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    UNITED NATIONS ENVIRONMENT PROGRAMME
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    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 195 





    Hexachlorobenzene








    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.


    Environmental Health Criteria  195





    First draft prepared by Mr R. Newhook and Ms W. Dormer,
    Health Criteria, Canada



    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, 1997

         The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
    Labour Organisation, and the World Health Organization. The main
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    the effects of chemicals on human health and the quality of the
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    with chemical accidents, coordination of laboratory testing and
    epidemiological studies, and promotion of research on the mechanisms
    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Hexachlorobenzene.

    (Environmental health criteria ; 195)

    1. Hexachlorobenzene - toxicity  2.Hexachlorobenzene - adverse effects
    3. Environmental exposure        I. Series

    ISBN 92 4 157195 0                 (NLM Classification: QV 633)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR HEXACHLOROBENZENE

    PREAMBLE

    ABBREVIATIONS

    PREFACE

    1. SUMMARY AND CONCLUSIONS

         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 animals and  in vitro tests
         1.7. Effects on humans
         1.8. Effects on other organisms in the
                laboratory and field
         1.9. Evaluation of human health risks and
                effects on the environment
                1.9.1. Health effects
                1.9.2. Environmental effects
         1.10. Conclusions

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

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Sources, uses and production processes
         3.2. World production levels
         3.3. Entry into the environment

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Environmental transport and degradation
         4.2. Bioaccumulation and biomagnification

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
                5.1.1. Air
                5.1.2. Water
                5.1.3. Soil
                5.1.4. Sediment
                5.1.5. Biota
                5.1.6. Food and drinking-water
         5.2. General population exposure
                5.2.1. Human tissues and fluids
                5.2.2. Intake from ambient air
                5.2.3. Intake from drinking-water
                5.2.4. Intake from foods
                5.2.5. Apportionment of intakes
                5.2.6. Trends in exposure of the general
                        population over time
                5.2.7. Occupational exposure during
                        manufacture, formulation or use

    6. KINETICS AND METABOLISM

         6.1. Aquatic and terrestrial biota
         6.2. Mammals

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
         7.2. Short-term and subchronic exposure
         7.3. Long-term toxicity and carcinogenicity
         7.4. Mutagenicity and related end-points
         7.5. Reproductive and developmental toxicity
         7.6. Immunotoxicity

    8. EFFECTS ON HUMANS

         8.1. General population exposure
         8.2. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Short-term exposure
                9.1.1. Aquatic biota
                9.1.2. Terrestrial biota
         9.2. Long-term exposure
                9.2.1. Aquatic biota
                9.2.2. Terrestrial biota

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

         10.1. Evaluation of human health risks
                10.1.1. Exposure
                10.1.2. Health effects
                10.1.3. Approaches to risk assessment
                        10.1.3.1  Non-neoplastic effects
                        10.1.3.2  Neoplastic effects
         10.2. Evaluation of effects on the environment

    11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH AND
         THE ENVIRONMENT

    12. FURTHER RESEARCH
         12.1. Environment
         12.2. Human health

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RÉSUMÉ ET CONCLUSIONS

    RÉSUMEN Y CONCLUSIONES
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
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                                     * * *

         A detailed data profile and a legal file can be obtained from the
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                                     * * *

         This publication was made possible by grant number 5 U01 ES02617-
    15 from the National Institute of Environmental Health Sciences,
    National Institutes of Health, USA, and by financial support from the
    European Commission and the Federal Ministry for the Environment,
    Nature Conservation and Nuclear Safety, Germany.

    Environmental Health Criteria

    PREAMBLE

    Objectives

         In 1973 the WHO Environmental Health Criteria Programme was
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         The first Environmental Health Criteria (EHC) monograph, on
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         The original impetus for the Programme came from World Health
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    Content

         The layout of EHC monographs for chemicals is outlined below.

    *    Summary - a review of the salient facts and the risk evaluation
         of the chemical
    *    Identity - physical and chemical properties, analytical methods
    *    Sources of exposure
    *    Environmental transport, distribution and transformation
    *    Environmental levels and human exposure
    *    Kinetics and metabolism in laboratory animals and humans
    *    Effects on laboratory mammals and  in vitro test systems
    *    Effects on humans
    *    Effects on other organisms in the laboratory and field
    *    Evaluation of human health risks and effects on the environment
    *    Conclusions and recommendations for protection of human health
         and the environment

    *    Further research
    *    Previous evaluations by international bodies, e.g., IARC, JECFA,
         JMPR

    Selection of chemicals

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    FIGURE 1

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR HEXACHLOROBENZENE

     Members

    Dr D. Arnold, Health Canada, Tunney's Pasture, Ottawa, Ontario Canada

    Dr A. Göcmen, Department of Pediatrics, Faculty of Medicine,
         Hacettepe University, Hacettepe, Ankara, Turkey

    Professor B. Jansson, Institute of Applied Environmental Research,
         ITM-Solna, Stockholm University, Stockholm, Sweden

    Dr J. Jarrell, Foothills Hospital, Calgary Regional Health
         Authority, Calgary, Alberta, Canada

    Dr A. Langley, South Australian Health Commission, Rundle Mall,
         Australia ( Chairman)

    Mr R. Newhook, Bureau of Chemical Hazards, Environmental
         Substances Division, Health Canada, Tunney's Pasture, Ottawa,
         Ontario, Canada ( Rapporteur)

    Dr D. Peakall, Wimbledon, London, United Kingdom
         ( Vice-chairman)

    Dr A.G. Smith, Medical Research Council Toxicology Unit,
         Hodgkin Building, University of Leicester, Leicester,
         United Kingdom

    Dr J. Sunyer, Department of Epidemiology and Public Health,
         Institut Municipal d'Investigacio Medica, Barcelona, Spain

    Dr A. van Birgelen, National Health and Environmental Effects
         Research Laboratory, Pharmacokinetics Branch, US Environmental
         Protection Agency, Research Triangle Park, North Carolina, USAa

    Dr J. Vos, National Institute of Public Health and the Environment
         (RIVM), Hygiene, Bilthoven, The Netherlands

              

    a    Dr A. Van Birgelen's present address: National Institute of
         Environmental Health Sciences, Research Triangle Park, North
         Carolina, USA

     Observers

    Dr J. de Gerlache, Solvay SA, Department of Chemical Safety and
         Toxicology, Brussels, Belgium (Representing EURO CHLOR)

    Dr Roger Drew, Toxicology Information Section, Safety, Health &
         Environment Division, ICI Australia Operations Pty Ltd., ICI
         House, Melbourne, Victoria, Australia (Representing European
         Centre for Ecotoxicology and Toxicology of Chemicals)

     Secretariat

    Dr G.C. Becking, Interregional Research Unit, International
         Programme on Chemical Safety, Research Triangle Park, North
         Carolina USA ( Secretary)

    Ms W. Dormer, Bureau of Chemical Hazards, Environmental
         Substances Division, Health Canada, Tunney's Pasture, Ottawa,
         Ontario, Canada ( Temporary Adviser to Secretariat)

    Dr J. Wilbourn, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

    IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR HEXACHLOROBENZENE

         A WHO Task Group on Environmental Health Criteria for
    Hexachlorobenzene met in Geneva from 26 February to 1 March 1996.
    Dr G.C. Becking, IPCS, welcomed the participants on behalf of Dr M.
    Mercier, Director of the IPCS, and the three cooperating organizations
    (UNEP/ILO/WHO).  The group reviewed and revised the draft and made an
    evaluation of the risks for human health and the environment from
    exposure to hexachlorobenzene.

         The first draft was prepared by Mr R. Newhook and Ms W. Dormer,
    Health Canada, Ottawa, Canada.  These authors also prepared the draft
    reviewed by the Task Group, which incorporated the comments received
    following circulation of the first draft to IPCS Contact Points for
    Environmental Health Criteria monographs.

         The IPCS gratefully acknowledges the financial and other support
    of the Health Protection Branch, Health Canada.  This support was
    indispensable for the completion of this monograph.

         Dr G.C. Becking (IPCS, Central Unit, Inter-regional Research
    Unit) and Dr P.G. Jenkins (IPCS, Central Unit, Geneva) were
    responsible for the overall scientific content and the technical
    editing, respectively, of this monograph.

         The efforts of all who helped in the preparation and finalization
    of this publication are gratefully acknowledged.

    ABBREVIATIONS

    BCF            bioconcentration factor
    BMF            biomagnification factor
    DL             detection limit
    HCB            hexachlorobenzene
    i.p.           intraperitoneal
    ND             not detectable
    PCT            porphyria cutanea tarda
    p,p'DDE        1,1'-(2,2-dichloroethylidene)-bis[4-chlorobenzene]
    SER            smooth endoplasmic reticulum
    T3             triiodothyronine
    T4             thyroxine

    PREFACE

         The preparation of comprehensive Environmental Health Criteria
    (EHC), as outlined in the Preamble of this monograph, is an extremely
    time-consuming and resource-intensive procedure.  Often countries have
    prepared recent comprehensive reviews on chemicals as required by
    their national legislation, and the International Programme on
    Chemical Safety (IPCS) has been asked by Member States to determine
    how best to utilize such national reviews during the preparation of
    international EHC.  Utilizing such national documents should avoid
    duplication of effort and result in the more rapid production of more
    concise IPCS EHC monographs.

         This monograph on hexachlorobenzene has been prepared using as
    background document the review (Supporting Document) prepared under
    the Canadian Environmental Protection Act (CEPA), dated June 1993. 
    From this document, staff of Health Canada have chosen only the most
    relevant studies for assessing the human and environmental risks from
    exposure to hexachlorobenzene.  These have been described from the
    original references and supplemented by additional information
    published more recently.  This has resulted in a concise monograph,
    yet one that supplies sufficient information for the reader to
    understand the basis for the conclusions reached by the Task Group.

         Readers who wish to consult the text of the Canadian Supporting
    Document can obtain a copy from the Director, IPCS, World Health
    Organization, Geneva, Switzerland.

    1.  SUMMARY AND CONCLUSIONS

    1.1  Identity, physical and chemical properties, and
         analytical methods

         Hexachlorobenzene (HCB) is a chlorinated organic compound with
    moderate volatility. It is practically insoluble in water, but is
    highly lipid-soluble and bioaccumulative. Technical grade HCB contains
    up to 2% impurities, most of which is pentachlorobenzene. The
    remainder includes the higher chlorinated dibenzo- p-dioxins,
    dibenzofurans and biphenyls. Analysis of HCB in environmental media
    and biological materials generally involves extraction of the sample
    into organic solvents, often followed by a clean-up step, to produce
    organic extracts for gas chromatography/mass spectrometry (GC/MS) or
    gas chromatography with electron capture detection (GC/ECD).

    1.2  Sources of human and environmental exposure

         HCB was at one time used extensively as a seed dressing to
    prevent fungal disease on grains, but this use was discontinued in
    most countries in the 1970s. HCB continues to be released to the
    environment from a number of sources, including the use of some
    chlorinated pesticides, incomplete combustion, old dump sites and
    inappropriate manufacture and disposal of wastes from the manufacture
    of chlorinated solvents, chlorinated aromatics and chlorinated
    pesticides.

    1.3  Environmental transport, distribution and transformation

         HCB is distributed throughout the environment because it is
    mobile and persistent, although slow photodegradation in air and
    microbial degradation in soil do occur. In the troposphere, HCB is
    transported long distances and removed from the air phase through
    deposition to soil and water. Significant biomagnification of HCB
    through the food chain has been reported.

    1.4 Environmental levels and human exposure

         Low concentrations of HCB are present in ambient air (a few
    ng/m3 or less) and in drinking-water and surface water (a few
    ng/litre or less) in areas that are distant from point sources around
    the world. However, higher levels have been measured near point
    sources. HCB is bioaccumulative and has been detected in
    invertebrates, fish, reptiles, birds and mammals (including humans)
    distant from point sources, particularly in fatty tissues of organisms
    at higher trophic levels. Mean levels in adipose tissue of the human
    general population in various countries range from tens to hundreds of
    ng/g wet weight. Based on representative levels of HCB in air, water
    and food, the total intake of HCB by adults in the general population
    is estimated to be between 0.0004 and 0.003 µg/kg body weight per day.
    This intake is predominantly from the diet. Owing to the presence of
    HCB in breast milk, mean intakes by nursing infants have been

    estimated to range from < 0.018 to 5.1 µg/kg body weight per day in
    various countries. The results of most studies on the levels of HCB in
    foods and human tissues over time indicate that exposure of the
    general population to HCB declined from the 1970s to the mid-1990s in
    many locations. However, this trend has not been evident during the
    last decade in some other locations.

