          13/59               0/30
        10 000                                                                             3/30
                                                                                                         

    a   The data are combined from the experiments BT1, BT2, BT9 and BT15 conducted by Maltoni et al. (1984).
        Control animals from several experiments are combined in the 0 ppm group. Animals were exposed
        4 h/day, 5 days/week for 52 weeks; the follow-up was until the death of the animals or until week
        83 (BT1), 90 (BT2), 90 (BT9) or 95 (BT15). Tumours were scored at the time of death. Adapted from
        Reitz et al. (1996)


    FIGURE 4

    carcinoma in female F-344 rats. This exposure duration-related effect
    was not observed in mice and hamsters, except angiosarcoma at all
    sites in hamsters.

         The lowest reported dose (13 mg/m3) to cause a statistically
    significant increase in tumour incidences was demonstrated for mammary
    adenocarcinoma in female rats (Maltoni et al. 1981; BT15). Although
    this tumour type is common in untreated rats and no clear
    dose-response relationship was shown (probably due to reduced survival
    in the high-dose groups, Maltoni et al., 1984; BT1, BT2, BT9, BT15),
    the increase in tumour rate was considered by the Task Group to be of
    toxicological relevance, since the incidence was increased compared to
    concurrent and historical controls of the same colony (Maltoni et al.,
    1981, 1984) and similar results on mammary gland tumours were
    presented in further studies on rats (Drew et al., 1983) and other
    species (Lee et al., 1978; Maltoni et al., 1981, 1984; Drew et al.,
    1983) (see also Table 33; Fig. 4).

    b)  Mice

         In mice, the spectrum of tumours induced by long-term inhalation
    exposure is similar to that observed in rats, but an increase in lung
    tumours was only observed in mice (Lee et al., 1978; Maltoni et al.,
    1981; Drew et al., 1983, see also Table 32). At a dose level of
    130 mg/m3, incidences in angiosarcoma (liver, extrahepatic or all
    sites combined), lung carcinoma, and mammary gland carcinoma showed a
    statistically significant increase (Lee et al., 1978; Drew et al.,
    1983). Doses lower than 130 mg/m3 were not investigated, but at the
    dose levels investigated, the angiosarcoma frequencies were higher in
    mice than in rats (Lee et al., 1978). No clear-cut relationship with
    time of exposure (6-18 months) and incidence of ASL was observed; this
    could, however, have been due to decreased survival and shorter
    follow-up after longer exposure time (Drew et al., 1983).

    c)  Other species

         Limited data are available on other species. In experiment BT8
    with male Syrian golden hamsters, low frequencies of ASL, acoustic
    duct tumours and melanomas were observed. In addition, an increased
    incidence in forestomach and skin epithelial tumours was reported, but
    these tumours were also observed in controls, there was no
    dose-response relationship and a statistical evaluation was not
    presented (Maltoni et al., 1981).

         Female hamsters were exposed to a single dose for different
    exposure periods (Drew et al., 1983). Angiosarcomas (all sites), skin
    tumours and increased incidences in mammary gland carcinoma and
    stomach adenomas (glandular portion of the stomach) were reported
    (Drew et al., 1983).

         In a study reported only as an abstract, Caputo et al. (1974)
    reported increased incidences in skin acanthoma and lung
    adenocarcinoma in rabbits exposed to VC.


        Table 32.  Inhalation studies on the long-term toxicity/carcinogenicity of vinyl chloride in experimental animalsa
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rat;                     0, 130, 650, 1300,        1) > 650: survival ¡# (f, in m at > 1300);                Maltoni et
    Sprague-Dawley; 13       6500, 15 600,                > 15 600: body weight ¡# (m, in f at 26 000);          al. (1981,
    weeks; 30 rats/sex;      26 000;  52 weeks;        2) 29-30 m and 29-30 f per group;                         1984)
    untreated control        4 h/d, 5 d/week;          3) ASL in m: 0, 0, 1, 0, 6*, 3, 3 and in                  [BT1]b
                             83 weeks c                   f : 0, 1, 2, 6*, 7*, 10*, 4; Zymbal gland
                                                          carcinoma in m: 0, 0, 0, 3, 1, 3, 10* and in f:
                                                          0, 0, 0, 1, 1, 4, 6*; hepatoma in f:
                                                          0, 0, 0, 5, 2, 1, 0;
                                                          nephroblastoma in m: 0, 0, 1, 2, 5*, 4, 3
                                                          and in f:  0, 1, 4*, 4*, 1, 1, 2;
                                                          neuroblastoma in m: 0, 0, 0, 0, 2, 2, 2 and in f:
                                                          0, 0, 0, 0, 2, 1, 5*;
                                                          mammary adenocarcinoma in f:  0, 2, 2, 1, 2, 0, 3

    Rat;                     0, 260, 390, 520;         1) > 130: survival ¡# (m, in f at 520);                   Maltoni et
    Sprague-Dawley;          52 weeks; 4 h/d,          2) 59-60 rats per treatment group, control                al. (1981,
    13 weeks; 60             5 d/week; 91 weeks c         65 m and 100 f;                                        1984)
    rats/sex, control                                  3) ASL in m: 0, 0, 1, 7* and in f: 0, 1, 5*, 5*;          [BT2]b
    85 m and 100 f;                                       mammary adenocarcinoma in f: 1, 3, 6*, 5;
    untreated control                                     nephroblastoma in m: 0, 8*, 8*, 5* and in f:
                                                          0, 2, 3, 2

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rat; Sprague-Dawley;     0, 130; 52 weeks;         1) survival ¡# (f);                                       Maltoni et
    13 weeks; 150 rats       4 h/d, 5 d/week;          2) 144 m and 150 f, control 48 m and 50 f;                al. (1981,
    per sex, control 50 m    90 weeks c                3) ASL in m: 0, 2 and in f: 0, 12*;                       1984)
    and 50 f;                                             mammary adenocarcinoma in f: 5, 59*;                   [BT9]b
    untreated control                                     no significant effects on incidences of other
                                                          tumour types

    Rat;                     0, 2.6, 13, 26, 65;       1) > 2.6 survival ¡# (m+f);                               Maltoni et
    Sprague-Dawley;          52 weeks; 4 h/d,          2) 58-60 m and 60 f per group;                            al. (1981,
    13 weeks; 60 rats/sex;   5 d/week;                 3) ASL in m: 0, 0, 0, 0, 1 and in f:  0, 0, 0, 1,         1984)
    untreated control        95 weeks c                   4; mammary adenocarcinoma in f: 6, 12, 22*,            [BT15]b
                                                          21*, 15*; nephroblastoma in m: 0, 0, 0, 0, 1;
                                                          hepatoma in f: 0, 0, 0, 0, 1

    Rat; Spague-Dawley;      0, 6500; life time        1) survival & body weight ¡#                              Maltoni &
    13 weeks (pregnant       (up to 69 weeks);         2) 60, 54  dams, progeny 158, 63 m and 149, 64 f          Cotti (1988)
    rats) or gestation day   4 h/d, 5 d/week           3) tumour incidences in % (#):
    12 (embryos); see        for 7 weeks, than            ASLd : 0, 50.0 in dams and 0, 56.2 in m and
    number of animals for    7 h/d, 5 d/week;             0, 73.0 in f progeny; hepatocellular carcinoma:
    for evaluation;          none                         0, 9.2 in dams, 0.6, 42.2 in m and 0, 60.3 in f
    untreated control                                     progeny mammary carcinoma: 7.4, 7.4 in dams, 5.4,
                                                          4.7 in f progeny; neuroblastomad: 0, 59.2 in dams,
                                                          0, 48.4 in m and 0, 42.8 in f progeny

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rat; Fischer-344;        0 or 260; 6, 12,          1) survival ¡* (exposure periods > 6 mo);                 Drew et al.
    8-9 weeks, 2nd           18, 24 mo, 2nd            2) 112 (control), 76, 55, 55, 55 per exposure             (1983)
    experiment:  2, 8,       experiment 6 or              period; 2nd experiment 6 mo exposure: 112
    14, 20 mo (6 mo          12 mo exposure               (control), 76, 52, 51, 53 per age group; 2nd
    exposure) or 2, 8,       at different age;            experiment 12 mo exposure: 112 (control), 55,
    14 mo (12 mo             6 h/d, 5 d/week;             54, 49 per age group;
    exposure); n.g. (only    life span                 3) ASL: 1, 4*, 11*,13*, 19*; angiosarcoma all
    f, see number of                                      sites: 2, 4, 12*, 15*, 24*; mammary fibroadenoma:
    rats for evaluation);                                 24, 28*, 28*, 24*, 26*; mammary adenocarcinoma:
    n.g.                                                  5, 6, 11*, 9*, 5*; neoplastic liver nodules: 4,
                                                          15*, 20*, 7*, 6*; hepatocellular carcinoma: 1, 3,
                                                          4*, 8*, 9*; 2nd experiment 6 mo exposure: ASL: 1,
                                                          4*, 2, 0, 0; angiosarcoma all sites: 2, 4, 2, 0,
                                                          0; mammary fibroadenoma: 24, 28*, 23*, 17, 20;
                                                          mammary adenocarcinoma: 5, 6, 2, 3, 2; neoplastic
                                                          liver nodules: 4, 15*, 10*, 2, 4; hepatocellular
                                                          carcinoma: 1, 3, 6*, 0, 1;
                                                          2nd experiment 12 mo exposure: ASL: 1, 11*, 5*,
                                                          2; angiosarcoma all sites: 2, 12*, 5*, 2; mammary
                                                          fibroadenoma: 24, 28*, 16*, 15; mammary
                                                          adenocarcinoma: 5, 11*, 4, 0; neoplastic liver
                                                          nodules: 4, 20*, 4, 4; hepatocellular carcinoma:
                                                          1, 4*, 1, 0;

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rat; Wistar; 11          0, 130, 650, 1300,        1) > 130: survival & body weight ¡#                       Maltoni et
    weeks; control 40 m,     6500, 15 600,             2) 38, 28, 28, 27, 25, 26, 27;                            al. (1981,
    other groups 30 m;       26 000; 52 weeks;         3) (#):ASL: 0, 0, 1, 3, 3, 3, 8; hepatoma: 0, 0,          1984)
    untreated control        4 h/d, 5 d/week;             0, 0, 1, 2, 0; nephroblastoma: 0, 1, 0, 2, 0,          [BT17]b
                             113 weeks c                  2, 1; neuroblastoma: 0, 0, 0, 0, 1, 1, 3;
                                                          Zymbal gland carcinoma: 0, 0, 0, 0, 0, 2, 2

    Rat; Wistar; newly       0 or 13 000;              1) mortality !# (9 m and 10 f still alive at week         Feron et al.
    weaned; 62 rats/sex;     52 weeks, 10 rats            52); body weights ¡* (f+m); blood clotting time        (1979a,b)
    treated control          per dose per sex             ¡#; liver function ¡# (BSB-retention test);            Feron &
                             sacrificed at week           relative liver, kidney and spleen weight !*;           Kroes
                             4, 13, 26 (see               degree of tubular nephrosis !# (f+m); focal            (1979)
                             section 7.2); 7 h/d,         degeneration of myocardium and thickened walls
                             5 d/week; none               of arteries # (f+m); haematopoietic activity
                                                          in the spleen !# (f+m); distended liver
                                                          sinusoids # (f+m);
                                                       2) 62 m and 62 f per group;
                                                       3) cumulative tumours (#):ASL: 0, 3 in m and 0, 6
                                                          in f ;  Zymbal gland tumour: 0, 7 in m and 0, 4
                                                          in f; tumour of nasal cavity: 0, 10 in m and
                                                          0, 10 in f;

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rat; CD; 2 mo;           0, 130, 650, 2600;        1) > 650: survival ¡# (m+f);                              Lee et al.
    36 rats/sex;             12 mo, 4 rats/dose        2) 35, 36, 36, 34 m and 35, 36, 34, 36 f;                 (1978)
    treated control          per sex terminated        3) tumours combined for all exposure periods:
                             at month 1, 2, 3, 6,         ASL: 0, 0, 2, 6 in m and 0, 0, 10*, 15* in f;
                             9; 6 h/d, 5 d/week;          lung angiosarcoma: 0, 0, 0, 4 in m and 0, 0,
                             none                         3, 9* in f; other tumours not related to VC
                                                          treatment

    Rat [no further data     0, 14, 25, 266,           1) no data                                                Kurlyandski
    provided]                3690; 52 weeks;           2) 70, 50, 39, 43, 51 m                                   et al.
                             4.5 h/d, 5 d/week         3) ASL: 0, 0, 7.7, 9.3, 11.8%;                            (1981)
                                                          other angiosarcomas: 0, 1.0, 2.5, 0, 3.9%
                                                          other liver tumours: 2.8, 2.0, 2.6, 11.6, 13.7%
                                                          haemoblastoma: 4.3, 14.0, 15.4, 34.9, 2.0%
                                                          other tumours: 21.5, 28.1, 15.4, 9.3, 23.5%

    Mouse; Swiss;            0, 130, 650, 1300,        1) > 130: survival ¡# (m+f); > 1300: body weight ¡#       Maltoni et
    11 weeks; 30 mice        6500, 15 600,             (m, in f at > 650);                                       al. (1981,
    per sex, control         26 000; 30 weeks;         2) 80, 30, 30, 30, 29, 30, 26 m and 70, 30, 30,           1984)
    80 m and 70 f;           4 h/d, 5 d/week;             30, 30, 30, 30 f;                                      [BT4]b
    untreated control        51 weeks c                3) combined (f+m) tumours (#): ASL: 0, 1, 18, 14,
                                                          16, 13, 10; liver angioma: 0,1, 11, 5, 5, 7, 6;
                                                          extrahepatic angiosarcoma: 1, 1, 3, 7, 8, 1, 1;
                                                          lung tumour: 15, 6, 41, 50, 40, 47, 46;
                                                          mammary carcinoma in f : 1, 13, 12, 9, 10, 9, 14

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Mouse; Swiss CD-1;       0 or 130; 6, 12,          1) survival ¡* (all exposure periods);                    Drew et
    8-9 weeks, 2nd           18 mo, 2nd                2) 71 (control), 67, 47, 45 per exposure period;          al. (1983)
    experiment: 2, 8,        experiment 6 or 12  mo       2nd experiment 6 mo exposure: 71 (control), 67,
    14  mo (6 or 12 mo       exposure at                  49, 53 per age group; 2nd experiment 12 mo
    exposure); n.g. (only    different age;               exposure: 71 (control), 47, 46, 50 per age group;
    f, see number of         6 h/d, 5 d/week;          3) angiosarcoma (all sites): 1, 29*, 30*, 20*;
    mice for evaluation);    lifespan                     mammary gland carcinoma: 2, 33*, 22*, 22*; lung
    n.g.                                                  carcinoma: 9, 18*, 15*, 11*; 2nd experiment 6 mo
                                                          exposure: angiosarcoma (all sites): 1, 29*, 11*,
                                                          5; mammary gland carcinoma: 2, 33*, 13*, 2; lung
                                                          carcinoma: 9, 18*, 13*, 7;
                                                          2nd experiment 12 mo exposure: angiosarcoma
                                                          (all sites): 1, 30*, 17*, 3;
                                                          mammary gland carcinoma: 2, 22*, 8*, 0; lung
                                                          carcinoma: 9, 15*, 9*, 3;

    Mouse; CD-1; 2 mo;       0, 130, 650, 2600;        1) > 650: survival ¡# (tumour development), all           Lee et al.
    total 36 mice/sex;       1, 2, 3, 6, 9, and           mice in high-dose group and females in mid-dose        (1978)
    treated control          12 mo (4 mice per            group died or were terminated at mo 10-12;
                             group per sex  per        2) 26, 29, 29, 33 m and 36, 34, 34, 36 f;
                             exposure period);         3) tumours combined for all exposure periods:
                             6 h/d, 5d/week;              bronchioloalveolar adenoma (#):1, 8, 10, 22 in m
                             none                         and 0, 4, 12, 26 in f; ASL: 0, 3, 7*, 13* in m
                                                          and 0, 0, 16*, 13* in f; extrahepatic angiosarcoma:
                                                          0, 5*, 2, 0 in m and 0, 1, 3, 9* in f; mammary
                                                          tumours(#): 0, 9, 3, 13 in f; incidences exposure
                                                          time-dependent

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Hamster; Syrian          0, 130, 650, 1300,        1) > 130: survival ¡#;                                    Maltoni et
    golden; 11 weeks;        6500, 15 600,             2) see initial number of hamsters;                        al. (1981,
    30 m, 60 m in            26 000;  30 weeks;        3) (#): ASL: 0, 0, 0, 2, 0, 1, 0;                         1984)
    control;                 4 h/d, 5 d/week;             acoustic duct tumour: 0, 0, 0, 3, 1, 2, 1;             [BT8]b
    untreated control        79 weeks c                   melanoma: 0, 1, 1, 0, 0, 1, 2, 1;
                                                          forestomach tumour:  3, 3, 4, 9, 17, 10, 10;
                                                          skin epithelial tumour: 3, 9, 3, 7, 3, 1, 7;


    Hamster; Syrian          0 or 520; 6, 12,          1) survival ¡* (all exposure periods);                    Drew et al.
    golden; 8-9 weeks,       18 mo, 2nd                2) see tumour incidences;                                 (1983)
    2nd experiment: 2, 8,    experiment 6 or           3) tumour incidences in control and at different
    14, 20 mo (6 mo          12 mo exposure at            exposure periods: angiosarcoma (all sites): 0/143
    exposure) or 2, 8,       different age;               (control), 13/88*, 4/52*, 2/103; mammary
    14 mo (12 mo             6 h/d, 5 d/week;             carcinoma: 0/143, 28/87*, 31/52*, 47/102*;
    exposure); n.g.          life span                    stomach adenoma: 5/138, 23/88*, 3/50*, 20/101*;
    (only f, see number                                   skin carcinoma: 0/133, 2/80; 9/48*, 3/90; 2nd
    of hamster for                                        experiment 6 mo exposure: angiosarcoma (all
    evaluation); n.g.                                     sites): 0/143 (control), 13/88*, 3/53*, 0/50,
                                                          0/52; mammary carcinoma: 0/143, 28/87*, 2/52*,
                                                          0/50, 1/52; stomach adenoma: 5/138, 23/88*,
                                                          15/53*, 6/49*, 0/52; skin carcinoma: 0/133, 2/80;
                                                          0/49, 0/46, 0/50; 2nd experiment 12 mo exposure:
                                                          angiosarcoma (all sites): 0/143 (control),
                                                          4/52*, 1/44, 0/43;
                                                          mammary carcinoma: 0/143, 31/52*, 6/44*, 0/42;
                                                          stomach adenoma: 5/138, 3/50*, 10/44*, 3/41;
                                                          skin carcinoma: 0/133, 2/80; 0/38, 0/30;

    Table 32. (cont'd)
                                                                                                                                

    Species; strain; age     Doses in mg/m3;           1) Effects other than tumours                             Reference
    at start of              exposure period;             (dose in mg/m3);
    experiment; initial      frequency of treatment;   2) number of animals for
    number of animals per    post-exposure                histopathological evaluation of
    dose per exposure        observation period           neoplastic effects;
    period; type of                                    3) type of tumour: number of animals
    control;                                              with this tumour/dose group (unless
                                                          otherwise given)
                                                                                                                                

    Rabbit; n.g.; n.g.;      0, 26 000;                1) n.g.;                                                  Caputo
    40 exposed to VC,        15 mo; 4 h/d,             2) see tumour incidences;                                 et al.
    20 controls (no data     5 d/week; n.g.            3) tumour incidences: skin acanthoma: 0/20                (1974)
    about sex);                                           (control), 12/40*; lung adenocarcinoma 0/20, 6/40
    treated control
                                                                                                                                

    a * = significant at P < 0.05;  #: no statistical evaluation;  f = females;  m = males;  mo = months;  n.g. = not given
    b Study number in experiments done by Maltoni and coworkers
    c Animals were kept until spontaneous death or sacrificed  at the end of given post exposure observation period
    d Presumably significant in all exposed groups

    Table 33.  Summary of tumour types induced by long-term inhalation exposure to vinyl chloride
    Lowest reported dose that significantly increased tumour incidences by tumour type (dose in mg/m3)
                                                                                                                                    

    Species  Liver         Angiosarcoma   Other       Lung       Mammary      Nephro-   Skin       Neuro-     Stomach     Zymbal
             angiosarcoma  (other sites)  liver       carcinoma  gland        blastoma  tumour     blastoma   tumour      gland
                                          tumours                carcinoma                                                tumour
                                                                                                                                    

    Rat      130 in f c    extrahepatic   neoplastic             13 in        260 in               6500 in    fore-       26 000
             520 in m c    260 in f b,d   nodules                f h          m b,g                f b,k      stomach     in f + m f
                           lung           260 in f                            650 in                          papilloma
                           2600 in f e    b,d                                 f g                             78 000 in
                                          hepato-                                                             f + m i
                                          cellular
                                          carcinoma
                                          260 in
                                          f d

    Mouse    650 in        130 in m b,e               130 in     130 in
             f + m e                                  f b,d      f b,d
                           all sites
                           130 in f b,d

    Rabbit                                                                              acanthoma
                                                                                        26 000,
                                                                                        n.d.
                                                                                        about sex
    Hamster                all sites                             520 in                 b,j                               adenoma
                           520 in                                f b,d                  carcinoma                         520 in
                           f b,d                                                        520 in f                          f b,d
                                                                                        b,d
                                                                                                                                    

    a   Exposure in all studies 4-7 h/day, 5 days/week, exposure period at least 6 months
        f = females;  m = males;  n.d. = no data
    b   The lowest dose tested with the study design described in the cited study
    c   Maltoni et al. (1981; BT9)  f   Maltoni et al. (1981; BT1)       i   Maltoni et al. (1981; BT6)
    d   Drew et al. (1983)          g   Maltoni et al. (1981; BT1, BT2)  j   Caputo et al. (1974)
    e   Lee et al. (1978)           h   Maltoni et al. (1981; BT15)      k   Maltoni & Cotti (1988)


    7.7.3  The effect of age on susceptibility to tumour induction

         Recently there has been some concern about early-life sensitivity
    to vinyl chloride (Hiatt et al., 1994; Cogliano et al., 1996).
    However, there is contradictory evidence (Drew et al., 1983 versus
    Groth et al., 1981) concerning the effects of age on ASL induction in
    rats, but final conclusions on increased susceptibility in 6- to
    8-weeks-old animals could not be drawn from these data. The
    discrepancy in results with rats is probably due to differences in
    strain and/or experimental design. However, there is evidence from
    other studies that there is possibly a higher sensitivity to liver
    tumour induction in different rat strains in the first weeks of life,
    a life-phase much earlier than that studied by Drew et al. (1983).
    Studies on DNA adduct formation support these results.

         F-344 rats, hamsters and mice (Swiss and B6C3F1) of different
    age at the beginning of the exposure period (2, 8, 14 or 20 (not mice)
    months old) were exposed to VC using the same experimental design and
    same exposure period (Drew et al., 1983; see Table 32 for details).

         For ASL in rats, angiosarcoma at all sites and mammary carcinoma
    in all three species, neoplastic nodules in rats and lung carcinoma in
    Swiss mice, the tumour response was highest in young animals
    (2-month-old) exposed for 6 or 12 months. The validity of the
    demonstrated age-related effects is limited in this study because only
    statistical evaluation in comparison to control or to all other
    groups, but not related to each other exposure group, was performed.
    In addition, exposure later in life automatically shortens the period
    of follow-up, and thus tends to lead to an apparent elevated
    sensitivity at young age.

         The effect of age on the susceptibility to induction of ASL in
    Sprague-Dawley rats was also studied by Groth et al. (1981; see Table
    30 for details). Rats aged 6, 18, 32 or 52 weeks were exposed to VC at
    the same dose level and exposure period. In contrast to Drew et al.
    (1983), the results of this study demonstrated that the older the rats
    were at the start of the exposure period, the greater was the tumour
    incidence. The maximum incidence was observed in male rats 52 weeks
    old at first exposure and in females 32 weeks old at first exposure
    (significantly increased compared to 6- or 18-week-old females). For
    males the effect of age was statistically significant.

         Exposure of 1-day-old rats of the same strain to high VC
    concentrations for 5 weeks (BT14, see Table 30) revealed a remarkably
    higher incidence of ASL, extrahepatic angiosarcoma and hepatoma
    compared with 11-week-old rats exposed within the same experimental
    design (BT10; Maltoni et al., 1981; see Table 30). However, these
    experiments were not concurrent, and the tumour response in different
    series from this laboratory has been variable (Tables 31, 32).

         Maltoni & Cotti (1988) exposed 13-weeks-old pregnant
    Sprague-Dawley rats and their progeny from the 12th day of gestation
    to VC (Table 32). Although no statistical evaluation was performed it

    seems that there was no significant difference between the dams and
    the progeny concerning incidences in ASL, mammary carcinoma, and
    neuroblastoma. The incidence of hepatocellular carcinoma, however, was
    9% in dams and 42% in male and 60% in female progeny. In this study
    the duration of exposure (and also of latency) was up to 69 weeks for
    the progeny, but 56 weeks for the dams.

         Laib et al. (1985a; see Table 30) presented evidence for
    dose-related increased induction of ATPase-deficient liver foci in
    Wistar and Sprague-Dawley rats, discussed as preneoplastic
    hepatocellular lesions, after a 3-week exposure to low concentrations
    (> 52 mg/m3). The increased induction of these foci was restricted
    to a well-defined period of highest sensitivity beginning with rapid
    liver growth in 7- to 21-day-old rats. No induction of these foci was
    reported in adult rats exposed to 5200 mg/m3 for 70 days after
    partial hepatectomy (no further details) (Laib et al., 1985b).

         Comparative investigations on the alkylation of liver DNA in
    young and adult Wistar rats exposed under the same exposure conditions
    confirmed the age-related sensitivity of rats to VC (section 6.5.1 and
    Table 26.)

    7.7.4  The effect of gender on susceptibility to tumour induction

         There is evidence that female rats of various strains are more
    susceptible to liver tumour induction than males. Maltoni et al.
    (1981, 1984) reported in all studies on Sprague-Dawley rats (BT1, BT2,
    BT9, BT15; see Table 32) a higher incidence of ASL in female rats
    compared with males after long-term inhalation. Similar results were
    presented by Feron et al. (1979a,b) on Wistar rats, Lee et al. (1978)
    on CD rats (Table 32) and Groth et al. (1981, Table 30) on
    Sprague-Dawley rats. In inhalation experiments with pregnant
    Sprague-Dawley rats, the investigators observed a higher incidence of
    ASL and hepatocellular carcinoma in the female progeny than in the
    males (Maltoni & Cotti, 1988; Table 32).

         After long-term oral administration of VC (Table 29), incidences
    of ASL (BT11, Sprague-Dawley rats; Maltoni et al., 1981), neoplastic
    liver nodules and hepatocellular carcinoma (Wistar rats; Feron et al.,
    1981 (not ASL) and Til et al., 1991) were higher in females than in
    males. Interestingly, preneoplastic alterations in the liver, like
    increased basophilic foci (Til et al., 1991; Table 29) or
    ATPase-deficient foci (Laib et al., 1985a; Table 30), were observed in
    female rats at lower doses than in males.

         Although statistical analysis of sex differences was not
    performed, in rats there is a tendency towards a higher susceptibility
    to VC-induced ASL in female animals. Data on species other than rats
    are not sufficient for an assessment of sex differences (Table 30,
    32).

    7.7.5  Carcinogenicity of metabolites

         CAA was reported to induce hepatocellular tumours in B6C3F1 mice
    when administered orally in drinking-water (Daniel et al., 1992). CEO
    caused local tumours after repeated subcutaneous injection and skin
    tumours in mice in classical initiation-promotion experiments (CEO
    used as an initiator and 12-O- n-tetradecanoylphorbol-13-acetate as a
    promoter), whereas CAA did not under comparable conditions (Zajdela et
    al., 1980).

    7.8  Genotoxicity

         Genotoxicity studies on VC  in vitro and  in vivo in laboratory
    animals are given in sections 7.8.1 and 7.8.2, respectively.
    Genotoxicity studies on the metabolites of VC are described in section
    7.8.3, and the mutagenic/promutagenic properties of DNA adducts formed
    by the reactive VC metabolites CEO and CAA are discussed in section
    7.8.4. Data on gene mutation and cytogenetic damage in humans exposed
    to VC are given in section 8.4. A summary on the genotoxicity of VC
     in  vitro and  in vivo, including human data, is presented in Table
    36.

    7.8.1  In vitro studies

         Relevant studies on the genotoxicity of VC  in vitro are
    presented in Table 34. Genotoxic activity of VC has been detected in
    several  in  vitro test systems, predominantly after metabolic
    activation.

         VC is mutagenic in the Ames test in the presence of metabolic
    activation in  Salmonella typhimurium strains TA100, TA1530 and
    TA1535 but not in TA98, TA1537 and TA1538 (Rannug et al., 1974;
    Bartsch et al., 1975; McCann et al., 1975; De Meester et al., 1980;
    Shimada et al., 1985) indicating that the mutations are the result of
    base-pair substitutions (transversion and transition) rather than
    frameshift mutations. This is in agreement with the finding that
    etheno-DNA adducts formed by the reactive metabolites CEO and CAA (see
    section 6.5.1) are converted to actual mutations by base-pair
    substitutions (see section 7.11.2 and 8.4). Barbin et al. (1997)
    examined p53 mutations in VC-induced rat liver tumours and detected in
    12 samples (11 ASL, 1 HCC) only one deletion but 12 base-pair
    substitutions (transversion and transition).

         In some studies, VC has been shown to also exert mutagenic
    activity in  S. typhimurium without addition of S9-mix (McCann et
    al., 1975; De Meester et al., 1980; Shimada et al., 1985), but the
    mutagenic effect was enhanced by addition of a metabolic activation
    system (De Meester et al., 1980; Shimada et al., 1985; Victorin &
    Ståhlberg, 1988). This increase was more pronounced when liver
    extracts were derived from animals pretreated with an enzyme inducer
    (Aroclor 1254) (De Meester et al., 1980). The reason for the mutagenic


        Table 34.  Genotoxicity of vinyl chloride in vitroa
                                                                                                                      

    Test type     Test organism;     Exposure conditions;              Results     Results             Reference
                  species strain     comments                          with MA     without MA
                                                                                                                      

    Ames test     Bact.;             20% VC in atmosphere;                                             Rannug et al.
                  Salmonella         up to 90 min                      +           -                   (1974)
                  typhimurium                                          -           -
                  TA1535                                               -           -
                  TA1536                                               -           -
                  TA1537
                  TA1538

    Ames test     Bact.;             0.2, 2, 20% VC in atmosphere;                 n.g.                Bartsch et al.
                  S. typhimurium     1.5-48 h; dose- and               +                               (1975)
                  TA1530             time-dependent effect             +
                  TA1535                                               -
                  TA1538                                               -
                  G-46

    Ames test     Bact.;             20% VC in atmosphere;                                             McCann et al.
                  S. typhimurium     3, 6, 9 h;                        -           -                   (1975)
                  TA98               time-dependent effect             +           +
                  TA100                                                +           +
                  TA1535                                               -           -
                  TA1538

    Ames test     Bact.;             1) 2-20% VC in                                                    De Meester et
                  S. typhimurium     atmosphere; 16 h;                 +           +                   al. (1980)
                  TA1530             dose-dependent effect

    Ames test     Bact.;             0.1-10% VC in atmosphere;                                         Shimada et al.
                  S. typhimurium     18 h;                             -           -                   (1985)
                  TA98               dose-dependent effect             +           +
                  TA100                                                +           +
                  TA1535                                               -           -
                  TA1537                                               -           -
                  TA1538

    Table 34. (cont'd)
                                                                                                                      

    Test type     Test organism;     Exposure conditions;              Results     Results             Reference
                  species strain     comments                          with MA     without MA
                                                                                                                      

    Ames test     Bact.;             VC in DMSO added to soft                                          Laumbach et
                  S. typhimurium     agar and bacteria                 n.g.        -                   al. (1977)
                  TA100

    Ames test     Bact.;             83 mM VC in liquid                            n.g.                Bartsch et al.
                  S. typhimurium     suspension; 30 min                -                               (1975)
                  TA1530                                               -
                  TA1535                                               -
                  G-46

    Gene          Bact.;             10.6 mM VC in medium;             +           -                   Greim et al.
    mutation      Escherichia        2 h                                                               (1975)
    assay         coli
                  K12

    Forward       Yeast              16, 32, 48 mM VC in               +           -                   Loprieno et
    mutation      cells;             medium; 1 h;                                                      al. (1977)
    assay         Schizo-            dose-dependent effect
                  saccharomyces
                  pombe P1


    Forward       Yeast              16 or 48 mM VC in medium;         +           -                   Loprieno et
    mutation      cells;             5-240 min; time-dependent                                         al. (1976)
    assay         S. pombe           effect
                  SP.198

    Table 34. (cont'd)
                                                                                                                      

    Test type     Test organism;     Exposure conditions;              Results     Results             Reference
                  species strain     comments                          with MA     without MA
                                                                                                                      

    Reverse       Yeast cells;       incubated with 0.275              n.g.        -                   Shahin (1976)
    mutation      Saccharomyces      or 0.55% VC in DMSO;
    assay         cerevisiae         4-48 h
                  XV185-14C

    Forward       Fungi;             VC solution in ethanol            -           -                   Drozdowicz &
    mutation      Neurospora         for 3-4 h or 25, 50%                                              Huang (1977)
    assay         crassa             VC in atmosphere for
                  Ema 5297           3.5 or 24 h

    Gene          Plant;             plant cutings exposed             n.g.        +                   Van't Hof &
    mutation/     Tradescantia       to VC in atmosphere;                                              Schairer (1982)
    deletion      spec.              6 h; positive at
    assay         clone 4430         > 195 mg/m3

    Cell          mammalian          5, 10, 20, 30% VC in              +           -                   Drevon &
    gene          cells;             atmosphere; 5 h;                                                  Kuroki (1979)
    mutation      Chinese            dose-dependent effect
    assay         hamster
                  V79

    HGPRT         human cells;       25-400 µM VC in                   +           n.g.                Weisman (1992)
    gene          B-lymphoblastoid   medium for 24 h;
    mutation      line               cells with
    assay                            metabolizing system

    Gene          yeast cells;       48 mM VC in incubation            +           -                   Loprieno et al.
    conversion    S. cerevisiae      medium; 180-360 min                                               (1976)
    assay         D4

    Gene          yeast cells;       incubation in 0.275               n.g.        -                   Shahin (1976)
    conversion    S. cerevisiae      or 0.55% VC in DMSO;
    assay         D5                 4-48 h

    Table 34. (cont'd)
                                                                                                                      

    Test type     Test organism;     Exposure conditions;              Results     Results             Reference
                  species strain     comments                          with MA     without MA
                                                                                                                      

    Gene          yeast cells;       2.5% VC in atmosphere             +           -                   Eckardt
    conversion    S. cerevisiae      for 1 h                                                           et al. (1981)
    assay         D7RAD

    Cell          mammalian          10, 20, 30, 40, 50% VC            +           n.g.                Styles (1980)
    trans-        cells;             in atmosphere; no data
    formation     BHK C1 13          about exposure period
    assay

    Cell          mammalian          18, 180, 1315, 2662               n.g.        +                   Tu et al. (1985)
    trans-        cells;             mg/m3 VC in atmosphere;
    formation     BALB/c-3T3         24 h; dose-dependent
    assay         C1 1-13            effect

    Rec-assay     Bact.;             initial 22 mM; 24 h               n.g.        -                   Elmore et al.
    (DNA repair)  B. subtilis                                                                          (1976)
                  168M or MC-1

    Unscheduled   mammalian          5.0, 7.5 or 10% VC in             +           n.g.                Shimada et
    DNA           cells; rat         atmosphere;                                                       al. (1985)
    synthesis     hepatocytes        18 h; dose-dependent
                                     effects

    SCE assay     human cells;       10, 25, 50, 75, 100% VC           +           -                   Anderson et
                  stimulated         in atmosphere; 3 h;                                               al. (1981)
                  lymphocytes        dose-dependent effect
                                                                                                                      

    a Bact. = bacteria;  DMSO = dimethylsulfoxide;  MA = metabolic activation;  n.g. = not given;  SCE = sister-chromatid
      exchange; + = positive;  - = negative


    activity in the Ames test in the absence of S9-mix has been suggested
    to be a result of non-enzymic breakdown of VC or an internal bacterial
    metabolism (Bartsch et al., 1976; Shimada et al., 1985), but the
    origin of the direct mutagenic effect remains unclear.

         Positive results in the Ames test were also observed with
    metabolic activation by extracts prepared from human liver biopsies
    (Bartsch et al., 1975). Mutagenicity of VC was dependent on
    concentration (Bartsch et al., 1975; De Meester et al., 1980; Shimada
    et al., 1985) and exposure duration (Bartsch et al., 1975; McCann et
    al., 1975). VC was mutagenic when plates were exposed to a VC
    atmosphere in a closed (Bartsch et al., 1975 and Table 34) or in a
    dynamic flow-through system (Victorin & Ståhlberg, 1988). No mutagenic
    effect was observed when VC was dissolved in aqueous solution with
    (Bartsch et al., 1975) or without (Rannug et al., 1974; Laumbach et
    al., 1977) metabolic activation, probably due to rapid loss of VC in
    aqueous solution by evaporation (Bartsch et al., 1975).

         Other gene mutation assays in bacteria (Greim et al., 1975),
    yeast cells (Loprieno et al., 1976, 1977) and mammalian cells (Drevon
    & Kuroki, 1979) revealed positive results exclusively in the presence
    of metabolic activation. Mutagenic effects were also reported in a
    human cell line containing cloned cytochrome P450IIE1, which is
    capable of metabolizing VC (Weisman, 1992). Gene mutation was also
    detected in plant cuttings  (Tradescantia) exposed to VC (Van't Hof &
    Schairer, 1982). No mutagenicity was observed in  Neurospora crassa
    with or without addition of exogenic activation system (Drozdowicz &
    Huang, 1977) but the validity of this study is limited by
    contradictory documentation.

         In gene conversion assays, positive results were reported with
     Saccharomyces cerevisiae in the presence of a metabolic activation
    system (Loprieno et al., 1976; Eckardt et al., 1981). No mutagenic
    effects were observed without metabolic activation (Shahin, 1976).

         VC exposure induced unscheduled DNA synthesis in rat hepatocytes
    (Shimada et al., 1985) and increased sister-chromatid exchange in
    human lymphocytes after addition of an exogenic activation system
    (Anderson et al., 1981). No growth inhibition was detected in DNA
    repair-deficient bacteria without metabolic activation (Elmore et al.,
    1976).

         Cell transformation assays revealed positive results with
    (Styles, 1980) or without (Tu et al., 1985) metabolic activation.

    7.8.2  In vivo studies

         Key studies on the genotoxicity of VC  in vivo are documented in
    Table 35. VC exposure induced gene mutation and mitotic recombination
    in  Drosophila melanogaster but not gene mutation in mammalian germ
    cells. VC showed  in vivo clastogenic effects, increased sister
    chromatid exchanges and induced DNA breaks. VC induced also gene
    conversion and forward mutations in host-mediated assays.

         Mutagenic activity of VC was reported in the mitotic
    recombination assay (Vogel & Nivard, 1993) and the sex-linked
    recessive lethal (SLRL) assay (Magnusson & Ramel, 1976; Verburgt &
    Vogel, 1977; Magnusson & Ramel, 1978) on  D. melanogaster. The lowest
    effective concentration in the SLRL assay was 2210 mg/m3 with a 2-day
    exposure period and 78 mg/m3 after 17 days of exposure (Verburgt &
    Vogel, 1977). In the same study, negative results were observed at
    higher exposure concentrations with a 2-day exposure period in assays
    on  D. melanogaster for dominant lethals, translocations (not
    tabulated) and sex chromosome loss. These results were discussed by
    the authors as a consequence of a saturation effect observed in the
    SLRL test (Verburgt & Vogel, 1977). However, sex chromosome loss was
    observed in studies by Ballering et al. (1996) in  D. melanogaster
    exposed to higher concentrations.

         No mutagenic activity was detected in the dominant lethal assay
    with mice (Anderson et al., 1976; Himeno et al., 1983) and rats (Short
    et al., 1977). No mutagenicity was reported in the mouse spot test
    (Peter & Ungváry, 1980). Chromosomal aberrations in rats (Anderson &
    Richardson, 1981) and hamsters (Basler & Röhrborn, 1980) were reported
    and mouse bone marrow micronucleus tests (Jenssen & Ramel, 1980;
    Richardson et al., 1983) gave positive results.

         VC exposure (260, 650 and 1300 mg/m3) induced single-strand
    breaks dose-dependently in the liver DNA of NMRI mice (Walles &
    Holmberg, 1984; Walles et al., 1988). Increased frequencies of
    sister-chromatid exchange and chromosome aberrations were observed in
    the bone marrow of Chinese hamsters after exposure to 1.25, 2.5 or 5%
    (v/v) for 24 h (Basler & Röhrborn, 1980).

    7.8.3  Genotoxicity of VC metabolites

         Metabolic activation of VC is necessary to form the genotoxic
    metabolites. The metabolites themselves are genotoxic in the absence
    of metabolic activation (see also section 6.3). The VC metabolites,
    chloroethylene oxide (chloro-oxirane), chloroacetaldehyde, and
    chloroacetic acid were investigated for genotoxicity.  In vitro
    studies discussed in this section were performed without metabolic
    activation unless otherwise stated. Information on the mechanism of
    mutagenesis is presented in section 6.5 and 7.11.2.

         Chloroethylene oxide (CEO) was found to be the most effective VC
    metabolite regarding forward mutation and gene conversion in yeast
    (Loprieno et al., 1977), gene mutation in mammalian cells (Huberman et
    al., 1975) and reverse mutation in bacteria (Malaveille et al., 1975;
    Rannug et al., 1976; Hussain & Osterman-Golkar, 1976). The mutational
    specificity of CEO was investigated in  Escherichia coli, using  trpA
    mutant strains. In this system, CEO induced all types of base-pair
    substitutions (except one, which was not tested) (Barbin et al.,
    1985b). GC -> AT transitions were the most frequent, followed by
    AT -> TA transversions. This metabolite inhibited growth in DNA
    repair-deficient bacteria (Elmore et al., 1976; Laumbach et al.,
    1977).


        Table 35.  Genotoxicity of vinyl chloride in vivoa
                                                                                                                          

    Species/Strain/Sex   Test type           Test conditions; comments                        Results     References
                                                                                                                          

    Gene mutation

    Mouse/CD-1/m         dominant lethal     20 mice/group exposed to 0, 7800,                -           Anderson et
                         assay               26 000 or 78 000 mg/m3 for 6 h/d for                         al. (1976, 1977)
                                             5 d before 8 wk mating; survival 100,
                                             90, 95 and 45%

    Rat/CD/m             dominant lethal     12 mice/group exposed to 0, 130, 650,            -           Short et al.
                         assay               or 2600 mg/m3 for 6 h/d, 5 d/wk; one                         (1977)
                                             mating during week 11 of exposure;
                                             no mortality

    Mouse/CD-1/m         dominant lethal     a) 13 m exposed to 26 000 mg/m3 for              -           Himeno et al.
                         assay               4 h/d for 5 d (11 controls) before 7 wk                      (1983)
                                             mating; b) 20 m exposed 4 h/d, 5 d/wk
                                             to 13 000 mg/m3 for 10 wk before 3 wk
                                             mating

    Mouse/C57BL/f        mouse spot test     44 pregnant mice exposed to 12 000 mg/m3         -           Peter &
                                             for 5 h on gestation day 10 (51 controls)                    Ungváry (1980)

    Mouse/Swiss/n.d.     host-mediated       4-6 mice exposed orally to 700 mg/kg bw.         +           Loprieno et al.
                         forward mutation    in olive oil; yeast cells (S. pombe                          (1976)
                         assay               SP.198) inoculated in peritoneum for
                                             3, 6 or 12 h

    D. melanogaster/     dominant lethal     m exposed to 0 or 78 000 mg/m3 for 2 d;          -           Verburgt &
    Berlin K/m           assay               total number of eggs per group at                            Vogel (1977)
                                             least 6950; increase not significant; no
                                             differences in hatchability (> 80%)

    D. melanogaster/     Drosophila          a) m exposed to 0, 1, 10, 20% VC in air          +           Magnusson &
    Karsnäs/m            SLRL test           for 3 h (at least 491 chromosomes tested);                   Ramel (1978)
                                             b) m exposed to 0, 1, or 10% VC for 3 h
                                             after pretreatment with 1% phenobarbiturate
                                             solution for 24 h;
                                             a) positive at > 1% VC; no dose dependency;
                                             pretreatment in b) increased mutagenicity

    D. melanogaster/     Drosophila          50 m/group exposed continuously a) to 0,         +           Verburgt &
    Berlin K/m           SLRL test           78, 520, 2210, 26 000, 78 000, 130 000 mg/m3                 Vogel (1977)
                                             for 2 d or b) to 0, 78, 2210 mg/m3 for 17 d;
                                             a) positive at > 2210 mg/m3, no clear dose
                                             response;
                                             b) positive at > 78 mg/m3

    Mitotic
    recombination


    D. melanogaster/     mitotic             eye mosaic assay; 48- to 72-h-old larvae         +           Vogel &
    LS/f + m             recombination       exposed to 5200 mg/m3 for 17 h; light spots                  Nivard (1993)
                         assay               of at least 500 eyes scored in adult f
                                             (control 250 eyes scored); survival not
                                             reduced

    Chromosomal
    abnormalities

    Rat/Wistar/m         cytogenetic         24 m/group exposed to 3900 mg/m3 for             +           Anderson &
                         assay               a) 5 d (6 h/d) or b) 3 mo (6 h/d, 5 d/wk);                   Richardson
                                             bone marrow sampled 24 h after exposure                      (1981)
                                             period; increased number of cells with any
                                             abnormality, significant in a)

    Hamster/Chinese/     cytogenetic         2 m + 2 f per group exposed to 2.5% for 6,       +           Basler &
    f+ m                 assay               12, or 24 h; 5 m + 5 f exposed to 5% VC                      Röhrborn
                                             for 24 h; bone marrow samples prepared 26 h                  (1980)
                                             after start of exposure; control 7 m + 7 f;
                                             increased aberrations at > 6 h (gaps
                                             excluded), effect dose related

    Table 35. (cont'd)
                                                                                                                          

    Species/Strain/Sex   Test type           Test conditions; comments                        Results     References
                                                                                                                          

    Mouse/CBA/m          micronucleus        3 m exposed to 0 or 5% VC for 4 h; bone          +           Jenssen &
                         assay               marrow examined 30 h after exposure                          Ramel (1980)

    Mouse                micronucleus        0, 260, 860 or 2600 mg/m3 for 2 × 4 h            +           Rodics et al.
    CFLP                 assay                                                                            (1981)

    Mouse/               micronucleus        10 f and 10 m exposed to 0 or 130 000 mg/m3      +           Richardson
    C57BI/6J/f + m       assay               for 6 h; bone marrow examined 24 or 48 h                     et al. (1983)
                                             after exposure

    D. melanogaster/     sex                 m exposed to 0 or 78 000 mg/m3 for 2 d and       -           Verburgt &
    Berlin K/m           chromosome          chromosomes analysed in progeny (at least                    Vogel (1977)
                         loss                6725 m + f per group)

    D. melanogaster/     sex                 m exposed to 0 or 126 000 mg/m3 for 48 h;        +           Ballering et
    ring-X/m             chromosome          chromosome loss determined in F1 (at                         al. (1996)
                         loss                least n = 428; 3 broods)

    Other effects

    Rat/Wistar/m         host mediated       20-30 rats exposed to 0 or 1% VC for 24          +           Eckardt et al.
                         gene conversion     h, starting 1 h after yeast cell                             (1981)
                         assay               (S. cerevisiae D7RAD) injection (i.v.)

    Mouse/NMRI/f         alkaline elution    3-5 f per group; exposure to 1300 mg/m3          +           Walles &
                         assay in liver      for 39, 60, 117, 234 h (6 h/d, 5 d/ wk)                      Holmberg
                         DNA                 and sacrificed a) 2 h or b) 18 h (exposed                    (1984)
                                             for 36, 114, 231 h) after exposure period;
                                             concurrent control sacrificed after 36 or
                                             231 h; positive in a) at 39 h, in b) at 114 h

    Table 35. (cont'd)
                                                                                                                          

    Species/Strain/Sex   Test type           Test conditions; comments                        Results     References
                                                                                                                          

    Hamster/Chinese      SCE assay           2 m + 2 f per group exposed to 1.25 or 2.5%      +           Basler &
    f + m                                    VC for 6, 12, or 24 h; bone marrow samples                   Röhrborn
                                             prepared 26 h after start of exposure;                       (1980)
                                             control 4 m + 4 f; dose- and time-dependent
                                             effect
                                                                                                                          

    a d = day;  f = females;  m = males;  mo = months;  n.d. = no data;  SCE = sister-chromatid exchange;
      SLRL = sex-linked recessive lethals; wk = weeks;  + = positive;  - = negative


         CAA was 450 times less mutagenic than CEO in the Ames test but
    more active than the concurrent positive control ethylene oxide
    (Rannug et al., 1976). Positive results were reported with CAA in gene
    mutation assays in bacteria (Malaveille et al., 1975; Bartsch et al.,
    1975; McCann et al., 1975; Hussain & Osterman-Golkar, 1976; Elmore et
    al., 1976; Laumbach et al., 1977; Perrard, 1985), yeast cells
    (Loprieno et al., 1977), mammalian cells (Huberman et al., 1975), in a
    human lymphoblast cell line (Sanchez & Recio, 1991) and in human cells
    using shuttle vectors (Matsuda et al., 1995).

         With chloroacetic acid no enhancement of the mutation frequency
    could be detected in bacteria (Bartsch et al., 1975; Malaveille et
    al., 1975; Rannug et al., 1976) or mammalian cells (Huberman et al.,
    1975).

         Evidence for mutagenic activity of photoreaction products formed
    from VC was presented by Victorin & Ståhlberg (1991). Mixtures of VC
    (up to 260 mg/m3) and nitrogen dioxide (but not VC alone) were
    mutagenic in  S. typhimurium TA100 after 40 min UV irradiation of the
    gas mixture before exposure of bacteria.

         CEO but not CAA showed a similar toxicity/mutagenic profile to VC
    in the  hprt locus in a metabolically competent human
    B-lymphoblastoid cell line (Chiang et al., 1997; see also section
    8.4.2).

    7.8.4  Other toxic effects of VC metabolites

         In the above studies on the genotoxic effects of CAA (see section
    7.8.3), this compound appeared to be highly cytotoxic in various
    cellular systems. CAA has also a high acute toxicity in animals, with
    a LD50 value of 0.15 mmol/kg body weight. Kandala et al. (1990)
    showed  in vitro the concentration-dependant reversible inhibition of
    DNA synthesis by CAA in rat and mouse cells without a reduction in
    thymidine uptake or formation of nucleotides. In isolated rat
    hepatocytes, CAA stimulates lipid peroxidation (Sood & O'Brien, 1993).

    7.8.5  Mutagenic and promutagenic properties of DNA adducts formed by
           VC metabolites

         The major DNA adduct of VC, 7-(2'-oxoethyl)guanine (7-OEG), lacks
    miscoding properties (Barbin et al., 1985a). In contrast,
    1, N6-ethenoadenine (Epsilon A), 3, N4-ethenocytosine (Epsilon C)
    and  N2,3-ethenoguanine (Epsilon G) showed miscoding properties
    (Singer, 1996; see Table 37). The promutagenic properties of the
    etheno adducts involve mainly base-pair substitution mutations
    (Grollman & Shibutani, 1994). Site-specific mutagenesis studies in  E.
    coli and in mammalian cell lines have shown that both Epsilon G and
    Epsilon C can induce G:C -> A:T transitions; Epsilon C can also lead
    to C:G -> A:T transversions (Cheng et al., 1991; Moriya et al.,
    1994). Epsilon A can induce misincorporation of G, C, or A during
    replication, thus inducing the base-pair substitutions A:T -> C:G,
    A:T -> G:C or A:T -> TA (Basu et al., 1993; Pandya & Moriya, 1996).

    7.8.6  Mutations in VC-induced tumours

         Barbin et al. (1997) examined the presence of  p53 gene
    mutations (the function of the  p53 gene is described in
    section 8.4.2) in ASL and HCC tumours induced by VC in Sprague-Dawley
    rats. Mutations were found in 11/25 ASL and 1/8 HCC. A twelve-base
    deletion was found in one tumour; all others were base-pair
    substitutions. Nine of the point mutations were observed at A:T base
    pairs and of three G:C -> A:T transitions (Table 43).

         Mutations of the  p53 gene were also found in tumours from vinyl
    chloride-exposed autoclave workers with liver angiosarcoma (ASL) and
    hepatocellular carcinoma (HCC) (Hollstein et al., 1994; Boivin et al.,
    1997; see also section 8.4 and Table 43). To date (1998) 11 out of 15
    (73%) ASL from VC-exposed workers have been shown
    immunohistochemically to have mutant p53 protein. Furthermore, a
    statistically significant trend for mutant p53 protein has been found
    in the serum of VC-exposed workers (Smith et al., 1998). In contrary
    to studies in humans, no mutations were found in codons 12, 13 and 61
    of the Ki- ras gene in rat liver tumours induced by VC, but mutations
    were found involving codon 61 of the Ha- ras proto-oncogene (Froment
    et al., 1994; Boivin-Angèle et al., in press) (see Table 44 and
    section 8.4.2).

         Connexin genes have been shown to restore normal cell growth when
    transfected into certain tumorigenic cells and thus are considered to
    form a family of tumour suppressor genes. Mutations of the  connexin
     37 (Cx37) gene in rat liver tumours (22 hepaticangiosarcomas and 3
    hepatocellular carcinomas) induced by VC were analysed by
    PCR-single-strand conformation polymorphism analysis and DNA
    sequencing. The results suggested that  Cx37-mediated gap junctional
    intercellular communication may be disturbed in most of these
    angiosarcomas but mutation of the  Cx37 gene is rare (Saito et al.,
    1997).

    7.9  Factors modifying toxicity

         Concurrent administration of ethanol (5% in drinking-water until
    termination at month 30) and VC (1560 mg/m3, inhalation 4 h/day,
    5 days/week for 1 year) to male Sprague-Dawley rats (80 rats per group
    for histopathological evaluation) resulted in increased incidences of
    ASL from 23% after exposure to VC alone to 50% in rats exposed to VC
    and ethanol versus 0% in ethanol-treated rats and 0% in concurrent
    controls. Ethanol had an additive effect on the incidence of
    hepatocellular carcinoma (VC 43%, VC-ethanol 60%, ethanol 10%, control
    1.3%) and lymphosarcoma (VC 7.5%, VC-ethanol 14%, ethanol 5%, control
    2.5%) (Radike et al., 1981). This effect may be due to the interaction
    of ethanol with VC metabolism.

         Induction of certain enzymes of the mixed-function oxidase system
    by pretreatment with phenobarbital (Jaeger et al., 1974, 1977;
    Reynolds et al., 1975a,b,c) or the mixture of polychlorinated


        Table 36.  Summary of genotoxic effects induced by exposure to vinyl chloride in vitro and in vivoa
                                                                                                                               

                            In vitro                                                      In vivo
                                                                                                                         
       Bacteria     Yeast    Plants    Mammalian      Human           Insects             Mammalia                Humansc
                                                                                                                               

       GM   DD     GM  GC      GM     GM  DD  CT     GM  SCE       GM   AN   MR      GM  CA  MN  DD  SCE      GM  CA  MN  SCE

       +    -b     +   +       +      +   +   +      +   +         +    -    +       -   +   +   +   +        +   +   +   +
                                                                                                                               

    a  AN = aneuploidy;  CA = chromosomal aberration;  CT = cell transformation;  GM = gene mutation;  GC = gene conversion;
       DD = DNA damage; MN = micronuclei;  MR = mitotic recombination;  SCE = sister-chromatid exchange
    b  Single study, only tested without metabolic activation
    c  These results are described in Table 42 (section 8.4.1)

    Table 37.  Evidence for base-pair substitutions caused by etheno-DNA adducts
                                                                                                                                     

    Ethenobase           Base            Base-pair                   System used                              Reference
                         incorporated    substitution                for study
                         opposite
                         adducta
                                                                                                                                     

    1,N6-ethenoadenine   C               AT -> GC      in vivo       bacteriophage M13-Nhei in E. coli       Basu et al.
    (epsilon-A)                          transition                                                          (1993)
                         A               AT -> TA      in vivo       single-strand vector shuttle in         Pandya & Moriya
                         C               AT -> CG                    E. coli or simian kidney (COS) cells;   (1996)
                                         transversions

    3,N4-ethenocytosine  A               CG -> TA      in vivo       single-strand vector shuttle in         Moriya et al.
    (epsilon-C)                          transition                   E. coli or simian kidney               (1994)
                         T               CG -> AT      in vitro      (COS) cells;                            Zhang et al.
                                         transversion                E. coli DNA polymerase                  (1995)
                                                                     I system

                                                       in vivo       M13AB28 in SOS-(UV)-induced             Jacobsen &
                                                                     E. coli                                 Humayun (1990)
                                                       in vivo       M13 glyU phage transfection             Borys et al.
                                                                     of E. coli tester strain                (1994)

                                                       in vitro      E. coli DNA polymerase I system         Simha et al.
                                                                                                             (1991);
                                                                                                             Palejwala et al.
                                                                                                             (1991)

    N2,3-ethenoguanine   T               GC -> AT      in vivo       E. coli DNA synthesis by M13G*1         Cheng et al. (1991)
    (epsilon-G)                          transition                  assay
                                                       in vitro      E. coli DNA polymerase I (Klenow        Singer et al. (1991)
                                                                     fragment); exonuclease-free Klenow;
                                                                     Drosophila melanogaster polymerase
                                                                     alpha-primer compex;
                                                                     human immunodeficient virus-I
                                                                     reverse transcriptase (HIV-RT)
                                                       in vitro      E. coli DNA-dependent RNA               Mroczkowska &
                                                                     polymerase                              Kusmierek (1991)

    Table 37. (cont'd)
                                                                                                                                     

    Ethenobase           Base            Base-pair                   System used                              Reference
                         incorporated    substitution                for study
                         opposite
                         adducta
                                                                                                                                     

    1,N2-ethenoguanine   A               GC -> TA      in vitro      E. coli DNA polymerase I                Langouet et al.
                         G               GC -> CG                    (exonuclease-free Klenow)               (1997)
                                         transversions
                                                                                                                                     

    a  A = adenine;   C = cytosine;   G = guanine;   T = thymine


    biphenyls (Arochlor 1254) (Reynolds et al., 1975a,b; Conolly et al.,
    1978) enhanced acute hepatotoxicity in rats as measured by increased
    activity of hepatic enzymes and/or focal hepatic necrosis.
    Administration of SKF-525A, an inhibitor of the mixed-function oxidase
    system, 30 min prior to VC exposure in phenobarbital-pretreated rats,
    inhibited the enhancing effect of phenobarbital on VC hepatotoxicity
    (Jaeger et al., 1977). Application of cysteine, a rate-limiting
    precursor in hepatic glutathione (detoxification of reactive
    chemicals), via drinking-water prior to VC exposure protected Arochlor
    1254-pretreated rats against acute VC hepatotoxicity (Conolly &
    Jaeger, 1979).

    7.10  Mechanisms of toxicity - mode of action

    7.10.1  Mechanisms of VC disease

         Based on evidence of immunological abnormalities, such as
    hyperimmunoglobinaemia and circulating immune complexes in workers
    with "vinyl chloride disease" (section 8.3), Ward et al. (1976) have
    proposed a possible mechanism for the vascular changes associated with
    this disease. Reactive VC metabolite(s) bind(s) to a protein,
    resulting in a structurally abnormal protein. This protein would react
    as an antigen and initiate an immune response with B-cell
    proliferation and hyperimmunoglobinaemia. Circulating immune complexes
    formed by interaction of this antigen and antibodies would precipitate
    in the extremities of exposed humans in response to the cold and
    activate the complement sequence. The cryoprecipitates and reactions
    secondary to the complement activation are proposed to produce
    vascular occlusion and fibrinogen/fibrin conversion. The mechanism is
    supported by findings of IgG deposition with associated complement C3
    and fibrin in histological lesions (Grainger et al., 1980). The
    resulting vascular insufficiency would explain the observed clinical,
    radiological and histological findings in skin, skeletal and soft
    tissues, and lungs (section 8.3) in workers occupationally exposed to
    high concentrations of VC (Ward et al., 1976). No further studies were
    identified that would directly confirm this mechanism, and the degree
    to which it has been accepted is not clear. The available evidence
    does not seem sufficient to suggest an autoimmune disease as a
    pathogenetic mechanism. Further studies will be needed to establish
    the true significance of the possibly transient immunological
    abnormalities in VC-induced disorders.

    7.10.2  Mechanism of carcinogenesis

         There is a large body of data showing that VC acts as a genotoxic
    carcinogen. After metabolic activation to CEO by CYP2E1, VC exerts
    various genotoxic effects (including gene mutations and chromosomal
    aberrations) in different organisms, including bacteria, yeasts,
    mammalian cells in culture, Drosophila, rodents and humans (Table 36).
    Among the mutagenic events induced by VC, base-pair substitutions
    appear, so far, to be the most frequent. VC in the presence of an
    activation system has a transforming activity on mammalian (rodent)
    cells in culture (see Table 34).

         Studies  in vitro have demonstrated that metabolically activated
    VC and its electrophilic metabolites CEO and CAA can alkylate nucleic
    acid bases. 7-OEG, the major DNA adduct formed by VC and CEO does not
    exhibit promutagenic properties. In contrast, four minor adducts,
    Epsilon A, Epsilon C, N2,3-Epsilon G and 1,N2-Epsilon G, show
    promutagenic properties, inducing mainly base-pair substitution
    mutations and a low level of frameshift mutations.

         7-OEG and three etheno adducts (Epsilon A, Epsilon C,
    N2,3-Epsilon G) have been detected in DNA from rats and mice exposed
    to VC. Highly variable background levels of Epsilon A and Epsilon C
    were found in all the tissues examined. Following exposure of rats to
    VC, significantly elevated levels of Epsilon A and Epsilon C were
    measured in most tissues, except the brain; there was also no
    significant increase of Epsilon A levels in the kidney and spleen.

         The liver is one of the primary targets for VC-induced
    carcinogenesis in rats and humans. It is also, by far, the major
    tissue involved in VC activation in rats. Following exposure of rats
    to VC, the distribution of etheno adduct levels (induced by the
    exposure) is rather homogeneous within the organism. Epsilon C was
    shown to accumulate as a function of length of exposure in at least
    three organs (liver, kidney and lung). In contrast, Epsilon A
    accumulated in the liver but not in the kidney and lung. In addition,
    adduct levels (Epsilon A, Epsilon C) did not decrease in the liver,
    for at least two months following the end of exposure. Etheno adducts
    are formed as endogenous background levels in various tissues in
    humans; no data are available on etheno adduct levels in humans
    exposed to VC.

         Mutations have been found in liver tumours associated with
    exposure to VC. In human ASL, the Ki-ras gene is activated through a
    GC -> AT mutation at base 2 of codon 13. Mutations, all AT -> TA
    transversions, have been described in the  p53 gene in three human
    ASL. The Ki-ras gene activation is not found in rat ASL. However, 44%
    of rat ASL were found to contain a mutated  p53 gene: most mutations
    were base-pair substitutions, involving mainly A:T base pairs. The
    data suggest the existence of hot spots for mutations in the  p53
    gene, and one mutation found in two rat ASL was equivalent to the
    same mutation characterized in one human ASL associated with VC
    exposure. The Ha-ras gene is activated in rat HCC induced by VC,
    through an AT -> TA transversion in codon 61.

         The mutation spectra observed in liver tumours (ASL and/or HCC)
    associated with VC exposure in humans and rats are clearly distinct
    from those observed in sporadic liver tumours or in hepatic tumours
    associated with other exposures. In rats, the substitution mutations
    found at A:T base pairs in the  ras and  p53 genes are consistent
    with the promutagenic properties of Epsilon A and with the
    accumulation and persistence of this lesion in hepatic DNA.

         Altogether, available data suggest that etheno adducts could be
    involved in the initiation of hepatocarcinogenesis by VC. However,
    they cannot explain the observed tissue- and cell-specificity.

         More studies on the formation and repair of etheno adducts at the
    cellular level (cell specificity), as well as at the molecular (gene
    and DNA sequence) level, are warranted. Carcinogenesis is a multi-step
    process and, obviously, there is a need for quantitative evaluation of
    other critical biological end-points, such as effects of VC on
    apoptosis, cell proliferation or intercellular communication  in
     vivo.
    

    8.  EFFECTS ON HUMANS

         Only reports on effects for humans of exposure to VC have been
    considered here and not reports where exposure has been to a number of
    chemicals, e.g., at landfills, in factories manufacturing a number of
    chemicals or in the PVC processing industry.

    8.1  General population exposure

         After an accident in Schönebeck, Germany in June 1996, involving
    the derailment of a train carrying VC and subsequent fire, 325 persons
    were documented as having acute symptoms but these correlated with
    exposure to the pyrolytic products (e.g., HCl) and not to VC itself.
    But a study on 29 persons exposed as a result of this accident showed
    a significant increase in chromosomal aberrations compared to an
    unexposed control group (Hüttner & Nikolova, 1998; see also Table 42
    and section 3.2.3).

         A case has been reported of epithelioid haemangioendothelioma
    involving liver, bone and lungs in a man living for over 8 years
    several hundred metres from a toxic waste dump next to a chemical
    plant producing VC (Shin et al., 1991).