    1.5  Kinetics and metabolism in laboratory animals and humans
         There is a lack of toxicokinetic information for humans. HCB is
    readily absorbed by the oral route in experimental animals and poorly
    via the skin (there are no data concerning inhalation). In animals and
    humans, HCB accumulates in lipid-rich tissues, such as adipose tissue,
    adrenal cortex, bone marrow, skin and some endocrine tissues, and can
    be transferred to offspring both across the placenta and via mothers'
    milk. HCB undergoes limited metabolism, yielding pentachlorophenol,
    tetrachlorohydroquinone and pentachlorothiophenol as the major
    metabolites in urine. Elimination half-lives for HCB range from
    approximately one month in rats and rabbits to 2 or 3 years in
    monkeys.

    1.6 Effects on laboratory animals and in vitro tests

         The acute toxicity of HCB to experimental animals is low (1000 to
    10 000 mg/kg body weight). In animal studies, HCB is not a skin or eye
    irritant and does not sensitize the guinea-pig.

         The available data on the systemic toxicity of HCB indicate that
    the pathway for the biosynthesis of haem is a major target of
    hexachlorobenzene toxicity. Elevated levels of porphyrins and/or
    porphyrin precursors have been found in the liver, other tissues and
    excreta of several species of laboratory mammals exposed to HCB.
    Porphyria has been reported in a number of studies in rats with
    subchronic or chronic oral exposure to between 2.5 and 15 mg HCB/kg
    body weight per day. Excretion of coproporphyrins was increased in
    pigs ingesting 0.5 mg HCB/kg body weight per day or more (no effects
    were observed at 0.05 mg HCB/kg body weight per day in the latter
    study). Repeated exposure to HCB has also been shown to affect a wide
    range of organ systems (including the liver, lungs, kidneys, thyroid,
    skin, and nervous and immune systems), although these have been
    reported less frequently than porphyria.

         HCB is a mixed-type cytochrome-P-450-inducing compound, with
    phenobarbital-inducible and 3-methylcholanthrene-inducible properties.
    It is known to bind to the Ah receptor.

         In chronic studies, mild effects on the liver (histopathological
    changes, enzyme induction) occurred in several studies of rats exposed
    to between 0.25 and 0.6 mg HCB/kg body weight per day; the NOELs in
    these studies were 0.05 to 0.07 mg HCB/kg body weight per day.
    Concentrations of neurotransmitters in the hypothalamus were altered
    in mink dams with chronic dietary exposure to 0.16 mg HCB/kg body
    weight per day, and in their offspring exposed throughout gestation

    and nursing. Calcium homoeostasis and bone morphometry were affected
    in subchronic studies on rats at 0.7 mg HCB/kg body weight per day,
    but not at 0.07 mg/kg body weight per day.

         The carcinogenicity of HCB has been assessed in several adequate
    bioassays on rodents. In hamsters fed diets yielding average doses of
    4, 8 or 16 mg/kg body weight per day for life, there were increases in
    the incidence of liver cell tumours (hepatomas) in both sexes at all
    doses, haemangioendotheliomas of the liver at 8-16 mg/kg body weight
    per day, and adenomas of the thyroid in males at the highest dose.
    Dietary exposure of mice to 6, 12 and 24 mg/kg body weight per day for
    120 weeks resulted in an increase in the incidence of liver cell
    tumours (hepatomas) in both sexes at the two higher doses (not
    significant, except for females at the highest dose).  In utero,
    lactational and oral exposure of rats to HCB in diets yielding average
    lifetime doses ranging from 0.01 to 1.5 mg/kg body weight per day
    (males) or 1.9 mg/kg body weight per day (females) for up to 130 weeks
     post utero produced increased incidences, at the highest dose, of
    neoplastic liver nodules and adrenal phaeochromocytomas in females and
    of parathyroid adenomas in males. In another long-term study on rats,
    exposure for up to 2 years to diets yielding average HCB doses of 4-5
    and 8-9 mg/kg body weight per day induced increases in the incidences
    of hepatomas and of renal cell adenomas at both doses in both sexes,
    and of hepatocellular carcinomas, bile duct adenomas/ carcinomas and
    adrenal phaeochromocytomas and adrenal cortical adenomas in females.
    High incidences of liver tumours have also been reported in some more
    limited studies in which single dietary concentrations were
    administered to small groups of female rats. In addition, it has been
    reported that, following subchronic dietary exposure to HCB, mice,
    hamsters and rats developed tumours in the liver, bile duct, kidney,
    thymus, spleen and lymph nodes. Dietary exposure to HCB promoted the
    induction of liver tumours by polychlorinated terphenyl in mice and by
    diethylnitrosamine in rats.

         Except in the case of renal tumours in male rats (which appear at
    least in part to be the result of hyaline droplet nephropathy) and
    hepatomas in rats (which may result from hyperplastic responses to
    hepatocellular necrosis), mechanistic studies that address the
    relevance to humans of the tumour types induced by HCB have not been
    identified.

         HCB has little capability to induce directly gene mutation,
    chromosomal damage and DNA repair. It exhibited weak mutagenic
    activity in a small number of the available studies on bacteria and
    yeast, although it should be noted that each of these studies has
    limitations. There is also some evidence of low-level binding to DNA
     in vitro and  in vivo, but at levels well below those expected for
    genotoxic carcinogens.

         In studies of reproduction, oral exposure of monkeys to as little
    as 0.1 mg HCB/kg body weight per day for 90 days affected the light
    microscopic structure and ultrastructure of the surface germinal

    epithelium, an unusual target for ovarian toxins. This dose also
    caused ultrastructural injury to the primordial germ cells. These
    specific target sites, which are damaged further at higher doses, were
    associated with otherwise normal follicular, oocyte and embryo
    development, suggesting specificity of HCB action within the site of
    the ovary. Male reproduction was only affected at much higher doses
    (between 30 and 221 mg/kg body weight per day) in studies on several
    non-primate species.

         Transplacental or lactational exposure of rats and cats to
    maternal doses of between 3 and 4 mg/kg body weight per day was found
    to be hepatotoxic and/or affected the survival or growth of nursing
    offspring. In some cases, these or higher doses reduced litter sizes
    and/or increased the number of stillbirths. (Adverse effects on
    suckling infants have generally been observed more frequently, and at
    lower doses, than embryotoxic or fetotoxic effects). The offspring of
    mink with chronic exposure to as little as 1 mg HCB/kg diet
    (approximately 0.16 mg/kg body weight per day) had reduced birth
    weight and increased mortality to weaning. Although skeletal and renal
    abnormalities have been observed in fetuses in some studies of rats
    and mice exposed to HCB during gestation, these were either not
    clearly related to treatment or occurred at doses that were also
    maternally toxic. In two studies, one of which included lactational
    and  postnatal exposure, neurobehavioural development of rat pups was
    affected by  in utero exposure to HCB at oral maternal doses of 0.64
    to 2.5 mg HCB/kg body weight per day.

         The results of a number of studies have indicated that HCB
    affects the immune system. Rats or monkeys exposed to between 3 and
    120 mg HCB/kg body weight per day had histopathological alterations in
    the thymus, spleen, lymph nodes and/or lymphoid tissues of the lung.
    Chronic exposure of beagle dogs to 0.12 mg/kg body weight per day
    caused nodular hyperplasia of the gastric lymphoid tissue. In a number
    of studies on rats, humoral immunity and, to a lesser extent, cell-
    mediated immunity were enhanced by several weeks exposure to HCB in
    the diet, while macrophage function was unaltered. As little as 4 mg
    HCB/kg diet (approximately 0.2 mg/kg body weight per day) during
    gestation, through nursing and to 5 weeks of age increased humoral and
    cell-mediated immune responses and caused accumulation of macrophages
    in the lung tissue of rat pups. In contrast, HCB has been found to be
    immunosuppressive in most studies with mice; doses of as little as
    0.5-0.6 mg/kg body weight per day for several weeks depressed
    resistance to infection by  Leishmania or to a challenge with tumour
    cells, decreased cytotoxic macrophage activity of the spleen, and
    reduced the delayed-type hypersensitivity response in offspring
    exposed  in utero and through nursing. In a number of studies on
    various strains of rats, short-term or subchronic exposure to HCB
    affected thyroid function, as indicated by decreased serum levels of
    total and free thyroxine (T4) and often, to a lesser extent,
    triiodothyronine (T3).

    1.7  Effects on humans

         Most data on the effects of HCB on humans originate from
    accidental poisonings that took place in Turkey in 1955-1959, in which
    more than 600 cases of porphyria cutanea tarda (PCT) were identified.
    In this incident, disturbances in porphyrin metabolism, dermatological
    lesions, hyperpigmentation, hypertrichosis, enlarged liver,
    enlargement of the thyroid gland and lymph nodes, and (in roughly half
    the cases) osteoporosis or arthritis were observed, primarily in
    children. Breast-fed infants of mothers exposed to HCB in this
    incident developed a disorder called pembe yara (pink sore), and most
    died within a year. There is also limited evidence that PCT occurs in
    humans with relatively high exposure to HCB in the workplace or in the
    general environment.

         The few available epidemiological studies of cancer are limited
    by small size, poorly characterized exposures to HCB and exposure to
    numerous other agents, and are insufficient to assess the
    carcinogenicity of HCB to humans.

    1.8  Effects on other organisms in the laboratory and field

         In studies of the acute toxicity of HCB to aquatic organisms,
    exposure to concentrations in the range of 1 to 17 µg/litre reduced
    production of chlorophyll in algae and reproduction in ciliate
    protozoa, and caused mortality in pink shrimp and grass shrimp, but
    did not cause mortality in freshwater or marine fish. In longer-term
    studies, the growth of sensitive freshwater algae and protozoa was
    affected by a concentration of 1 µg/litre, while concentrations of
    approximately 3 µg/litre caused mortality in amphipods and liver
    necrosis in large-mouth bass.

    1.9  Evaluation of human health risks and effects on the environment

    1.9.1  Health effects

         The Task Group concluded that the available data are sufficient
    to develop guidance values for non-neoplastic and neoplastic effects
    of HCB.

         For non-neoplastic effects, based on the lowest reported NOEL
    (0.05 mg HCB/kg body weight per day), for primarily hepatic effects
    observed at higher doses in studies on pigs and rats exposed by the
    oral route, and incorporating an uncertainty factor of 300 (× 10 for
    interspecies variation, × 10 for intraspecies variation, and × 3 for
    severity of effect), a TDI of 0.17 µg/kg body weight per day has been
    derived.

         The approach for neoplastic effects is based on the tumorigenic
    dose TD5 i.e., the intake associated with a 5% excess incidence of
    tumours in experimental studies in animals. Based on the results of
    the two-generation carcinogenicity bioassay in rats and using the 

    multi-stage model, the TD5 value is 0.81 mg/kg body weight per day
    for neoplastic nodules of the liver in females. Based on consideration
    of the insufficient mechanistic data, an uncertainty factor of 5000
    was used to develop a health-based guidance value of 0.16 µg/kg body
    weight per day.

    1.9.2  Environmental effects

         The Task Group pointed out that there are very few experimental
    studies on which an environmental risk assessment can be made. Levels
    of HCB in surface water are generally several orders lower than those
    expected to present a hazard to aquatic organisms, except in a few
    extremely contaminated locations. However, HCB concentrations in the
    eggs of sea birds and raptors from a number of locations from around
    the world approach those associated with reduced embryo weights in
    herring gulls (1500 µg/kg), suggesting that HCB has the potential to
    harm embryos of sensitive bird species. Similarly, levels of HCB in
    fish at a number of sites worldwide are within an order of magnitude
    of the dietary level of 1000 µg/kg associated with reduced birth
    weight and increased mortality of offspring in mink. This suggests
    that HCB has the potential to cause adverse effects in mink and
    perhaps other fish-eating mammals.