         There have been several reports on the possible increased
    prevalence of congenital malformations in populations exposed to
    emissions from polymerization facilities (Edmonds et al., 1975, 1978;
    Infante, 1976; Thériault et al., 1983; Rosenman et al., 1989) but none
    of these studies showed a statistically significant correlation
    between developmental toxicity and proximity to the facility
    (Clemmesen, 1982; Hemminki & Vineis, 1985). A number of studies (e.g.,
    Goldberg et al., 1995; Dolk et al., 1998) examined risk for cancer and
    for adverse reproductive outcome in relation to proximity to
    landfills. Although VC is one of the potential emissions from the
    landfills, these studies do not directly address the population
    exposure to VC and were not further considered.

         In England and Wales, from 1975-1987 data, there were no
    confirmed non-occupationally exposed cases of ASL (Elliott &
    Kleinschmidt, 1997). In the USA, five non-occupational cases were
    reported living within 1.6 km of a VC plant (Brady et al., 1977).

    8.2  Controlled human studies

         Three men and three women were exposed twice daily with a 6-h
    interval for three successive days to 0, 0.4, 0.8, 1.2, 1.6 or 2.0%
    VC. The NOEL was between 0.8 and 1.2%. Above this, dizziness, nausea,
    dulling of vision and auditory cues were reported (Lester et al.,
    1963).

         Thirteen male volunteers were exposed to 130, 650 and 1300 mg/m3
    for 7.5 h and subjective and neurological responses were measured
    before the subject entered the chamber, 15 min after entrance and at
    1-h intervals thereafter; 24-h post-exposure urine and blood samples

    were taken and tested. No significant adverse effects were noted with
    the exception of some dryness of eyes and nose at 1300 mg/m3. The
    exposure had no noticeable effect on neurological responses nor did it
    produce significant changes in the results of mental, coordination or
    manual dexterity tests conducted during the exposure period. All
    clinical laboratory studies performed in the post-exposure period were
    normal and not significantly different from pre-exposure values
    (Baretta et al., 1969).

    8.3  Occupational exposure

    8.3.1  Overview

         VC was first produced commercially in the late 1920s. Various
    effects caused by exposure to VC were reported: cardiac arrhythmia in
    experimental animals (Oster et al., 1947); hepatic abnormalities in VC
    workers (Tribukh et al., 1949; Filatova et al., 1958), acroosteolysis,
    Raynaud-type-phenomenon and sclerodermoid skin lesions (Lelbach &
    Marsteller, 1981). But it was not until it was found that VC could
    cause cancer in animals (Viola et al., 1971; Maltoni et al., 1974) and
    humans (Creech & Johnson, 1974) that levels of VC in the workplace
    were drastically reduced. Some VC workers, in particular autoclave
    cleaners, were estimated to have been exposed to as much as
    2600 mg/m3 (1000 ppm) in the 1950s or earlier, reducing to a tenth of
    this level by the mid-1970s (Table 20). After 1975 levels were usually
    2.6-13 mg/m3 (1-5 ppm) in many countries, but in some countries where
    production plants were not modernized, workers were or are exposed to
    high levels of VC (Fucic et al., 1990a; Gáliková et al., 1994; Hozo et
    al., 1996, 1997; see also Table 21).

         It should be noted that the non-neoplastic and neoplastic effects
    described in the following sections are due in most cases to the high
    exposure of workers to VC before 1974. No cases of ASL (section 8.3.1)
    have been reported to the International Register of Cases among (West)
    European workers first exposed after 1972 (Storm & Rozman, 1997). This
    is not the case for Eastern European countries where the old
    regulation of 194 mg/m3 (75 ppm) in the working environment was valid
    until recently (Hozo et al., 1997).

    8.3.2  Non-neoplastic effects

    8.3.2.1  Acute toxicity

         In acute VC intoxication, the symptoms described include vertigo,
    nausea and headache. At higher concentrations, VC exerts narcotic
    effects and at one time was considered as a possible anaesthetic
    (Patty et al., 1930; Peoples & Leake, 1933; Oster et al., 1947).

         VC caused almost immediate death of VC polymerization workers in
    two incidents of accidental poisoning. No values were given but the
    strong smell and the narcotic effects of VC were reported (Danziger,
    1960).

         Concentrations of VC of the order of 26 000 mg/m3 (1%) in the
    air induce unconsciousness and cardiac arrhythmia. Exposure of two
    workers to 2.5% VC for 3 min caused dizziness, disorientation and a
    burning sensation in the soles of the feet. There was complete
    recovery except for a slight headache lasting 30 min (Danziger, 1960).

         A man whose hands were accidentally sprayed with VC developed
    erythema and some second-degree burns which healed without
    complication (Harris, 1953). A patient complaining of eye burns from
    VC recovered 48 h after the eye was rinsed for 15 min with saline
    (McLaughlin, 1946).

    8.3.2.2  Effects of short- and long-term exposure

         Concentrations of VC in the region of 2590 mg/m3 (1000 ppm),
    which were not unusual prior to 1974, over periods ranging from
    1 month to several years, have been reported to cause a specific
    pathological syndrome found in VC workers called the "vinyl chloride
    illness". Symptoms described were earache and headache, dizziness,
    unclear vision, fatigue and lack of appetite, nausea, sleeplessness,
    breathlessness, stomachache, pain in the liver/spleen area, pain and
    tingling sensation in the arms/legs, cold sensation at the
    extremities, loss of libido and weight loss (Thiess & Versen, 1974).
    Clinical findings included scleroderma-like changes in the fingers
    with subsequent bony changes in the tips of the fingers described as
    acroosteolysis, peripheral circulatory changes similar to Raynaud's
    disease, and enlargement of the liver and spleen with a specific
    histological appearance, and respiratory manifestations (Lange et al.,
    1974; Suciu et al., 1975; Veltmann et al., 1975; Lelbach & Marsteller,
    1981).

    8.3.2.3  Organ effects

    a)  Skin and skeletal tissues

         Occupational acroosteolysis has largely affected the most highly
    exposed workers involved in scraping the insides of autoclaves in the
    PVC production process (Harris & Adams, 1967; section 3). It is a rare
    bone disease resulting in de-calcification of the terminal phalanges
    of the hands and other extremities (Cordier et al., 1966; Wilson et
    al., 1967; Markowitz et al., 1972). In these cases, acroosteolysis was
    often preceded by soreness and tenderness, numbness, pallor and
    cyanosis of the extremities especially the hands, a Raynaud-type
    phenomenon caused by reversible constriction of the arterioles.
    Sclerodermoid-like changes appear in the skin of the hands and
    forearms and osteolytic and sclerotic lesions of the bones,
    particularly the extremities and sacroiliac joints (Lange et al.,
    1974). Most of the abnormalities disappeared and bones showed signs of
    healing a year or two after the men had stopped work (Harris & Adams,
    1967). A chronothermodynamic study of Raynaud's phenomenon secondary
    to past exposure to VC showed that, although reduced, the symptoms
    were still present after 8 years (Fontana et al., 1996).

         A review of five studies from four countries involving 725
    workers at risk from VC exposure showed that 3% developed
    acroosteolysis; 10% Raynaud-type phenomenon and 6% sclerodermoid skin
    lesions (Lelbach & Marsteller, 1981). Genetic susceptibility has been
    suggested as a possible reason that not all workers who had been in
    contact with VC developed symptoms (Black et al., 1983, 1986). The
    scleroderma-like syndrome induced by VC exposure appears to be
    different from that of other (systemic) scleroderma (Ostlere et al.,
    1992). It has a shorter incubation period (1 month to 3 years compared
    to 4 to 44 years) (Ishikawa et al., 1995) and there are immunological
    differences (section 8.3.2.3f).

    b)  Hepatic effects

         Exposure to VC is associated with hepatomegaly and/or
    splenomegaly and with various histological lesions in the liver (Lange
    et al., 1974; Ho et al., 1991). In one carefully described study,
    advanced portal hypertension with histological findings of
    non-cirrhotic fibrosis was diagnosed in 17 of 180 VC polymerization
    workers (Lelbach & Marsteller, 1981).

         Focal hepatocellular hyperplasia and focal mixed hyperplasia
    (hyperplasia of sinusoidal cells along with hyperplasia of
    hepatocytes) are early histological alterations indicative of VC
    exposure (Tamburro et al., 1984). The precursor stage of ASL is
    characterized by subcapsular fibrosis, progressive portal fibrosis and
    a borderline increase of intralobular connective tissue, all
    associated with focal stimulation and proliferation of sinusoidal
    lining cells and hepatocytes. Transition to angiosarcoma is preceded
    by focal dilatation of sinusoids with enlarged dedifferentiated lining
    cells often containing peg-like hyperchromatic polymorphic nuclei
    (Popper & Thomas, 1975; Gedigk et al., 1975).

         There is a great similarity between the histological sequences in
    the liver of rodents exposed by inhalation to VC (chapter 7; Spit et
    al., 1981) and the lesions observed in VC-exposed workers (Popper et
    al., 1981).

         Twenty of the 39 "liver disease deaths" reported in an Italian
    study of highly exposed PVC workers were due to liver cirrhosis, the
    remainder being due to miscellaneous liver disorders. A statistical
    evaluation was not possible (Pirastu et al., 1990). In another study,
    two of 21 heavily exposed VC workers died from sequelae to
    noncirrhotic portal fibrosis and portal hypertension (Lelbach, 1996).
    In the USA and European cohort studies of VC-exposed workers (study
    descriptions are given in section 8.3.3), deaths from chronic
    non-malignant diseases of the liver had a low SMRs of 62 and 88; in
    the European study this was significantly less than expected (Wong et
    al., 1991; Simonato et al., 1991).

    c)  Cardiovascular effects

         Some old studies reported statistically non-significant increased
    mortality due to cardiovascular diseases among workers exposed to VC
    (Ebihara, 1982; Greiser et al., 1982).

         Laplanche et al. (1992) report an elevated incidence of
    circulatory system diseases other than Raynaud's disease (RR 1.4, 95%
    CI 1.0-1.8) in a 7-year follow-up of a cohort of 1100 VC workers. The
    increased risk was mainly due to hypertension and "other circulatory
    disorders". Likewise, another study with a 5-year follow-up on the
    incidence of arterial hypertension (AH) and coronary heart disease
    (CHD) in 105 VC and PVC workers exposed to VC at between 4 and
    1036 mg/m3 showed that exposed workers had significantly higher blood
    pressure than controls. The estimated relative risk (RR) for AH in
    exposed workers was twice as high as in the controls, while there was
    no significant difference regarding CHD. There was an
    exposure-response relationship between the intensity of exposure and
    the incidence of AH (Kotseva, 1996).

         In contrast, both the large cohort studies reported a
    statistically significant deficit in the mortality from cardiovascular
    diseases, with SMRs of 87 and 81. In the USA study, the mortality was
    even lower for the subcategory of arteriosclerotic heart disease (SMR
    74.5, 95% CI 81.6-89.2 (Simonato et al., 1991; Wong et al., 1991). In
    the Canadian study (Thériault & Allard, 1981), there was a
    statistically non-significant 20% deficit in cardiovascular mortality,
    based on 25 exposed cases.

    d)  Respiratory effects

         Adverse respiratory effects reported in older case studies
    included increased incidence of emphysema (Suciu et al., 1975),
    decreased respiratory volume and vital capacity, respiratory
    insufficiency (Suciu et al., 1975), decreased respiratory oxygen and
    carbon dioxide transfer (Lloyd et al., 1984), pulmonary fibrosis of
    the linear type (Suciu et al., 1975), abnormal chest X-rays (Lilis et
    al., 1975) and dyspnoea (Walker, 1976). This is probably due in part
    to confounding by smoking and presence of PVC-resin dust, which is
    known to cause respiratory lesions (Mastrangelo et al., 1979; Lilis,
    1981).

         Both large cohorts (Wong et al., 1991; Simonato et al., 1991)
    found a deficit in the mortality from non-malignant respiratory
    diseases (SMR 81.6, and 77, respectively). Despite overall deficit in
    mortality from respiratory diseases, Wong et al. (1991) found an
    excess of emphysema/chronic obstructive pulmonary disease (COPD)
    mortality, which, however, was highest among workers with a duration
    of exposure less than 10 years.

    e)  Neurotoxicity

         In patients with chronic occupational exposure, neurological
    disturbances include sensory-motor polyneuropathy (Perticoni et al.,
    1986; Podoll et al., 1990), trigeminal sensory neuropathy, slight
    pyramidal signs and cerebellar and extrapyramidal motor disorders
    (Langauer-Lewowicka et al., 1983). Psychiatric disturbances included
    neurasthenic or depressive syndromes (Penin et al., 1975).
    Sleeplessness (Gnesina et al., 1978; Gnesina & Pshenitsina, 1980;
    Langauer-Lewowicka et al., 1983; Gnesina & Teklina, 1984) and loss of
    sexual functions (see below) were frequently encountered. Pathological
    EEG alterations were found in a high proportion of patients (Penin et
    al., 1975; Stœblová et al., 1981).

    f)  Immunotoxicity

         The major immunological abnormalities reported in VC disease
    patients include hyperimmunoglobulinaemia with a polyclonal increase
    in IgG, cryoglobulinaemia, cryofibrinogenaemia, and  in vivo
    activation of complement (Ward et al., 1976). Immunofluorescent
    examinations of skin and lung biopsies have demonstrated the
    deposition of IgG with associated complements C3 and fibrin in
    relation to the histological lesions described in small blood vessels
    (Grainger et al., 1980). A statistically significant increase in
    circulating immune complexes was observed in workers exposed to VC,
    compared to unexposed workers (Ward et al, 1976) . The increase in
    circulating immune complexes was greatest in women and in those with
    duties involving exposure to relatively higher levels of VC
    (Bogdanikowa & Zawilska, 1984).

         Bencko et al. (1988) found significantly elevated IgA, IgG and
    IgM levels in the serum of workers exposed to low levels of VC
    (< 10 mg/m3), but found that in workers with excessive exposures to
    VC (> 10 mg/m3) there was a significant drop in IgG level.

         The antinuclear antibody (ANA) test is negative or at low titre
    in VC disease (Ward et al., 1976), whereas it is often positive in
    other scleroderma-like disorders.

         There is much heterogeneity within VC disease, in terms of skin
    involvement, severity, and organ involvement, and it is clear that
    this could have an immunological background. Systemic sclerosis may be
    a genetically linked autoimmune disease. Many autoimmune diseases show
    statistically significant associations with certain
    human-leukocyte-associated antigen (HLA) alleles. Black et al. (1983,
    1986) compared the HLA frequencies and autoantibodies in workers with
    VC disease ( n=44), asymptomatic workers ( n=30), systemic sclerosis
    ( n=50) and normal (blood donor) controls ( n=200). The HLA-DR5
    allele occurred significantly more frequently in VC disease (36%) and
    systemic sclerosis (30%) compared to asymptomatic workers (3%) and
    normal controls (16%). Eleven out of 21 men with severe VC disease had

    HLA markers B8, DR3 whereas none of the 23 workers with mild disease
    were positive for these markers, suggesting that this haplotype
    favours progression of the disease.

         Splenomegaly has been detected in a number of VC-exposed workers
    (Falk et al, 1974; Suciu et al., 1975; Veltmann et al., 1975; Makk et
    al., 1976; Ho et al., 1991). Hyperplastic sinusoidal cells were found
    in some specimens.

    g)  Reproductive toxicity

         The reproductive effects of VC have been reviewed (Uzych, 1988;
    Little, 1993; Olsen et al., 1995).

         VC has been cited in several early case series from different
    countries as being responsible for male sexual dysfunctions such as
    potency troubles, "pathological changes in the ejaculates", decreased
    androgen secretion or undefined sexual disorders (Suciu et al., 1975;
    Veltman et al., 1975; Walker, 1976; Sanotsky et al., 1980; Makarov,
    1984) in exposed workers, but there is a lack of controlled studies.
    Similarly, various female sexual dysfunctions have been reported after
    long term exposure to VC (Makarov et al., 1984).

         The possible risk, arising from human male exposure to VC, for
    pregnancy and fetal loss among the wives of workers was first raised
    after a report by Infante et al. (1976a,b) suggesting that fetal loss
    was significantly more among wives of exposed workers. Data for the
    wives of 95 VC polymerization workers in the USA were contrasted with
    data for the partners of PVC fabrication workers and rubber workers
    (total 158). Prior to exposure, the fetal death rates for controls and
    polymerization workers were 6.9 and 3.1% (age adjusted, respectively).
    After exposure, the rates were 6.8 and 10.8%, respectively. Weaknesses
    in the study were in the method of age adjustment, that information
    was obtained from interviews with male workers only (and not their
    wives), and that there were no data on maternal age or on smoking and
    other abuses.

         In a study on 534 VC production and polymerization workers whose
    wives were under 45 on 1 January 1984, 82 men were exposed to VC
    before their spouses' pregnancies. The crude rate of abortions (no. of
    spontaneous abortions / no. of pregnancies) was 8.9 for exposed and
    8.8 for unexposed (total number of pregnancies: 90 and 1027,
    respectively). Adjustment for confounders did not suggest a
    significant relationship between spontaneous abortion and paternal
    exposure to VC (Mur et al., 1992).

         No statistically significant correlation could be found between
    exposure to VC and congenital central nervous system (CNS) defects
    among the children of fathers working at VC polymerization facilities
    in Kanawha County, USA (Edmonds et al., 1975, 1978), but the study
    data were not sufficient for a clear evaluation (Uzych, 1988).

         In a Chinese study of 236 female workers exposed for more than 1
    year to VC and 239 controls using retrospective (levels 3.9 to
    89.3 ppm) and prospective (0.2 to 130.7 ppm) epidemiology, VC did not
    appear to influence involuntary infertility, pregnancy outcome or
    course of parturition, although the incidence of toxaemia in pregnancy
    was found to be higher among female workers exposed to higher
    concentrations in the prospective study (Bao et al., 1988; Jiangl,
    1990).

         An investigation into reproductive function in 2736 workers
    exposed to VC in 13 PVC factories and 3442 workers in other factories
    not exposed to VC showed no significant differences in reproductive
    outcome. However, in the female exposed group, the incidence of
    pregnancy complication was significantly higher than that of the
    control group, suggesting that VC may effect the pregnancy process in
    female workers (Huang, 1994).

         There have been studies on female workers in the PVC processing
    industry (Lindbohm et al., 1985; Ahlborg et al., 1987), but, as VC was
    not the only source of exposure, these studies were not considered
    here.

    8.3.3  Neoplastic effects

         After the case series published in 1974 (Creech & Johnson, 1974)
    on hepatic angiosarcoma among workers exposed to vinyl chloride,
    several further case series and small epidemiological studies, mainly
    with emphasis on hepatic tumours, were published in the 1970s and
    1980s. They show that VC can cause the rare liver tumour (ASL). Other
    (non-ASL) cancer sites/types reported for which some of these studies
    have indicated an association with VC exposure are: liver (e.g.,
    non-angiosarcoma) tumours, particularly hepatocellular carcinoma;
    respiratory system; digestive system other than the liver; lymph and
    haematopoietic tissue; brain and other central nervous system;
    malignant melanoma.

         The early studies, together with a prepublication report of the
    USA cohort study (see below) were summarized by Sir Richard Doll
    (Doll, 1988). More recently, the studies performed in Sweden, Italy,
    the United Kingdom and Norway were updated and analysed together
    (L'Abbé et al., 1989; Simonato et al., 1991). Parts of the European
    study have also been published separately. An updated American study
    (Wong et al., 1991) combined many smaller studies conducted earlier in
    the USA. These two studies provide the most informative data on the
    health effects associated with exposure to VC. Four smaller
    prospective studies on VC exposure workers have been conducted in
    Canada (Thériault & Allard, 1981), Germany (Weber et al., 1981;
    Greiser et al., 1982), France (Laplanche, 1987, 1992) and the
    former-USSR (Smulevich et al., 1988). The complete description of two
    additional studies (Frentzel-Beyme et al., 1978; Huang, 1993a,b) was
    not available to the Task Group and were not further considered.

         The epidemiological studies on VC/PVC workers are described as
    follows:

    * Simonato et al. (1991) (European/IARC study), which incorporates
    populations reported by: Byrén et al. (1976), Molina et al. (1981),
    Hagmar et al. (1990) (Sweden); Fox & Collier (1977), Jones et al.
    (1988) (United Kingdom); Heldaas et al. (1984, 1987) (Norway); Belli
    et al. (1987), Pirastu et al. (1990, 1991, 1998) (Italy);

    * Wong et al. (1991) (USA study)a, which incorporates populations
    reported by Tabershaw & Gaffey (1974), Monson et al. (1975); Nicholson
    et al. (1975), Ott et al. (1975), Waxweiler et al. (1976), Buffler et
    al. (1979), Cooper (1981), Dahar et al. (1988), Wu et al. (1989);

    * Thériault & Allard (1981) Canada;

    * Weber et al. (1981), Greiser et al. (1982) Germany;

    * Laplanche et al. (1987, 1992) France;

    * Smulevich et al. (1988) former-USSR

         The USA study consisted of 10 173 men who had worked for at least
    one year in jobs involving exposure to VC prior to January 1973 in 37
    plants in the USA. Observation covered the years 1942-1982, and the
    observed mortality was compared with the expected rates, based on USA
    national rates for white males, standardized for age, and calendar
    time. The race was actually known for only 666 workers, among which 3%
    were African. Altogether 1536 members of the cohort were identified as
    having died, the vital status of 725 individuals (7.88%) remained
    unknown, and death certificates were not obtained for 97 (6.3%). These
    deaths were included in the calculation of the overall SMR, but not in
    any cause-specific SMRs (which leads to an underestimation of all
    disease-specific SMRs by 6.3%).The deaths were coded using the 7th ICD
    revision, where the numbers 155 and 156 comprise liver (155, both
    primary and secondary) and bile duct and gall bladder tumours (156).
    The average length of employment was approximately 16 years, and 46%
    of the cohort were employed before 1955, thus providing a possible
    latency of more than 27 years for this group. The levels of exposure
    were not known. The all-causes SMR was 90.1 (95% CI 85.6-94.7), based
    on a total of 1536 deaths. The SMR for all cancers was 105.1
    (94.4-116.5).

         The European/IARC study comprised a total of 14 351 subjects from
    19 factories. After exclusion of short-term employees (< 1 year),
    females, deaths outside the observation period, members of more than
    one cohort, 12 706 subjects remained for the analysis. The follow-up

              
    a  After the Task Group meeting, a report of an update of the USA
       study became available. A summary of it is presented in Appendix
       3.

    was 97.7% complete, the average length of follow up 17 years, and the
    total number of person-years 222 746. National rates of mortality,
    specific for age and five-year calendar periods, were used for the
    comparison. The observation period was different for different
    factories, starting for most from 1955, and extended until 1986.
    Calendar period-specific job exposure matrices (JEMs) were developed
    for 13 of the 19 factories. These JEMs were developed using job title
    as a basic unit in which exposure is assessed. Estimates of exposure
    were assigned,  a priori, by a group of industrial hygienists on the
    basis of the historical information available from the companies.

         These estimates have been used both for qualitative and
    quantitative dose-response analysis. In particular, a cumulative dose
    was computed for each subject by multiplying the number of years spent
    in a specific job by the time-specific estimates in ppm and then
    summing up all the periods.

         The 7th (for liver tumours, codes 155-156), 8th and 9th revisions
    (155) of ICD were used (thus combining primary and secondary tumours
    of the liver and tumours of extrahepatic bile ducts). A statistically
    significant deficit in over-all mortality was observed (SMR 88, 95% CI
    83-93), while for all malignant neoplasms, the SMR was 104 (CI
    95-114), with 445 cancer deaths observed.

         The Canadian study (Thériault & Allard, 1981) studied the
    mortality of 1659 workers in a chemical industry complex in Schwanigan
    who had worked for no less than 5 years in the company between 1943
    and 1972. Out of the total, 48 (2.9%) could not be traced. The
    observation period was 20 years or more for 315 workers (70%), and the
    duration of exposure no less than 10 years for 340 (75%). Since
    several episodes of unconsciousness among workers were reported, the
    exposure to VC had probably been high: no measurement data were
    available. The causes of death during 1948-1972 of the cohort was
    determined from death certificates. In the analysis, those exposed to
    VC for more than 5 years (451) were compared with those exposed for
    less than 6 months (870). In addition, the mortality of the exposed
    subcohort was compared to the age-standardized mortality expected for
    Quebec in the year 1971. For cancer cases, medical records were
    consulted for the verification of the diagnosis. The overall mortality
    was similar in the exposed and non-exposed cohorts, and gave an SMR of
    0.83 for the VC-exposed cohort in comparison to the Quebec figures.

         Smulevich et al. (1988) reported results from a retrospective
    cohort study of workers employed in some of the oldest Soviet chemical
    plants producing VC and PVC. The study comprised 2195 men and 1037
    women employed for at least one month in the plants. Subjects were
    followed from 1939 to 1977. Information on specific occupation within
    the plant, duration of exposure, date and cause of death, and
    postmortem results (for cancer deaths) were collected for all member
    of the cohort. No information was provided on the means for doing the
    follow-up nor on losses to follow-up. Workers were classified into
    those with high level exposure to VC (> 300 mg/m3), moderate levels

    (30-300 mg/m3)  and  low  levels (< 30 mg/m3). Mortality for the
    cohorts was compared with rates of the city of the plant for the years
    1959, 1969 and 1975. There were 288 deaths registered in the cohort,
    including 63 from cancer. The SMR for all cancers was 1.06.

         A prospective cohort study of 1100 workers exposed to VC in
    various French plants and 1100 unexposed subjects was initiated in
    1980 (Laplanche et al., 1987, 1992). Unexposed controls were matched
    to cases by age, plant and physician. Subjects were followed until
    December 1988 for vital status, other health outcomes and occupation.
    Information was collected on complete occupational history, smoking
    and drinking habits, and medical history (see also section 8.3.2.3c
    and Table 39).

         Weber et al. (1981) and Greiser et al. (1982) reported a historic
    prospective cohort study of 7021 male workers who had been or were
    working on 31 December 1974 in VC/PVC plants in Germany and Austria
    (follow-up 10.5 years). The control cohort consisted of 4910 Germans
    and Austrians from the same chemical companies but not having contact
    with VC (follow-up 15.5 years). SMR for liver tumours was 1523, with
    no details of the number of ASL. For lymphatic tumours and leukaemia
    there was a SMR of 214. No information was given on subtypes. A
    summary of findings on selected neoplasms for the epidemiological
    studies on workers exposed to VC is given in Tables 39 and 40.

    8.3.3.1  Liver and biliary tract cancers

    a)  Features of angiosarcoma

         Angiosarcoma of the liver (ASL), also known as
    haemangioendothelial sarcoma, is an extremely rare liver tumour and is
    difficult to diagnose. ASL constitutes only 2% of all primary tumours
    of the liver in the general population. It has been associated only
    with exposure to VC, Thorotrast (a contrast medium used in X-ray
    radiography in the 1930s-1950s) and arsenic (Creech & Johnson, 1974;
    Falk et al., 1974). In England and Wales, from 1975 to 1987, there was
    an annual incidence of 1.4 cases per 10 million population (Elliott &
    Kleinschmidt, 1997). Regular international surveillance of cases of
    ASL from VC exposure show that 118 cases were registered by 1985
    (Forman et al., 1985), 173 by 1993 (Lee et al., 1996), and 197 by 1999
    (Association of Plastics Manufacturers in Europe, 1999) (Table 38).

         The most prominent clinical symptoms are abdominal pain,
    weakness, fatigue and weight loss with hepatosplenomegaly, ascites and
    jaundice being the common clinical signs. It is suggested that
    patients with non-cirrhotic portal fibrosis and a history of VC
    exposure should be followed-up for likely ASL (Lee et al., 1996).
    However, Lelbach (1996) noted that, strikingly, except for the final
    stages, there was little impairment of hepatic function in ASL
    patients. The average latent period between starting work in an
    occupation involving VC exposure and ASL diagnosis/death for 99 cases
    was 22 years (Purchase et al., 1987; Lelbach, 1996).

        Table 38. Number of vinyl chloride-associated ASL cases
    reported per country in 1972
                                                                            

    Country           ASL cases      ASL cases       ASL cases up to 1999
                      up to 1985a    up to 1993b     [changes since 1993] c
                                                                            

    USA               35             44              50  [+6]
    Germany           26 (West)      41              40  [-1]
    France            18             28              31  [+3]
    United Kingdom    9              20              21  [+1]
    Canada            10             13              13
    Croatia           4              4               12  [+8]
    Slovakia          2              2               6  [+4]
    Italy             4              8               8
    Sweden            5              5               5
    Japan             2              3               4  [+1]
    Belgium           2              2               2
    Norway            1              1               1
    Spain                            1               1
    Australia                        1               1
    Brazil                                           1  [+1]
    Israel                                           1  [+1]

    Total d           118            173             197
                                                                            

    a From: Forman et al. (1985)
    b From: Lee et al. (1996)
    c Association of Plastics Manufacturers in Europe (1999)
    d It should be noted that from several countries known
      to be producers of PVC, there is no information regarding
      ASL cases.

         Any treatment is generally unsuccessful and survival after
    diagnosis usually averages less than 12 months. Hepatic failure and
    intra-abdominal haemorrhage are the usual terminal effects (Riordan et
    al., 1991; Lee et al., 1996). Liver transplantation might be the only
    chance of survival (Hayashi et al., 1990). If ASL is detected early
    enough, surgical resection and adjuvant chemotherapy is a possibility;
    subsequent hepatic recurrence could be treated by radiation therapy
    and chemoembolization (Paliard et al., 1991; Neshiwat et al., 1992;
    Hozo et al., 1997).

    b)  Results of epidemiological studies

         In addition to the index tumour, ASL, several case series have
    been published on VC-exposed workers who had liver tumours other than
    ASL, in particular hepatocellular carcinoma (HCC) (Koischwitz et al.,
    1981; Evans et al., 1983; Dietz et al., 1985; Pirastu et al., 1990,
    1991; Lelbach, 1996; Makita et al., 1997; Saurin et al., 1997). In the
    USA study, statistically significantly elevated relative risk was
    observed for the cancers of liver and biliary tract (SMR 641, CI
    450-884). Mortality was related to the duration of exposure (SMR 182,
    1235, and 1284 for workers with exposure duration of < 10, 10-20 and
    > 20 years, respectively), and to the latency period (SMR 386, 590,
    and 1218 for latency periods of < 20, 20-30 and > 30 years,
    respectively. The risk was higher for workers hired before 1950 (SMR
    780) than in for those hired 1950-1959 (SMR 440) or since 1960 (SMR
    419). The risk was highest among workers hired at an early age (SMR
    1611, 813 and 346 for those hired at < 25, 25-34 and > 35 years of
    age. The authors noted, however, that those hired early and young were
    likely to have longer duration of exposure and latency.

         A total of 15 angiosarcomas were recorded on the death
    certificates. Although no expected numbers were calculated, this must
    be in a very marked excess, since the annual incidence of liver
    angiosarcoma is approximately 2 per 10 million, which would in this
    cohort lead to an expected number of approx. 0.05. The authors noted
    that, when the 15 angiosarcomas were excluded, there remained 22 other
    liver and biliary tract tumours; this represents an excess (5.7
    expected, SMR 386,  P < 0.02). This is likely to be an overestimate,
    since some of these other liver cancers were likely to be
    angiosarcomas.

         In the European study, the SMR for liver neoplasms was 286 (95%
    CI 183-425, and it increased with increasing latency (SMR 0, 253, 388
    and 561 for latencies < 10, 10-19, 20-29 and > 30 years,
    respectively), duration of exposure (SMR 94, 327, 310, 714 and 1111
    for duration of employment of < 10, 10-14, 15-19, 20-24 and
    > 25 years, respectively), ranked level of exposure, and cumulative
    exposure (SMR 348, 400, 1429 and 1667 for < 2000, 2000-6000,
    6000-10 000 and > 10 000 ppm-years, allowing for a 15-year
    latency). A clear exposure-response relationship was seen between
    ranked level of exposure (ppm) as well as cumulative exposure
    (ppm-years) to VC and liver cancer mortality, with autoclave workers
    having the highest risk (Table 41; Simonato et al., 1991). This
    relationship is even more evident taking only those liver cancers
    defined histologically as ASL. In addition, for those VC workers not
    defined as autoclave workers, an exposure-response relationship could
    be seen for those diagnosed as having ASL and non-ASL liver cancers
    (Pirastu et al., 1990, 1991; Simonato et al., 1991).