    1.10  Conclusions

    a)   HCB is a persistent chemical that bioaccumulates owing to its
         lipid solubility and resistance to breakdown.

    b)   Animal studies have shown that HCB causes cancer and affects a
         wide range of organ systems including the liver, lungs, kidneys,
         thyroid, reproductive tissues and nervous and immune systems.

    c)   Clinical toxicity, including porphyria cutanea tarda in children
         and adults, and mortality in nursing infants, has been observed
         in humans with high accidental exposure.

    d)   Various measures are warranted to reduce the environmental burden
         of HCB.

    e)   The following health-based guidance values for the total daily
         intake (TDI) of HCB in humans have been suggested: for non-cancer
         effects, 0.17 µg/kg body weight/day; for neoplastic effects,
         0.16 µg/kg body weight/day.

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

    2.1  Identity

         Hexachlorobenzene (HCB) is a chlorinated aromatic hydrocarbon
    with the chemical formula C6Cl6. Its CAS registry number is 118-74-1.

    CHEMICAL STRUCTURE 1

    Synonyms:      perchlorobenzene, pentachlorophenyl chloride, phenyl
                   perchloryl

    Trade names:   Amatin, Anticarie, Bunt Cure, Bunt-No-More, Co-op Hexa,
                   Granox NM, Julin's Carbon Chloride, No Bunt, No Bunt
                   40, No Bunt 80, No Bunt Liquid, Sanocide, Smut-Go,
                   Snieciotox, HexaCB

    2.2 Physical and chemical properties

         Some physical and chemical properties of HCB are listed in
    Table 1. At ambient temperature, HCB is a white crystalline that is
    virtually insoluble in water, but is soluble in ether, benzene and
    chloroform (NTP, 1994). It has a high octanol/water partition
    coefficient, low vapour pressure, moderate Henry's Law constant and
    low flammability. Technical grade HCB is available as a wettable
    powder, liquid and dust (NTP, 1994). Technical grade HCB contains
    about 98% HCB, 1.8% pentachlorobenzene and 0.2% 1,2,4,5-
    tetrachlorobenzene (IARC, 1979), and it is known to contain a variety
    of impurities, including hepta- and octachlorodibenzofurans,
    octachlorodibenzo- p-dioxin and decachlorobiphenyl (Villanueva et
    al., 1974; Goldstein et al., 1978).

    Table 1.  Physical and chemical properties of hexachlorobenzenea

                                                                      

    Property                                      Value
                                                                      

    Relative molecular mass                       284.79

    Melting point (°C)                            230

    Boiling point (°C)                            322 (sublimates)

    Density (g/cm3 at 20°C                        1.5691

    Vapour pressure                               0.0023
    (Pa at 25°C)

    Log octanol/water partition coefficient       5.5

    Water solubility                              0.005
    (mg/litre at 25°C)

    Henry's Law Constant (caluclated)b            131
    (Pa/mol per m3)

    Conversion factors                            1 ppm = 11.8 mg/m3
                                                  1 mg/m3 = 0.08 ppm
                                                                      

    a     From ATSDR (1990); Mackay et al. (1992)
    b     The Henry's Law Constant has been calculated using the
          tabled values for aqueous solubility and vapour pressure

    2.3  Analytical methods

         Analytical methods for the determination of HCB in environmental
    samples and biological tissues vary depending upon the matrix and
    representative methods for various matrices, and are summarized in
    Tables 2 and 3.

        Table 2.  Analytical methods for determining hexachlorobenzene in environmental samplesa

                                                                                                                             

    Sample        Sample preparation                       Analytical     Sample         Recovery      Reference
    matrix                                                 methodb        detection
                                                                          limit
                                                                                                                             

    Water         Extract with dichloromethane,            GC/ECD         0.05 mg/kg     95 ± 10-20%   US EPA (1982)
                  exchange to hexane,
                  concentrate; Florisil column
                  chromatography as a clean-up

    Water         Extract with dichloromethane             GC/MS          1.9 mg/kg      No data       US EPA (1982)
                  at pH 11 and 2, concentrate

    Air           Glass fibre filter and XAD2              HRGC/          0.18 pg/m3     >99%          Hippelein et al. (1993)
                  traps separated by a PUF                 LRMS
                  disk; extraction with toluene

    Air           Polyurethane foam (PUF)                  GC/ECD         <0.1 µg/m3     94.5±8%       Lewis & MacLeod (1982)
                  sampling cartridge, extraction
                  with diethyl ether in hexane

    Air           Polyurethane foam (PUF)                  GC/ECD         low pg/m3      93±1.1%       Oehme & Stray (1982)
                  plugs, extraction with hexane,                          range (not
                  fractionation by HPLC                                   specified)

    Air           Porous polyurethane foam                 GC/ECD         No data        Tenax more    Billings &
                  (PUF), or Tenax-GC resin;                                              effective     Bidleman (1980)
                  filters refluxed with                                                  than PUF in
                  dichloromethane and                                                    retaining HCB
                  chlorinated solvents removed
                  and refluxed with hexane;
                  clean-up by alumina
                  chromatography
                                                                                                                             

    Table 2 contd.

                                                                                                                             

    Sample        Sample preparation                       Analytical     Sample         Recovery      Reference
    matrix                                                 methodb        detection
                                                                          limit
                                                                                                                             

    Air           Adsorb on Amberlite XAD-2                GC/PID         0.014 mg/m3    approx        Langhorst &
                  resin separated by a silanized                                         95 ± 12%      Nestrick (1979)
                  glass wool plug, desorption
                  with carbon tetrachloride.

    Air           Trace Atmospheric Gas Analyser                          approx         No data       Thomson et al. (1980)
                  using negative atmospheric                              0.35 µg/m3
                  pressure chemical ionization
                  for trace gas analysis;
                  collection from ambient air and
                  transfer into a carrier of CO2
                  for analysis

    Soil,         Hexane extraction                        GC/ECD         10 mg/kg       78±2.6% to    DeLeon et al. (1980)
    chemical                                                                             96.5±3.6%
    waste
    disposal
    site samples

    Soil          Extract with dichloromethane             GC/MS          18 mg/kg       No data       US EPA (1986b)
                                                                           5 mg/kg

    Sediment      Solvent extraction subjected             GC/MS                         46%           Lopez-Avila et al.
                  to acid-base fractionation;                                                          (1983)
                  base/neutral fraction subjected
                  to silica gel chromatography
                                                                                                                             

    Table 2 contd.

                                                                                                                             

    Sample        Sample preparation                       Analytical     Sample         Recovery      Reference
    matrix                                                 methodb        detection
                                                                          limit
                                                                                                                             

    Wastes,       Extract with dichloromethane             GC/MS          190 mg/kg      No data       US EPA (1986b)
    non-water                                                              50 mg/kg
    miscible

    Wastes, soil  Extract with dichloromethane             GC/MS          20 µg/litrec   No data       US EPA (1986b)
                                                                                                                             

    a    Portions of the table were taken from ATSDR (1990)
    b    GC = gas chromatography; ECD = electron capture detector; MS = mass spectrometry; PID = photoionization detector;
         HRGC = high-resolution gas chromatography; LRMS = low-resolution mass spectrometry
    c    Identification limit; detection limits for actual samples are several orders of magnitude higher depending upon the
         sample matrix and extraction procedure employed.

    Table 3.  Analytical methods for determining hexachlorobenzene in biological materials

                                                                                                                             

    Sample        Sample preparation                       Analytical     Sample         Recovery      Reference
    matrix                                                 method         detection
                                                                          limit
                                                                                                                             

    Fish tissue   Grind with sodium sulfate, extract       GC/ECD         approx         No data       Oliver & Nicol (1982)
                  with hexane/acetone, clean-up by                        0.05 µg/kg
                  Na2SO4/Alumina/silica gel/Florisil
                  column followed by a H2SO4 column
                  on silica gel

    Fish tissue   Extraction with hexane/isopropanol,      GC/ECD         No data        No data       Lunde & Ofstad (1976)
                  solvent and sulfuric acid
                  partitioning

    Fish tissue   Sulfuric acid digestion, silica gel      GC/ECD         10-15 µg/kg    93%           Lamparski et al. (1980)
                  column chromatography, methylation,
                  alumina column chromatography

    Oyster        Extraction with acetone/acetonitrile,    GC/ECD         No data        No data       Murray et al. (1980)
    tissue        partitioning into petroleum ether,
                  silica gel chromatography

    Adipose       Extraction with hexane, subjected        GC/ECD         No data        87.4-92.6%    Watts et al. (1980)
    tissue        to Florisil clean-up and one-fraction
    (chicken)     elution

    Adipose       Extraction (solvent not specified),      HRGC/MS        12 µg/kg       No data       Stanley (1986)
    tissue        bulk lipid removal, Florisil
                  fractionation

    Adipose       Extraction with benzene/acetone,         GC/ECD         0.12 µg/kg     79-95%        Mes (1992)
    tissue        Florisil fractionation
                                                                                                                             

    Table 3 contd.

                                                                                                                             

    Sample        Sample preparation                       Analytical     Sample         Recovery      Reference
    matrix                                                 method         detection
                                                                          limit
                                                                                                                             

    Blood/urine   Extraction with carbon tetrachloride,    GC/PID         4.1 µg/kg      83%           Langhorst &
                  silica gel column chromatography,                       (urine)                      Nestrick (1979)
                  concentrate                                             16 µg/kg
                                                                          (blood)

    Blood         Extraction with hexane, concentrate      GC/ECD         No data        No data       US EPA (1980)

    Blood         Extraction with hexane/isopropanol       GC/ECD         No data        No data       Lunde & Bjorseth (1977)

    Breast milk   Extraction with acetone/benzene,         GC/ECD         33 µg/kg       70-82%        Mes et al. (1993)
                  Florisil fractionation
                                                                                                                             

    GC = gas chromatography; ECD = electron capture detector; PID = photoionization detector; HRGC = high-resolution gas
    chromatography; MS = mass spectrometry

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Sources, uses and production processes

         Industrial synthesis of HCB may be achieved through the
    chlorination of benzene at 150-200°C using a ferric chloride catalyst
    or from the distillation of residues from the production of
    tetrachloroethylene (US EPA, 1985a). HCB may also be synthesized by
    refluxing hexachlorocyclohexane isomers with sulfuryl chloride or
    chlorosulfonic acid in the presence of a ferric chloride or aluminum
    catalyst (Brooks & Hunt, 1984).

         Historically, HCB had many uses in industry and agriculture. The
    major agricultural application for HCB used to be as a seed dressing
    for crops such as wheat, barley, oats and rye to prevent growth of
    fungi. The use of HCB in such applications was discontinued in many
    countries in the 1970s owing to concerns about adverse effects on the
    environment and human health. HCB may continue to be used for this
    purpose in some countries; for example, HCB was still used in 1986 as
    a fungicide, seed-dressing and scabicide in sheep in Tunisia (Jemaa et
    al., 1986). However, it is uncertain as to whether HCB is still used
    for this purpose.

         In industry, HCB has been used directly in the manufacture of
    pyrotechnics, tracer bullets and as a fluxing agent in the manufacture
    of aluminum. HCB has also been used as a wood-preserving agent, a
    porosity-control agent in the manufacture of graphite anodes, and as a
    peptizing agent in the production of nitroso and styrene rubber for
    tyres (Mumma & Lawless, 1975). It is likely that some of these
    applications have been discontinued, although no information is
    available.

         Although HCB production has ceased in most countries, it is still
    being generated inadvertently as a by-product and/or impurity in
    several chemical processes. HCB is formed as a reaction by-product of
    thermal chlorination, oxychlorination, and pyrolysis operations in the
    manufacture of chlorinated solvents (mainly carbon tetrachloride,
    trichloroethylene and tetrachloroethylene) (Government of Canada,
    1993). The concentrations of HCB in distillation bottoms was estimated
    to be 25%, 15% and 5%, respectively, for tetrachloroethylene, carbon
    tetrachloride and trichloroethylene (Jacoff et al., 1986). While HCB
    could potentially also be a contaminant in the final product, it was
    not detected (detection limit 5 mg/litre) in carbon tetrachloride and
    tetrachloroethylene in an investigation in Canada (personal
    communication to Health Canada by Mr John Schultiess, Dow Chemical
    Canada Inc., 1991). Analysis of production lots of tri- and
    tetrachloroethylene produced in Europe in 1996 failed to detect HCB at
    a detection limit of 2 µg/litre solvent (personal communication to the
    IPCS by Mr C. de Rooij, Solvay Corporation Europe, 1996).

         HCB is also generated as a waste by-product during the
    manufacture of chlorinated solvents, chlorinated aromatics and
    pesticides (Jacoff et al., 1986). The waste streams from the
    production of pentachloronitrobenzene (PCNB), chlorothalonil and
    dacthal are expected to contribute the bulk of HCB released from the
    pesticide industry (Brooks & Hunt, 1984), although HCB can also be
    generated as a waste by-product from the production of
    pentachlorophenol, atrazine, simazine, propazine and maleic hydrazide
    (Quinlivan et al., 1975; Mumma & Lawless, 1975). These pesticides are
    also known to contain HCB as an impurity in the final product, usually
    at levels of less than 1% HCB when appropriate procedures are used for
    the synthesis and purification stages (Tobin, 1986). When such
    procedures are not met, the level of HCB could be much higher (e.g.,
    pentachloronitrobenzene has been reported to contain 1.8-11% HCB
    (Tobin, 1986)). However, owing to many voluntary and regulatory
    pressures, it is unlikely that such high levels of HCB are present in
    today's pesticide formulations, but no information is available to
    substantiate this point.

         The chlor-alkali industry produces chlorine (Cl2), hydrogen and
    caustic soda (NaOH) by electrolysis of purified and concentrated
    sodium chloride (NaCl). Processes using graphite anodes are known to
    produce HCB as a by-product (Quinlivan et al., 1975; Mumma & Lawless,
    1975; Alves & Chevalier, 1980) owing to the reaction of chlorine with
    graphite anode materials such as carbon and oils. Depending on the
    purification procedures, the final products might also be contaminated
    with HCB. In some countries, graphite anodes have been replaced by
    dimensionally stabilized anodes (DSA), which do not generate HCB
    (Government of Canada, 1993).

         Incineration is an important source of HCB in the environment.
    Emission levels from incinerators are very site-specific, and
    therefore generic levels are difficult to estimate. Earlier
    information yielded a crude estimate of the total HCB released from
    all municipal incinerators in the USA to be 57-454 kg/year (US EPA,
    1986a), but levels currently emitted are not known.

    3.2  World production levels

         Few recent data on the quantities of HCB produced are available.
    Worldwide production of pure HCB was estimated to be 10 000
    tonnes/year for the years 1978-1981 (Rippen & Frank, 1986). An
    estimated 300 tonnes was produced by three manufacturers in the USA in
    1973 (IARC, 1979). HCB was produced/imported in the European Community
    at 8000 tonnes/year in 1978 (Rippen & Frank, 1986), and a company in
    Spain used to produce an estimated 150 tonnes of HCB annually (IARC,
    1979). Approximately 1500 tonnes of HCB were manufactured annually in
    Germany for the production of the rubber auxiliary PCTP (BUA, 1994),
    but this production was discontinued in 1993. No further centres of
    HCB manufacture in Europe or North America have been identified.
    Production of HCB has declined as a result of restrictions on its use
    starting in the 1970s.

         Considerable amounts of HCB are inadvertently produced as a by-
    product in the manufacture of chlorinated solvents, chlorinated
    aromatics and chlorinated pesticides. Jacoff et al. (1986) estimated
    that approximately 4130 tonnes of HCB are generated annually as a
    waste product in the USA and that nearly 77% of this is produced from
    the manufacture of three chlorinated solvents: carbon tetrachloride,
    trichloroethylene and tetrachloroethylene. The remainder is produced
    by the chlorinated pesticide industry. In 1977, about 300 tonnes of
    HCB were generated in Japan as a waste by-product in the production of
    tetrachloroethylene, almost all of which was incinerated (IARC, 1979).
    It was estimated that >5000 tonnes HCB/year were produced as a by-
    product during tetrachloroethylene production in the Federal Republic
    of Germany in 1980 (Rippen & Frank, 1986). However, recent estimates
    for Europe from ECSA (European Chlorinated Solvent Association; P.G.
    Johnson (1996) personal communication to IPCS) indicate that up to
    4000 tonnes/year of HCB are produced as a by-product during certain
    tetrachloroethylene production processes and that over 99% of this by-
    product was incinerated at high temperatures.

    3.3  Entry into the environment

         Currently, the principal sources of HCB in the environment are
    estimated to be the manufacture of chlorinated solvents, the
    manufacture and application of HCB-contaminated pesticides, and
    inadequate incineration of chlorine-containing wastes. It should be
    noted that only a small fraction of the HCB generated as a by-product
    may be released, depending on the process technology and waste-
    disposal practices employed. For example, according to the US Toxic
    Chemical Release Inventory (TRI), releases of HCB from the ten largest
    processing facilities were 460 kg, most of this to air, compared with
    almost 542 000 kg transferred offsite as waste. The TRI data are not
    comprehensive, since only certain types of facilities are required to
    report (ATSDR, 1994). ECSA (P.G. Johnson, personal communication to
    IPCS) estimated that European emissions of HCB were about 200 kg/year
    in 1993.

         As discussed in the previous section, HCB is a contaminant of a
    number of chlorinated pesticides. Since most current applications for
    these products are dispersive, most HCB from this source will be
    released to the environment.

         Substantial quantities of HCB are also contained in the wastes
    generated through the manufacture of chlorinated solvents and
    pesticides. In the mid-1980s in the USA, 81% of these HCB-containing
    wastes were disposed of by incineration, compared to 19% via
    landfilling (Jacoff et al., 1986). It is likely that the amount of HCB
    wastes disposed of by incineration has since increased, although
    information has not been found to confirm this point. HCB can be
    emitted from incinerators as a result of incomplete thermal
    decomposition of these wastes and as a product of incomplete
    combustion (PIC) from the thermal decomposition of a variety of
    chlorinated organics such as Kepone, mirex, chlorobenzenes, 

    polychlorinated biphenyls, pentachlorophenol, polyvinyl chloride and
    mixtures of chlorinated solvents (Ahling et al., 1978; Dellinger et
    al., 1991).

         Although only a small proportion of the HCB-containing waste
    generated in the USA is landfilled, HCB may continue to leach to
    groundwater from previously landfilled HCB waste sites. The
    contribution of this route is uncertain, although HCB is not easily
    leached, and landfills containing HCB are now designed to prevent
    leachate losses into adjacent water systems (Brooks & Hunt, 1984). HCB
    emission into the atmosphere from landfills containing HCB wastes
    occurs from slow volatilization and from displacement of the
    contaminated soil (Brooks & Hunt, 1984).

         HCB has been detected in emissions from a number of industries,
    including paint manufacturers, coal and steel producers, pulp and
    paper mills, textile mills, pyrotechnics producers, aluminum smelters,
    soap producers and wood-preservation facilities (Quinlivan et al.,
    1975; Gilbertson, 1979; Alves & Chevalier, 1980), probably reflecting
    the use of products contaminated with HCB. Municipal and industrial
    wastewater facilities may also discharge HCB-contaminated effluents
    (Environment Canada/Ontario Ministry of the Environment, 1986; King &
    Sherbin, 1986), probably owing to inputs from industrial sources.

         Long-range transport plays a significant role as a means of
    redistribution of HCB throughout the environment. Wet deposition
    (deposition via rain or snowfall) is the primary mechanism for
    transport of HCB from the atmosphere to aquatic and terrestrial
    systems in Canada (Eisenreich & Strachan, 1992). For example, it is
    estimated that long-range transport and total deposition to the
    Canadian environment is approximately 510 kg/year, an amount that is
    similar to that from all other sources combined (Government of Canada,
    1993).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Environmental transport and degradation

         HCB is distributed throughout the environment because it is
    mobile and resistant to degradation. Volatilization from water to air
    and sedimentation following adsorption to suspended particulates are
    the major removal processes from water (Oliver, 1984a; Oliver &
    Charlton, 1984). Once in the sediments, HCB will tend to accumulate
    and become trapped by overlying sediments (Oliver & Nicol, 1982).
    Although HCB is not readily leached from soils and sediments, some
    desorption does occur and may be a continuous source of HCB to the
    environment, even if inputs to the system cease (Oliver, 1984a; Oliver
    et al., 1989). Chemical or biological degradation is not considered to
    be important for the removal of HCB from water or sediments (Callahan
    et al., 1979; Mansour et al., 1986; Mill & Haag, 1986; Oliver & Carey,
    1986). In the troposphere, HCB is transported over long distances by
    virtue of its persistence, but does undergo slow photolytic
    degradation (the half-life is approximately 80 days; Mill & Haag,
    1986), or is removed from the air phase via atmospheric deposition to
    water and soil (Bidleman et al., 1986; Ballschmiter & Wittlinger,
    1991; Lane et al., 1992a, 1992b). In soil, volatilization is the major
    removal process at the surface (Kilzer et al., 1979; Griffin & Chou,
    1981; Schwarzenbach et al., 1983; Nash & Gish, 1989), while slow
    aerobic (half-life of 2.7-5.7 years) and anaerobic biodegradation
    (half-life of 10.6-22.9 years) are the major removal processes at
    lower depths (Beck & Hansen, 1974; Howard et al., 1991).

    4.2  Bioaccumulation and biomagnification

         The bioaccumulative properties of HCB result from the combination
    of its physicochemical properties (high octanol/water partition
    coefficient) and its slow elimination due to limited metabolism
    related to its high chemical stability. Organisms generally accumulate
    HCB from water and from food, although benthic organisms may also
    accumulate HCB directly from sediment (Oliver, 1984b; Knezovich &
    Harrison, 1988; Gobas et al., 1989). The uptake of HCB in benthic
    invertebrates has been investigated in a number of laboratory and
    field studies. The results demonstrated that some HCB in sediments is
    available to infaunal species. Reported bioaccumulation factorsa
    (BAF) for invertebrates in HCB-containing sediments range from 0.04 to
    0.58 in high-organic-content sediment to 1.95 in low-organic-content 

              

    a    Defined as tissue concentration (wet weight) divided by sediment
         concentration (dry weight). BAFs from Oliver (1984b) were divided
         by 6.67 to convert tissue dry weight to wet weight.

    sediment (Oliver, 1984b; Knezovich & Harrison, 1988; Gobas et al.,
    1989). The bioavailability of sediment-bound HCB is inversely related
    to sediment organic carbon content (Knezovich & Harrison, 1988), and
    varies with the type and size of the organisms and their feeding
    habits (Boese et al., 1990), the extent of contact with sediment pore
    and interstitial waters (Landrum, 1989), and the surface area of the
    substrate (Swindoll & Applehans, 1987). Landrum (1989) suggested that
    the bioavailability of sediment-sorbed chemicals declines as the
    contact time between the sediment and a contaminant increases. For
    example, Schuytema et al., (1990) observed that addition of HCB-spiked
    sediments did not result in a significant increase in the uptake of
    HCB by the worm ( Lumbriculus variegatus), amphipods ( Hyalella
     azteca and  Gammarus lacustris), and fathead minnows ( Pimephales
     promelas) in a laboratory recirculating water/sediment system.
    However, there was a substantial increase of HCB levels in bed
    sediment, suggesting that sediment served as a more effective sink for
    HCB than the organisms.

         The biomagnification factor (BMF) for HCB in the earthworm
     Eisenia andrei after exposure via food was 0.068 on a wet weight
    basis (0.071 on a lipid basis) (Belfroid et al., 1994a), the biota
    lipid-to-soil accumulation factor, defined as the ratio of the
    concentration in the animal to that on the soil, was 215 g soil dry
    weight/g lipid (Belfroid et al., 1994b), and the bioconcentration
    factors (BCFs) for earthworms kept in water were found to be between
    48 × 104 and 62 × 104 ml water/g lipid (Belfroid et al., 1993).