        Table 39.  Summary of findings on selected neoplasms for the epidemiological
    studies on workers exposed to VC
                                                                                                                                        

    Cause of        European/IARC         USA study       Weber et       Smulevich et      Thériault      Laplanche         All
    mortality       study (Simonato       (Wong et        al. (1981)     al. (1988)        & Allardt      et al.            studies d
                    et al., 1991)         al., 1991)                                       (1981)         (1992)
                    Obs/Exp               Obs/Exp         Obs/Exp        Obs/Exp           Obs/Exp        Exposed/          Obs/Exp
                    SMR                   SMR             SMR            SMR               SMR            Non-expos. RR     SMR
                    (95% CI)              (95% CI)        (95% CI)       (95% CI)          (95% CI)       (95% CI)          (95% CI)
                                                                                                                                        

    All causes      1438/1636.4           1536/1705.27    414/434.7      -                 59/71.07       40/43
                    88                    90              95                               83             1.0
                    (83-93)               (86-95)                                                         (0.6-1.5)

    All malignant   445/427.8             359/341.7       79/82.9        63/58.88          20/16.37                         966/927.65
    neoplasms       104                   105             103 b          107               122            1.3               104
                    (95-114)              (94-116)                                                        (0.7-2.3)         (98-111)

    Liver cancer/   24/8.4                37/5.77         12/0.9         0/n.a             8/0.14         3                 81/19.21
    angiosarcoma    286                   641             1523                             5714                             533
    (ASL)           (183-425)             (450-884)                                        8 ASL (+2 ASL  3 ASL             (423-622)
                    16 ASL out of         15 ASL in                                        undiagnosed)
                    17 liver cancer       death
                    deaths with           certificates.
                    histopathology        21 ASL in
                                          international
                                          register

    Brain           14/13.1               23/12.76        2/1.3          4/2.61            0/0.6                            43/30.37
                    107                   181             162            153               0                                142
                    (59-180)              (114-271)                                                                         (103-191)

    Lung            144/148.3             111/115.87      24/26.6        1/1.2             2/5.78 c                         282/297.75
                    97                    96              96             83                34                               95
                    (82-114)              (79-116)                                                                          (84-106)

    Table 39.
                                                                                                                                        

    Cause of        European/IARC         USA study       Weber et       Smulevich et      Thériault      Laplanche         All
    mortality       study (Simonato       (Wong et        al. (1981)     al. (1988)        & Allardt      et al.            studies d
                    et al., 1991)         al., 1991)                                       (1981)         (1992)
                    Obs/Exp               Obs/Exp         Obs/Exp        Obs/Exp           Obs/Exp        Exposed/          Obs/Exp
                    SMR                   SMR             SMR            SMR               SMR            Non-expos. RR     SMR
                    (95% CI)              (95% CI)        (95% CI)       (95% CI)          (95% CI)       (95% CI)          (95% CI)
                                                                                                                                        

    Lymphatic and   29/32.7               37/36.28        15/7.7         10/2.2            1/1.67                           92/80.55
    haematopoietic  89                    102             214            454               60                               114
                                          (72-141)                                                                          (92-140)

    Lymphomas       18/19.3 a             24/21.8 a                      5/1.2
                    93                    110                            417

    Stomach         49/45.1               10/16.01        18/14.4        21/24.7           -                                98/100.21
                    109                   63              138            85                                                 98
                    (80-144)              (30-115)                                                                          (79-119)
                                                                                                                                        

    a Lymphoma and malignant myeloma
    b As reported in original paper
    c All respiratory neoplasms
    d Calculated by the Task Group. All studies except Laplanche et al. (1992)  who did not provide observed and expected values

    Table 40. Analysis of liver, brain and lung cancer mortality in the USA
    and European cohort by duration of exposure
                                                                                           

    Organ      Study               < 10 years             10-19 years          20 + years
                                                                                           

                                SMR      (observed)    SMR     (observed)   SMR     (observed)
                                                                                           

    Liver    USA (Wong          182      (6)           1236    (20)         1285    (11)
             et al., 1991)

             Europe (Simonato   0        (0)           253     (8)          432     (16)
             et al., 1991)

    Brain    USA                165      (13)          121     (4)          386     (6)

             Europe             59       (2)           113     (6)          136     (6)

    Lung     USA                93       (59)          114     (37)         75      (15)

             Europe             95       (73)          107     (51)         83      (20)
                                                                                           


         Of the 17 liver cancer deaths, for which histopathological data
    were available, 16 were classified as angiosarcomas. For the remaining
    seven, the histological type remained unknown. The Task Group noted
    that even if they all had been cancers other than angiosarcoma, the
    relative risk of liver tumours other than angiosarcoma would not have
    been elevated (expected number equiv. 8).

         For 2643 workers from Norway and Sweden, cancer incidence
    information was also available. The only site for which a
    statistically significantly elevated risk was observed was the liver
    (SIR 303, CI 122-623).

         In the Canadian study, there was an excess of digestive tract
    cancers (14 cases, SMR 259,  P < 0.01) that was fully accounted for
    by cancers of the liver (8 cases). All liver cancers were
    angiosarcomas.

         Hospital admission diagnoses were studied among 714 present and
    1575 previous workers, identified from national Labour Insurance
    Bureau records, with exposure to VC (Du & Wang, 1998). The frequencies
    of different diagnoses were compared with similar data on workers in
    the manufacture of optical instruments or of motorcycles. Eight cases
    of primary liver cancer were observed among the VC-exposed workers
    (out of 1044 admissions), while the number was 9/3667 for the optical
    workers, and 9/5861 for motorcycle manufacturers, which gave 4.5 (95%
    CI 1.5 to 13.3) and 6.5 (2.3-18.4) as age-adjusted morbidity odds
    ratios (MOR), calculated from a linear regression model, for the
    VC-exposed workers, compared to the two comparison groups. Increased
    MORs (of borderline significant) were also observed for haematopoietic
    cancer, chronic liver disease and liver cirrhosis, as well as other
    chronic diseases, and accidents.

         Two updates of parts of the Italian cohort (Pirastu et al., 1991)
    have recently appeared. An elevated mortality of liver cancer (11
    observed, 5.7 expected cases, SMR 193) was observed in Marghera. In an
    extended survey for hepatic cancers, four further cases were
    uncovered. There were 5 angiosarcomas, 5 hepatocellular carcinomas, 3
    cirrhotic carcinomas, and in two cases the histology was not known
    (Pirastu et al., 1997). In three other subcohorts (Pirastu et al.,
    1998), the pooled SMR for liver cancer was 364 (7 observed cases, 90%
    CI 108-390).

         A survey of 5291 workers from 13 PVC manufacturing plants in 12
    cities in China using 6276 workers unexposed to VC as controls was
    carried out between 1982 and 1989. Although no cases of ASL were
    reported, the mortality from liver cancer in male workers exposed to
    VC was significantly higher than those of the control group and of the
    male general population in the middle cities in China. Among malignant
    tumours, liver cancer ranked first in exposed males. The authors found
    that the average age for persons who were diagnosed with liver cancer
    was significantly lower than that of the control group (Huang,
    1993a,b).


        Table 41.  Mortality data for liver cancer according to the exposure
    variables a
                                                                                                        

    Exposure variable           O        SMR       95% CI            15 years of latency
                                                                                          
                                                                   SMR              95% CI
                                                                                                        

    Job title

    Ever autoclave worker       11       896       447-1603        1358              678-2430
    Never autoclave worker b    13       181       97-130          284               151-485

    Duration of
    employment (years)

    1-9                         4        94        26-239          205               56-525
    10-14                       5        327       106-763         602               196-1406
    15-19                       4        310       84-794          310               84-794
    20-24                       6        714       262-1555        714               162-1555
    > 25                        5        1111      361-2593        1111              361-2593


    Ranked level of
    exposure (ppm)

    Low (< 50)                  3 (4)    119       25-347          227 (244)         47-664 (67-625)
    Intermediate (50-499)       3 (7)    161       33-471          250 (551)         52-731 (222-1136)
    High (> 500)                12 (12)  567       293-991         719 (719)         371-1255 (371-1255)
    Unknown                     6 (1)    317       177-691         486 (125)         182-1079 (3-697)

    Cumulative exposure
    (ppm-years)

    0-1999                      4 (9)    99        27-254          191  (348)        52-490  (159-662)
    2000-5999                   4 (4)    351       96-898          460  (400)        125-1177 (109-1024)
    6000-9999                   4 (7)    800       218-2048        851  (1429)       232-2179 (574-2943)
    > 10 000                    3 (3)    1429      295-4175        1667  (1667)      344-4871 (344-4871)
    Unknown                     9 (1)    357       163-678         536  (100)        245-1017   (2-557)

    Table 41. (cont'd)
                                                                                                        

    Whole cohort                24       286       183-425         445                 285-663
                                                                                                        

    a From: Simonato et al. (1991); O = observed number of deaths;
      SMR = standardized mortality ratio; Cl = confidence interval.
      The values in parentheses were determined in analyses including
      the estimated job-exposure matrices

    b In Norway, the longest-held job was used. In Sweden job rotation
      was practiced, and no one was classified as an autoclave worker


    8.3.3.2 Brain and central nervous system (CNS)

         Statistically significant increases of brain and CNS tumours
    after occupational exposure to VC were reported in USA surveys by
    Waxweiler et al. (1977) and Cooper (1981), as well as in Sweden (Byrén
    et al., 1976) and Germany (Greiser et al., 1982).

         In the USA (study of Wong et al., 1991), the relative risk was
    elevated for cancers of the brain and other CNS cancers (SMR 180.2, CI
    114.1-270.6). Mortality was highest in the group with the longest
    duration of exposure (SMR 164.7, 120.8 and 385.9, for workers with the
    duration of exposure < 10 years, 10-20 years and > 20 years,
    respectively), while no trend with latency was observed (SMR 183.8,
    158.3 and 210.7, for latencies of < 20, 20-30 and > 30 years).
    Workers hired early did not exhibit higher risk than those hired late
    (SMR 156, 164 and 256, for employees hired before 1950, 1950-1960 and
    after 1960, respectively. It was noted that most of the cases came
    from the two plants with the highest rate of ASL.

         In the European study, the SMR for brain cancer was 107
    (CI 59-180). The small number of cases (total 14) made the assessment
    of the relationship between duration of exposure and latency
    difficult, but the risk was highest after longest latency (SMR 59,
    113, 59 and 407 after a latency of < 10, 10-20, 20-30 and
    > 30 years) and after longest duration of exposure (SMR 106, 78 and
    183 for a duration of exposure of < 10, 10-20 and > 20 years).
    There were even fewer cases for the assessment of the relationship
    between estimated exposure and cancer risk (8 cases altogether), but
    the point estimates were higher for higher estimated exposures (SMR
    91, 42 and 128 for low, intermediate and high exposure), while little
    covariation between estimated cumulative exposure and relative brain
    cancer risk was observed (SMR 0, 162 and 120 for cumulative exposures
    of < 50, 50-499 and > 500 ppm-years).

         In the cancer incidence aspect of the European study, a
    non-significantly elevated SIR was observed for cancer of the brain
    (SIR 159 CI 68-312).

    8.3.3.3  Respiratory tract

         The study by Monson et al. (1974) first suggested an association
    between VC and lung cancer.

         In the USA study, the SMR for lung cancer was 95.8
    (CI 78.7-115.5).

         In the European study, the SMR for lung cancer was 97
    (CI 82-114). It did not show any consistent relationship with duration
    of employment, latency, ranked level of exposure or cumulative
    exposure; the SMR was similar for ever- and never-autoclave workers.

         In the cancer incidence aspect of the European study, a
    non-significantly elevated SIR was observed for cancer of the lung
    (SIR 152, CI 95-230).

         In the Canadian study, the mortality from respiratory cancer was
    low (relative risk in comparison to the unexposed cohort 0.36, and SMR
    based on Quebec data, 34, based on two cases). Smoking habits, as
    studied by a questionnaire, were similar in the exposed and
    non-exposed cohorts.

    8.3.3.4  Lymphatic and haematopoietic cancers

         There were indications of increased risk of cancer of the
    lymphatic and haematopoietic systems in several early studies (Monson
    et al., 1975; Waxweiler et al., 1976; Greiser et al., 1982; Smulevich
    et al., 1988).

         In the Wong et al. (1991) USA study, the SMR for lymphatic and
    haematopoietic cancer was 102 (CI 71.6-140.7, while that for lymphoma
    and reticulosarcoma was 102.0 (CI 71.6-140.7).

         In the European study, the overall SMR for lymphosarcoma was 170
    (CI 69-351), based on seven cases. No cases were observed in the
    groups with a latency of 20-30 or > 30 years, and six out of the
    seven subjects had worked less than 10 years in VC-exposure
    conditions.

    8.3.3.5  Malignant melanoma

         There was a relationship between VC exposure and malignant
    melanoma of the skin in PVC production workers in the early Norwegian
    study (Heldaas et al., 1984, 1987).

         In the European study, a non-significant, elevated risk was
    observed for melanoma, and the risk was higher in the incidence part
    of the study (SIR 184, CI 79-302). However, the risk was limited to
    one country only (Norway).

    8.3.3.6  Breast cancer

         Infante & Pesák (1994) noted that there had been no follow-up
    study to that of Chiazze et al. (1977), who observed an excess in
    breast cancer mortality. Although a subsequent study among these
    researchers (Chiazze et al., 1980) did not identify a significantly
    elevated odds ratio in relation to VC exposure, the statistical power
    used in the study has been questioned (Infante & Pesák, 1994). There
    have been no other reports on breast cancer in humans, but in most
    Western countries women have not been working in jobs involving VC
    exposure. In some countries, however, e.g., China and Eastern Europe,
    women are/were probably exposed to higher VC levels than in Western
    countries (see Table 21) but epidemiological studies are not
    available. Mammary carcinoma has been reported in animal studies with
    inhalative and oral exposure to VC (see section 7.7.2).

         No breast cancer was observed in the study by Smulevich et al.
    (1988).

    8.3.3.7  Other cancer sites

         In the European study, a non-significantly elevated risk was also
    observed for urinary bladder (21 deaths observed, SMR 146, CI 91-224)
    and, in the incidence part, for cancer of the stomach (SIR 150,
    CI 80-256).

    8.4  Genotoxicity studies

    8.4.1  Cytogenetic studies of VC-exposed workers

         Table 42 summarizes the results of cytogenetic studies of
    chromosomal aberrations (CA), micronucleus formation (MN) and
    sister-chromatid exchanges (SCEs) in the peripheral blood lymphocytes
    of VC workers compared to controls. Studies on the genotoxicity of VC
    have been reviewed (Uzych, 1988; Giri, 1995). Although in many studies
    the exposure concentrations and duration of exposure were only
    estimated, a dose-response relationship and a "normalization" of
    genotoxic levels with time after reduction of exposure can be seen.

         There was a clear relationship between incidence of CA and the
    exposure concentrations/type of work (Purchase et al., 1978). The same
    groups of workers showed lower or no effects after the exposure
    concentration was reduced to < 13 mg/m3 (< 5 ppm) (Hansteen et al.,
    1978; Anderson et al., 1980; Fucic et al., 1996). That such levels do
    not cause an increase in CA was confirmed by several studies (Picciano
    et al., 1977; Rössner et al., 1980; de Jong et al., 1988).

         SCEs increased with the level of exposure to VC of workers
    (Sinués et al., 1991). SCEs were generally not detected in blood
    samples from workers exposed to VC at < 5 ppm.

         In a micronucleus assay, workers exposed to VC had a much higher
    frequency of micronucleated lymphocytes than the controls. However, a
    significant decrease in the number of micronucleated lymphocytes was
    found within 15 days after the last exposure, but even 90 days after
    the last exposure (peak of 780 mg/m3) the frequency, although
    decreased, was still above the control value (Fucic et al., 1994). A
    similar effect had been shown with SCE frequencies (Fucic et al.,
    1992).

         Chromosomal aberrations were measured in peripheral blood
    lymphocytes from 29 subjects potentially exposed to VC after an
    accidental release into the environment (Hüttner & Nikolova, 1998).
    The control group consisted of 29 non-exposed people, matched
    regarding age, gender and smoking habits. The exposed group showed a
    statistically significant increase in the mean frequency of aberrant
    cells (1.47% versus 1.07% in the control group).


        Table 42.  Chromosome analysis in human T-lymphocytes (in vivo)
    after vinyl chloride exposure during work at PVC polymerization
    plants or due to other accidental exposure a
                                                                                                                                 

    Test                No. workers;    Additional              Duration          Exposure         Result     Reference
                        No. controls    information             of exposure       level
                                                                (years)           (mg/m3)
                                                                                                                                 

    HPRT mutation       24; 23          worked on post-         average 7         average < 13     -          Hüttner &
    using T-cell                        chlorination of PVC                                                   Holzapfel (1996)
    cloning assay                       in an open system
                                        where free VC
                                        evaporated

    DNA single          16              3 groups of VC/PVC      average 13        average 150      -          Du et al. (1995)
    strand breakage     104             workers                 average 16        5                -
                        122                                     average 16        2                -

    Chromosomal         11; 10          PVC workers             4-28              peaks >1300      +          Ducatman et
    aberrations                                                 (average 15)                                  al. (1975)
                        7; 3                                    9-29              50-75            +          Funes-Cravioto
                                                                                                              et al. (1975)
                        45; 93                                  0.5-12            n.g.             +          Szentesi et al. (1976)
                        57; 24          VC/PVC workers          10.7 (average     10-100           +          Purchase et al. (1978)
                                        classified according    for autoclave
                        21; 6           to type of work         workers)          < 13             +          Anderson et al. (1980)
                        23; 8           (1974)                                    < 13             -
                                        same as Purchase
                                        et al. (1978)

    Chromosomal         20; 20          with clinical                                              +          Fleig & Thiess (1974,
    aberrations                         symptoms; without                                          -          1978)
                                        clinical symptoms
                        39; 16          1974                    > 10              > 65             +          Hansteen et al. (1978)
                        37; 32          same workers 1977                         2.6              -
                        3;  9                                   10-27             50-400           +          Kucerová et al. (1979)
                        37; 12                                  n.g.              2-111            +          Katosova & Pavlenko (1985)
                        43; 22                                  average 11.2      2-41             +          Hrivnak et al. (1990)

    Table 42. (cont'd)
                                                                                                                                 

    Test                No. workers;    Additional              Duration          Exposure         Result     Reference
                        No. controls    information             of exposure       level
                                                                (years)           (mg/m3)
                                                                                                                                 

                        19; 20                                  average 15        130; peaks of    +          Fucic et al. (1990b)
                        67; n.g.        breaks occurring at     average 15        5000 13; peaks   +          Fucic et al. (1990a)
                                        non-random sites                          of 5000
                        10; n.g.                                8-25;             av 13; short     +          Garaj-Vrhovac et al. (1990)
                                                                average 15        peaks higher
                        n.g             PVC workers             5                 26               +          Zhao et al. (1994)
                                        PVC workers             2                 26               -
                                        PVC workers             > 7               4                -
                                        residents on site       > 8               0.2              -
                        209; 295        3 groups                average 4         < 2 to > 13      -          Picciano et al. (1977)
                        31; 35          1977                    2-3               < 10             -          Rössner et al. (1980)
                                        same group 1978                           peak < 30        -
                        66; 39          1976-1977               1-11; average 6   3 peaks up       -          de Jong et al. (1988)
                        29; 29          exposure of general     for short time    to 26 unknown    +          Hüttner & Nikolova
                                        population after        (approx. 1 h)     concentration               (1998)
                                        accidental release
                                        of VC

    Micronucleus        19; 20                                  average 15        130; peaks of 5000          +Fucic et al. (1990b)
    assay               32              24 h to 90 days         10                peak of 780      +          Fucic et al. (1994)
                                        following a peak        5                 mg/m3 every      +
                                        exposure of                               3 months
                                        780 mg/m3

    Table 42. (cont'd)
                                                                                                                                 

    Test                No. workers;    Additional              Duration          Exposure         Result     Reference
                        No. controls    information             of exposure       level
                                                                (years)           (mg/m3)
                                                                                                                                 

    Sister-chromatid    9; 8                                    10-27             50-400           +          Kucerová et al. (1979)
    exchange            16, 16                                  > 10              2.6              -          Hansteen et al. (1978)
                        21; 6                                   3.5               < 13            (-)         Anderson et al. (1981)
                        31; 35                                  2-3               < 10             -          Rössner et al. (1980)
                        31; 41                                  > 2               3-44; peaks of   +          Sinués et al. (1991)
                        21; 41                                                    130
                                                                                  1-20
                        15; 10                                  1.5-35            13; peaks of     +          Fucic et al. (1992)
                                                                                  5000
                                                                                  0.3; peaks of    -          Fucic et al. (1996)
                                                                                  130
                                                                                                                                 

    a HPRT = hypoxanthine guanine phosphoribosyltransferase; n.g. = not given


    8.4.2  Mutations at the hypoxanthine guanine phosphoribosyltransferase
           (hprt) locus

         With the use of the hprt lymphocyte clonal assay it is possible
    to determine the mutation frequency of the  hprt gene and to
    characterize its mutant spectra. Induced mutagenesis in the
    lymphocytes of PVC production workers was measured by selecting mutant
    T-cells with the  hprt gene in medium containing 6-thioguanine. The
    exposed workers had similar mutation frequencies (about 8 × 10-6) as
    controls (Hüttner & Holzapfel, 1996).

         The types and frequencies of mutations caused by VC in a human
    B-lymphoblastoid line expressing cytochrome P-450 2EI (H2E1 cells)
    were investigated by Chiang et al. (1997). VC was found to be toxic
    and mutagenic to H2E1 cells as a function of incubation time when they
    were exposed to 7.5% VC in air. This exposure resulted in 75% survival
    and an hprt mutant frequency of 42 × 10-6 after 48 h, compared to
    6 × 10-6 for unexposed cells. Exposure to 0.8 to 15.0% VC in air
    produced similar mutation frequencies but without a clear
    dose-response relationship, perhaps due to saturation of metabolic
    activation. Ten percent (5/50) of VC-induced mutations showed
    detectable deletions. Both CEO and CAA showed dose-dependent increases
    in cell killing and mutant frequency. VC and CEO displayed similar
    toxicity/mutation profiles and a similar frequency of large deletions,
    whereas CAA showed greater toxicity and a larger frequency of deletion
    mutations.

    8.4.3  Mutations in ASL from VC-exposed workers

    8.4.3.1  p53 gene

         Normal and cancer cells appear to differ through discrete changes
    in specific genes controlling proliferation and tissue homoeostasis.
    The  p53 tumour suppressor gene is present in every cell of the human
    body and is located on the short arm of the human chromosome 17 p.
    (Lane, 1994). It is mutated in about half of all cancer types arising
    from a wide spectrum of tissues (Harris, 1996).

         The encoded wild-type p53 protein, a 393 amino acid nuclear
    phosphoprotein, activates the transcription of several genes,
    including some involved in cell cycle control (e.g., p21), and has
    been implicated in DNA repair processes, DNA replication and apoptosis
    (Lane, 1994; Semenza & Weasel, 1997). The majority of cancer-related
    mutations in  p53 cluster in several "hot-spot" regions of the
    protein that have been highly conserved through evolution. These
    regions occur in the sequence-specific DNA-binding core domain of the
    protein between amino acid residues 102 and 292 (Lane, 1994). The
    mutations in  p53 found in malignancies could thus result in
    substitutions of amino acid residues in these regions that are
    critical for the determination of its structure and function (Cho et
    al., 1994; Brandt-Rauf et al., 1996).

         The  p53 gene was examined in tumours from four highly exposed
    (before 1974) autoclave workers with ASL and one other VC worker with
    hepatocellular carcinoma (HCC) (Hollstein et al., 1994). Two A to T
    mutations in a highly conserved domain of the coding sequence (codon
    249: AGG to TGG, Arg to Trp; and codon 255: ATC to TTC, Ile to Phe)
    were found one each in the tumour but not in other normal cells of two
    of the ASL patients (both smokers). A further A to T missense  p53
    mutation (codon 179: CAT to CTT) was found in a cell line from a
    further VC-associated liver tumour patient (Boivin et al., 1997; see
    Table 43). Such mutations are uncommon in human cancers (2.7% of a
    total of 5085 cancers and 8% of a total of 290 primary liver cancers;
    Hollstein et al., 1996). Furthermore,  p53 mutations are uncommon in
    sporadic (non-VC-induced) ASL (2/21 cases, 9%), supporting the
    evidence linking VC exposure and ASL containing an increased frequency
    of  p53 mutations with a mutational spectrum (A to T) (Soini et al.,
    1995). To date (1998) 11 out of 15 (73%) ASL from VC-exposed workers
    have been shown immunohistochemically to have mutant p53 protein.
    Further, a statistically significant trend for mutant p53 protein has
    been found in the serum of VC-exposed workers (Smith et al., 1998);
    this study is continuing (Li et al., 1998a,b).

          p53 gene mutations were also found in 11 out of 25 (44%) ASL in
    Sprague-Dawley rats induced by VC and 1 in 8 HCCs (Barbin et al.,
    1997; see Table 43). This is a higher mutation rate than that found in
    humans but again the majority of missense mutations involved were A:T
    base pairs. The A:T -> T:A transversion observed in the first
    nucleotide of codon 253 in two rat ASL is equivalent to the same
    transversion characterized previously in codon 255 in one human ASL
    associated with VC exposure (Trivers et al., 1995).

    8.4.3.2  ras genes

         The  ras gene family, Ha- ras, Ki- ras and N- ras, are genes
    coding for p21 and are frequently activated by point mutations in
    codons 12, 13 and 61. These activated genes seem to play a key role in
    the development of spontaneous or carcinogen-induced mammalian tumours
    (Barbacid, 1987). In a study of  ras oncogene mutations in tumours of
    VC-exposed workers, 15 of 18 ASLs were found to contain a G to A
    transition at the second base of codon 13 (GGC to GAC) of the
    Ki- ras-2 gene (Marion et al., 1991, 1996; see Table 44). This
    mutation leads to the substitution of glycine by aspartic acid at
    amino acid residue 13 in the encoded p21 protein.

         Ki- ras-2 gene mutations were found in codon 12 in 5/19 sporadic
    ASL and in 2/5 thorotrast-induced ASL in humans. All seven mutated
    tumours contained a G -> A transition at base 2. In addition, 4 of
    these tumours (3 sporadic, 1 thorotrast-induced) contained a second
    mutation in the Ki- ras gene, a G -> T transversion of the first
    base of codon 12 (Przygodzki et al., 1997).

        Table 43. Comparison of mutation spectra in the p53 gene in
              liver tumours in humans and rats a
                                                                                              

    Species    Tumour origin          No. mutations/     No. and types    References
                                      no. of cases       of mutations
                                                                                              

    Humans     VC-associated          3/6                3 A:T -> T:A     Hollstein
               ASL                                                        et al. (1994)

               cells cultured                            [CAT -> CTT]     Boivin
               from                                      (codon 179)      et al. (1997)
               VC-associated
               liver tumour

    Rats       VC-associated          11/25              5 A:T -> T:A     Barbin et al.
               ASL                                       2 A:T -> G:C     (1997)
                                                         2 A:T -> C:G
                                                         3 G:C -> A:T
                                                         one 12 base-pair
                                                         deletion
                                                         1 deletion

               HCC                    1/8                1 A:T -> T:A
                                                                                              

    a Adapted from Barbin et al. (1997); ASL = angiosarcoma of the liver;
      HCC = hepatocellular carcinoma

    Table 44. Mutagenesis of ras proto-oncogenes in VC-associated
    liver tumours in humans and rats
                                                                                        

    Tumour       Gene        Codon     No.           Base pair      References
    origin a     involved              mutations/    change/
                                       No. tumours   Codon
                                                     change
                                                                                        

    Human        Ki-ras 2    Codon     15/18         G -> A/        Marion et al.
    ASL          gene        13                      GGC -> GAC     (1991, 1996);
                                                                    DeVivo et al.
                                                                    (1994)

    Rat          Ki-ras 2              0/10                         Froment et al.
    ASL          gene                                               (1994);
                                                                    Boivin-Angèle
                                                                    et al. (in press)

    Rat          Ha-ras      Codon     5/8           AT -> TA/      Froment et al.
    HCC          gene        61                      AT -> TA       (1994);
                                                                    Boivin-Angèle
                                                                    et al. (in press)
                                                                                        

    a  ASL = angiosarcoma of the liver; HCC = hepatocellular carcinoma

         In studies in VC-induced ASL and HCC tumours in rats, no
    mutations were found in Ki- ras genes but there were mutations at
    codon 61 of the Ha- ras proto-oncogene (Froment et al., 1994;
    Boivin-Angèle et al., in press).

    8.5  Studies on biological markers

    8.5.1  Excretion of metabolites

         The concentration of the VC metabolite thiodiglycolic acid in the
    urine has been found to correlate with VC exposure in workers and has
    been suggested as a biological marker for VC (Müller et al., 1978)
    (see also section 5.3).

    8.5.2  Genetic assays

         Increased levels of chromosomal abnormalities, compared to
    control populations, were found in workers exposed to high levels of
    VC but not in workers exposed to less than 13 mg/m3 (5 ppm) (see
    Table 42). The micronucleus assay and mitotic activity have been
    suggested as methods for determining recent VC exposure (Fucic &
    Garaj-Vrhovac, 1997; see section 8.4).

    8.5.3  Enzyme studies

         Ever since the 1970s there has been disagreement as to the value
    of monitoring levels of enzymes as a measure of VC exposure or as a
    sign of VC disease. Liver function tests may be of limited value in
    detecting VC-induced liver disease because, although hepatocytes are
    the primary site of VC metabolism, they are not the target of toxicity
    (Lelbach & Marsteller, 1981). Individual studies of VC-exposed
    populations have reported abnormalities in one or more liver function
    tests, such as aspartate aminotransferase (ASAT), alanine
    aminotransferase (ALAT) and alkaline phosphatase (AP) (Lilis et al.,
    1975; Waxweiler et al., 1977). However, Sugita et al. (1986) concluded
    that VC probably had not affected these enzymes after adjusting for
    confounding factors. This was confirmed by Du et al. (1995) who showed
    that ASAT, ALAT and AP were mainly affected by the presence of
    hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus
    (anti-HCV).

         Gamma glutamyl transpeptidase (GGT) is thought to be associated
    with VC exposure (Langauer-Lewowicka et al., 1983; Du et al., 1995)
    and, according to the latter, this is the only enzyme that correlates
    with VC exposure levels. It should be noted that GGT is readily
    elevated in alcohol drinkers, so the value of this enzyme as a
    biomarker of VC-induced liver injury becomes questionable. In workers
    showing VC-induced liver dysfunction (VC levels 2.6-54 mg/m3; 1 to
    21 ppm), ALAT was the earliest parameter raised, then serum GGT (Ho et
    al., 1991). Ho et al. (1991) also reported that 10 of 12 workers with
    VC-induced liver dysfunction showed improvements in liver function
    tests after removal from exposure. There are case reports of
    individuals whose angiosarcomas were first detected by abnormal liver
    function tests (Makk et al., 1976), but liver function abnormalities
    appear to be a relatively late finding (Falk & Steenland, 1998). No
    published studies have been identified that evaluate the effectiveness
    of medical surveillance in occupational groups with VC exposures below
    2.6 mg/m3 (1 ppm).

    8.5.4  von Willebrand factor

         The immunoquantitation of the level of the von Willebrand factor
    (vWf; factor VIII-related antigen, a large multimeric plasma
    glycoprotein in the blood clotting system) in 107 VC exposed workers
    was performed using an enzyme-linked immunosorbent assay (ELISA)
    (Froment et al., 1991). The vWf level was slightly but significantly
    higher in the VC-exposed workers than in the control group. The vWf
    serum level of three patients with hepatic angiosarcoma was markedly
    elevated.

    8.5.5  p53 and ras proteins

         Mutant p53 and p21 proteins or their antibodies can be detected
    in sera from healthy workers exposed to VC (Marion et al., 1996;
    Semenza & Weasel, 1997; Smith et al., 1998; Li et al., 1998a,b). A
    dose-response relationship between estimated cumulative exposure and

    the frequency of these onco-proteins has been reported (Table 45).
    Statistically significantly elevated frequencies were observed even in
    the group with lowest estimated exposure (cumulative exposure
    < 40 ppm-years) (Li et al., 1998b). However, exposure estimations
    were crude. In addition, similar findings have not been reported for
    other VC-exposed groups.

    8.6  Susceptible subpopulations

    8.6.1  Age susceptibility

         Evidence from animal studies suggests that there may be
    early-life sensitivity to VC (section 7.7.3), but there is also
    contradictory evidence. There has been concern that children living
    near landfill sites might be particularly susceptible to VC formed and
    released there (Hiatt et al., 1994; Cogliano et al., 1996). However,
    there is no epidemiological evidence to support this.

    8.6.2  Immunological susceptibility

         Individual susceptibility may influence the development of VC
    disease, since not all highly exposed workers developed clinical
    symptoms or signs (Wilson et al., 1967; Black et al., 1986). Studies
    conducted in a single population of VC-exposed workers have shown that
    susceptibility for the disorder seems to be increased in the presence
    of the human-leukocyte-associated antigen HLA-DR 5 or a gene in
    linkage disequilibrium with it and an antigen associated with the
    haplotype A1, B8, while DR3 seems to favour progression of the disease
    (section 8.3.2.3e). The significance of this finding is unclear
    without replication in another VC-exposed population.

    8.6.3  Polymorphic genes in VC metabolism

         Levels of CYP2E1 can vary considerably among individual humans
    (Guengerich et al., 1991) and are a possible cause of differences of
    susceptibility to VC.

         El Ghissassi et al. (1995b) analysed the  GSTM1 genotype in 133
    Caucasian individuals who had had a high exposure to VC for several
    years and had (or had not) clinical signs of chronic injury (see also
    Froment et al., 1991, section 8.5.4). Of the 133 individuals, 62
    workers had non-neoplastic symptoms, while 8 had liver cancer. The
    frequency of  GSTM1 null genotype in the whole group of exposed
    workers was 61.7% (82 of 133) and 62.5% in patients with liver cancer.
    In case-control studies reported by others, the frequency of  GSTM1
    null genotype ranged from 41 to 53% for Caucasians.


        Table 45. p53 and p21 mutations (as detected by serum biomarkers analysis)
    in relation to estimated vinyl chloride exposure (Li et al., 1998a)
                                                                                                                           

    Estimated      Total no. of  Both biomarkers    No. of workers with   No. of workers with   Adjusted OR      95% CI
    exposure       workers       negative           mutation in           mutation in
    (ppm-years)                                     either p53 or p21     both p21 and p53
                                                                                                                           

    0              43            38                 5                     0                     1
    < 500          42            20                 21                    1                     11.1             3.3-37.5
    501-2500       45            20                 21                    4                     12.8             4.1-40.2
    2501-5000      31            6                  19                    6                     29.9             9.0-99.1
    > 5000         54            15                 22                    17                    31.2             10.4-94.2
                                                                                                                           
        

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Laboratory experiments

         VC has been shown to be mutagenic in several  in vitro and  in
     vivo test systems derived from organisms belonging to different
    taxonomic levels. The details referring to bacterial, fungal and
    mammalian cell lines or to whole organisms like insects or plants are
    discussed in section 7.6. The carcinogenic effects of VC are addressed
    in section 7.7. The following chapter focuses on investigations of
    other signs of toxicity relevant to organisms that may be exposed to
    VC in the environment. Standard tests on survival and reproduction
    were not available. Care must be taken when interpreting the toxicity
    results available as many were obtained from static tests using
    nominal exposure concentrations. Such tests will have large losses of
    VC due to volatilization, thus reducing the actual exposure to VC.

    9.1.1  Microorganisms

    9.1.1.1  Water

         A consortium of anaerobic microorganisms (species not identified;
    initially obtained from municipal sludge) was used for testing VC
    toxicity. Both batch and semi-continuous assays were conducted. VC had
    an inhibitory effect on the total gas production, beginning at a
    concentration of 5.4 mg/litre and resulting in an EC50 value of
    approximately 40 mg/litre, as seen in the batch assay over 3.5 days.
    In the semi-continuous assay lasting 15 days, the threshold was
    greater than 64 mg/litre (the highest concentration tested), probably
    due to volatilization of VC (Stuckey et al., 1980).

         The growth of five mixed bacterial populations (isolated from
    natural aquatic systems) was not affected, as compared to controls, in
    liquid cultures (closed flasks; 21°C; over 5 weeks) containing up to
    900 mg VC/litre (Hill et al., 1976b).

         The toxicity of waste effluents of a VC production plant to the
    green alga  Chlorella sp. was tested before and after the wastes were
    treated by neutralization procedures (addition of aqueous solutions of
    NaOH and catalysts). The crude effluents consisted of VC (15-18%,
    weight), di-, tri- and pentachloroethanes (45%), dichloroethylene
    (27%), dichloropropane (6%), ethyl chloride (1%) and unidentified
    substances (1%). This mixture led to a weak inhibition of algal growth
    (measured by changes in optical density at 678 nm), with a 72-h EC50
    value of 1495 mg/litre (which corresponds to a VC concentration of
    224 mg/litre). It should be noted that other compounds present in the
    effluent may also have contributed to the toxicity. The corresponding
    EC50 values of the neutralized waste samples (filtrates and extracts
    of precipitates; composition not analysed) ranged from 4000 to
    > 100 000 mg/litre (Demkowicz-Dobrzanski et al., 1993).

    9.1.1.2  Soil

         Soil (aquifer) microcosms enriched for methanotrophic activity
    transformed up to 90% of the 1-17 mg/litre influent VC with no
    apparent toxic effects (Dolan & McCarty, 1995a,b). However, when both
    VC and 1,1-dichloroethylene were present, about 75% less
    transformation of VC and a marked decrease in methane oxidation rate
    was observed (Dolan & McCarty, 1995a). Toxic effects, measured as
    decreased methane uptake, were seen during degradation of VC (VC
    concentrations: up to saturated solutions; solubility: 2.7 mg/ml) by a
    culture of mixed methanotrophs (seeded with soil from a defunct
    landfill). A mixture of VC and trichloroethylene (TCE) and a triple
    mixture of VC, cis-dichloroethylene (c-DCE) and TCE showed cumulative
    toxicity (Chang & Alvarez-Cohen, 1996).

         The nitrifying soil bacterium  Nitrosomonas europaea had a
    turnover-dependent loss of (ammonia-dependent) O2 uptake activity
    after co-metabolic transformation of VC (Rasche et al., 1991).

    9.1.2  Aquatic organisms

    9.1.2.1  Invertebrates

         VC reduced the population doubling time of a ciliated protozoon,
     Tetrahymena pyriformis, population cultured  in vitro (Sauvant et
    al., 1995). The IC50 value was 540 mg/litre (8.6 mmol/litre).

         During a 96-h assay VC had no effect on the survival of the
    free-living nematode  Panagrellus redivivus at concentrations ranging
    from 10-3 to 10 -8 mol/litre (0.6-62 500 µg/litre), but it reduced the
    developmental success of this species. The molting rate from the
    fourth larval stage to adult (determined on progeny of 150 to 300
    gravid females per assay; three replications) was significantly
    decreased relative to controls, and that primarily at VC
    concentrations of 6.3-6300 µg/litre (Samoiloff et al., 1980).

         The effects of waste effluents from a VC plant described in
    section 9.1.1.1 (test with  Chlorella sp.) were also tested with the
    crustacean  Daphnia  magna (n = 3 × 10 per experiment; age: 6-24 h).
    The test parameter for the latter was lethality, which was determined
    by procedures based on ISO 6341-1982 (ISO, 1989). Crude waste produced
    a 24-h LC50 value of 80.7 mg/litre (related to VC: 12 mg/litre). The
    neutralized wastes (filtrates and extracts of precipitates) were less
    toxic, reflected by the higher LC50 values ranging from 445 to
    > 100 000 mg/litre (Demkowicz-Dobrzanski et al., 1993).

    9.1.2.2  Vertebrates

         The acute toxicity of VC to fish was examined with a few
    freshwater species; 96-h LC50 values of 1.22 g VC/litre and 1.06 g
    VC/litre were reported for bluegill  (Lepomis macrochirus) and
    largemouth bass  (Micropterus salmoides), respectively, but without

    giving further details (Hann & Jensen, 1974). Brown et al. (1977)
    exposed Northern pikes  (Esox lucius) to 388 mg VC/litre; 10 days
    after exposure all test animals (n=15) were dead (versus 1 of 20 in
    controls during 120 days of observation). However, the test conditions
    (e.g., handling of controls, water quality) were not sufficiently
    described in this study. Tests of zebra fish ( Brachydanio rerio;
    n = 10 per group) according to OECD guideline 203 (OECD, 1984), which
    was adapted to volatile chemicals, resulted in LC50 values (based on
    mean measured test concentrations) of 240 mg/litre (24 h) or
    210 mg/litre (48 h, 72 h and 96 h). The no-observed-effect
    concentration (NOEC) regarding mortality was 128 mg/litre (Groeneveld
    et al., 1993).

         Estimated benchmark values, concentrations believed to be
    non-hazardous, to freshwater fish derived by several methods ranged
    from 87.8 to 28 879 µg/litre (Suter, 1996). The Tier II secondary
    acute value and secondary chronic value were reported to be
    1570 µg/litre and 87.8 µg/litre, respectively. The lowest chronic
    benchmark for fish was estimated to be 28 879 µg/litre, with a
    corresponding fish EC20 of 14 520 µg/litre.

    9.2  Field observations

    9.2.1  Aquatic organisms

         A field study of benthic invertebrates (Dickman et al., 1989;
    Dickman & Rygiel, 1993) was carried out during 1986-1991 at 15 sites
    of the Niagara River watershed (Canada) near a PVC plant. The VC
    discharge in 1986 was estimated to be more than 32 kg (accompanied by
    unknown quantities of organotin). The density and diversity of several
    invertebrate groups (Amphipoda, Culicoidae, Chironomidae, Isopoda,
    Hirudinea, Oligochaeta, Gastropoda, Trichoptera) was found to be low
    as compared to a reference site. Chironomids (Diptera) turned out to
    be the best indicators. They were absent at the sampling site closest
    to the factory's discharge pipe, and their numbers increased with
    increasing distances. Those collected nearest to the discharge site
    primarily belonged to the genus  Polypedilum, which is known to be
    pollution tolerant. Nevertheless, individuals of this genus showed a
    high proportion of larval mentum (labial plate) deformities (38%
    versus 1.7-5.7% at reference sites). Altogether, the frequencies of
    deformities at the discharge site fell significantly  (P = 0.05) from
    47% measured in 1986-1989 to 25% in 1991, which correlated with the
    lower levels of VC (figures not given) being released into the river
    in 1990-1991 (Dickman & Rygiel, 1993).
    

    10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1  Evaluation of human health effects

    10.1.1  Hazard identification

    10.1.1.1  Non-neoplastic effects

    a)   Human data

    i)   Skin, connective tissue and bone

         Among the non-neoplastic effects of vinyl chloride (VC) exposure,
    disorders of the skin, connective tissue and bone are the most
    specific and well-characterized. These include acroosteolysis,
    Raynaud's phenomenon and sclerodermoid skin lesions. These conditions
    were quite common in early studies, which may have involved exposures
    to high levels of several hundred ppm. Acroosteolysis occurred
    primarily in PVC production workers who had been involved in reactor
    cleaning. Data on mortality from connective tissue disorders, a
    relatively rare category of death, have not been provided in published
    studies, nor are there sufficient data to estimate an
    exposure-response relationship.

    ii)   Non-neoplastic liver disease

         Non-neoplastic liver disease was also well-documented in early
    studies of workers with high levels of exposure to VC. In one
    carefully described study, "advanced portal hypertension" with
    histological findings of non-cirrhotic fibrosis was diagnosed in 17
    out of 180 VC polymerization workers. Histological alterations
    reported in liver biopsy specimens obtained from VC monomer workers in
    another series included focal hepatocytic hyperplasia and focal mixed
    hyperplasia; these lesions were infrequent in the comparison group.
    Reversible changes in liver function tests have been reported in VC
    workers exposed to 2.6-54 mg/m3 (1-21 ppm). Despite evidence for the
    induction of non-malignant liver disease from clinical studies, there
    has been no evidence of excess mortality from studies of large
    cohorts. There are also insufficient data to estimate exposure
    response.

    iii)   Respiratory disease

         There is some evidence for respiratory effects from both
    morbidity and mortality studies of VC workers, but this may be related
    to PVC-resin dust rather than VC monomer. Positive findings from
    mortality studies are limited to one cohort. Therefore, the literature
    does not clearly implicate respiratory disease as an effect of
    exposure to VC monomer.

    iv)   Reproductive effects

         Although animal studies implicate the reproductive system as a
    potential target organ for vinyl chloride toxicity, studies in humans
    have not been adequate to confirm these effects or to rule them out.

    v)   Cardiovascular disease

         A few morbidity studies have reported an elevated incidence of
    circulatory diseases among VC-exposed workers. Cardiovascular disease
    mortality is significantly lower than expected in the two large
    cohorts.

    vi)   Susceptible subpopulations

         There is no strong evidence for the existence of susceptible
    sub-populations in humans. It has been suggested that specific HLA
    types and genetic polymorphisms in VC-metabolizing enzymes may be
    factors in human susceptibility to VC-related diseases.

    b)   Experimental animal data

         VC has been tested in several animals species and strains for
    acute, short-term and long-term effects. Signs of acute toxicity
    include congestion of internal organs, neurotoxic effects and
    circulatory disturbances. In short-term studies VC caused mainly liver
    damage, degenerative changes in the testes, degeneration and
    inflammation in the lungs and degenerative lesion in the kidneys.
    Immunological alterations in connection with VC exposure have also
    been described. Reproductive performance or fertility were not
    affected.

    10.1.1.2  Neoplastics effects

    a)   Human data

         In 1974, a case report associated exposure to VC with the
    occurrence of angiosarcoma of the liver (ASL). Further case series and
    small epidemiological studies were reported shortly thereafter. At a
    later stage two studies, one in the USA and one in Europe, combined
    data from those studies and updated the mortality follow-up. Apart
    from these two large studies, four more smaller studies have been
    conducted and fully reported and were also considered by the Task
    Group.

         There is a five-fold excess risk for liver cancer among workers
    exposed to VC, mostly in PVC polymerization plants where the highest
    exposures to VC occurs. The largest part of this excess risk is due to
    the excess risk for ASL. In the European study, there was a 45-fold
    excess risk for ASL in workers exposed to more than 10 000 ppm-years
    compared to those exposed to less than 2000 ppm-years. In the European
    study histopathological confirmation was available for 17 out of 24

    liver cancers; of those confirmed 16 were ASL. In the USA study 21 out
    of 37 liver cancer deaths were registered as ASL. In the Canadian
    study all 8 liver cancer deaths were ASL, as was the case for the 3
    liver cancer deaths in the French study. No information is available
    concerning ASLs in the German study while no liver cancers were
    diagnosed in the Russian study. It is probable that some ASLs
    occurring among VC-exposed workers have remained undiagnosed and have
    been coded in the death certificates as liver cancers unspecified or
    as other liver-associated disease.

         Several studies examined the risk specifically for hepatocellular
    carcinoma (HCC) of the liver. No excess was observed in the European
    study, nor in the Canadian or French studies. Data from the USA study
    and also from the update of the Italian component of the European
    cohort seem, however, to indicate that there is also an excess for
    HCC. This is of smaller magnitude than that observed for ASL. The
    interpretation of the results for HCC is complicated because of the
    uncertainties concerning the accuracy of diagnosis of angiosarcomas
    and HCC using death certificate information and the absence of compete
    histopathological confirmation of the diagnoses of liver cancer in the
    studies. Although the results are not fully consistent between
    studies, the data suggest that there may be a small excess risk for
    HCC.

         Four out of five studies reporting results for brain tumours
    identified a moderate excess risk with an SMR of 1.42 for the combined
    data from five studies (43 observed, 95% CI 1.03-1.91). The risk
    tended to increase with duration of exposure/employment in the
    European and USA study. Furthermore, in the USA study, the highest
    risk occurred in the two plants where most ASL cases had been
    diagnosed, and where presumably the highest VC exposure had occurred.
    In the European study where the dose-response relationship was
    examined, no association was seen with cumulative exposure to VC. The
    overall epidemiological evidence is suggestive of a possible risk
    among VC workers.

         Some of the smaller early studies had reported an increase in
    lung cancer among VC workers. There was no indication of an excess
    risk, however, in the two largest studies (European and USA) or in the
    other four smaller studies. There was no association either with
    duration of exposure/employment in the USA or the European study, nor
    with cumulative exposure to VC in the European study.

         Excess risk for malignant lymphomas had been reported in some
    early small studies. No excess risk, however, was observed in the two
    largest cohorts (USA and European) or in the Canadian cohort. An
    excess risk for the combined category leukaemia and lymphoma was
    observed in the Russian and the German study. In interpreting these
    results it should be noted that the studies used different disease
    classification and in some occasions grouped lymphomas with malignant
    myeloma. The overall results exclude the presence of any large
    increased risk for lymphomas or leukaemia.

    b)   Experimental animal data

         VC is a multispecies, multiorgan carcinogen. It induces benign
    and malignant tumours in several organs of various species, both in
    males and females. The most prominent feature is the induction of the
    rare angiosarcomas, especially in the liver. This phenomenon has been
    demonstrated in different strains of mice and rats, as well as in
    hamsters. Other tumours include nephroblastomas and neuroblastomas,
    hepatocellular carcinomas, mammary gland carcinomas and lung adenomas.

         VC is genotoxic, causing alterations and damage to DNA. VC
    metabolites bind to the DNA yielding promutagenic DNA adducts.
    Mutations and chromosomal abnormalities have been described in many
     in vitro and  in vivo systems. These genotoxic processes play a
    significant role in tumorigenesis, while cell proliferation, secondary
    to the VC-induced cell toxicity, may also be involved in the process.

    10.1.2  Dose-response analysis

    10.1.2.1  Non-neoplastic effects

    a)   Human data

         The published studies examining non-neoplastic diseases in
    VC-exposed subjects do not provide dose-response information.

    b)   Experimental animal data

         Several short-term and long-term studies have been assessed for
    establishing the NOAEL of VC. Liver cell polymorphism (variation in
    size and shape of hepatocytes and their nuclei) reported in the
    feeding study by Til et al. (1991) is recommended for quantifying
    non-cancer risks from oral exposure to VC. The severity and incidences
    of this liver lesion were statistically significantly increased at a
    daily dose of 1.3 mg/kg body weight but not at 0.13 mg/kg per day
    (Table 46), the no-observed-adverse-effect level (NOAEL) therefore
    being 0.13 mg/kg per day. Basophilic liver cell foci induction in the
    study of Til et al. (1991) occurred at lower concentrations, but it
    was not considered by the Task Group to be a manifestation of
    hepatocytic toxicity.

         A lowest-observed-adverse-effect level (LOAEL) of 26 mg/m3 was
    established based on a subchronic (3-12 months) inhalation toxicity
    study in male rats by Bi et al. (1985). The basis for the estimation
    was the increased relative liver weight and mild testicular
    degeneration (Table 47), both effects being more pronounced in a
    dose-related manner at the two higher dose levels tested (260 and
    7800 mg/m3). A recent inhalation two-generation reproduction study
    with VC in rats, using exposure concentrations of 26, 260 and 2860
    mg/m3 (Shah, 1998), yielded the same LOAEL value. In this study,
    increased relative liver weights and hypertrophy of centrilobular
    hepatocytes were found in parental animals at all dose levels and a
    dose-dependent manner.

    10.1.2.2  Neoplastic effects

    a)   Human data

         In most epidemiological studies dose-response analyses were not
    available. Of the two largest studies conducted in the USA and Europe,
    the USA study examined only duration of exposure and did not examine
    dose-response. In the European study a calendar period-, job- and
    plant-specific job exposure matrix was used. Expert judgement was used
    to estimate exposures for the early time periods when no measurements
    were available. The use of such a matrix implies that, when assigning
    the exposure index to individuals in the cohorts, a certain degree of
    misclassification occurs tending to underestimate the strength of a
    dose-response relationship.

         All of the results in this section are from the European study
    (Simonato et al., 1991) unless otherwise noted. A clear dose-response
    relationship was found only for ASL alone or in combination with other
    primary liver cancers.

         In all the analyses of liver cancer in the European cohort there
    is a clear relationship with increasing estimated doses. The effect is
    most evident for ASL, for which the risk estimate in the highest
    exposure groups is two and half times larger than for all liver
    cancers (Tables 48 and 49). These results are consistent with the
    analyses published by Wu and colleagues in the updating of one of the
    USA subcohorts. In this study, the average cumulative exposure score
    to VC was 6 times higher for ASL cases than for other liver cancer
    cases and control subjects.

         Results from the regression models in the European study
    indicated that cumulative dose appears as the most powerful
    determinant of ASL, followed by time since first exposure. This can
    also be seen from Table 50. The results from the regression models
    indicated that there was only a small or no effect of calendar period
    and age of hire. Both duration and intensity of exposure correlated
    with liver cancer risk (see Table 41).

         Dose-response analyses for lung cancer, brain tumours and
    lymphomas are reported in section 8.3.

    b)   Experimental animals data

         Studies using short- and long-term oral and inhalation exposure
    were carried out to assess the carcinogenic activity of VC (section
    7.7.) For assessing carcinogenic risk, pivotal studies have been
    selected where the study design, exposure levels, observation period
    and histopathological examinations are regarded as suitable for
    assessing risk.

        Table 46. Type and incidence of treatment-related liver-cell polymorphism
    of rats orally exposed to vinyl chloride (from Til et al., 1991)
                                                                              

                              Males                         Females
                                                                              
    N (total/group)  100   100    100   50          100     100      100    50
    Dose mg/kg       0     0.014  0.13  1.3         0       0.014    0.13   1.3
    per day
    Liver cell               No of animals with liver cell polymorphism of
    polymorphisms                       varying severity
                                                                              
      Slight         27    23     26    19          46      41       49     23
      Moderate       4     4      7     10b         14      13       8      15a
      Severe         1     1      1     3           2       3        4      9c
                                                                              

    a  P < 0.05
    b  P < 0.01
    c  P < 0.001

    Table 47. Damage of testes induced by different concentration
    of vinyl chloride (from Bi et al., 1985)
                                                                                 

    Group          No. of     Slight     Moderate    Severe     Total     %
                   animals    damage     damage      damage
                                                                                 

    Control        74         9          3           2          14        18.9
    10 ppm a       74         14         5           3          22        29.7
    100 ppm b      74         19         5           3          27        36.5 d
    3000 ppm c     75         29         8           5          42        56.0 e
                                                                                 

    a  26 mg/m3
    b  260 mg/m3
    c  7770 mg/m3
    d  P < 0.05
    e  P < 0.001

        Table 48. Maximum likelihood estimates for final model with
    cumulative exposure and years since first employment
    for deaths from liver cancer (N = 24) a
                                                                          

    Exposure variable     Relative risk      95% confidence interval
                                                                          

    Cumulative exposure
    (ppm-years)

    < 500                 1.0
    500-1999              1.2                0.1-11.4
    2000-5999             4.6                1.0-21.0
    6000-9999             12.2               2.5-59.6
    > 10 000              17.1               3.1-93.6

    Years since first employment

    0-19                  1.0
    20-24                 5.6                1.4-22.4
    > 25                  6.8                1.7-27.4
                                                                          

    a  From: Simonato et al. (1991)

    Table 49. Maximum likelihood estimates for final model with
    cumulative exposure and years since first employment
    for deaths from angiosarcoma of the liver (N = 22) a
                                                                          

    Exposure variable     Relative risk      95% confidence interval
                                                                          

    Cumulative exposure (ppm-years)

    < 2000                1.0
    2000-5999             6.8                1.1-41.7
    6000-9999             24.7               4.1-150.1
    >10 000               45.4               7.3-281.1

    Years since first employment

    0-19                  1.0
    20-24                 4.7                1.0-22.8
    >25                   6.2                1.4-29.0
                                                                          

    a  From: Simonato et al. (1991)

    Table 50. Absolute risk of angiosarcoma of the liver
              per 100 000 (Simonato et al., 1991)
                                                                          

                                   Cumulative exposure (ppm-years)
                                                                        
    Years since            < 2000     2000-5999     6000-9999   >10 000
    first employment
                                                                          

    0-19                   1.0        6.8           24.4        44.8
    20-24                  4.7        32.0          115.6       212.5
    >25                    6.2        42.2          152.3       280.0
                                                                          

         For oral exposure, it is recommended that female rats from the
    Feron et al. (1981) study be used to quantify risk for VC, because the
    incidence of liver tumour-bearing animals is greater than in males,
    giving a more conservative estimate. Rats with either neoplastic liver
    nodules, hepatocellular carcinomas and/or ASLs should be included for
    quantification. These lesions are all dose-related. The neoplastic
    nodules, while not malignant, have the potential to progress to
    malignancy. While it is uncertain that VC induces tumour types other
    than ASL in humans, tumour type concordance is not considered to be
    necessary, and thus inclusion of all liver tumours is desirable as a
    conservative approach.

         If quantification is desired for ASL only, then the male rat is
    recommended because the incidences for this end-point are higher in
    males (Table 51). Including animals with angiosarcomas in other organs
    is unnecessary because the only other site with significantly
    increased incidences of this tumour type is the lung, and, with one
    exception, all animals with ASL also had liver tumours.

         For inhalation exposure, several studies have been conducted in
    different species (section 7.7). Four experiments with similar design
    and experimental conditions, carried out by Maltoni et al. (1981,
    1984) in rats, were used for assessing carcinogenic risk after VC
    inhalation exposure. Out of the treatment-related carcinogenic
    responses, ASL, all vascular tumours of the liver and all liver
    tumours combined were considered to be suitable for assessing risk
    (Table 52). Induction of ASL is a special feature of VC and since this
    tumour type was also observed in exposed humans, this end-point was
    considered especially relevant for quantification of risk.

         For ASL, increased incidence was observed in both males and
    females. A clear dose-response relationship could be established in
    female rats, and the effect was also suggestive in males. A similar
    trend could be observed if all vascular tumours or all liver tumours
    were considered. The other tumours, however, occurred only at low
    incidences. The lowest dose at which ASL and other vascular tumours
    were detected was 26 mg/m3 in females and 65 mg/m3 in males.


        Table 51. Tumour incidences in oral feed study with vinyl chloride
    in Wistar rats (from Feron et al., 1981)
                                                                                                

    Dose        Neoplastic  Hepato-cellular  Liver           Liver            Mammary
    (mg/kg      liver       carcinomas       angio-sarcomas  tumour-bearing   adeno-carcinomas
    bw)         nodules                                      rats
                                                                                                

    Females

    0           2/57        0/57             0/57            2/57             3/57
    1.7         26/57       4/58             0/57            28/58            2/58
    5.0         39/59       19/59            2/59            49/59            4/59
    14.1        44/57       29/57            9/57            56/57            7/57

    Males

    0           0/55        0/55             0/55            0/55
    1.7         1/58        1/58             0/58            2/58
    5.0         7/56        2/56             6/56            11/56
    14.1        23/59       8/59             27/59           41/59
                                                                                                


        Table 52. Liver tumours in inhalation studies on rats
    (from Maltoni et al., 1981, 1984)
                                                                           

    Exposure    Exposure       Number of   % ASL    % liver     % all liver
    (mg/m3,     (mg/m3,        animals              vascular    tumours b
    4 h/d,      continuous) a                       tumours b
    5 d/w)
                                                                           

    Males

          0        0           222          0           0           0
        2.6      0.3            58          0           0           0
         13        2            59          0           0           0
         26        3            59          0           0           0
         65        8            60        1.7         1.7         1.7
        130       15           174        1.1         2.3         2.3
        260       31            60          0         1.7         1.7
        390       46            60        1.7         1.7         1.7
        520       62            60       11.7        15.0        16.0
        650       77            29        3.4         3.4         4.4
       1300      155            30          0           0           0
       6500      774            30       20.0        20.0        20.0
     15 600     1857            29       10.3        10.3        10.3
     26 000     3095            30       10.0        10.0        11.0

    Females

          0        0           239          0           0           0
        2.6      0.3            60          0           0           0
         13        2            60          0           0           0
         26        3            60        6.7         6.7         6.7
         65        8            60        6.7         8.3         8.3
        130       15           180        7.2        10.6        10.6
        260       31            60        1.7         1.7         1.7
        390       46            60        8.3         8.3         8.3
        520       62            60        8.3        11.7        15.0
        650       77            30        6.7        10.0        10.0
       1300      155            30       20.0        20.0        36.7
       6500      774            30       23.3        23.3        30.0
     15 600     1857            30       33.3        40.0        43.3
     26 000     3095            30       13.3        13.3        13.3
                                                                           

    a Exposure calculated to correspond to 24 h/day, 7 days/week
    b % of animals with tumours were added, because no individual
      animal data were available.

         Nephroblastomas and neuroblastomas have also been observed in
    some studies in rats after VC exposure. These rare tumours appeared in
    a dose- and time-dependent manner; the doses required for tumour
    induction were, however, higher than those for ASL.

         Several inhalation studies of VC in mice have been carried out.
    The induced spectrum of tumours was similar to that in rats:
    angiosarcomas and angiomas of the liver and other organs, mammary
    gland and lung tumours. In one study (Maltoni et al., 1981, 1984), a
    clear dose-response relationship was observed for ASL as well as for
    all vascular tumours in the female mice (Table 53). The lowest
    carcinogenic dose was 130 mg/m3, higher than that in rats.

         Mammary gland adenocarcinomas were observed in several VC
    studies. Four inhalation studies with VC in Sprague-Dawley rats
    (Maltoni et al., 1981, 1984) were evaluated (Table 54). A
    statistically significantly increased incidence in mammary gland
    carcinoma was observed in three of the four studies. However, in none
    of these studies was a clear dose-response relationship observed.
    Increased incidences of mammary carcinomas, without a dose-response
    relationship, were also observed in Swiss mice after inhalation
    exposure (Maltoni et al., 1981, 1984). Drew et al. (1983) exposed
    Fischer-344 rats to 0 or 261 mg/m3 either for 6 or 12 months.
    Increased incidences of mammary adenocarcinomas were observed in the
    animals exposed at different ages but, since only one exposure level
    was used, a dose-response relationship could not be established. In
    Syrian hamsters, using similar study design but an exposure level of
    520 mg/m3 (Drew et al., 1983), a high incidence of mammary tumours
    was observed in animals exposed early in life.

         In two other mouse studies (Lee et al., 1978; Drew et al., 1983),
    elevated incidences of both mammary gland carcinomas and other mammary
    tumours were observed. However, these studies were also inadequate for
    risk assessment. In summary, increased incidence of mammary gland
    carcinomas were observed in several experiments where animals were
    exposed to VC, either orally or by inhalation, indicating
    treatment-related carcinogenic effect. However, the lack of
    dose-response or the use of a single dose excluded the use of these
    data for risk assessment.

    10.1.3  Human exposure

         The aim of this section is to estimate present levels of exposure
    to VC of the general population and of subpopulations with special
    exposure, such as those living near point sources of VC and those
    exposed at work. The purpose is to indicate worst-case scenarios
    rather than average or most likely exposures.

         The data available are very limited both in time and space. Often
    the distance of the sampler from the point source or the sampling and
    averaging times have not been reported. This makes the comparison of
    results from different studies difficult.


        Table 53.  Incidences of different tumour types in Swiss mice after inhalation exposure to vinyl chloride
    (from Maltoni et al., 1981, 1984 BT4)
                                                                                                                             

    Exposure     Effective      ASL     Angiosarcoma     Angioma     Angioma           Total            Mammary     Lung
    (mg/m3)      number                 (other organs)   (liver)     (other            vascular         gland       adenoma
                                                                     organs)           tumours
                                                                                                                             

    Males

          0         80           0          0              0           1                  1               0           8
        130         30           1          1              0           1                  3               0           3
        650         30           9          2              6           2                 17               0          24
       1300         30           6          2              1           1                 10               1          24
       6500         29           6          4              2           0                 12               0          18
     15 600         30           2          0              2           2                  6               0          23
     26 000         26           1          0              1           2                  4               0          20

    Females

          0         70           0          1              0           0                  1               1           7
        130         30           0          0              1           4                  5              13           3
        650         30           9          1              5           1                 17              12          17
       1300         30           8          5              4           2                 10               9          26
       6500         30          10          4              3           1                 12              10          22
     15 600         30          11          1              5           1                  6               9          24
     26 000         30           9          1              5           2                  4              14          26
                                                                                                                             

    Table 54. Incidence of mammary gland carcinomas in Sprague-Dawley
    rats and Swiss mice after inhalation exposure to vinyl
    chloride (from Maltoni et al., 1981, 1984) a
                                                                                             

    Exposure     BT15              BT1             BT2           BT9            BT4
    (mg/m3)      (rat)             (rat)           (rat)         (rat)          (mouse)
                                                                                             

         0       6/60 (10)         0/29            1/100 (1)     5/50 (10)       1/70 (1.4)
       2.6       12/60 (20)
        13       22/60 (36.6) d
        26       21/60 (35) c
        65       15/60 (25)
       130                         2/30 (6.6)                    59/150 (39) d   13/30 (43.3) d
       260                                         3/60 (5)
       390                                         6/60 (10) c
       520                                         5/60 (8) b
       650                         2/30 (6.6)                                    12/30 (40) d
      1300                         1/30 (3.3)                                    9/30 (30) d
      6500                         2/30 (6.6)                                    10/30 (33.3) d
    15 600                         0/30                                          9/30 (30) d
    26 000                         3/30 (10)                                     14/30 (46.6) c
                                                                                             

    a Values are no. of tumour / no. of animals, with percentages in parentheses; statistical
      significance compared to the concurrent control group (two tailed Fischer)
    b P < 0.05
    c P < 0.01
    d P < 0.001


    10.1.3.1  General population

         The main sources of VC exposure for the general population are
    VC/PVC plants, biodegradation of chlorinated solvents in landfills,
    spills of chlorinated solvents from, for instance, dry cleaning shops,
    and the metal and electronic industry. In addition, small amounts of
    VC may be liberated from PVC.

         There are no known natural sources of VC. Concentrations of VC in
    ambient air samples were reported to range from < 0.013 to 26 µg/m3.
    These data were collected in the 1970s and 1980s from rural, remote,
    suburban and urban sites. The concentrations measured in rural and
    suburban/urban sites were similar. There is a lack of recent data on
    ambient air, making it difficult to conclude whether there has been a
    historical reduction in ambient concentrations. The exposure to VC via
    inhalation by the general population (non-occupational exposure) is
    estimated not to exceed 10 µg/kg body weight per day, using the
    derivation method described in Environmental Health Criteria 170:
    Assessing Human Health Risks of Chemicals: Derivation of Guidance
    Values for Health-based Exposure Limits (IPCS, 1994).