         Field studies indicate that exposure via food is important for
    organisms at higher trophic levels, as significant biomagnification
    has been observed in several studies in natural aquatic ecosystems. In
    Lake Ontario, Oliver & Niimi (1988) observed that tissue residue
    concentrations increased from plankton (mean = 1.6 ng/g wet weight) to
    mysids (mean = 4.0 ng/g wet weight) to alewives (mean = 20 ng/g wet
    weight) to salmonids (mean = 38 ng/g wet weight). Braune & Norstrom
    (1989) used field data on body burdens of HCB in the herring gull
    ( Larus argentatus) and one of its principal food items, the alewife
    ( Alosa pseudoharengus) in a Great Lakes food chain to calculate a
    biomagnification factor (whole body, wet weight basis) of 31.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

         HCB has been detected in air, water, sediment, soil and biota.
    Representative levels reported in various environmental media in many
    countries are presented in Tables 4, 5 and 6.

    5.1.1  Air

         HCB is widely dispersed in ambient air, and is generally present
    at low concentrations. Mean concentrations of HCB in air removed from
    point sources in Canada, Norway, Sweden, Germany, the USA, the Arctic
    and the Antarctic range from 0.04 to 0.6 ng/m3 (Table 4). Levels of
    HCB in air are generally similar between urban, rural and remote
    sites, reflecting the persistence and long-range transport of this
    substance.

         Airborne concentrations of HCB measured in the USA near nine
    chlorinated solvent and pesticide plants in 1973 and 1976 were much
    higher than background levels (Spigarelli et al., 1986).
    Concentrations as high as 24 µg/m3 were detected in the immediate
    vicinity of one plant, while the maximum concentration of HCB distant
    from the site was 0.36 µg/m3. The highest levels were associated with
    the production of perchloroethylene, trichloroethylene and carbon
    tetrachloride, and with plants where onsite landfill and open pit
    waste disposal were practiced. More recently, Grimalt et al. (1994)
    reported that airborne concentrations of HCB in a community in the
    vicinity of a organochlorine factory built in 1898 in Catalonia,
    Spain, averaged 35 ng/m3, compared with 0.3 ng/m3 in Barcelona, the
    reference community for this study. It is not known how representative
    the data from these studies are, as HCB releases are expected to be
    minimized from industries using appropriate modern technology and
    waste management practices.

         No data are available on the levels of HCB in indoor air.

        Table 4.  Levels of hexachlorobenzene in ambient air (ng/m3)

                                                                                                                             

    Location                      Year         Detection     Mean       Rangea         Reference
                                               limit
                                                                                                                             

    Canada (Windsor, Ontario)     1987-1990    0.03          0.13       ND-0.44        Environment Canada (1992)

    Canada (Ontario)
    - industrial/urban areas      1985-1989    0.007         0.167      0.07-0.31      Lane et al. (1992b)
    - rural areas                                            0.094      0.02-0.31

    Canada (Egbert, Ontario)      1988-1989       -          >0.054     0.00004-0.64   Hoff et al. (1992)

    Canada (Walpole Island)       1988-1989    0.02          0.15       ND-0.34        Environment Canada (1992)

    Canadian High Arctic          1987                       0.15       ND-0.154       Patton et al. (1989)
    (Beaufort Sea)

    Bear Island (Arctic)
    - summer
    - winter                                   0.001         0.04       0.029-0.045    Oehme & Stray (1982)
                                               0.001         0.111      0.059-0.188

    Southern Ocean and            1990                       0.06       0.04-0.078     Bidleman et al. (1993)
    Antarctica

    Enewetak Atoll                1979                       0.10       0.095-0.13     Atlas & Giam (1981)
    (Pacific Ocean)

    Spitzbergen
    - summer                                   0.001         0.071      0.05-0.085     Oehme & Stray (1982)
    - winter                                   0.001         0.086      0.071-0.095
                                                                                                                             

    Table 4 contd.

                                                                                                                             

    Location                      Year         Detection     Mean       Rangea         Reference
                                               limit
                                                                                                                             

    Germany (Hamburg -            1986-1987                  0.6        0.3-2.5        Bruckmann et al. (1988)
    residential, suburban
    and industrial sites)

    South Germany                 1986-1990                  0.21       0.058-0.52     Morosini et al. (1993)

    Norway (Lillestrom)                        0.001         0.162      0.055-0.234    Oehme & Stray (1982)

    Sweden (Aspvreten)            1984                       0.067      0.054->0.165   Bidleman et al. (1987)

    Sweden (Stockholm)            1983-1985                  0.07       0.054->0.130   Bidleman et al. (1987)

    Spain
      - (near organochlorine      1989 & 1992     -          35         11-44          Grimalt et al. (1994)
         compounds factory)
      -  hospital in Barcelona                    -          0.3        0.25-0.4

    USA (Portland, Oregon)        1984                       0.075      0.05-0.11      Ligocki et al. (1985)

    USA - chemical production                                           ND-24000       Spigarelli et al. (1986)
     plants

    USA - urban areas             1975-1979    0.1           0.5        ND-4.4         Carey et al. (1985)
                                                                                                                             

    a    ND = not detected
        5.1.2  Water

         Levels of HCB in freshwater in Europe and North America are
    generally below 1 ng/litre (Table 5), although higher values have been
    reported in aquatic systems that receive industrial discharges and
    surface run-off. In the connecting channels to the Great Lakes in
    Canada, HCB levels were often found to exceed 1.0 ng/litre,
    particularly near point sources. Levels in the St. Clair River near
    the Dow Chemical outfall were as high as 87 ng/litre in 1985 and
    75 ng/litre in 1986 (Oliver & Kaiser, 1986).

         Mean concentrations of HCB in seawater rarely exceed 1 ng/litre
    (Table 5) (Ernst, 1986; Burton & Bennett, 1987). In the Nueces Estuary
    in Texas, USA, the highest level (0.61 ng/litre) was found near
    sewage outfalls (Ray et al., 1983a). Higher concentrations (up to
    196 ng/litre) were observed in the Forth Estuary in Scotland, near
    domestic and chemical industry discharges (Rogers et al., 1989).

    5.1.3  Soil

         Data identified on levels of HCB in soil are quite limited and
    are summarized in Table 6. The most extensive data are from the 1972
    US National Soils Monitoring Program, in which the concentrations of a
    variety of pesticides were determined at 1483 sites from 37 states
    (Carey et al., 1979). HCB was detected at 11 sites, with a range of
    concentrations in positive samples from 10 to 440 µg/kg dry weight. Of
    24 samples of agricultural soil in British Columbia, Canada, where HCB
    had last been applied as a seed treatment 10-15 years prior to the
    survey, 6 had detectable HCB residues of between 1.3 and 2.2 ng/g dry
    weight (Wilson & Wan, 1982).

         Mean concentrations of HCB reported from uncontaminated soil in
    Europe were found to range from 0.3 ng/g in Switzerland (Müller, 1982)
    to 5.1 ng/g in a Swedish rural heathland soil (Thomas et al., 1985)
    (it was not indicated whether concentrations were on a dry or wet
    weight basis). Soil from a farming area in Italy contained 40 ng/g
    (dry or wet weight basis not indicated) (Leoni & D'Arca, 1976). HCB
    levels were not markedly increased by long-term application of sludge
    to land in Germany at a rate of 50 to 500 tons per ha and averaged
    2.8 ng/g (dry or wet weight basis not  indicated) (Witte et al.,
    1988a,b). Monitoring programmes in Germany yielded average levels of
    HCB contamination of soil ranging from approximately 1 ng/g dry weight
    in the North Rhine-Westphalia (1990) to approximately 6 ng/g dry
    weight in Baden-Württemberg (1988) (BUA, 1994).

        Table 5.  Concentrations of hexachlorobenzene (ng/litre) in drinking-water and surface water

                                                                                                                             

    Location                      Year         Detection     Mean       Rangea         Reference
                                               limit
                                                                                                                             

    Drinking-water

    Canada (Ontario)              1980         0.01          0.1        0.06-0.2       Oliver & Nicol (1982)

    Canada (Maritime Provinces)   1985-1988    2.0                      ND             Environment Canada (1989)

    Croatia
    - Sisak                       1988-1989    0.5           1.0a       <1-4           Fingler et al. (1992)
    - Zagreb                                                 2.0a       1-3

    USA                           1977-1981    100           ND                        US EPA (1985b)

    Surface water

    Canada
    - Lake Superior               1986         0.007         0.026      0.018-0.040    Stevens & Neilson
    - Lake Huron                                             0.033      0.018-0.073    (1989)
    - Georgian Bay                                           0.041      0.032-0.054
    - Lake Erie                                              0.078      0.025-0.260
    - Lake Ontario                                           0.063      0.020-0.113

    Canada-St. Clair River        1985                                  0.30-87        Oliver & Kaiser (1986)
      - tributaries to                                                  0.08-0.79
        St. Clair R.
                                                                                                                             

    Table 5 contd.

                                                                                                                             

    Location                      Year         Detection     Mean       Rangea         Reference
                                               limit
                                                                                                                             

    Canada (Atlantic Region);     1979-1989    2.0                      ND-2.2         Leger 1991
    lakes, streams, reservoirs,
    estuaries, coastal waters

    Germany (Elbe)                1990           -           12         3-62           BUA (1994)

    Greece (Strimon River)        1985-1986    -             1.52       0.5-2.8        Kilikidis et al. (1992)

    Italy (tributaries to
    Adriatic Sea)                 1977-1978    1.0                      ND             Galassi & Provini (1981)

    Mediterranean Sea             1982-1983    0.1           2.13       ND-12.6        El-Dib & Badawy (1985)

    Netherlands/Belgium           1993         10            <10        <10            RIWA (1993)

    Netherlands                   1987           -           <10        ND-100         De Walle et al. (1995)

    North Sea (coastal waters
    and estuaries)                1979-1980                  2.7        0.03-15        Ernst (1986)

    Scotland (Forth Estuary)      1987         0.01                     <0.01-196      Rogers et al. (1989)

    Scotland (Forth Estuary)      1990                                  0.7-8.0        Harper et al. (1992)

    Spain (Ebre Delta)            1985-1986    0.0005        0.041      ND-1.0         Grimalt et al. (1988)

    USA (Texas-estuary)           1980                       0.24       <0.01-0.61     Ray et al. (1983a)

    USA (coastal, surface                      <0.1                     <0.1-26        Cross et al. (1987)
     microlayer)

                                                                                                                             

    a     median value

    Table 6.  Levels of hexachlorobenzene in soil (ng/g dry weight)

                                                                                                                             

    Source                             Year         Detection     Mean        Rangea           Reference
                                                    limit
                                                                                                                             

    Canada (British Columbia)                       1.0                                        Wilson & Wan (1982)
    - agricultural soils                                                      <1.0-2.2
    - near a former grain                                                     260 ng/g
      treatment plant     

    Czech/Polish Border                  -             -          3.25        0.47-4.8         Holoubek et al. (1994)
    (Giant Mountains)     

    Germany (contaminated soil)        1989                                   0.3-339          Hagenmaier et al. (1992)

    India                              1987                       24a         0-165            Nair & Pillai (1989)

    Italy (farming area)               1971-1972                  40                           Leoni & D'Arca (1976)

    Netherlands - Ochten               1993            -          18          5.1-66           Hendriks et al. (1995)
                - Gelderse Poort                                  80          73-89

    Netherlands                        1987            -          <10         <80              De Walle et al. (1995)

    Sweden                                                        5.1                          Thomas et al. (1985)

    USA                                1968-1973                              10-440           Carey et al. (1979)

    USA (chemical plants)                           0.002                     ND-5 700 000     Spigarelli et al. (1986)

    USA (hazardous waste sites)        1977-1978                              20 000-400 000   Davis & Morgan (1986)

    USA (5 locations near Love                      0.1           1.04-5.6    0.15-26.3        Ding et al. (1992)
     Canal)
                                                                                                                             

    a    ng/g wet weight
             Levels in soil are highest near industrial sources of HCB. Levels
    as high as 12 600 ng/g dry weight were reported at one landfill site
    in Canada (Wilson & Wan, 1982), and 570 µg/g (dry or wet weight not
    indicated) on the grounds of a chlorinated solvent and pesticide
    production plant in the USA (Spigarelli et al., 1986). Soils near a
    former grain treatment plant in Canada contained 260 ng/g dry weight
    of HCB (Wilson & Wan, 1982). Levels of HCB in soils from contaminated
    floodplains in the Netherlands ranged from 5.1 to 89 ng/g dry weight
    (Hendriks et al., 1995).