         Concentrations (probably daily means) of VC measured in ambient
    air from industrial areas were reported to be < 8000 µg/m3 in the
    1970s and < 200 µg/m3 and 4800 µg/m3 in the 1980s in different
    geographical areas. Monthly mean concentrations measured in the
    vicinity of one plant during the 1990s ranged from 0.1 to 1.3 µg/m3.
    Exposure of the general population living in the vicinity of
    industrial areas was estimated not to exceed 3000 µg/kg per day in the
    1970s, 70-1800 µg/kg per day in the 1980s and 0.5 µg/kg per day in the
    1990s.

         VC concentrations in air sampled from the vicinity of waste sites
    ranged from < 0.08 to 104 µg/m3. These concentrations were reported
    in air sampled during the 1980s and 1990s; no historical trend could
    be established. Exposure of the general population living in the
    vicinity of landfills was estimated to be < 300 µg/kg per day.
    There are no data on VC concentrations in air from other areas
    contaminated with chlorinated hydrocarbons.

         Sources of VC in indoor air have included PVC products, smoking,
    paints and aerosol propellants. Up to the 1970s, the VC concentration
    in PVC exceeded 1000 mg/kg, and consequently VC was detected in indoor
    air and cars. Since the late 1970s the VC content in PVC has been
    regulated to approximately 1 mg/kg, therefore VC concentrations are
    now unlikely to be significant in indoor air, except where there are
    nearby external sources such as landfills, etc.

         The general population may be exposed to VC in drinking-water. In
    the majority of water samples analysed, VC was not present at
    detectable concentrations. The maximum VC concentration reported in
    drinking-water was 10 µg/litre, leading to a maximum exposure of
    0.2 µg/kg per day. There is a lack of recent data on concentrations in

    drinking-water, but these levels are expected to be below 10 µg/litre.
    In groundwater near point sources, very high (up to 200 mg/litre)
    concentrations of VC have been observed and well water nearby may be a
    very significant source of VC: daily intakes may reach 5000 µg/kg per
    day. Some recent studies have identified VC in PVC-bottled
    drinking-water at levels below 1 µg/litre. The frequency of occurrence
    of VC in such water is expected to be higher than in tap water.

         Dietary exposure to VC from PVC packages used for food has been
    calculated by several agencies, and, based upon estimated average
    intakes in the United Kingdom and USA, an exposure of < 0.0004 µg/kg
    per day was estimated for the late 1970s and early 1980s.

         Exposure of the general population may be higher in situations
    where large amounts of VC are accidentally released to the
    environment, such as a spill during transportation. However, such
    exposure is likely to be transient.

    10.1.3.2  Occupational exposure

         Staff working in plants where VC is manufactured or polymerized
    into PVC or at landfills may be occupationally exposed to VC.
    Occupational exposure to VC has continually decreased since the 1940s.
    Since the 1970s, occupational exposure level (OEL) values have been
    set at 2.6 to 18 mg/m3 in most European countries and the USA. Few
    data are available to determine how frequently the actual workplace
    exposures are within the OEL. Where data are available, compliance
    during the 1990s was reported in some European countries. Based upon
    an OEL of 18 mg/m3, an occupational exposure of 3000 µg/kg per day
    can be calculated. The most recently reported average occupational
    exposure in these countries was 0.3 mg/m3. This gives a daily dose of
    50 µg/kg per day. However, concurrent exposure levels of more than
    300 mg/m3 have also recently been reported in some countries.
    Exposure to VC in PVC processing plants has been historically, and is
    probably currently, much lower than in PVC/VC production plants.

    10.1.4  Risk characterization

         VC has been shown to be carcinogenic and toxic in both oral and
    inhalation experimental bioassays, as well as in human epidemiological
    studies. Experimental studies have also shown that it is genotoxic and
    must be activated through a rate-limited pathway. In order to perform
    quantitative risk assessment using animal bioassays, it will be
    necessary to utilize a physiologically based pharmacokinetic model
    (PBPK) to derive the concentration of active metabolite at the
    critical target site, the liver, as well as to extrapolate dose from
    animals to humans. The PBPK model should be validated, taking into
    account the known metabolic pathways and using metabolic constants
    determined experimentally, and should not introduce too many unknown
    parameters. The Task Group was not in a position to evaluate

    accurately the available pharmacokinetic models for their suitability
    for risk assessment. Furthermore, in order to estimate the risk
    predictions from epidemiological studies, original data on exposed
    human populations, at the level of the individual, are required.

         Some of the published PBPK models and risk assessments are
    reviewed in Annex 2.

    10.2  Evaluation of effects on the environment

         VC is released to the environment from plants where it is
    manufactured and/or used in the production of PVC. The most important
    releases are emissions to the atmosphere, but VC may also be released
    in waste water. It may also be formed in the environment as a product
    of the biodegradation of chlorinated C2 solvents. This route of VC
    formation may lead to emissions of VC from areas contaminated with
    chlorinated C2 solvents, such as landfills.

         The maximum VC concentration reported in surface water is
    0.6 mg/litre. VC is unlikely to be bioaccumulated to a significant
    extent in aquatic organisms.

         The only toxicity study which was deemed of sufficient quality to
    evaluate the effects of VC on aquatic organisms gave a 48-h LC50 of
    210 mg/litre for a freshwater fish. There is a paucity of chronic
    toxicity data for aquatic organisms. Despite these limitations, owing
    to the rapid volatilization of VC, the low concentrations in surface
    water and the low acute toxicity to fish, VC is not expected to
    present a hazard to aquatic organisms.

         There is a paucity of data for terrestrial organisms.
    

    11.  RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH

    11.1  Public health

         The following measures should be taken:

    *    worldwide application of production technologies leading to low
         residual VC levels in PVC;

    *    implementation and enforcement worldwide of steps that guarantee
         minimal emissions of VC at production sites;

    *    identification, surveillance and emission and exposure control of
         contaminated areas such as landfill sites.

    11.2  Occupational health

         Since VC is a genotoxic carcinogen, exposures should be kept as
    low as possible, using the best available technology worldwide.

         More information, education and training of workers potentially
    exposed to VC regarding the risks involved and safe working procedures
    and habits is required.

         Monitoring and record-keeping of exposure and record-keeping of
    exposed workers are needed.
    

    12.  FURTHER RESEARCH

         The following topics need further research:

    *    follow-up of existing VC cohorts with quantitative exposure
         assessment;

    *    epidemiological studies of populations with defined and low
         exposure to VC;

    *    evaluation of the efficacy and usefulness of the medical
         surveillance of VC-exposed workers;

    *    validation of effects and susceptibility biomarkers for VC;

    *    the role of post-DNA-damage events in the carcinogenicity of VC
         and their relationships with target organ or cell type
         specificity;

    *    evaluation of the sensitivity to VC in early childhood and
         determination of possible mechanisms involved;

    *    the possibility of carcinogenicity of VC in mammary gland tumours
         and the mechanism involved;

    *    optimization of remediation of contaminated sites;

    *    studies on the toxicity of VC to aquatic and terrestrial
         organisms.
    

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Vinyl chloride was evaluated by the International Agency for
    Research on Cancer (IARC, 1979) and the evaluation was updated in
    Supplement 7 (IARC, 1987). There was sufficient evidence for
    carcinogenicity of vinyl chloride in humans and sufficient evidence
    for carcinogenicity in animals; the overall evaluation was that vinyl
    chloride is carcinogenic to humans.

         In the WHO Guidelines for Drinking-water Quality (WHO, 1996),
    using results from the rat bioassay of Til et al. (1983) and applying
    the linearized multistage model, the human lifetime exposure for a
    10-5 excess risk of ASL was calculated to be 20 µg/day. It was also
    assumed that in humans the number of cancers at other sites may equal
    that of ASL, so that a correction (factor of 2) for cancers other than
    ASL is justified. VC concentrations in drinking-water of 5 µg/litre
    were calculated as being associated with excess risks of 10-5.
    

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    ANNEX 1. REGULATIONS CONCERNING VINYL CHLORIDE

    1.  Regulations regarding VC levels in PVC materials and
        food and drink

         According to EC regulations PVC materials intended to come in
    contact with foodstuffs must not contain VC at levels > 1 mg/kg; the
    limit in the packed food is 10 µg/kg (CEC, 1978). The corresponding
    German regulation additionally includes commodities, toys and tricks,
    and articles which are for toiletry use (German Federal Health Office,
    1998). The US FDA proposed to restrict the VC content of polymers used
    for food contact to 5-50 µg/kg (US FDA, 1986).

         A limit value of 2 µg/litre was issued by the US EPA for
    drinking-water (US EPA, 1995b) and by the US FDA for bottled water
    (Anon, 1993). The Maximum Contaminant Level of the Californian
    Department of Health Services (DOHS) is 0.5 µg/litre (US EPA, 1995b).
    In Germany, there are recommendations to tolerate 2 µg/litre in
    drinking-water (German Federal Health Office, 1992).

    2.  Occupational exposure limit values for vinyl
        chloride

         Some examples of present exposure limit values are given in
    Table 55.


        Table 55.  Occupational exposure limit values for vinyl chloride
                                                                                                            

    Country/organization                Exposure limit      Value    Value       Reference
                                        description         (ppm)    (mg/m3)
                                                                                                            

    Europe; United Kingdom;             personal 8-h TWA    7        18.2        CEC (1978); HSC (1995);
    Germany; Finland                                                             BIA (1997)
                                                            5        12.8        Finnish Government
                                                                                 (1992)

    Europe; United Kingdom;             working area        3        8           CEC (1978); Finnish
    Germany; Finland                    (annual)                                 Government (1992);
                                                                                 HSC (1995); BIA (1997)

    Czech Republic, Slovakia,           MACKa                        10          Bencko & Ungváry
    Hungary and Poland                                                           (1994)

    USA                                 15 min              5        12.8        OSHA (1998)
                                        8 h                 1        2.6         OSHA (1998)
                                        TLV 8-h TWA         1        2.6         ACGIH (1999)
                                                            0b                   NIOSH (1997)
                                                                                                            

    a Maximal allowable concentration (K indicates the carcinogenic properties of VC)
    b No detectable exposure
      TLV = threshold limit value; TWA = time weighted average;
      OSHA = US Occupational   Safety and Health Administration;
      ACGIH = US American Conference of Governmental and Industrial
      Hygienists Inc.; HSC = UK Health and Safety Commission;
      BIA = German Professional Associations
      Institute for Occupational Safety; Finnish Government = Government
      Resolution 919/92, Finland
        


    ANNEX 2.  PHYSIOLOGICAL MODELLING AND RECENT RISK ASSESSMENTS

    1.  Physiological modelling of toxicokinetic data for vinyl chloride

         Physiologically based toxicokinetic (PBTK) models intend to
    predict the dose of active metabolites reaching target tissues in
    different species, including humans, and thereby to improve the
    toxicokinetic extrapolation in cancer risk assessments. PBTK models
    have also been used as a tool to examine the behaviour of VC in
    mammalian systems.

         The model of Chen & Blancato (1989), also cited as a US EPA
    (1987) model, proposed a PBTK model based on the styrene model of
    Ramsey & Andersen (1984) with four compartments, representing the
    liver, a fat compartment that includes all of the fatty tissues, a
    richly-perfused tissue compartment that includes all organs except the
    liver, and a slowly perfused compartment that includes muscular and
    skin tissues. Liver was assumed to be the sole metabolizing organ, and
    the metabolism of VC was assumed to occur via one pathway following
    Michaelis-Menten-kinetics and saturable at high concentration levels.
    Physiological parameters (e.g., body weight, lung weight, ventilation
    rate, tissue volume and blood flows to various tissue groups) were
    reference values from US EPA. This model was validated by Clement
    International Corporation (1990) with gas uptake experiments in rats
    and with data sets available in the literature (Gehring et al., 1978).
    At concentrations < 65 mg/m3 the model fitted observed data, but
    at higher concentrations the model predicted a greater amount of VC
    metabolism than observed.

         A second model (Gargas et al., 1990) was a generic model of
    volatile chemical kinetics in a recirculated closed chamber, which was
    used to identify global metabolic parameters in the rat for a number
    of chemicals including VC. It incorporated a second, linear metabolic
    pathway (presumed to be glutathione conjugation) in parallel with the
    saturable (oxidative) pathway.

         Continuing on from these above models, Clement International
    Corporation (1990) re-fitted the one- and two-pathway descriptions to
    gas uptake data and then compared their predictions to measurements of
    total metabolism by Gehring et al. (1978) and Watanabe et al. (1976b).
    Two refinements to the model were investigated: 1) reaction of VC with
    glutathione (GSH), or 2) the products of both the saturable and the
    linear pathways were assumed to react with GSH. Neither description
    fitted both total metabolism and GSH depletion data and the authors
    suggested a new PBTK model featuring two saturable oxidative pathways,
    both producing reactive metabolites. Clewell et al. (1995a) developed
    a more elaborate model of VC based on the suggestions from Clement
    International Corporation (1990). The initial metabolism of VC was
    hypothesized to occur via two saturable pathways (one representing
    high affinity, low capacity oxidation by CYP2E1 and one representing
    low affinity, high capacity oxidation by other P-450 isozymes),
    producing in both cases chloroethylene oxide (CEO) as an intermediate
    product. CAA (from CEO) was modelled as the major substrate in GSH

    conjugation, with a lesser amount of CEO as the glutathione
    transferase substrate. The model was similar to that proposed by Chen
    & Blancato (1989) with regard to number and type of compartments,
    physiological parameters and the assumption that metabolism of VC
    takes place solely in the liver. Partition coefficients taken from
    literature data (Gargas et al., 1989) were used. The metabolic
    parameters for the two oxidative pathways were estimated from gas
    uptake experiments conducted by Clement International Corporation
    (1990). In this model it is assumed that the reactive VC metabolites
    were further degraded to carbon dioxide, or reacted with GSH or with
    cellular material. Parameters for subsequent metabolism were taken
    from the PBTK model for vinylidene chloride (D'Souza & Andersen, 1988)
    and were also used for species other than the rat after appropriate
    allometric scaling, i.e., metabolic capacity scales approximately
    according to body weight raised to 3/4 power (Andersen et al.,
    1987). Support for the use of this principle for VC comes from data on
    the metabolism of VC in non-human primates (Buchter et al., 1980). In
    humans there is no evidence of a low-affinity high-capacity oxidation
    by other P-450 isozymes so this parameter was set at zero for humans.
    There is a wide variability of human CYP2E1 activity of about an order
    of magnitude, whereas in inbred strains typically used in animal
    studies the variability in CYP2E1 activity is small. The Clewell model
    was then used to calculate dose metrics for ASL in animal bioassays
    (Maltoni et al., 1981, 1984; Feron et al., 1981) as well as for human
    inhalation exposure (see Table 56).

         Reitz et al. (1996) developed a PBTK model for VC similar to that
    proposed by Clewell et al. (1995a) with a single saturable pathway
    based on a model for methylene chloride (Andersen et al., 1987) with
    modifications on the size of liver compartment and allometric
    constants. Partition coefficients were obtained from Gargas et al.
    (1989). Metabolic parameters were calculated from gas uptake
    experiments with male and female Sprague-Dawley rats. Metabolic
    parameters for mice and humans were estimated from these experimental
    data on rats and interspecies ratios obtained from literature
    (Andersen et al., 1987). The model has been validated against data on
    total metabolism in the rat (Watanabe et al., 1976b), gas uptake data
    in the mouse, and inhalation data in the human on exhaled
    concentrations of VC following VC exposure (Baretta et al., 1969).

    2.  Recent risk assessments of VC

    2.1  Simonato et al. (1991)

         Simonato et al. (1991) performed a regression analysis from
    epidemiological data (see sections 8.2 and 8.3) to assess the relative
    risk of liver cancer and ASL in occupational exposure to VC using the
    variables cumulative exposure (ppm-years) and years since first
    employment (Tables 48 and 49). On the basis of this regression
    analysis and including cumulative exposure and years since first
    exposure in the model, the absolute risk of ASL per 100 000 was
    calculated (Table 50).

    2.2  Clewell et al. (1995b)

         A PBTK model was used to predict the total production of reactive
    metabolites from VC in the animal bioassays and in human exposure
    scenarios. These measures of internal exposure were then used in the
    linearized multistage model (LMS) (Crump, 1984) to predict the risk
    associated with lifetime exposure to VC in air or drinking-water.

         The most appropriate toxicokinetic dose metric for a reactive
    metabolite was considered to be the total amount of the metabolite
    generated divided by the volume of the tissue in which it is produced
    (Andersen et al., 1987), which, in the case of VC and ASL, would be
    the total amount of metabolism divided by the volume of the liver.
    Specifically, the average amount generated in a single day is used,
    averaged over the lifetime (i.e., the lifetime average daily dose, or
    LADD). The use of a dose rate such as LADD, rather than total lifetime
    dose, has been reported to provide a better cross-species
    extrapolation of chemical carcinogenic potency (D'Souza & Andersen,
    1988). According to the authors, a body surface area adjustment is no
    longer necessary when using a LADD.

         The animal bioassays used are shown in Table 56. The 95% upper
    confidence limits on the human risk estimates for lifetime exposure to
    2.6 µg VC/m3 (1 ppb) were then calculated on the basis of each of the
    sets of bioassay data, using the LMS model. The risk estimates on
    inhalation studies in rats agreed with those in mice and were also
    comparable with those from studies on rat diet. The estimates on oral
    gavage were much higher (× 6), which the authors suggested might be
    due to the use of corn oil.

        Table 56. Human risk estimates (per million) for lifetime exposure to
    2.6 µg VC/m3 (1 ppb) air based on the incidence
    of ASL in animal bioassay a
                                                                             

    Animal bioassay     95% UCL risk/million     Reference
    study               per ppb
                                           
                        Males       Females
                                                                             

    Mouse inhalation    1.52        3.27        Maltoni et al. (1981, 1984)
    Rat inhalation      5.17        2.24        Maltoni et al. (1981, 1984)
    Rat diet            3.05        1.10        Feron et al. (1981)
    Rat gavage          8.68        15.70       Maltoni et al. (1981, 1984)
                                                                             

    a From: Clewell et al. (1995b); UCL = the 95% upper confidence limit of the
      human risk estimates for lifetime exposure to 2.6 µg VC/m3 (1 ppb)

         Risk calculations were also carried out on the basis of
    epidemiological data using a linear relative risk dose-response model
    (see Table 57). A PBTK model was run for the exposure scenario
    appropriate to each of the selected subcohorts from each of the
    studies.

        Table 57. Human risk estimates (per million) for lifetime inhalation
    of 2.6 µg VC/m3 (1 ppb) air based on the incidence of
    ASL in human epidemiological studies a
                                                                       

          95% UCL risk/million per ppb b     Epidemiological study
                                                                       

                  0.71-4.22                   Fox & Collier (1977)
                  0.97-3.60                   Jones et al. (1988)
                  0.40-0.79                   Simonato et al. (1991)
                                                                       

    a  From: Clewell et al. (1995b)
    b  The range of risk estimates reflects uncertainty in
       the appropriate value for P0, the background
       probability of death from liver cancer. The lower
       risk estimate was calculated using the value
       of P0 used in the study of Fox & Collier (1977),
       while the higher risk estimate was calculated using
       an estimate of the lifetime liver cancer mortality
       in the USA population (Chen & Blancato, 1989).
       Therefore there is not a true range but a
       reflection of two assumptions about the background
       rate of liver cancer in humans.

    To obtain an estimate of the carcinogenic potency, the resulting
    internal dose metrics were multiplied by the appropriate durations to
    obtain the cumulative internal doses, which were then input into the
    relative risk model together with observed and expected liver cancer
    deaths for each subcohort. A 95% upper confidence limit on the
    lifetime risk per ppb of VC was estimated to compare results with the
    animal-based results obtained with the LMS model. The estimates from
    the three epidemiological studies compared well with those from the
    toxicokinetic animal-based studies. From the Simonato data, a 0.4 to
    0.8 × 10-6 risk per ppm VC was estimated, which Clewell et al.
    (1995b) noted is about 30 below the published inhalation unit risk of
    8.4 × 10-6 (µg/m3)-1. A carcinogenic risk estimate of ASL from a
    lifetime exposure to 1 µg VC/litre in human drinking-water was
    1.14 × 10-6 (µg/litre)-1 and was derived from Feron's study on male
    rats after dietary administration of VC. This value was compared with
    the published unit risk of 5.4 × 10-5 (µg/litre)-1 (US EPA, 1995a).

    2.3  Reitz et al. (1996)

         Reitz et al. (1996) used a PBTK model to calculate LADDs and
    these were fit to a LMS model. The data generated in rats were used to
    predict ASL incidence in mice and were found to fit with the data from
    Maltoni's experiment BT 4 and those of Lee et al. (1978).

         The PBTK model was used to calculate LADDs for humans: mg VC
    metabolites formed/day per litre of liver tissue for conditions
    thought likely to have been present in the workplace in past years
    (i.e., VC concentrations 50-2000 ppm; 8 h/day; 5 days/week and 10 or
    20 years/70 years). From these estimates of dose the LMS model was
    used to estimate the likelihood that tumours would be produced based
    on the rat model. These results were then compared with the actual
    data from Simonato et al. (1991). Predictions using this PBTK model
    were substantially higher (10-35 fold) than actually observed in
    humans (see Table 58). But the PBTK-based value for the 95% UCL for
    excess lifetime risk associated with continuous inhalation of 1 µg/m3
    was 5.7 × 10-7, compared with the much higher risk, 8.4 × 10-5, using
    conventional risk estimates (US EPA, 1995a). Reitz et al. (1996)
    concluded that even using the PBTK model, the risk of ASL is
    overestimated and suggested that the livers of humans are less
    sensitive to the carcinogenic effect of reactive VC metabolites than
    the livers of the commonly used inbred laboratory rodents.

    2.4  Storm & Rozman (1997)

         Storm & Rozman (1997) use a no-threshold (LMS model and benchmark
    dose approach with linear extrapolation) and threshold (NOEL/LOEL and
    benchmark dose uncertainty factor approaches) models and compare them
    with the present occupational exposure limits in the 0.5 to 5 ppm
    range (Table 59). Although VC is a genotoxic carcinogen, the authors
    argued that for VC a threshold exists because DNA adducts formed by
    reaction with vinyl chloride metabolites are repaired by DNA
    glycosylase in both rat and human liver  in vitro (Dosanjh et al.,
    1994; Saparbaev et al., 1995), and only when repair capability is
    exceeded does cancer develop (Swenberg et al., 1995).

         Storm & Rozman (1997) used Maltoni's inhalation study with
    Sprague-Dawley rats (Maltoni et al., 1981) and, after adjusting all
    exposures to reflect equivalent continuous human exposures and then to
    LADD in mg/kg-day, used these dose measures in the low-dose
    extrapolation models. (Occupational exposures were derived by
    converting appropriately derived LADDs to equivalent occupational
    exposures, assuming an inhalation rate of 10 m3/working day and that
    exposures occurred 8 h/day, 50 weeks/year for 45 years).

         No-threshold models evaluated were the LMS model for
    extrapolation of genetic carcinogen dose-response curves to low doses,
    and the benchmark dose approach (BMD) with linear extrapolation (US
    EPA, 1996). Maximum likelihood estimates (MLE) and 95% UCL  (qi*) on


        Table 58. Predicted versus observed ASL incidence for humans
    assuming occupational exposure to VC a
                                                                                              

       Ppm          Years      Ppm-years              Linearized multistage   Human observed
                    exposed    prediction based on    (incidence/100 000)
                               animal studies
                               (incidence/100 000)
                                                                                              

       100           10            1000                    374 b               6.2 e
        50           20            1000                    376 b               6.2 e
       200           20            4000                   1465 b              42.2 f
         1           45              45                     21 c                 0 g
                                                          6-11 d
                                                                                              

    a From: Storm & Rozman (1997)
    b Derived by Reitz et al. (1996) assuming an occupational exposure of
      5 days/week, 50 weeks/year
    c Calculated from unit risk derived by Reitz et al. (1996), assuming
      occupational rather than continuous exposures
    d Calculated from human risk/million per ppb based on Simonato et al. (1991)
      derived by Clewell et al. (1995b), assuming occupational rather than
      continuous exposures
    e Derived by Simonato et al. (1991) for exposure < 2000 ppm-years
      and > 25 years since first employment
    f Derived by Simonato et al. (1991) for exposure 2000-5999 ppm-years
      and > 25 years since first employment
    g No ASL reported among workers first exposed in or after 1974 when the
      OSHA permissible exposure limit (PEL) of 1 ppm was promulgated.


    the linear coefficient  (q i) were derived using a LMS model. The
    resultant linear coefficients from these and the results from Reitz et
    al. (1996) described above using the PBTK model were then used to
    derive safe levels of occupational exposure. For the BMD approach, a
    computer programme was used to derive MLEs as well as 95% lower bound
    (LB) estimates for specified risk levels along with  X2
    goodness-of-fit statistics, in this case  P > 0.01. The MLE and LB
    of both the exposure associated with 10% incidence (ED10 and LED10)
    and the exposure associated with 1% incidence (ED01 and LED01),
    respectively, were used for linear extrapolation to zero (US EPA,
    1996). "Safe" levels of occupational exposure were derived from the
    slopes of these lines.

         Threshold models evaluated included a) the LOEL/NOEL
    uncertainty factor approach traditionally used for non-carcinogenic
    effects and b) the BMD and uncertainty factor approach being developed
    as a replacement for the former. A NOEL of 13 mg/m3 (5 ppm) was
    derived from the Maltoni et al. (1981) bioassay in rats. An
    uncertainty factor of 2 was applied to account for the half-lifetime
    exposure duration of the VC study, a standard uncertainty factor of 10
    to account for potential intraspecies variability in susceptibility,
    an interspecies uncertainty factor of 3 or 0.3 to cover the assumption
    that humans were more or less sensitive than rats in this study giving
    total uncertainty factors of 60 or 6, respectively. The same factors
    were applied to MLE and LB estimates of dose using the BMD
    curve-fitting approach.

         The  X2 goodness-of-fit  P value for the BMD curve was only
    acceptable when the apparent outliers at 100 and 250 ppm and high-dose
    responses at 500, 2500 and 6000 ppm were eliminated, and these values
    were therefore also eliminated in the LMS model for purpose of
    comparison.

         Both no-threshold models based on administered dose provide
    estimates of occupational safe levels of about 0.004 ppm, at least two
    orders of magnitude lower than the present accepted "safety" limit
    value of 0.5-5 ppm when using an acceptable level of risk of 1 in
    100 000 (1 × 10-5). With the PBTK model, estimates were about
    0.04 ppm. For threshold models, using the BMD curve-fitting approach,
    with an ED01 and LED01 point of departure, occupational levels of 0.1
    to 0.7 ppm, respectively, were estimated for humans less or more
    sensitive than rats. Estimations based on the rat NOEL approach gave
    values of 0.4 to 4 ppm, respectively, for humans more and less
    sensitive than rats.


        Table 59. Comparison of estimated safe levels for occupational
    exposure to VC (from Storm & Rozman, 1997)
                                                                                          

    No-threshold                                     Slope            Risk 1/100 000
    models                                           (mg/kg-day)-1    assuming
                                                                      occupational
                                                                      exposure a (ppb)
                                                                                          

    Linearized       Administered dose b   MLE        1.4 × 10-2       4.3
    multistage                             UCL        1.8 × 10-2       3.4
                     PBTK dose c           MLE        1.6 × 10-3      39.4
                                           UCL        2.0 × 10-3      31.2
                     US EPA d              UCL        2.9 × 10-1       0.2
    Benchmark        ED01-Point of         MLE        1.4 × 10-2       4.3
    dose             departure             LB         1.8 × 10-2       3.4
                                                                                          

    Threshold                                    BMD b     Uncertainty    Risk 1/100 000
    models                                       (mg/kg-   factor         assuming
                                                 day)                     occupational
                                                                          exposure a (ppm)
                                                                                          

    Benchmark        Humans less       MLE       0.7        6 e          0.7
    dose-ED01        sensitive         LB        0.5        6 e          0.7
                     Human = rat       MLE       0.7       20 f          0.2
                     sensitivity       LB        0.5       20 f          0.2
                     Humans more       MLE       0.7       60 g          0.1
                     sensitive         LB        0.5       60 g          0.1
                                                                                          



    Table 59. (cont'd)
                                                                                          
                                                 LADD       Uncertainty  Risk 1/100 000
                                                 (mg/kg-    factor       assuming
                                                 day)                    occupational
                                                                         exposure a (ppm)
                                                                                          

    Rat NOEL         Humans less                 3.6        6 e          3.8
    (5 ppm)          sensitive
                     Human = rat                 3.6        20 f         1.1
                     sensitivity
                     Humans more                 3.6        60 g         0.4
                     sensitive
                                                                                          

    a  Occupational exposures assume 10 m3/day inhalation rate, 5 days/week, 50 weeks/year,
       for 45 years averaged over a lifetime of 70 years (Note: Levels are ppb for
       no-threshold models, ppm for threshold models)
    b  Derived using a computer programme
    c  Slope from Reitz et al. (1996)
    d  Slope from US EPA Health Effects Assessment Summary Tables (US EPA, 1995)
    e  Safety factors of 10 for intraspecies, 0.3 for interspecies extrapolation and
       2 for half-lifetime exposure
    f  Safety factors of 10 for intraspecies extrapolation and 2 for
       half-lifetime exposure
    g  Safety factors of 10 for intraspecies, 3 for interspecies extrapolation, and
       2 for half-lifetime exposure

    MLE = maximum likelihood estimate;
    UCL = 95% upper confidence limit;
    LB  = 95% lower bound on dose
        


    ANNEX 3. EXECUTIVE SUMMARY OF VINYL CHLORIDE PANEL REPORT

     Executive summary of

    Mundt KA, Dell LD, Austin RA, Luippold RS, Noess R & Bigelow C.
     Epidemiological study of men employed in the vinyl chloride industry
    between 1942 and 1972:  I. Re-analysis of mortality through December
     31, 1982; and II. Update of mortality through December 31, 1995.
    Final Report. Arlington, Virginia: The Vinyl Chloride Panel, Chemical
    Manufacturers Association, January 8, 1999. 178 pagesa

         A cohort of 10 109 men who were employed for at least one year in
    vinyl chloride exposed jobs between 1942 and 1972 at any one of
    37 facilities in the USA or Canada was followed for mortality. Through
    December 31, 1995, a total of 3191 deaths had occurred among cohort
    members. A re-analysis of mortality through December 1982, at which
    time 1569 deaths had occurred, was conducted to establish baseline
    results against which the updated mortality results could be compared.
    The re-analysis of mortality through December 1982 was necessary for
    four reasons: (1) the cohort was reduced from 10 173 to 10 109 after
    the removal of study subjects who were duplicates or were not eligible
    for cohort inclusion; (2) a substantial proportion of cohort members
    previously lost to follow-up were identified and restored to the
    cohort; (3) an appropriate referent population, based on regional
    mortality rates, was constructed and used for the mortality update
    through 1995; and (4) the number of categories of death that could be
    evaluated in the analysis increased from 61 to 92 causes of death.

         Through 1995, mortality from all causes of death was 17% lower
    than state mortality weighted according to person-years accumulated
    among employees in the state where the plant was located. This result
    was similar to the 16% deficit seen for mortality from all causes of
    death through 1982. Mortality from all cancers, however, showed a
    deficit of 4% through 1995, in contrast with the 2% excess seen as of
    1982. Specific cancers showing meaningful excesses both through 1982
    and through 1995 included cancers of the liver and biliary tract,
    brain, and connective and soft tissues. However, several causes of
    death previously believed to be related to vinyl chloride exposure
    were not seen in excess, including lung cancer, cancers of lymphatic
    and haematopoietic tissue, emphysema and pneumoconioses and other lung
    diseases, including chronic obstructive pulmonary disease (COPD).

              
    a  This summary is reprinted by permission of the Vinyl Chloride
       Health Committee. This study, which is an update of the Wong et
       al. (1991) study, was not available at the Task Group meeting and
       thus did not affect the evaluation of the health risks of vinyl
       chloride. It is printed here as additional information to the
       reader.

         Through 1995, mortality from liver and biliary tract cancer,
    including angiosarcoma of the liver, was significantly increased
    (SMR=359; 95% CI: 284-446) although the excess was smaller than that
    observed through 1982 (SMR=428; 95% CI: 304-585). The SMR for liver
    and biliary tract cancer increased with duration of exposure from 83
    (95% CI: 33-171) to 215 (95% CI: 103-396) to 679 (95% CI: 483-929) to
    688 (95% CI: 440-1023) for those exposed from 1 to 4 years, 5 to 9
    years, 10 to 19 years and 20 years or more, respectively. The SMR for
    liver and biliary tract cancer also increased with time since first
    exposure from 0 (no deaths observed) to 287 (95% CI: 131-544) to 323
    (95% CI: 200-493) to 434 (95% CI: 322-572) for those 1 to 9 years, 10
    to 19 years, 20 to 29 years, and 30 or more years since first
    exposure, respectively. Results of a Cox proportional hazards model
    that fitted age at first exposure, duration of exposure, and year of
    first exposure indicated that duration of exposure was most strongly
    associated with increased risk of mortality from liver and biliary
    tract cancer. The adjusted hazards ratio for 1 to 4 years, 5 to 9
    years, 10 to 19 years and 20 years or more duration of exposure were
    1.0 (referent group), 2.8 (95% CI: 1.0-7.3), 9.0 (95% CI: 4.0-20.7)
    and 6.0 (95% CI: 2.5-14.4), respectively. This confirms the recognized
    association between vinyl chloride exposure and liver and biliary
    tract cancer, mainly due to a large excess of angiosarcoma of the
    liver.

         Mortality from brain cancer showed an excess (SMR=142; 95% CI:
    100-197) that was slightly smaller than that seen in the re-analysis
    through 1982 (SMR=169; 95% CI: 105-255). Since 1982, an additional 14
    brain cancer deaths were observed (12.2 expected). The SMRs for brain
    cancer were elevated among those exposed for 5 to 9 years (SMR=193;
    95% CI: 96-346) and those exposed for 20 years or more (SMR=290; 95%
    CI: 132-551). Results of a Cox proportional hazards model adjusted for
    duration of employment showed that age at employment of 35 years or
    older and longer duration of employment were both associated with
    increased risk of mortality from brain cancer, and these associations
    were not confounded. The association of brain cancer deaths with vinyl
    chloride exposure is uncertain, as the older age at first employment
    in the vinyl chloride industry suggests that these cohort members
    might have sustained exposure to some other carcinogen prior to
    employment in vinyl chloride.

         Mortality from cancers of the connective and soft tissues also
    showed an excess (SMR=270; 95% CI: 139-472), based on 12 deaths.
    Through 1982, mortality from connective and soft tissue cancers was
    also elevated (SMR=367; 95% CI: 147-755), based on seven observed
    deaths. This result was not reported in earlier investigations of this
    cohort because mortality for this cause of death category had not been
    previously evaluated. Although the total number of deaths due to this
    rare cause was small, the observed excess is potentially important for
    two reasons. First, very little is known about the risk factors for
    connective and soft tissue cancers, a category including numerous
    histological types of cancer. Second, some of these cancers may have

    been mis-diagnosed or mis-reported angiosarcomas of the liver, one
    form of soft tissue sarcoma known to be related to vinyl chloride
    exposure.

         No excesses in mortality were seen for lung cancer or cancers of
    the lymphatic and haematopoietic system. In contrast to the previous
    report which showed an excess of mortality from emphysema and chronic
    obstructive disease, mortality from emphysema and mortality from
    pneumoconioses and other respiratory diseases (PORD), the category
    which included chronic obstructive pulmonary disease, each showed
    deficits (SMR=61; 95% CI: 40-89 for emphysema and SMR=73; 95% CI:
    60-88 for PORD). The previously published findings with respect to
    mortality due to these causes of death may have resulted from
    methodological errors.

         In conclusion, this update of the industry-wide cohort confirmed
    a strong association between duration of employment in the vinyl
    chloride industry prior to 1974 and cancers of the liver and biliary
    tract, mostly resulting from a large excess of deaths due to
    angiosarcoma of the liver. This association has been observed in all
    similar studies and represents one of the most consistent effects
    observed in the occupational health literature. Cancers of the
    connective and soft tissues, though occurring in relatively small
    numbers, also appear to be related to employment in the industry. The
    elucidation of the actual mechanism for this observed association will
    require further investigation. The brain cancer mortality excess
    observed in the analyses through 1982 is less clearly associated with
    vinyl chloride, and may reflect risk factors other than vinyl chloride
    present in the early years of the industry or reflecting exposures
    sustained prior to employment in this industry. Since 1982, no such
    excess has occurred.

         This study represents one of the largest and longest-followed
    cohorts potentially exposed to substantial levels of vinyl chloride.
    The brain cancer and emphysema excesses previously reported are not
    sustained, however, the brain cancer excess remains unexplained.
    Except for deaths due [to] cancers of the liver and biliary tract, and
    to a lesser extent cancers of connective and soft tissues, the
    mortality patterns for this cohort remain at or below that expected in
    the general population.
    

    RESUME

         La présente monographie traite du chlorure de vinyle monomère
    lui-même, à l'exclusion de son polymère, le chlorure de polyvinyle
    (PVC). Le problème de l'exposition à des mélanges contenant du
    chlorure de vinyle n'est pas abordé.

    1.  Identité, propriétés physiques et chimiques et méthodes d'analyse

         Dans les conditions ambiantes, le chlorure de vinyle se présente
    sous la forme d'un gaz incolore inflammable à l'odeur douceâtre. Sa
    tension de vapeur est élevée, de même que la valeur de sa constante
    pour la loi d'Henry; sa solubilité dans l'eau est relativement faible.
    Il est plus lourd que l'air et il est soluble dans presque tous les
    solvants organiques. On le transporte à l'état liquide sous pression.

         A la température ambiante et en l'absence d'air, le chlorure de
    vinyle pur et sec est très stable et non corrosif. Toutefois,
    au-dessus de 450°C ou en présence d'hydroxyde de sodium ou de
    potassium, il peut subir une décomposition partielle. Sa combustion
    dans l'air donne naissance à du dioxyde de carbone et à du chlorure
    d'hydrogène. En présence d'air et d'oxygène, des peroxydes très
    explosifs peuvent se former, ce qui exige une surveillance permanente
    et la limitation de la teneur en oxygène, en particulier dans les
    installations de récupération du chlorure de vinyle. En présence
    d'eau, il se forme de l'acide chlorhydrique.

         Du point de vue industriel, ce sont les réactions de
    polymérisation conduisant au chlorure de polyvinyle qui sont
    techniquement les plus importantes, mais les réactions d'addition des
    halogènes sur la double liaison, qui conduisent au
    1,1,2-trichloréthane ou au 1,1-dichloréthane, ont aussi leur
    importance.

         On peut surveiller la concentration de chlorure de vinyle dans
    l'atmosphère en piégeant le composé sur un support adsorbant et en
    procédant à une analyse par chromatographie en phase gazeuse après
    désorption liquide ou thermique. Pour le dosage dans l'air ambiant, il
    peut être nécessaire d'utiliser plusieurs supports adsorbants ou
    pièges froids disposés en série pour mieux capter le composé. Les pics
    de concentration sur les lieux de travail peuvent se mesurer au moyen
    d'instruments à lecture directe utilisant notamment des détecteurs à
    ionisation de flamme ou à photo-ionisation. Pour le contrôle en
    continu, ont utilise des analyseurs basés sur la spectrophotométrie
    infrarouge ou sur la chromatographie en phase gazeuse avec détection
    par ionisation de flamme et qui sont munis d'un système
    d'enregistrement et de traitement des données. Pour doser le chlorure
    de vinyle dans les liquides et les solides, on a recours à l'injection
    directe, à l'extraction et de plus en plus, à la technique de l'espace
    de tête ou à celle de purgeage-piégeage. Pour l'analyse de ces
    échantillons, on utilise aussi la chromatographie en phase gazeuse
    avec détection par ionisation de flamme ou spectrométrie de masse.

    2.  Sources d'exposition humaine dans l'environnement

         Le chlorure de vinyle n'existe pas à l'état naturel, même si on
    en a décelé la présence dans les gaz qui s'échappent des décharges et
    dans les eaux souterraines, par suite de la décomposition de rejets de
    solvants constitués d'hydrocarbures chlorés, ou encore dans
    l'environnement des lieux de travail où on fait usage de ce genre de
    solvants. Il y a également du chlorure de vinyle dans la fumée de
    cigarette.

         La production industrielle du chlorure de vinyle utilise deux
    réactions principales: a) l'hydrochloration de l'acétylène et b) le
    craquage thermique (à environ 500°C) du 1,2-dichloréthane produit par
    chloration ou oxychloration directes de l'éthylène par le chlore ou
    par un mélange HCl + air/O2. Ce procédé est actuellement le plus
    couramment utilisé.

         La production mondiale de PVC et par conséquent celle de chlorure
    de vinyle monomère a été d'environ 27 millions de tonnes en 1998.
    Vingt pour cent des matières plastiques utilisées dans le monde sont à
    base de PVC et ce polymère se retrouve dans presque tous les secteurs
    de l'industrie. Environ 95% de la production mondiale de chlorure de
    vinyle sert à la fabrication de PVC. Le reste est utilisé pour la
    production de solvants chlorés, essentiellement du
    1,1,1-trichloréthane (10 000 tonnes par an).

         Trois procédés principaux sont utilisés pour la production
    industrielle du PVC: la polymérisation en suspension (80% de la
    production mondiale), la polymérisation en émulsion (12%) et la
    polymérisation en masse (8%). La plupart des études de cas faisant
    état des effets nocifs du chlorure de vinyle concernent des usines
    produisant du PVC par polymérisation en suspension (on dit aussi
     polymérisation en perles).

         On a signalé des émissions de chlorure de vinyle lors d'accidents
    survenus dans des usines produisant du PVC ou pendant le transport.
    Dans de nombreux pays, on récupère le chlorure de vinyle résiduel non
    polymérisé lors de la production de PVC ou qui se trouve dans les
    rejets gazeux ou les eaux usées. Faute de certaines précautions, il
    est possible de retrouver du chlorure de vinyle dans les résines et
    autres produits à base de PVC.

         Le taux de chlorure de vinyle résiduel présent dans le PVC est
    réglementé dans de nombreux pays depuis la fin des années 1970. Depuis
    lors, les émissions de chlorure de vinyle dues à la décomposition
    thermique du PVC sont soit indétectables, soit très faibles.

         Des dioxines peuvent se former lors de la production de chlorure
    de vinyle. Les quantités qui sont répandues dans l'environnement sont
    controversées.

    3.  Transport, distribution et transformation dans l'environnement

         En raison de sa forte tension de vapeur, le chlorure de vinyle
    libéré dans l'environnement devrait exister presque uniquement en
    phase gazeuse. Il existe des indices de dépôts sous forme liquide.

         Le chlorure de vinyle est relativement peu soluble dans l'eau et
    sa capacité d'adsorption aux particules et aux solides en suspension
    est faible. C'est par volatilisation que le composé s'élimine le plus
    rapidement des eaux de surface. La demi-vie de volatilisation à partir
    des eaux de surface varie d'environ 1h à 40 h.

         A partir du sol, la demi-vie de volatilisation est, selon les
    calculs, égale à 0,2-0,5 jours. On estime que les pertes de chlorure
    de vinyle (au bout d'un an sous un mètre de terre) vont de 0,1 à 45%,
    selon le type de sol. Le coefficient de sorption pédologique tiré des
    données physico-chimiques indique que le potentiel de sorption du
    composé est faible et que par conséquent il est très mobile dans le
    sol. Il existe une autre voie importante de distribution dans
    l'environnement, à savoir le lessivage qui peut entraîner le chlorure
    de vinyle jusqu'aux nappes d'eau souterraines où il est susceptible de
    persister pendant des années.

         Les études de laboratoire portant sur des organismes aquatiques
    révèlent une certaine tendance à la bioaccumulation, mais pas de
    bioamplification le long de la chaîne alimentaire.

         A quelques exceptions près, le chlorure de vinyle ne se laisse
    pas facilement dégrader par les groupements de microorganismes
    inadaptés dans les conditions ambiantes. On estime que la demi-vie de
    biodégradation par des micro-organismes non acclimatés est de l'ordre
    de plusieurs mois ou années. Toutefois, certaines cultures
    microbiennes enrichies ou pures (par exemple  Mycobacterium sp.) sont
    capables de décomposer le chlorure de vinyle lorsque les conditions
    culturales sont optimales. Les principaux produits de dégradation sont
    l'acide glycolique ou le dioxyde de carbone après conversion aérobie
    et l'éthane, l'éthylène, le méthane ou le chlorométhane après
    transformation anaérobie. Souvent, les microorganismes aérobies
    décomposent plus rapidement le chlorure de vinyle que les
    microorganismes anaérobies.

         Le principal processus atmosphérique est la réaction avec les
    radicaux OH produits par voie photochimique; la demi-vie
    troposphérique résultant de ce processus est de 1 à 4 jours. Les
    réactions de photolyse réalisées dans des conditions expérimentales
    donnent naissance à plusieurs composés importants, comme le
    chloracétaldéhyde, le formaldéhyde et le chlorure de formyle.

         On pense que les réactions de photolyse, de même que l'hydrolyse
    chimique, sont de peu d'importance en milieu aqueux. Toutefois, la
    présence de photosensibilisateurs peut faciliter la transformation du
    chlorure de vinyle.

         On a des raisons de penser que le chlorure de vinyle réagit avec
    le chlore ou les chlorures utilisés pour la désinfection de l'eau pour
    donner du chloracétaldéhyde et autres composés indésirables. Il existe
    d'autres interactions possibles, notamment avec les sels, dont un
    grand nombre sont susceptibles de former des complexes avec le
    chlorure de vinyle, ce qui peut en accroître la solubilité.

         Parmi les méthodes utilisées (avec des succès divers) pour
    éliminer le chlorure de vinyle présent dans l'eau, on peut citer le
    lavage, l'extraction, l'adsorption et l'oxydation. Certaines méthodes
    de biopurification (applicables aux eaux souterraines et aux sols)
    associent l'évaporation ou d'autres techniques à un traitement
    microbien. Le chlorure de vinyle présent dans les rejets gazeux peut
    être recyclé, incinéré ou décomposé par voie microbienne. La majeure
    partie du chlorure de vinyle produit industriellement se retrouve à
    l'état lié dans des articles en PVC. L'incinération de ces produits
    comporte un risque de formation de PCDD, de PCDF et d'autres dérivés
    chlorés indésirables.

    4.  Concentrations dans l'environnement et exposition humaine

         La population dans son ensemble est très peu exposée au chlorure
    de vinyle.

         La concentration de chlorure de vinyle dans l'air ambiant est
    faible, généralement inférieure à 3 µg/m3. La population peut être
    davantage exposée lorsque de grandes quantités de chlorure de vinyle
    sont libérées accidentellement dans l'environnement, par exemple en
    cas de déversement pendant le transport. Il s'agit cependant d'une
    exposition qui a toutes chances d'être passagère. A proximité de sites
    industriels où l'on produit du chlorure de vinyle et du PVC ou près de
    décharges, on a enregistré des concentrations beaucoup plus élevées
    (pouvant aller respectivement jusqu'à 8000 µg/m3 et 100 µg/m3).

         La principale voie d'exposition professionnelle est la voie
    respiratoire et alle intervient principalement dans les usines qui
    produisent du chlorure de vinyle et du PVC. Dans les années 1940 et
    1950, l'exposition professionnelle au chlorure de vinyle était de
    plusieurs milliers de mg/m3; elle atteignait encore plusieurs
    centaines de mg/m3 dans les années 1960 et au début des années
    1970.Une fois reconnu le risque cancérogène inhérent au chlorure de
    vinyle, la norme d'exposition à ce composé a été fixée au cours des
    années 1970 à environ 13-26 mg/m3 (5-10 ppm) dans la plupart des
    pays. Le respect de ces directives a fait fortement chuter la
    concentration du chlorure de vinyle sur les lieux de travail, mais au
    cours des années 1990 on a tout de même fait état de concentrations
    plus élevées et ce pourrait encore être le cas actuellement dans
    quelques pays.

         Il est arrivé que l'on trouve du chlorure de vinyle dans les eaux
    de surface, dans les sédiments et dans les boues d'égout, avec des
    concentrations maximales respectivement égales à 570 µg/litre,
    580 µg/kg et 62 000 µg/litre. Des échantillons de sol prélevés près

    d'une teinturerie abandonnée se sont révélés présenter une forte
    teneur en chlorure de vinyle (jusqu'à 900 mg/kg). On a mis en évidence
    des concentrations de l'ordre de 60 000 µg/litre ou davantage dans des
    eaux souterraines ou dans des eaux de lessivage provenant de zones
    contaminées par des hydrocarbures chlorés. Des teneurs élevées
    (jusqu'à 200 mg/litre) ont également été mises en évidence, 10 ans
    après le repérage des premières fuites, dans l'eau de puits situés à
    proximité d'une usine de PVC.

         Les quelques données disponibles montrent que les tissus des
    petits vertébrés aquatiques et des poissons peuvent contenir du
    chlorure de vinyle.

         Dans la majorité des échantillons d'eau de boisson analysés, le
    chlorure de vinyle n'était pas présent à des concentrations
    décelables. La concentration maximale dont il ait été fait état était
    de 10 µg/litre dans de l'eau prête à être consommée. On manque de
    données récentes sur la concentration du composé dans l'eau de
    boisson, mais elle devrait être inférieure à 10 µg/litre. Si la source
    utilisée pour la boisson est contaminée, l'exposition peut être plus
    importante. Des études récentes ont permis de déceler la présence de
    chlorure de vinyle dans de l'eau minérale en bouteilles de PVC à une
    concentration inférieure à 1 µg/litre. On peut penser que la présence
    de chlorure de vinyle est plus fréquente dans ces eaux en bouteilles
    que dans l'eau du robinet.

         L'utilisation de PVC pour l'emballage peut entraîner la présence
    de chlorure de vinyle dans les denrées alimentaires, les produits
    pharmaceutiques et les cosmétiques. On en a décelé jusqu'à 20 mg/kg
    dans des liqueurs, jusqu'à 18 mg/kg dans des huiles végétales et
    jusqu'à 9,8 mg/kg dans du vinaigre. Depuis le début des années 1970,
    le nombre d'échantillons contrôlés positifs pour le chlorure de vinyle
    est moindre et la concentration est plus faible qu'auparavant, grâce
    aux mesures législatives prises par un certain nombre de pays.

         Plusieurs organismes ont calculé l'exposition au chlorure de
    vinyle due à la contamination des denrées alimentaires par leur
    emballage de PVC. En se basant sur valeur estimative moyenne de la
    dose ingérée au Royaume-Uni et aux Etats-Unis, on a calculé qu'à la
    fin des années 1970 et au début des années 1980, l'exposition devait
    être inférieure à 0,0004 µg/kg par jour. Une étude ancienne a mis
    évidence du chlorure de vinyle dans la fumée de tabac à des
    concentrations de quelques ng par cigarette.

    5.  Cinétique et métabolisme chez les animaux de laboratoire et
        l'Homme

         Après inhalation ou ingestion, le chlorure de vinyle est
    facilement et rapidement absorbé. Des études effectuées sur des
    animaux et des sujets humains, dans des conditions d'équilibre
    dynamique, ont montré qu'environ 40% de la dose inhalée étaient
    absorbés après exposition par la voie respiratoire. L'expérimentation

    animale montre que l'absorption peut dépasser 95% après ingestion.
    L'absorption percutanée de chlorure de vinyle à l'état gazeux est peu
    importante.

         Les données fournies par les études sur l'inhalation et
    l'ingestion de chlorure de vinyle par des rats montrent que le composé
    se répartit rapidement et largement dans l'organisme. Par suite d'une
    métabolisation et d'une excrétion rapides, son accumulation est
    limitée. Chez le rat, le passage transplacentaire se produit
    rapidement. On n'a pas connaissance d'études consacrées à la
    répartition du composé dans l'organisme après exposition par voie
    percutanée.

         Après inhalation ou ingestion, la principale voie métabolique
    consiste en une oxydation par le cytochrome P-450 (CYP2E1) qui conduit
    à la formation d'oxyde de chloréthylène, un époxyde à courte vie
    extrêmement réactif, qui se transpose très vite en chloracétaldéhyde.
    La principale réaction de détoxication de ces deux métabolites
    réactifs ainsi que de l'acide chloracétique, produit de
    déshydrogénation du chloracétaldéhyde, consiste en une conjugaison
    avec le glutathion catalysée par la glutathion- S-transférase. Les
    conjugués sont ensuite transformés en dérivés de la cystéine
    [ S-(2-hydroxyéthyl)cystéine,  N-acétyl- S-
    (2-hydroxyéthyl)cystéine,  S-carboxyméthylcystéine et acide
    thiodiglycolique] et ils sont excrétés dans l'urine. Un autre
    métabolite, le dioxyde de carbone, est excrété dans l'air exhalé.

         Les isozymes de la CYP2E1 et de la glutathion- S-transférase
    présentent d'importantes variations d'activité interspécifiques et
    interindividuelles.

         Après exposition par inhalation ou ingestion de faibles doses de
    chlorure de vinyle, le composé est éliminé par métabolisation et ses
    métabolites non volatils sont principalement excrétés par la voie
    urinaire. L'étude comparée de l'absorption après inhalation montre que
    relativement au poids corporel, le chlorure de vinyle est métabolisé
    moins rapidement par l'organisme humain que par l'organisme animal.
    Toutefois, si on tient compte de la superficie du corps, on constate
    que la clairance métabolique est comparable chez l'Homme et chez les
    autres mammifères. Lorsque l'exposition - toujours par inhalation ou
    ingestion - est plus importante, la principale voie d'excrétion chez
    l'animal consiste dans l'élimination du composé initial dans l'air
    expiré, ce qui témoigne de la saturation des voies métaboliques.
    Quelle que soit la dose, l'excrétion par la voie fécale est
    secondaire. On n'a pas trouvé d'étude qui soit spécialement consacrée
    à l'excrétion par la voie biliaire.

         On estime que l'oxyde de chloréthylène est le métabolite le plus
    important  in vivo, pour ce qui est des effets cancérogènes et
    mutagènes du chlorure de vinyle. Cet époxyde réagit sur d'ADN pour
    former un certain nombre d'adduits, principalement de la
    7-(2'-oxoéthyl)guanine (7-OEG) et, en moindre quantité, des

    éthénoadduits exocycliques comme la 1, N 6-éthénoadénine (Epsilon
    A), la 3, N 4-éthénocytosine (Epsilon C) et la  N2,3-éthénoguanine
    (Epsilon G). Contrairement à l'adduit principal, la 7-OEG, ces
    éthénoadduits avec l'ADN ont des propriétés promutagènes. On a pu
    doser la 7-OEG, la Epsilon A, la Epsilon C et la Epsilon G dans les
    divers tissus de rongeurs exposés à du chlorure de vinyle. On a mis au
    point des modèles toxicocinétiques à base physiologique pour rendre
    compte de la relation entre la dose aux tissus cibles et les points
    d'aboutissement toxicologique du chlorure de vinyle.

    6.  Effets sur les mammifères de laboratoire et les systèmes d'épreuve
        in vitro

         Administré par inhalation à des animaux de plusieurs espèces, le
    chlorure de vinyle s'est révélé d'une faible toxicité aiguë. La CL50
    à 2 h pour le rat, la souris, le cobaye et le lapin a été trouvée
    respectivement égale à 390 000, 293 000, 595 000 et 295 000 mg/m3. On
    ne possède aucune donnée sur la toxicité aiguë du composé par voie
    orale ou percutanée. L'inhalation brutale de chlorure de vinyle a un
    effet stuporeux. Chez des rats, des souris et des hamsters, la mort a
    été précédée d'un accroissement de l'activité motrice, d'ataxie et de
    convulsions suivies d'une défaillance respiratoire. Chez des chiens
    plongés dans un état stuporeux après exposition brutale à une
    concentration de 260 000 mg/m3, on a noté de graves arythmies
    cardiaques. Des rats, exposés par la voie respiratoire à du chlorure
    de vinyle, ont présenté un certain nombre d'anomalies
    anatomopathologiques telles que congestion des organes internes,
    notamment des poumons, du foie et des reins, et oedème pulmonaire.

         On ne dispose pas d'études ni de données appropriées qui
    permettent d'évaluer les effets de l'exposition par voie percutanée ou
    encore le pouvoir irritant ou sensibilisateur au niveau cutané.

         Une exposition de courte durée (13 semaines) au chlorure de
    vinyle par la voie orale a permis d'obtenir une valeur de 30 mg/kg
    pour la NOEL, c'est-à-dire la dose sans effet observable, le critère
    retenu étant l'augmentation du poids du foie.

         Chez plusieurs espèces, le principal organe cible après
    exposition de courte durée (jusqu'à 6 mois) par voie respiratoire se
    révèle être le foie. Chez des rats soumis à une dose de 26 mg/m3 (la
    dose la plus faible utilisée) on a constaté une augmentation du poids
    relatif du foie et des modification hépatocellulaires; à dose plus
    élevée (> 260 mg/m3), les anomalies hépatiques étaient plus
    prononcées et dépendaient de la dose. Les autres organes cibles
    étaient le rein, le poumon et le testicule. Les rats, les souris et
    les lapins se sont révélés plus sensibles que les cobayes et les
    chiens.

         Une exposition de longue durée par la voie respiratoire a
    entraîné une augmentation statistiquement significative de la
    mortalité chez certaines souches de rats à des doses ne dépassant pas

    260 mg/m3, chez des souris à la dose de 130 mg/m3 et chez des
    hamsters à la dose de 520 mg/m3 sur des durées d'exposition
    variables. Des rats exposés à une dose de 130 mg/m3 ont présenté une
    diminution du poids corporel et une augmentation du poids relatif de
    la rate ainsi qu'une dégénérescence hépatocellulaire et une
    prolifération des cellules pariétales des capillaires sinusoïdes. A
    dose plus élevée, on a noté une dégénérescence testiculaire, une
    néphrose tubulaire et des foyers de dégénérescence au niveau du
    myocarde. Chez des rats et des souris exposés par la voie respiratoire
    la dose sans effet nocif observable (NOAEL) est inférieure à 130
    mg/m3 pour ce qui est des effets cancérogènes.

         Des études d'alimentation de longue durée ont fait ressortir une
    augmentation de la mortalité, un accroissement du poids du foie et une
    modification de la morphologie de cet organe.

         Après exposition par la voie orale, on a observé un polymorphisme
    hépatocellulaire (variation de la taille et de la forme des
    hépatocytes et de leur noyau) chez des rats soumis à des doses de
    chlorure de vinyle ne dépassant pas 1,3 mg/kg de poids corporel. La
    NOAEL était égale à 0,13 mg/kg de poids corporel.

         Après administration prolongée à des rats de chlorure de vinyle
    dans des granulés de PVC par la voie alimentaire, on a observé un
    accroissement significatif de l'incidence des tumeurs au niveau du
    foie. Il s'agissait d'angiosarcomes à la dose quotidienne de 5,0 mg/kg
    p.c., et de nodules néoplasiques (femelles) ou de carcinomes
    hépatocellulaires (mâles) à la dose de 1,3 mg/kg p.c.

         Des études au cours desquelles on a fait inhaler du chlorure de
    vinyle à des rats Sprague-Dawley ont fait ressortir une relation
    dose-réponse dans le cas des angiosarcomes du foie et, à forte
    concentration, pour les carcinomes de la glande de Zymbal. En
    revanche, on n'a pas observé de relation dose-réponse bien nette dans
    le cas des hépatomes ou des angiosarcomes extrahépatiques, des
    néphroblastomes, des neuroblastomes ou des tumeurs des glandes
    mammaires. Chez la souris, le spectre tumoral induit par une
    exposition respiratoire de longue durée est analogue à celui que l'on
    observe chez le rat, mais on a aussi noté une augmentation des tumeurs
    pulmonaires propre à la souris. Chez des hamsters, on a relevé une
    augmentation de l'incidence des angiosarcomes hépatiques, des tumeurs
    des glandes mammaires et du conduit auditif, des mélanomes et des
    épithéliomas gastriques et cutanés.

         Un certain nombre de systèmes d'épreuve  in vitro ont permis de
    mettre en évidence les effets mutagènes et génotoxiques du chlorure de
    vinyle, surtout après activation métabolique. Le composé s'est révélé
    mutagène dans le test d'Ames sur les souches TA100, TA1530 et TA1535
    de  S. typhimurium, à l'exclusion des souches TA98, TA1537 et TA1538,
    ce qui dénote des mutations par substitution de paires de bases
    (transversion et transition) plutôt que des mutations par décalage du
    cadre de lecture. Ces résultats concordent avec une autre observation,

    à savoir que les éthénoadduits qui se forment lors de l'attaque de
    l'ADN par l'oxyde de chloréthylène et par le chloracétaldéhyde
    aboutissent effectivement à des mutations par substitution de paires
    de bases.

         D'autres tests de mutation génique effectués sur des bactéries,
    des levures et des cellules mammaliennes ont donné des résultats
    positifs, mais seulement en présence d'activation métabolique. Des
    effets mutagènes ont également été observés dans des lignées
    cellulaires humaines contenant le cytochrome P-450IIE1 obtenu par
    clonage, qui est capable de métaboliser le chlorure de vinyle. On a
    aussi décelé des mutations dans des fragments d'un végétal
     (Tradescantia) mis en présence de chlorure de vinyle. Des tests de
    conversion génique ont donné des résultats positifs dans le cas de
     Saccharomyces cerevisiae en présence d'un système d'activation
    métabolique. En présence de chlorure de vinyle, des hépatocytes de rat
    ont été le siège d'une synthèse non programmée de l'ADN et un
    accroissement des échanges entre chromatides-soeurs a été observé dans
    des lymphocytes humains après addition d'un système activateur
    exogène. Chez des bactéries dont le système de réparation de l'ADN
    était défectueux, on n'a pas décelé d'inhibition de la croissance en
    l'absence de système activateur. Les tests de transformation
    cellulaire ont donné des résultats positifs avec ou sans activation
    métabolique.

         Chez  Drosophila melanogaster, l'exposition au chlorure de
    vinyle a provoqué des mutations géniques et des recombinaisons
    mitotiques, mais ces effets n'ont pas été observés sur des cellules
    germinales de mammifères. Le composé a des effets clastogènes chez des
    rongeurs, il augmente les échanges entre chromatides-soeurs chez le
    hamster et provoque la rupture des brins de l'ADN chez la souris. Des
    tests par passage sur hôte (rat) ont montré que le chlorure de vinyle
    provoquait une conversion génique et les mutations directes chez des
    levures.

         L'oxyde de chloréthylène et le chloracétaldéhyde se sont révélés
    mutagènes dans un certain nombre de systèmes. L'oxyde de chloréthylène
    est un mutagène puissant, alors que le chloracétaldéhyde est fortement
    toxique. Ces deux composés sont cancérogènes pour la souris, l'oxyde
    de chloréthylène étant de loin le plus actif.

         Les mutations observées au niveau des gènes  ras et  p53 ont
    été analysées sur des tumeurs hépatiques induites chez des rats
    Sprague-Dawley par du chlorure de vinyle: dans les carcinomes, on a
    constaté la présence de substitutions de paires de bases au niveau du
    gène Ha- ras; dans les angiosarcomes, ces substitutions intéressaient
    le gène  p53. La présence de ces mutations concorde avec la
    formation, observée après exposition au chlorure de vinyle,
    d'éthénoadduits persistants dans l'ADN des hépatocytes, éthénoadduits
    dont on connaît le caractère promutagène.

         L'étude du mécanisme par lequel s'exerce l'effet cancérogène du
    chlorure de vinyle donne à penser que l'intermédiaire réactif que
    constitue l'oxyde de chloréthylène attaque l'ADN pour former des
    éthénoadduits, ce qui conduit à la substitution de paires de bases et
    à la transformation néoplasique.

    7.  Effets sur l'Homme

         L'exposition à des concentrations de l'ordre de 2590 mg/m3
    (1000 ppm), qui n'étaient pas rares avant 1974, pendant des périodes
    de 1 mois à plusieurs années, seraient à l'origine d'un syndrome
    pathologique particulier observé chez des ouvriers travaillant sur le
    chlorure de vinyle et appelé "maladie du chlorure de vinyle". Les
    symptômes évoqués consistaient en douleurs auriculaires et céphalées,
    étourdissements, troubles visuels, fatigue et perte d'appétit,
    nausées, insomnies, essoufflement, douleurs au niveau de l'estomac et
    dans la région du foie et de la rate, douleurs et picotements dans les
    membres, sensation de froid aux extrémités, diminution de la libido et
    perte de poids. Sur le plan clinique, on a relevé au niveau des doigts
    des modifications à type de sclérodermie évoluant vers des anomalies
    osseuses qualifiées d'acro-ostéolyse, avec des anomalies de la
    circulation périphérique identiques à celles qui sont caractéristiques
    de la maladie de Raynaud, une hypertrophie du foie et de la rate
    d'histologie particulière et des manifestations respiratoires.

         Les études sur l'Homme ne sont pas suffisantes pour pouvoir
    confirmer la présence d'effets sur la fonction de reproduction. Un
    certain nombre d'études font état d'une augmentation de l'incidence
    des affections de l'appareil circulatoire chez des ouvriers
    travaillant sur le chlorure de vinyle. Toutefois, les études
    effectuées sur des cohortes d'effectif plus important ont mis en
    évidence une diminution de la mortalité due aux maladies
    cardiovasculaires.

         Les études épidémiologiques fournissent une argumentation solide
    et cohérente tendant à prouver que l'exposition au chlorure de vinyle
    provoque une forme rare de cancer, l'angiosarcome du foie. On a
    également établi un lien entre certaines tumeurs cérébrales ou
    carcinomes hépatocellulaires et le chlorure de vinyle, sans qu'on
    puisse considérer les données obtenues à cet égard comme définitives.
    Les autres localisations où l'on a observé une augmentation des
    cancers sont le poumon, les tissus lymphatiques et hématopoïétiques et
    la peau.