    5.1.4  Sediment

         HCB strongly sorbs to sediment and suspended matter, and
    differences in the concentrations in the water as well as in the
    composition of the sediments and suspended matter result in a wide
    range of concentrations in this medium.

         In sediment samples collected from 1979 to 1989 in the Atlantic
    provinces of Canada, HCB was reported to be below the limit of
    detection of 0.2 ng/g dry weight in 140 of 152 samples (Leger, 1991).
    In surveys conducted from 1980 to 1983, HCB levels in sediments from
    the Great Lakes ranged from 0.02 to 840 ng/g dry weight (Oliver &
    Nicol, 1982; Fox et al., 1983; Kaminsky et al., 1983; Oliver &
    Bourbonniere, 1985; Bourbonniere et al., 1986; Oliver et al., 1989;
    IJC, 1989). Analyses of sediment cores from Lake Ontario indicated
    that levels of HCB have declined from the 1960s to the early 1980s but
    more recent data are not available to determine if this downward trend
    has continued (Oliver & Nicol, 1982; Oliver et al., 1989). HCB levels
    in sediment sampled from eight lakes in northern remote Canada (date
    of sampling not specified) ranged from 0.09 to 1.80 ng/g dry weight
    (Muir  et al., 1995).

         Levels as high as 5100 ng/g dry weight were detected in the Rhine
    River in Baden-Württemberg, Germany, in 1986 (BUA, 1994). The majority
    of sediment samples taken from the rivers Rhine and Elbe between 1980
    and 1990 contained levels of HCB between 10 and 500 ng/g dry weight,
    although levels below 1 ng/g dry weight were determined in some other
    locations (BUA, 1994). A Nordic study on chlorinated compounds in the
    Baltic, Kattegat and Skagerrak (œstfeldt et al., 1994) found HCB
    concentrations in sediment ranging from 1 to 20 ng/g loi (loss on
    ignition), the higher values occurring mainly in the Bothnian Bay. An
    extreme value of 63 ng/g loi was found in Öresund between Denmark and
    Sweden. Levels of HCB in sediment samples collected near effluent
    discharges along a stream in Pakistan ranged from <0.05 to 94.5 ng/g
    wet weight (Tehseen  et al., 1994).

         Higher levels of HCB in sediments were reported in studies
    conducted near point sources. As much as 280 000 ng HCB/g dry weight
    was detected in 1985 downstream of the Dow Chemical sewer discharges
    in the St. Clair River, USA (Oliver & Pugsley, 1986).

    5.1.5  Biota

         HCB has been detected in invertebrates, fish, reptiles, birds and
    mammals from around the world. Following the detection of HCB in
    tissues of wild birds by De Vos in 1967, high residues were often
    found in predatory birds, whereas minor quantities were detected in
    fish, mussels and birds of the aquatic environment (Vos et al., 1968;
    Koeman et al., 1969). Based on Canadian data from monitoring studies
    in birds, HCB levels declined sharply from the mid-1970s (the earliest
    data available) and into the early 1980s, after which they levelled
    off (Noble & Elliott, 1986; Environment Canada/Department of Fisheries
    and Oceans/Health and Welfare Canada, 1991).

         Levels of HCB in freshwater mussels in the Great Lakes and
    connecting channels have been found to range from 0.1 ng/g wet weight
    to 24 ng/g wet weight (Kauss & Hamdy, 1985; Innes et al., 1988;
    Muncaster et al., 1989). A similar range (4.4-26 ng/g wet weight) was
    observed in benthic amphipods, the pelagic amphipod  Pseudalibrotus
     litoralis and brittle stars from the Beaufort Sea (Hargrave et al.,
    1989). Lower levels (0.1-1.8 ng/g wet weight) were observed in mussels
    ( Mytilus galloprovincialis) from the Ebro Delta in the Western
    Mediterranean, and these levels were observed to decline from 1980 to
    1992 (Solé et al., 1994). Levels in marine species of clams and
    oysters from the USA were reported in several studies to be < 1 ng/g
    wet weight (Phelps et al., 1986; Eisenberg & Topping, 1984; Ray et
    al., 1983b). Similarly, levels in invertebrates, including mussels
    ( Mytilus edulis), soft clams ( Mya arenaria), lugworms ( Arenicola
     marina), and polychaetes ( Nereis diversicolor), were <1 ng/g
    fresh weight in the German Wadden Sea (Ernst, 1986). Bjerk & Brevik
    (1980) reported higher levels (50-350 ng/g wet weight) of HCB in crabs
    ( Carcinus maenas, Pagurus sp.), snails ( Littorina littorea),
    brittle stars ( Ophiura albida) and sea stars ( Asteroidea) from the
    contaminated Frierfjord in Norway, which receives discharge from
    various industries located in the region, and HCB and related
    compounds were reported to originate from one main source
    (unspecified) in the area. œstfeldt et al. (1994) found that mussels
    ( Mytilus edulis) from the Baltic contain higher levels of HCB
    (200-800 ng/g lipid weight) than mussels from Kattegat (11-20 ng/g
    lipid weight).

         In a 1981-1982 survey of HCB levels in fish from watersheds in
    Eastern Canada, whole body concentrations in brook trout ( Salvelinus
     fontinalis) and yellow perch ( Perca flavescens) ranged from below
    the limit of detection (4.2 ng/g in 1981; 0.2 ng/g in 1982) to 54 ng/g
    for trout and 15 ng/g wet weight for perch (Peterson & Ray, 1987).
    Relatively high body burdens of HCB have been observed in fish in Lake
    Ontario and connecting channels. HCB was not detected (ND) in juvenile
    spottail shiners ( Notropis hudsonius) from Lakes Superior and Erie
    (detection level = 1 ng/g wet weight) (Suns et al., 1983; Environment
    Canada/Department of Fisheries and Oceans/Health and Welfare Canada,
    1991), while mean body burdens in shiners in Lake Ontario ranged from
    ND to 13 ng/g wet weight, and those in the Detroit, Niagara, and

    St Clair rivers averaged 5 ng/g wet weight, ND to 8 ng/g wet weight,
    and 231 ng/g wet weight, respectively (Suns et al., 1985). Mean
    concentrations of HCB in the muscle tissue of various species of
    salmonids from Lake Ontario ranged from 5 to 37 ng/g wet weight (Niimi
    & Oliver, 1989).

         Levels of HCB measured in whole fish species taken from major
    rivers and lakes in the USA (including known contaminated areas)
    ranged from <2 to 913 ng/g wet weight (Kuehl et al., 1983; DeVault,
    1985; Schmitt et al., 1990; Kuehl & Butterworth, 1994). Levels in
    roach ( Rutilus rutilus L.) and perch ( Perca fluviatilis L.) from
    the "moderately polluted" Lahn River in Germany ranged from ND to
    233 ng/g wet weight, with a mean of 1 ng/g (Schuler et al., 1985).
    Concentrations of HCB in the whole bodies of carp ( Cyprinus carpio)
    from the mouth of tributaries to Lake Ontario and the Niagara River
    ranged from 52 to 1600 ng/g on a lipid basis (6.7 to 205 ng/g on a
    fresh weight basis). The highest values were measured near hazardous
    waste dumps and industrial facilities (as high as 1600 ng/g fat)
    (Jaffe & Hites, 1986). Brunn & Manz (1982) reported a mean whole-body
    concentration of HCB in fish (mainly trout) from inland rivers,
    streams, and ponds in Germany of 5 ng/g wet weight. The highest levels
    were recorded from fish caught in rivers.

         HCB levels in seawater are generally lower than those in
    freshwater, resulting in lower levels in edible parts of marine fish.
    In fish taken from the North Sea (species not reported), HCB levels in
    fish muscle tissues averaged 0.3-0.4 ng/g wet weight, with a maximum
    of 0.8 ng/g (Ernst, 1986). HCB concentrations in livers averaged
    42 ng/g wet weight for cod ( Gadus morhua) and 4 ng/g (range of
    0.2-14 ng/g) for flounder ( Platichthis flesus). These levels were
    comparable to levels measured in fish near the coast of southwest
    Greenland and in the North Atlantic Ocean. Livers of cod from the
    coast of southwest Greenland contained 32.4 ng/g on average, and those
    of hake ( Merluccius merluccius) from the North Atlantic Ocean
    averaged 40.5 ng/g) (Ernst, 1986). Levels of HCB were below the
    determination limit (DL) in cod liver (DL = 5 ng/g) and herring muscle
    (DL = 1 ng/g) of fish from the Clyde Sea near Scotland (Kelly &
    Campbell, 1994). Cod from the Firth of Forth had mean liver levels of
    38.7 ng/g wet weight, and levels in herring muscle of 2.0 and 2.3 ng/g
    wet weight were observed in fish from the Firth of Forth and North
    Sea, respectively (Kelly & Campbell, 1994). In surveillance monitoring
    of contaminants in fish from coastal waters near England and Wales,
    concentrations of HCB in livers of cod ( Gadus morhua), whiting
    ( Merlangius merlangus), dab ( Limanda limanda) and flounder
    ( Platichthys flesus) were 2-290, 5-230, 3-55 and 1-52 ng/g,
    respectively (all results on a wet tissue weight basis) (MAFF/HSE,
    1994). Levels of HCB in muscle tissues of herring ( Clupea harengus)
    from the Baltic Sea ranged from <1 to 39 ng/g (Hansen et al., 1985);
    concentrations in whitefish ( Coregonus lavaretus) and trout ( Salmo
     trutta) ranged from <1 to 9 ng/g fresh weight in a 1992 survey
    (Atuma et al., 1993).

         Fish taken from the contaminated waters of the Frierfjord in
    Norway contained mean concentrations of HCB in liver of 11 600 ng/g
    for saithe ( Pollachius virens), and 16 800 ng/g for cod ( Gadus
     morhua) (Bjerk & Brevik, 1980). Levels of HCB from fish taken from
    the uncontaminated Sogndalfjord were much lower, averaging 18 ng/g wet
    weight in livers of cod ( Gadus morhua), 8 ng/g in haddock
    ( Melanogrammus aeglefinus) and 1 ng/g in lemon sole ( Microstomus
     kitt) and flounder ( Platichthys flesus) (Skåre et al., 1985).
    Flounder ( Platichthis flesus) taken from the Elbe Estuary in
    Germany, downstream from Hamburg (a highly industrialized area),
    contained mean levels of HCB in muscle of 688 ng/g (range 84-1907 ng/g
    wet weight). Further downstream, towards the mouth of the river,
    levels were lower, averaging 12.5 ng/g (range 2-32 ng/g) (Kohler et
    al., 1986).

         The mean level of HCB in 15 snapping turtle eggs from Ontario,
    Canada was 27.1 ng/g wet weight (Bishop et al., 1995).

         The levels of HCB in birds have been similar across the various
    regions of Canada since the 1980s, probably as a combined result of
    emission reductions and the long-range transport of HCB to remote
    locations. Mean concentrations of HCB in herring gull eggs ( Larus
     argentatus) in 1991 ranged from 16 to 71 ng/g wet weight at various
    colonies in the Great Lakes, and were relatively uniform across lakes
    (Environment Canada/Department of Fisheries and Oceans/Health and
    Welfare Canada, 1991). These levels were approximately an order of
    magnitude lower than in 1974. The mean level of HCB in herring gull
    eggs from Norwegian coastal waters in 1981 was 120 ng/g wet weight
    (Moksnes & Norheim, 1986). In a study from the Netherlands, mean
    levels in eggs of common terns collected in 1987 were 0.03 µg/g wet
    weight and in those of black-headed gulls collected in 1988 were
    93 µg/g fat (Stronkhorst et al., 1993). Levels of HCB found in eggs of
    sea-bird species ( Haematopus ostralegus, Larus ridibundus, Larus
     argentatus and  Sterna hirundo) from the banks of a river near an
    organochlorine chemical plant in Germany were < 500 ng/g wet weight
    (Heidmann, 1986); mean levels of less than 15 ng/g wet weight were
    found in eggs of several species of land birds, including rooks
    ( Corvus frugilerus) and sparrow hawks ( Accipiter nisus) from
    agricultural, industrial and rural sites. Recent surveys have
    indicated similar levels of HCB in the eggs of five other predatory
    bird species across Canada (means ranged from 10 to 53 ng/g wet
    weight) (Noble & Elliott, 1986; Pearce et al., 1989; Noble et al.,
    1992). However, the mean level of HCB in peregrine falcon ( Falco
     peregrinus) eggs collected across Canada from 1980 to 1987 was
    279 ng/g wet weight, and concentrations ranged as high as 1060 ng/g
    wet weight (Peakall et al., 1990).

         HCB has been found to accumulate in lipids of the common
    goldeneye duck ( Bucephala clangula) that overwinter in the Niagara
    River (mean of 150 ng/g) (Foley & Batcheller, 1988) and the Detroit
    River (mean of 1700 ng/g) (Smith et al., 1985a) in the USA. Goldeneye
    wintering in the Baltic Sea contained average levels of 250 ng/g lipid

    (Falandysz & Szefer, 1982). Levels of HCB in the livers of silver
    seagulls taken from estuaries in Germany were lower in 1988 than 1989
    (approximately 80 and 150 ng/g fat, respectively, in samples from the
    River Ems estuary). Higher levels were observed for both years in
    liver samples of birds taken from the River Elbe estuary (>250 ng/g
    fat) (BUA 1994).

         In breast muscle tissue samples from various species of birds,
    HCB concentrations tend to be progressively greater at higher trophic
    levels (i.e., piscivores > molluscivores > omnivores > grazers)
    (Environment Canada/Department of Fisheries and Oceans/Health and
    Welfare Canada, 1991).

         In the blubber of marine mammals in the Canadian Arctic, mean
    levels of HCB were 19 ng/g wet weight for ringed seals ( Phoca
     hispida) and 491 ng/g wet weight for beluga whales ( Delphinapterus
     leucas) (Norstrom et al., 1990), while male belugas sampled in the
    Gulf of St. Lawrence contained up to 1340 ng/g (Béland et al., 1991).
    Blubber from male and female white-beaked dolphins ( Lagerorhunchus
     albirostris) collected near the Newfoundland coast averaged
    1110 ng/g and 880 ng/g wet weight, respectively. Lower levels
    (290 ng/g and 100 ng/g wet weight) were observed in blubber from male
    and female pilot whales ( Globicephala meleana), also collected near
    the Newfoundland coast (Muir et al., 1988). The higher levels observed
    in the dolphins may reflect greater exposure to HCB because of
    overwintering and feeding in the Gulf of St. Lawrence. Blubber of
    harbour porpoises ( Phocoena phocoena) collected in Poland between
    1989 and 1990 contained an average of 573 ng/g wet weight (Kannan et
    al., 1993), and those collected around the coast of Scotland between
    1989 and 1991 contained an average of 263 ng/g (Wells et al., 1994).
    Levels of HCB in the blubber of bottlenosed dolphins also collected
    off the coast of Scotland contained an average of 276 ng/g (Wells et
    al., 1994). Levels in the blubber of three species of dolphins from
    the Bay of Bengal, southern India, were low, ranging from 1.1 to
    13 ng/g wet weight (Tanabe et al., 1993). Harbour seals ( Phoca
     vitulina) found sick or dead in Norwegian waters due to a disease
    outbreak caused by a morbilli virus had a mean HCB level in the
    blubber of 27 ng/g wet weight (range of 5-94 ng/g) (Skaare et al.,
    1990).

         Limited data were found on levels of HCB in terrestrial mammals.
    In a 1973-1974 survey of HCB in the adipose tissue of fox ( Vulpes
     vulpes), doe ( Capreolus capreolus) and wild boar ( Sus scrofa) in
    Germany, HCB concentrations ranged from <10 to 3110 ng/g. The lowest
    levels were observed in the does, presumably because they are
    herbivorous, whereas foxes and wild boar feed on small animals and are
    therefore more affected by biomagnification of HCB (Koss & Manz,
    1976). Similar patterns were evident in a study from Sweden, in which
    rabbits ( Oryctolagus cuniculus, muscle), moose ( Alcaes alcaes,
    muscle), reindeer ( Rangifer tarandus, suet) and osprey ( Pandion
     haliaetus, muscle) were found to contain 9, 15, 51 and 330 ng HCB/g
    lipid weight, respectively (Jansson et al., 1993). The mean
    concentration in 66 serum samples taken in muskoxen in the Canadian

    Northwest Territories in 1989 was 2.8 ng/g (range of 1.1-7.5 ng/g)
    (Salisbury et al., 1992). The mean concentration of HCB in fat samples
    from 58 caribou from the same region ranged from 32.93 to 129.4 ng/g
    (lipid corrected) (Elkin & Bethke, 1995). The mean concentration of
    HCB in the livers and lipids of adult river otters ( Lutra
     canadensis) in western Canada were 3 ng/g and 30 ng/g wet weight,
    respectively, for females and 4 ng/g and 25 ng/g wet weight,
    respectively, for males (Somers et al., 1987). Concentrations of HCB
    in mink carcasses collected in Ontario in the late 1970s and early
    1980s ranged from < 0.5 to 10 ng/g wet weight (Proulx et al., 1987).
    In the Canadian north, the mean level of HCB in the fat of polar bears
    ( Ursus maritimus) hunted between 1982 and 1984 was 296 ng/g wet
    weight (Norstrom et al., 1990).

    5.1.6  Food and drinking-water

         HCB is commonly detected, at low levels, in food (Table 7).
    Levels of HCB tend to be highest in fatty foods and/or those that have
    been treated with HCB-contaminated pesticides. The most extensive data
    identified have been collected through the United States Food and Drug
    Administration (US FDA) Total Diet Study. The results of the surveys
    from 1982 to 1991 indicate that HCB is detectable (DL = 0.1 ng/g) in a
    small fraction of food items, most often dairy products, meats, and
    peanuts/peanut butter (KAN-DO Office and Pesticides Team, 1995).  In
    the most recent surveys, conducted during 1990-1991, mean levels were
    less than 1 ng/g for all products.

        Table 7.  Concentration (µg/kg wet weight unless otherwise specified) of hexachlorobenzene in various foods

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    Australia           cereals                              0.01               < 0.01-0.01        Kannan et al. (1994)
                        pulses                               0.02               0.01-0.05
                        oils                                 0.07               0.02-0.11
                        beverages                            0.03               0.02-0.04
                        vegetables                           0.01               < 0.01-0.02
                        fruits                               0.01               < 0.01-0.02
                        dairy products                       0.55               0.14-1.6
                        meat and fat                         0.46               0.01-3.0
                        fishes                               4.2                < 0.01-60

    Canada              fresh meat & eggs                    0.17               Davies (1988)b
                        root vegetables & potato             0.04
                        fresh fruit                          ND(<0.01)
                        leafy/other above-ground vegetables  0.02
                        2% milk                              0.16

    Canada              apples                               ND(<0.2)-2.6       OMAF/OME (1988)
                        peaches                              ND(<0.2)
                        tomatoes                             ND(<0.2)
                        potatoes                             ND(<0.2)
                        wheat                                ND(<0.2)
                        eggs                                 ND(<0.2)
                        hamburger                            0.39               0.2-0.57
                        prime beef                                              ND(<0.2)-0.21
                        pork                                 ND(<0.2)
                        chicken                              ND(<0.2)
                                                                                                                             

    Table 7 contd.

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    Germany             milk                                 0.22d              0.088-0.45d        Fürst et al. (1992)
                        cream                                0.98d              0.31-1.30d
                        butter                               4.86d              2.32-6.88d
                        cheese                               2.72d              2.16-3.70d

    India               cereals                              0.03               0.01-0.04          Kannan et al. (1992a)
                        pulses (edible seeds of legumes)     0.07               0.02-0.16
                        spices                               0.22               <0.01-0.54
                        oils                                 1.5                0.09-2.8
                        milk                                 0.03               0.01-0.10
                        butter                               1.7                0.86-2.4
                        fishes & prawn                       0.07               <0.01-0.55
                        meat & animal fat                    0.61               0.02-4.8

    Mexico              cheese                               16.67d             1                  Albert et al. (1990)

    Morocco             eggs                                 20.9               0.09-300           Kessabi et al. (1990)
                        poultry liver                        5.1                trace-30.0
                        bovine liver                         21.9               1.2-119.8
                        bovine kidney                        15.1               trace-133.0

    Papua New           cheese                               0.43                                  Kannan et al. (1994)
     Guinea             pork fat                             0.40
                        chicken                              0.20
                        striped mullet                       0.04
                        tilapia                              0.01               0.02-0.05
                        mud crab                             0.03               < 0.01-0.02
                        oyster                               0.02               < 0.01-0.05
                                                                                                                             

    Table 7 contd.

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    Solomon Islands     pork                                 0.14
                        chicken                              0.06
                        greenspotted kingfish                0.03               0.01-0.06          Kannan et al. (1994)
                        indian mackerel                      0.01               0.01
                        paddletail snapper                   0.01               0.01

    Southern Baltic     canned cod-livers                    60 ± 6             50-76              Falandysz et al. (1993)

    Spain               bologna - fresh                      2.57d                                 Ariño et al. (1992)
                                - cooked                     2.48d

    Spain               pork sausage                                                               Ariño et al. (1992)
                           - before curing                   6.63d
                           - after 30 days curing            6.0d

    Spain               ham - fresh                          3.46d                               Ariño et al. (1992)
                            - cured                          1.29d

    Spain               pork                                 2.86-3.9d                             Ariño et al. (1993)

    Spain               lamb  - chop, raw                    14.67d                                Conchello et al. (1993)
                              - chop, grilled                12.06d
                              - leg, raw                     8.53d
                              - leg, roasted                 7.02d

    Spain               chicken                              120 ± 10                              To-Figueras et al. (1986)
                        calf                                 249 ± 37
                        rabbit                               860 ± 159
                        pork                                 169 ± 20
                        sheep                                225 ± 35
                        butter                               315 ± 18
                                                                                                                             

    Table 7 contd.

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    United Kingdom      bread                                ND (10)            MAFF/HSE (1994)
                        milk                                 0.6
                        butter                               ND(10)
                        cheese                               3.33d
                        ewes' cheese                         ND(10)
                        pasta                                ND(10)
                        beef burgers                         ND(10)
                        canned meat                          10d
                        cooked meats                         10d
                        lamb                                 ND(10)
                        rabbit                               ND(10)
                        salami                               ND(10)

    United Kingdom      sausages                             ND(10)                                MAFF/HSE (1994)
                        pies and pasties                     ND(10)
                        salmon (tinned)                      2.0
                        breaded cod                          ND(2.0)
                        fish cakes                           2.0
                        mackerel                             20
                        plaice                               ND(2.0)
                        prawn products                       ND(2.0)
                        sardines (tinned)                    ND(2.0)
                                                                                                                             

    Table 7 contd.

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    United Kingdom      carrot                               0.0317                                Wang & Jones (1994)
                        potato                               3.35
                        cabbage                              0.0418
                        cauliflower                          0.0729
                        lettuce                              0.108
                        onion                                0.0014
                        bean                                 0.0101
                        pea                                  0.0039
                        tomato                               0.0139

    USA                 cheese, processed                    0.2                ND-0.5             US FDA
                        cheese, cheddar                      0.1                ND-0.5             (unpublished)c
                        beef, ground (regular)               0.1                ND-0.4
                        beef, chuck roast                    0.3                ND-1.0
                        beef, round steak                    0.2                ND-1.0
                        beef, loin/sirloin steak             0.2                ND-1.0

    USA                 lamb chop                            0.3                ND-1.0             US FDA
                        frankfurters                         0.1                ND-0.6             (unpublished)c
                        cod/haddock fillet                   ND(0.1)            ND-0.2
                        eggs, scrambled                      0.1                ND-0.3
                        eggs, fried                          0.2                ND-0.7
                        peanut butter                        0.2                ND-0.4
                        peanuts, dry roasted                 0.3                ND-1.0
                        watermelon                           0.1                ND-0.5
                        butter                               0.6                ND-1.0
                        cream                                0.1                ND-0.4
                                                                                                                             

    Table 7 contd.