         Le chlorure de vinyle a des effets mutagènes et clastogènes chez
    l'Homme. On a ainsi constaté que chez des ouvriers exposés à de fortes
    concentrations de chlorure de vinyle, la fréquence des aberrations
    chromosomiques, des micronoyaux et des échanges entre
    chromatides-soeurs dans les lymphocytes du sang périphériques, était
    plus élevée que chez les témoins. Dans de nombreuses études,

    l'intensité et la durée de l'exposition ne sont qu'estimatives, mais
    on peut néanmoins observer l'existence d'une relation dose-réponse et
    une "normalisation" des effets génotoxiques avec le temps lorsque
    l'exposition diminue.

         Des mutations ponctuelles ont été décelées au niveau des gènes
     p53 et  ras dans des tumeurs (angiosarcomes du foie) prélevées sur
    des ouvriers très exposés travaillant sur des autoclaves (avant 1974)
    ainsi que dans un carcinome hépatocellulaire dont était porteur un
    autre ouvrier également exposé au chlorure de vinyle.

         Parmi les marqueurs biologiques dont on a étudié la possibilité
    d'utilisation comme indicateurs d'une exposition au chlorure de
    vinyle, on peut citer a) l'excrétion de métabolites (par exemple
    l'acide thiodiglycolique), b) des marqueurs génétiques comme la
    présence d'anomalies chromosomiques ou de micronoyaux, c) le taux de
    certaines enzymes (par exemple celles qui sont mesurées dans les tests
    de la fonction hépatique), d) les oncoprotéines sériques et leurs
    anticorps en tant que biomarqueurs des effets induits par le chlorure
    de vinyle.

         Les enfants qui vivent à proximité de décharges et autres sources
    ponctuelles d'exposition au chlorure de vinyle pourraient courir un
    risque accru, compte tenu de la sensibilité plus forte constatée chez
    les jeunes animaux. On n'a toutefois pas de preuves directes d'une
    telle sensibilité chez l'Homme.

         C'est seulement dans le cas de l'angiosarcome du foie-seul ou en
    association avec d'autres tumeurs hépatiques - qu'une relation
    dose-réponse claire ressort des études épidémiologiques. Il n'existe
    qu'une seule étude épidémiologique qui ait produit des données
    suffisantes pour une estimation quantitative de la relation
    dose-réponse.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         On manque des données toxicologiques habituelles au sujet de la
    survie et de la reproduction des organismes aquatiques exposés au
    chlorure de vinyle. Il faut interpréter avec prudence les données
    disponibles car pour la plupart, elles proviennent de tests au cours
    desquels on n'a pas mesuré les concentrations auxquelles ces
    organismes étaient exposés et il n'a donc pas été tenu compte des
    pertes par volatilisation.

         La concentration la plus faible de chlorure de vinyle qui
    produise un effet sur des microorganismes a été trouvée égale à 40
    mg/litre. Il s'agit d'une valeur de la CE50 obtenue lors d'un test
    statique de 3,5 jours sur des microorganismes anaérobies pour lequel
    le critère retenu était l'inhibition de la respiration.

         La concentration la plus faible qui produise un effet sur des
    organismes supérieurs a été trouvée égale à 210 mg/litre (CL50 à 48 h
    pour un poisson d'eau douce); avec une concentration sans effet nocif
    observable (NOAEC) de 128 mg/litre. Chez d'autres espèces, on a
    constaté des effets à plus faible concentration, mais la portée
    écologique de ces effets n'a pas été vérifiée.

         On peut prévoir que la concentration de chlorure de vinyle sans
    effet nocif pour les poissons d'eau douce se situe entre 0,088 et
    29 mg/litre.

         On manque de données concernant des effets du chlorure de vinyle
    sur les organismes terrestres.
    

    RESUMEN

         Esta monografía se ocupa exclusivamente del cloruro de vinilo
    (VC) como monómero y no es una evaluación del cloruro de polivinilo
    (PVC), polímero del VC. No se tratan las exposiciones a mezclas con
    VC.

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         En condiciones normales, el VC es un gas incoloro, inflamable,
    con un olor ligeramente dulce. Tiene una presión de vapor alta, un
    valor elevado para la constante de la Ley de Henry y una solubilidad
    en agua relativamente baja. Es más pesado que el aire y soluble en
    casi todos los disolventes orgánicos. Se transporta en forma líquida
    bajo presión.

         A temperatura ambiente en ausencia de aire, el VC purificado seco
    es muy estable y no corrosivo, pero por encima de 450°C, o en
    presencia de hidróxido sódico o potásico, se puede producir una
    descomposición parcial. La combustión del VC en el aire produce
    anhídrido carbónico y cloruro de hidrógeno. En presencia de aire y de
    oxígeno, se pueden formar peróxidos muy explosivos, por lo que hay que
    mantener una vigilancia constante y limitar el contenido de oxígeno,
    en particular en las plantas de recuperación de VC. En presencia de
    agua se forma ácido clorhídrico.

         Desde el punto de vista industrial, las reacciones de
    polimerización para obtener PVC son técnicamente las más importantes,
    aunque también lo son las reacciones de adición con otros halógenos en
    el doble enlace, por ejemplo, para obtener 1,1,2-tricloroetano o
    1,1-dicloroetano.

         La concentración de VC en el aire se puede vigilar mediante su
    retención en adsorbentes y, tras la desorción líquida o térmica, el
    análisis por cromatografía de gases. En las mediciones del aire
    ambiente, se pueden necesitar varios adsorbentes en serie o colectores
    refrigerados para aumentar la eficacia de la retención. Las
    concentraciones máximas en los lugares de trabajo se pueden medir con
    instrumentos de lectura directa, por ejemplo basados en la detección
    por FID o la PID. En la vigilancia continua se han utilizado
    analizadores de rayos infrarrojos y de cromatografía de
    gases/detección de ionización de llama combinados con el registro y
    procesamiento de datos. En el análisis del VC en líquidos y sólidos se
    utilizan la inyección directa, la extracción y cada vez más las
    técnicas del espacio libre superior y de purga y retención. En estas
    muestras también se analiza el VC mediante cromatografía de gases,
    combinada, por ejemplo, con detectores de ionización de llama o de
    espectrometría de masas.

    2.  Fuentes de exposición humana y ambiental

         No se tiene conocimiento de que el VC se produzca de forma
    natural, aunque se ha encontrado en los gases de vertedero y en el
    agua freática como producto de la degradación de hidrocarburos
    clorados depositados como residuos de disolventes en los vertederos o
    en el entorno de lugares de trabajo en los que se utilizan dichos
    disolventes. El VC también está presente en el humo de los
    cigarrillos.

         La producción industrial de VC se lleva a cabo mediante dos
    reacciones principales: a) hidrocloración del acetileno; y b)
    descomposición térmica (a unos 500°C) del 1,2-dicloroetano producido
    mediante cloración directa (etileno y cloro) o la oxicloración
    (etileno, ClH y aire/O2) de etileno en el "proceso equilibrado". En
    la actualidad se utiliza más el segundo proceso.

         La producción mundial de PVC (y por consiguiente de VC) en 1998
    fue de unos 27 millones de toneladas. El PVC representa el 20% del
    material plástico utilizado y se emplea en la mayoría de los sectores
    industriales. Alrededor del 95% de la producción mundial de VC se
    utiliza para la fabricación de PVC. El resto se destina a la
    producción de disolventes clorados, fundamentalmente de
    1,1,1-tricloroetano (10 000 toneladas/año).

         Son tres los procesos principales que se utilizan en la
    fabricación comercial de PVC: suspensión (equivalente al 80% de la
    producción mundial), emulsión (12%) y en masa o a granel (8%). La
    mayoría de los estudios monográficos en los que se describen efectos
    adversos del VC se refieren a instalaciones que utilizan el proceso de
    suspensión (llamado también de dispersión).

         Hay varios informes de liberación de VC a causa de accidentes en
    instalaciones de fabricación de PVC o durante el transporte. En
    numerosos países se ha introducido la recuperación del VC no
    convertido residual procedente de la polimerización y de otras fuentes
    del proceso, como por ejemplo los efluentes de gases residuales y de
    agua. Cuando no se toman precauciones especiales, se puede detectar VC
    en resinas y productos de PVC.

         La concentración residual de VC en el PVC está reglamentada en
    muchos países desde finales de los años setenta. Desde entonces, la
    liberación de VC a partir de la degradación térmica del PVC no es
    detectable o se produce a niveles muy bajos.

         En la producción de VC se pueden formar dioxinas como
    contaminantes. Las concentraciones de dioxinas liberadas al medio
    ambiente son un tema polémico.

    3.  Transporte, distribución y transformación en el medio ambiente

         Debido a su alta presión de vapor, cabe esperar que el VC que se
    libera a la atmósfera se mantenga casi totalmente en la fase de vapor.
    Hay indicios de deposición húmeda.

         La solubilidad del VC en agua es relativamente baja y su
    capacidad de adsorción a la materia particulada y los sedimentos
    escasa. La volatilización es el proceso más rápido de eliminación del
    VC que se incorpora al agua superficial. Se han notificado semividas
    para la volatilización del agua superficial que oscilan entre
    alrededor de una y 40 horas.

         Las semividas de volatilización a partir del suelo se calcularon
    en 0,2-0,5 días. Las pérdidas estimadas de VC (tras un año bajo una
    cubierta de suelo de 1 m) oscilaron entre el 0,1% y el 45%, en función
    del tipo de suelo. Los coeficientes de sorción en el suelo estimados a
    partir de datos fisicoquímicos indican un potencial escaso y, por
    consiguiente, una movilidad alta en el suelo. Otra vía importante de
    distribución es la lixiviación a través del suelo hacia el agua
    freática, donde el VC puede persistir durante años.

         En experimentos de laboratorio con organismos acuáticos se
    observó una cierta bioacumulación, pero no hubo bioamplificación en la
    cadena alimentaria.

         Salvo en un pequeño número de excepciones, las agrupaciones
    microbianas no adaptadas no degradan fácilmente el VC en condiciones
    normales. Se estimó que las semividas de biodegradación máxima sin
    adaptación del VC eran del orden de varios meses o años. Sin embargo,
    los cultivos enriquecidos especiales o puros (por ejemplo,
     Mycobacterium spp.) son capaces de degradar el CV en condiciones de
    cultivo óptimas. Los productos principales de degradación fueron el
    ácido glicólico o el anhídrido carbónico tras la conversión aerobia y
    etano, eteno, metano o clorometano mediante transformación anaerobia.
    Con frecuencia, la reacción de degradación del CV es más rápida por
    vía aerobia que anaerobia.

         El proceso predominante de transformación en la atmósfera es la
    reacción con radicales OH producidos por vía fotoquímica, dando lugar
    a semividas en la troposfera estimadas en 1-4 días. Durante las
    reacciones experimentales de fotolisis se generan varios compuestos
    críticos, como cloroacetaldehído, formaldehído y cloruro de formilo.

         Se considera que las relaciones fotolíticas, así como la
    hidrólisis química, tienen escasa importancia en los medios acuosos.
    Sin embargo, la presencia de fotosensibilizadores puede potenciar la
    transformación del VC.

         Hay indicios de que el VC reacciona con el cloro o el cloruro
    utilizado en la desinfección del agua, produciendo de esta manera
    cloroacetaldehído y otros compuestos no deseados. Otra posibilidad de
    interacción es con las sales, muchas de las cuales tienen la capacidad
    de formar complejos con el VC, aumentando tal vez su solubilidad.

         Los métodos utilizados (con diferente éxito) para la eliminación
    del VC de las aguas contaminadas son la separación, la extracción, la
    adsorción y la oxidación. Algunas técnicas de biocorrección  in situ
    (para el agua freática o el suelo) combinan la evaporación y otros
    métodos con el tratamiento microbiano. El VC de los gases de desecho
    se puede reciclar, incinerar o degradar por medios microbiológicos. La
    mayor parte del CV de producción industrial se encuentra en los
    artículos de PVC. Con su incineración se corre el riesgo de que se
    formen dibenzodioxinas policloradas/dibenzofuranos policlorados y
    otros compuestos orgánicos clorados perjudiciales.

    4.  Niveles medioambientales y exposición humana

         La exposición de la población general al VC es muy pequeña.

         Las concentraciones atmosféricas de VC en el aire ambiente son
    bajas, normalmente inferiores a 3 µg/m3. La exposición de la
    población general puede ser mayor en situaciones en las cuales se haya
    producido una liberación accidental de grandes cantidades de VC a la
    atmósfera, por ejemplo por un escape durante el transporte. Sin
    embargo, esta exposición probablemente es transitoria. Cerca de zonas
    industriales y de eliminación de desechos de VC/PVC se han registrado
    concentraciones mucho más altas (hasta 8000 µg/m3 y 100 µg/m3,
    respectivamente).

         Las concentraciones en el aire de los espacios cerrados en casas
    adyacentes a vertederos alcanzaron concentraciones máximas de
    1000 µg/m3.

         La vía más importante de exposición ocupacional es la inhalación
    y se produce fundamentalmente en instalaciones de VC/PVC. La
    exposición ocupacional al VC ascendió a varios miles de mg/m3 en los
    años cuarenta y cincuenta y fue de varios cientos de mg/m3 en los
    sesenta y comienzo de los setenta. Tras el reconocimiento del peligro
    carcinogénico del VC, en los años setenta se establecieron en la
    mayoría de los países normas de exposición ocupacional de alrededor de
    13-26 mg/m3 (5-10 ppm). El cumplimiento de estas directrices ha
    reducido considerablemente las concentraciones de VC en los lugares de
    trabajo, pero incluso en los años noventa se han notificado
    concentraciones más altas, que se pueden encontrar todavía en algunos
    países.

         Ocasionalmente se ha detectado VC en aguas superficiales,
    sedimento y fangos cloacales, con máximos de 570 µg/litro, 580 µg/kg y
    62 000 µg/litro, respectivamente. Las muestras de suelo recogidas
    cerca de una tienda de productos químicos de limpieza abandonada
    contenían concentraciones muy elevadas de VC (hasta 900 mg/kg). Las
    concentraciones máximas de VC en el agua freática o lixiviada de zonas
    contaminadas por hidrocarburos clorados ascendieron a 60 000 µg/litro
    (o más). Se detectaron concentraciones altas (hasta 200 mg/litro) en
    el agua de un pozo cercano a una instalación de PVC 10 años después de
    las filtraciones.

         Los escasos datos disponibles ponen de manifiesto que el VC puede
    estar presente en los tejidos de pequeños invertebrados acuáticos y de
    peces.

         En la mayoría de las muestras de agua de bebida analizadas, no
    había VC presente en concentraciones detectables. La concentración
    máxima de VC notificada en agua de bebida tratada fue de 10 µg/litro.
    No se dispone de datos recientes sobre las concentraciones de VC en el
    agua de bebida, pero cabe prever que sean inferiores a 10 µg/litro. Si
    se utiliza agua contaminada como fuente de agua de bebida, se podrían
    producir exposiciones más elevadas. En algunos estudios recientes se
    ha identificado VC en agua de bebida embotellada en envases de PVC en
    concentraciones inferiores a 1 µg/litro. Probablemente sea más
    frecuente la presencia de VC en este tipo de agua que en la de grifo.

         El envasado con ciertos materiales de PVC puede producir la
    contaminación por CV de productos alimenticios, farmacéuticos o
    cosméticos, incluso licores (hasta 20 mg/kg), aceites vegetales (hasta
    18 mg/kg), vinagres (hasta 9,8 mg/kg) y colutorios (hasta 7,9 mg/kg).
    Gracias a las medidas legislativas adoptadas por numerosos países,
    desde comienzos de los años setenta se ha logrado una reducción
    significativa de las concentraciones de VC y/o en el número de
    muestras positivas.

         Varios organismos han calculado la exposición al VC a través de
    los envases de PVC utilizados para productos alimenticios y, teniendo
    cuenta el promedio de ingesta estimado en el Reino Unido y en los
    Estados Unidos, se calculó una exposición < 0,0004 µg/kg para finales
    de los años setenta y comienzos de los ochenta. En un estudio inicial
    se identificó VC en el humo del tabaco en concentraciones del orden de
    ng/cigarrillo.

    5.  Cinética y metabolismo en animales de laboratorio y en el ser
        humano

         Tras las exposición por inhalación o por vía oral, el VC se
    absorbe con rapidez y facilidad. La vía primaria de exposición al VC
    es la inhalación. En estudios realizados con animales y con personas
    en condiciones estables, después de la exposición por inhalación se
    absorbe aproximadamente el 40% del VC inspirado. En estudios de
    exposición oral con animales se observó una absorción de más del 95%.
    La absorción cutánea al VC en estado gaseoso no es significativa.

         Los datos obtenidos en estudios de administración oral y por
    inhalación en ratas indican una distribución rápida y generalizada del
    VC. La rapidez del metabolismo y la excreción limita la acumulación de
    VC en el organismo. En las ratas se produce un desplazamiento rápido
    del VC a través de la placenta. No se ha informado de estudios sobre
    distribución tras la exposición cutánea.

         La principal ruta de metabolismo del CV después de la inhalación
    o la ingestión oral consiste en la oxidación por el citocromo P-450
    (CYP2E1) para formar óxido de cloroetileno (CEO), epóxido muy reactivo
    de vida breve que reacciona de nuevo rápidamente para formar
    cloroacetaldehído (CAA). La reacción primaria de desintoxicación de
    estos dos metabolitos reactivos, así como del ácido cloroacético,
    producto de la deshidrogenación del CAA, es la conjugación con el
    glutatión en una reacción catalizada por la glutatión- S-transferasa.
    Los productos de la conjugación sufren ulteriores modificaciones para
    formar derivados de la cisteína con sustituciones
     (S-(2-hidroxietil)-cisteína,  N-acetil- S-(2-hidroxietil)
    cisteína,  S-carboximetil cisteína y ácido tiodiglicólico) y se
    excretan en la orina. Otro metabolito, el anhídrido carbónico, se
    exhala en el aire.

         Se sabe que el CYP2E1 y las isoenzimas de la
    glutatión-S-transferasa tienen variaciones individuales importantes de
    actividad interespecíficas e intraespecíficas.

         Tras la exposición por inhalación o por vía oral a dosis bajas,
    el CV se elimina metabólicamente y los metabolitos no volátiles se
    excretan fundamentalmente en la orina. En investigaciones comparativas
    de la absorción de VC por inhalación se puso de manifiesto una
    velocidad de eliminación metabólica en el ser humano menor que en los
    animales de laboratorio, en función del peso corporal. Sin embargo,
    una vez corregida con arreglo a la superficie corporal, la eliminación
    metabólica del VC en el ser humano es comparable a la observada en
    otras especies de mamíferos. Al aumentar la exposición oral o por
    inhalación, la vía más importante de excreción en los animales es la
    exhalación de VC inalterado, lo cual indica que hay una saturación de
    las rutas metabólicas. Con independencia de la dosis aplicada, la
    excreción de metabolitos por las heces es sólo una vía secundaria. No
    se encontraron estudios en los que se investigase específicamente la
    excreción por la bilis.

         Se considera que el CEO es el metabolito más importante  in vivo
    con respecto a los efectos mutagénicos y carcinogénicos del VC. El
    CEO reacciona con el ADN para producir el aducto principal
    7-(2'-oxoetil)guanina (7-OEG) y, a niveles más bajos, los aductos
    exocíclicos de eteno, 1, N 6-etenoadenina (Epsilon A),
    3, N4-etenocitosina (Epsilon C) y  N 2,3-etenoguanina (Epsilon G).
    Los aductos de eteno del ADN tienen propiedades promutagénicas, a
    diferencia del aducto principal 7-OEG. Se han medido las
    concentraciones de 7-OEG, Epsilon A, Epsilon C y Epsilon G en diversos

    tejidos de roedores expuestos al VC. Se han creado modelos
    toxicocinéticos con una base fisiológica para describir la relación
    entre la concentración en el tejido destinatario y los efectos finales
    tóxicos del VC.

    6.  Efectos en mamíferos de laboratorio y en sistemas de prueba
        in vitro

         La toxicidad aguda del VC administrado por inhalación a diversas
    especies parece ser baja. Se notificaron CL50 a las 2 horas para
    ratas, ratones, cobayas y conejos de 390 000, 293 000, 595 000 y
    295 000 mg/m3, respectivamente. No hay datos disponibles sobre la
    toxicidad aguda tras la administración oral o la aplicación cutánea.
    El VC tiene un efecto estupefaciente después de la administración
    aguda por inhalación. En ratas, ratones y hámsteres, la muerte estuvo
    precedida por un aumento de la actividad motora, ataxia y
    convulsiones, y a continuación colapso respiratorio. En perros se
    produjo una arritmia cardíaca grave en estado de narcosis tras la
    exposición por inhalación a 260 000 mg/m3. Después de la exposición
    aguda de ratas al VC por inhalación se observaron diversos efectos
    patológicos, entre ellos congestión de los órganos internos, sobre
    todo los pulmones, el hígado y los riñones, así como edema pulmonar.

         No hay estudios o datos importantes disponibles para la
    evaluación de los efectos de la exposición cutánea, la irritación de
    la piel o la propiedad de sensibilización del VC.

         De la exposición oral de ratas al VC durante un período breve de
    13 semanas se obtuvo una concentración sin efectos observados (NOEL),
    basada en el aumento de peso del hígado, de 30 mg/kg.

         En diversas especies, el principal órgano destinatario en la
    exposición breve (hasta 6 meses) al VC por inhalación fue el hígado.
    Con una concentración de 26 mg/m3 (la dosis más baja utilizada) se
    observaron en ratas un aumento del peso relativo del hígado y cambios
    hepatocelulares; a concentraciones superiores (> 260 mg/m3) se
    produjeron también cambios hepáticos más acentuados dependientes de la
    dosis. Otros órganos destinatarios fueron los riñones, los pulmones y
    los testículos. Las ratas, los ratones y los conejos parecen ser más
    sensibles que los cobayas y los perros.

         La exposición prolongada al VC por inhalación produjo un aumento
    estadísticamente significativo de la mortalidad en algunas estirpes de
    ratas con concentraciones de sólo 260 mg/m3, en ratones con 130
    mg/m3 y en hámsteres con 520 mg/m3 para diversos períodos de
    exposición. Las ratas expuestas a 130 mg/m3 mostraron una reducción
    del peso corporal y un aumento del peso relativo del bazo,
    degeneración hepatocelular y proliferación de las células de
    revestimiento de los sinusoides del hígado. La exposición de ratas a
    concentraciones más elevadas produjo una alteración degenerativa de

    los testículos, nefrosis tubular y degeneración focal del miocardio.
    En ratas y ratones expuestos por inhalación, la concentración sin
    efectos adversos observados (NOAEL) para los efectos no neoplásicos es
    inferior a 130 mg/m3.

         En estudios de alimentación crónica se puso de manifiesto un
    aumento de la mortalidad, un peso mayor del hígado y una alteración
    morfológica del hígado.

         Tras la exposición oral de ratas a concentraciones de sólo
    1,3 mg/kg de peso corporal se pudo observar polimorfismo de las
    células hepáticas (variación del tamaño y la forma de los hepatocitos
    y sus núcleos). La NOAEL fue de 0,13 mg/kg de peso corporal.

         En estudios prolongados de alimentación realizados en ratas con
    gránulos de VC y PVC se produjo un aumento significativo de la
    incidencia del angiosarcoma hepático (ASH) con 5,0 mg/kg de peso
    corporal al día y nódulos neoplásicos en el hígado (hembras) y
    carcinoma hepatocelular (CHC) (machos) con 1,3 mg/kg de peso corporal
    al día.

         En estudios de inhalación de VC en ratas Sprague-Dawley se
    observó una relación dosis-respuesta en el caso del ASH y, a
    concentraciones más altas, carcinoma de las glándulas de Zymbal. No se
    observó una dependencia clara de la dosis para el hepatoma o el
    angiosarcoma extrahepático, los nefroblastomas, los neuroblastomas o
    los tumores mamarios malignos. En ratones, el espectro de tumores
    inducidos por la exposición prolongada mediante inhalación es
    semejante al observado en ratas, pero se detectó sólo en ratones un
    aumento de los tumores pulmonares. En hámsteres se notificó un aumento
    de la incidencia de tumores de ASH, tumores de las glándulas mamarias
    y el conducto acústico, melanomas, tumores de estómago y del epitelio
    cutáneo.

         Se han detectado efectos mutagénicos y genotóxicos del VC en
    varios sistemas de prueba  in vitro, fundamentalmente después de la
    activación metabólica. El VC tiene un efecto mutagénico en la prueba
    de Ames con las cepas TA100, TA1530 y TA1535 de  S. typhimurium, pero
    no con las cepas TA98, TA1537 y TA1538, lo cual indica que las
    mutaciones son el resultado de la sustitución de pares de bases
    (transversión y transición) más que de mutaciones por desfase. Esto
    está en consonancia con el resultado de que los aductos de eteno del
    ADN formados por los metabolitos reactivos CEO y CAA se convierten en
    mutaciones reales mediante las sustituciones de pares de bases.

         Otras valoraciones de mutaciones genéticas en bacterias,
    levaduras y células de mamíferos han puesto de manifiesto resultados
    positivos exclusivamente en presencia de una activación metabólica. Se
    notificaron asimismo efectos mutagénicos en una línea de células
    humanas con citocromo P-450IIE1 clonado, que es capaz de metabolizar
    el VC. También se detectó una mutación genética en esquejes de plantas
     (Tradescantia) expuestos al VC. En las valoraciones de la conversión

    genética, se notificaron resultados positivos con  Saccharomyces
     cerevisiae en presencia de un sistema de activación metabólica. La
    exposición al VC indujo síntesis no programada de ADN en hepatocitos
    de rata y un aumento del intercambio de crómatidas hermanas en
    linfocitos humanos tras la adición del sistema de activación exógeno.
    No se detectó inhibición del crecimiento en bacterias deficientes en
    enzimas de reparación del ADN sin activación metabólica. En
    valoraciones de la transformación celular se obtuvieron resultados
    positivos con activación metabólica y sin ella.

         La exposición al VC indujo mutaciones genéticas y recombinación
    mitótica en  Drosophila melanogaster, pero no produjo ninguna
    mutación genética en células germinales de mamíferos. El VC mostró
    efectos clastogénicos en roedores, aumentó el intercambio de
    cromátidas hermanas de hámster e indujo el fraccionamiento del ADN en
    ratones. En valoraciones mediadas por huéspedes (ratas), el VC indujo
    una conversión genética y mutaciones adaptativas en levaduras.

         Se observó un efecto mutagénico del CEO y el CAA en diferentes
    sistemas de prueba. El CEO es un mutágeno potente, mientras que el CAA
    es muy tóxico. Ambos mostraron efectos carcinogénicos en ratones,
    siendo el CEO mucho más activo que el CAA.

         Se analizaron las mutaciones de los genes  ras y  p53 en
    tumores de hígado inducidos por el VC en ratas Sprague-Dawley: se
    encontraron sustiticiones de pares de bases en el gen Ha- ras en el
    carcinoma hepatocelular y en el gen  p-53 en el ASH. Estas mutaciones
    coinciden con la formación observada y la persistencia de aductos de
    eteno en el ADN del hígado, tras la exposición de ratas a VC, y con
    las propiedades promutagénicas conocidas de los aductos de eteno.

         Los estudios sobre los mecanismos de la carcinogenicidad del VC
    parecen indicar que el epóxido intermedio reactivo CEO tiene una
    interacción con el ADN para formar aductos de eteno, que dan lugar a
    una sustitución de pares de bases que lleva a una transformación
    neoplásica.

    7.  Efectos en el ser humano

         Se ha notificado que concentraciones de VC del orden de
    2590 mg/m3 (1000 ppm), que no eran raras antes de 1974, durante
    periodos comprendidos entre un mes y varios años provocaban un
    síndrome patológico específico observado en los trabajadores del VC,
    llamado "enfermedad del cloruro de vinilo". Los síntomas descritos
    fueron dolor de oídos y de cabeza, vértigo, visión borrosa, cansancio
    y falta de apetito, náuseas, insomnio, dificultad respiratoria, dolor
    de estómago, dolor en la zona del hígado/bazo, dolor y sensación de
    hormigueo en los brazos y las piernas, sensación de frío en las
    extremidades, pérdida de la libido y disminución del peso. Entre los
    resultados clínicos figuraron cambios en los dedos del tipo del
    escleroderma, con modificaciones óseas posteriores en la punta de los

    dedos descritas como acroosteólisis, cambios en la circulación
    periférica idénticos a los clásicos de la enfermedad de Raynaud y
    agrandamiento del hígado y del bazo con una aspecto histológico
    específico, así como manifestaciones respiratorias.

         Los estudios en seres humanos no han sido adecuados para
    confirmar los efectos en el sistema reproductor. En un pequeño número
    de estudios de morbilidad se ha notificado una elevada incidencia de
    enfermedades circulatorias entre los trabajadores relacionados con el
    cloruro de vinilo. Sin embargo, en estudios de cohortes amplios se ha
    observado una mortalidad más baja que la debida a enfermedades
    cardiovasculares.

         Hay pruebas manifiestas y convincentes obtenidas de estudios
    epidemiológicos de que la exposición al VC produce un tumor raro, el
    angiosarcoma hepático. También pueden asociarse con el VC casos de
    tumores cerebrales y carcinoma hepatocelular, aunque las pruebas no
    pueden considerarse definitivas. Otros puntos notificados como de una
    mayor incidencia de cáncer, pero de manera menos convincente, son el
    pulmón, los tejidos linfático y hematopoyético y la piel.

         El VC es mutagénico y clastogénico en el ser humano. Se ha
    observado un aumento de la frecuencia de aberraciones cromosómicas,
    micronúcleos e intercambio de cromátidas hermanas en los linfocitos de
    la sangre periférica de los trabajadores expuestos a concentraciones
    elevadas de VC en comparación con los testigos. Aunque en muchos
    estudios solamente se estimaron las concentraciones y la duración de
    la exposición, se puede observar una relación dosis-respuesta y la
    "normalización" de los efectos genotóxicos con el paso del tiempo
    después de la reducción de la exposición.

         Se han detectado mutaciones puntuales en los genes  p 53 y  ras
    en tumores de personas que trabajaban con autoclaves y que estaban
    muy expuestas (antes de 1974) afectadas de angiosarcoma hepático y en
    otro trabajador relacionado con el CV con carcinoma hepatocelular.

         Los marcadores biológicos investigados como indicadores de la
    exposición al VC o de los efectos inducidos por el VC son los
    siguientes: a) excreción de metabolitos del VC (por ejemplo, ácido
    tiodiglicólico), b) valoraciones genéticas (por ejemplo, anomalías
    cromosómicas o valoración de micronúcleos), c) concentraciones de
    enzimas (por ejemplo, en pruebas de la función hepática), d)
    oncoproteínas séricas (p21 y p53) y/o sus anticuerpos como
    biomarcadores de los efectos inducidos por el VC.

         Los niños que viven en lugares cercanos a vertederos y otras
    fuentes puntuales pueden correr un riesgo mayor, tomando como base las
    pruebas que parecen derivarse de la sensibilidad en las primeras fases
    de la vida en estudios realizados con animales. Sin embargo, no hay
    pruebas directas en el ser humano.

         En los estudios epidemiológicos solamente hay una relación
    dosis-respuesta clara para el angiocarcinoma hepático solo o en
    combinación con otros tumores del hígado. Sólo en un estudio
    epidemiológico hay datos suficientes para una estimación cuantitativa
    de la relación dosis-respuesta.

    8.  Efectos en otros organismos en el laboratorio y en el medio
        ambiente

         Se carece de datos normalizados de toxicidad relativos a la
    supervivencia y la reproducción de los organismos acuáticos expuestos
    al VC. Hay que interpretar con cautela los datos disponibles, porque
    la mayoría de ellos se obtuvieron en pruebas en las cuales no se midió
    la concentración de la exposición, por lo que no se tuvieron en cuenta
    las pérdidas debidas a la volatilización.

         La concentración más baja de VC que produjo un efecto en los
    microorganismos fue de 40 mg/litro. Fue un valor de la CE50 basado en
    la inhibición de la respiración de microorganismos anaerobios en la
    valoración de un lote durante 3,5 días.

         La concentración más baja que produjo un efecto en organismos
    superiores fue de 210 mg/litro (CL50 a las 48 horas para un pez de
    agua dulce), con una concentración sin efectos adversos observados
    (NOAEC) correspondiente de 128 mg/litro. Se han notificado efectos en
    otras especies debidos a concentraciones más bajas de VC, pero no se
    comprobó la importancia ecológica de dichos efectos.

         Las concentraciones de VC estimadas como no peligrosas para los
    peces de agua dulce se calculó que oscilaban entre 0,088 y 29
    mg/litro.

         Hay pocos datos sobre los efectos del VC en los organismos
    terrestres.
    
    


    See Also:
       Toxicological Abbreviations
       Vinyl Chloride (HSG 109, 1999)
       Vinyl chloride (ICSC)
       Vinyl chloride (WHO Food Additives Series 19)
       VINYL CHLORIDE (JECFA Evaluation)
       Vinyl chloride (PIM 558)
       Vinyl chloride (SIDS)
       Vinyl Chloride  (IARC Summary & Evaluation, Supplement7, 1987)
       Vinyl Chloride (IARC Summary & Evaluation, Volume 7, 1974)