                                                                                                                             

    Country             Food                                 Mean contenta      Range              Reference
                                                                                                                             

    Viet Nam            rice                                 0.03               <0.01-0.05         Kannan et al. (1992b)
                        pulses                               0.04               <0.01-0.18
                        oil                                  1.2
                        butter                               5.0
                        animal fat                           0.41               0.29-0.65
                        meat                                 0.11               0.03-0.18
                        fish                                 0.05               0.01-0.31
                        prawn                                0.03
                        shellfish                            0.04
                        crab                                 0.17
                        caviar                               3.8                1.9-7.2
                                                                                                                             

    a    ND = not detected (detection limit given in brackets).
    b    Fresh produce and meats grown in Ontario were purchased from four grocery stores in Toronto when locally grown produce
         was available (Ontario freshwater fish were not available and therefore, were excluded from analysis).  All food items
         were grouped into one of five composites for analysis, with the relative proportions of different food items in each
         composite calculated from the estimates of the amounts purchased per person per year by Ontario residents.
    c    The US Food and Drug Administration Total Diet Study conducted from April 1990 to April 1991; reporting residue levels
         in 234 individual food items collected from 3 cities in each of 4 geographical regions of the USA (data available from
         US FDA, Washington, DC).
    d    Originally reported on a fat basis, and subsequently converted to wet weight using percentage fat contents reported in
         NHW (1987).
             In a number of more limited recent surveys, HCB levels have been
    determined in commercial foods available in several countries from
    North America, Europe and Asia (Table 7). The results of these studies
    are consistent with the USA study described above, in that HCB has
    been detected primarily in fatty foods such as meats and dairy
    products. In these studies, mean concentrations are generally in the
    low ng/g range or less, although substantially higher concentrations
    have been reported in some surveys from Europe and Asia.

         The effects of cooking, curing and ripening on the HCB residues
    in pork meat products were investigated in Spain by Ariño et al.
    (1992). Neither cooking at 80-82°C for 100 min nor curing reduced the
    HCB content in pork bologna and pork sausage, respectively, whereas
    the level of HCB in dry-salted and cured ham declined by 42%
    throughout maturation.

         HCB has been detected infrequently, and at very low
    concentrations in drinking-water supplies (Table 5). Samples of
    drinking-water collected in 1980 from Canadian cities in the vicinity
    of Lake Ontario contained from 0.06 to 0.20 ng/litre, with a mean of
    0.1 ng/litre (Oliver & Nicol, 1982). In other Canadian and USA
    surveys, HCB was not detected (US EPA 1985b - DL = 100 ng/litre;
    Environment Canada, 1989 - DL = 2 ng/litre). Slightly higher
    concentrations of HCB (median of 1-2 ng/litre) were reported in
    Croatian drinking-water supplies drawn from a nearby polluted river
    (pollution sources were not identified) (Fingler et al., 1992).

    5.2  General population exposure

    5.2.1  Human tissues and fluids

         Owing to its persistence and lipophilicity, HCB is present at low
    levels in the fatty tissues of virtually all members of the general
    population. Levels of HCB in adipose tissues, breast milk, blood and
    follicular fluid of various populations from around the world are
    shown in Table 8. It should be noted that the quality of the studies
    given in Table 8 varies quite widely, from extensive national surveys
    to those with relatively few samples.

         Levels of HCB in human adipose tissue from around the world are
    generally <1 mg/kg (Table 8). Although available data are limited,
    concentrations of HCB reported in fat tissue are generally slightly
    higher in samples from European countries than from elsewhere in the
    world. The highest levels reported in recent surveys are from Spain
    (mean levels of approximately 3-6 mg/kg); the authors suggested that
    this reflected contamination of foods caused by its presence as an
    impurity in other pesticides (Camps et al., 1989; Gómez-Catalán et
    al., 1993, 1995). Concentrations of HCB increased with age in a number
    of these surveys, but there were no consistent differences in residue
    levels between the sexes (Mes et al., 1982; Williams et al., 1984,
    1988; Abbott et al., 1985; Mes, 1990; Mes et al., 1990; Gomez-Catalan
    et al., 1993; Kemper, 1993; Ludwicki & Góralczyk, 1994).

         In general, concentrations of HCB in breast milk in various
    countries or regions (Table 8) range widely, and appear to be related
    to the degree of industrialization and/or urbanization within the
    survey area. The levels of HCB in breast milk have been expressed on a
    whole milk basis, using the fat content reported by the authors or,
    where this was not reported, a fat content of 4.2% (NHW, 1987).
    Schechter et al. (1989a) reported that concentrations of HCB in breast
    milk in the mid-1980s were lowest in samples from Thailand
    (0.3 µg/litre whole milk) and Viet Nam (< 0.17 µg/litre ), somewhat
    higher in those from a semi-rural area of the USA (0.7-0.8 µg/litre),
    and higher still in German samples (12.6 µg/litre ) (numbers of
    samples in this study were extremely small, except for the German data
    (n=167)). In surveys summarized by Mes et al. (1986), mean HCB levels
    were 1 µg/litre whole milk in the USA, 2 µg/litre in Canada,
    3 µg/litre in Sweden, 4 µg/litre in Great Britain, and 35µg/litre in
    Germany. Still higher levels (48-89 µg/litre whole milk) have been
    reported in studies from Spain (Conde et al. 1993). Bates et al.
    (1994) reported that the concentrations of HCB in breast milk of
    primiparae from New Zealand increased linearly with age, but were not
    related to body mass index, fish intake, smoking status, type of
    residential water supply or location of residence (urban versus
    rural). In a study of body burdens of organochlorines in an indigenous
    population, Ayotte et al. (1995) reported that mean concentrations of
    HCB in the milk fat of 107 Inuit women from northern Quebec were
    several times higher than those in 50 Caucasian women from southern
    Quebec (57 and 1.2 µg/litre whole milk, respectively). Levels of
    organochlorine compounds in breast milk correlated with levels of
    omega-3 fatty acids in plasma phospholipids, indicating that
    consumption of marine organisms is an important source of exposure to
    these xenobiotics.

         In a HCB poisoning incident in Turkey (section 8.1), breast-fed
    infants were fatally intoxicated through their mothers' milk. In an
    early report of this incident (Peters et al., 1966), HCB was reported
    as being present in breast milk, although it was not quantified.
    However, elevated levels were measured (mean of 510 ng/g on a fat
    basis (approximately 21 ng/g on a wet weight basis) for 56 porphyric
    mothers) 20-30 years after the incident, compared with a mean of
    70 ng/g fat in 77 milk samples from women of families without
    porphyria or from areas outside of the endemic area (Peters et al.,
    1982; Gocmen et al., 1989).

        Table 8.  Levels of hexachlorobenzene in human tissues and fluids
              (mg/kg wet weight adipose tissue; mg/kg whole milk; µg/litre blood serum; µg/litre follicular fluid)

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    A.  Adipose tissue

    Australia                     31         0.14a (0.01-1.70) (fat basis)      1990-1991     Stevens et al. (1993)

    Canada                        108        0.026a (0.0073-0.118)              1985          Mes & Malcolm (1992),
                                                                                              Mes et al. (1990)

    Canada                        25         0.019a (max. value: 0.087)             -         Mes (1992)

    Canada                        141        0.071 (males)
                                             (0.018-0.244)
                                             0.109 (females)
                                             (0.019-0.373)                      1984          Williams et al. (1988)

    Canada                        99         0.095 (0.01-0.667)                 1976          Mes et al. (1982)

    Canada                        168        0.062 (0.001-0.52)                 1972          Mes et al. (1977)

    Federal Republic of Germany   93         (0.11-21.8)                        1971          Leoni & D'Arca (1976)

    Federal Republic of Germany   6          0.263 (0.083-0.753)                              van der Ven et al. (1992)

    India                         7          0.012 (0-0.064)                    1987          Nair & Pillai (1989)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    A.  Adipose tissue (contd)

    Italy                         28         0.491 (0.126-1.36)                 1973-1974     Leoni & D'Arca (1976)

    Japan                         39         0.044                              1986-1987     Kashimoto et al. (1989)

    Japan                         15         0.21 (0.10-0.42)                       -         Morita et al. (1975)

    Netherlands                   average    0.7a (fat basis)                   1968-1969     Greve & Van Zoonen (1990)
                                  of         1.2a (fat basis)                   1973-1975
                                  51/year    0.86a (fat basis)                  1976
                                             0.98a (fat basis)                  1977-1978
                                             0.85a (fat basis)                  1980
                                             0.80a (fat basis)                  1981
                                             0.58a (fat basis)                  1982
                                             0.49a (fat basis)                  1983
                                             0.42a (fat basis)                  1985
                                             0.38a (fat basis)                  1986

    New Zealand                   -          0.31                                  -          US EPA (1985a)

    Poland                        53         0.221 (0.068-0.937)                early 1980s   Szymczyœski et al. (1986)

    Poland                        277        0.31                               1989-1992     Ludwicki & Góralczyk (1994)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    A.  Adipose tissue (contd)

    Spain                         256        2.99                               1985-1988     Gómez-Catalán et al. (1993)
    (4 cities)

    Spain                         86         3.37  (0.42-12.53)                 1991          Gómez-Catalán et al.  (1995)
                                             (lipid basis)

    Spain                         171        5.55                               1982-1983     To-Figueras et al. (1986)

    Spain                         168        2.95 (0.2-17.37)                   1988-89       Ferrer et al. (1992)

    United Republic of Tanzania   9          0.003 (0.0013-0.0076)                   -        van der Ven et al. (1992

    United Kingdom                201        0.05 (n.d-0.29)                    1969-1971     Abbott et al. (1972)

    United Kingdom                236        0.19 (0.02-3.2)                    1976-1977     Abbott et al. (1981)

    United Kingdom                187        0.11 (0.03-0.32)                   1982-1983     Abbott et al. (1985)

    USA                           10         0.125 (0.03-0.47                        -        Barquet et al. (1981)

    USA                           6081       0.037a                             1974-1983     Robinson et al. (1990)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    A.  Adipose tissue (contd)

    USA                           763        0.118 (0.001-0.256)                1982          US EPA (1994)
                                  689        0.043 (0.032-0.054)                1984
                                  671        0.051 (0.043-0.059)                1986
    B.  Breast milkb

    Australia                     39         0.042 (rural)                      1970          Newton & Greene (1972)
                                  28         0.063 (urban)

    Australia                     137        0.007 (0.002-0.019) (rural)        1979-1980     Stacey et al. (1985)
                                  130        0.008 (0.002-0.017) (urban)

    Australia                     60         0.017 (0.0007-0.32)                    -         Quinsey et al. (1995)

    Australia                     128        0.0036a (<0.01-0.216)              1990-1991     Stevens et al. (1993)

    Brazil                        30         0.00048 (0.00024-0.0036)c          1987-1988     Beretta & Dick (1994)

    Canada                        412        0.0008 (max = 0.014)               1986          Mes et al. (1993)

    Canada                        210        0.002 (max.= 0.009)                1982          Mes et al. (1986)

    Canada                        100        0.002 (max.= 0.021)                1975          Mes & Davies (1979)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    B.  Breast milkb (contd)

    Canada                        536        0.0013c                            1989-1990     Dewailly et al. (1991)

    Canada                        127        0.00051                            1978          Frank et al. (1988)
                                  15         0.0004                             1979
                                  12         0.00028                            1980-1981
                                  13         0.00052                            1983-1984
                                  18         0.00026                            1985

    Finland                       143c       0.002c                             1984-1985     Mussalo-Rauhamaa et al. (1988)

    Finland                       50         0.0023 (0.0007-0.006)              1982          Wickström et al. (1983)

    France                        20         0.002 (0.00004-0.008)c             1990-1991     Bordet et al. (1993)

    Federal Republic of Germany   144        0.021c                             1984          Fürst et al. (1994)
                                  220        0.019c                             1985
                                  157        0.015c                             1986
                                  144        0.015c                             1987
                                  196        0.013c                             1988
                                  145        0.01c                              1989
                                  286        0.0095c                            1990
                                  113        0.0074c                            1991

    Federal Republic of           167        0.0126c                            1985-1987     Schecter et al. (1989a)
     Germany
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    B.  Breast milkb (contd)

    Federal Republic of           2709       0.048c                             1979-1981     BUA (1994)
     Germany                      3778       0.013c                             1986
                                  1897       0.014c                             1987
                                  2994       0.011c                             1988
                                  3256       0.01c                              1989
                                  5340       0.009c                             1990

    Former German                 483        0.007c                             1990-1991
     Democratic Republic

    India                         16         0.042 (0-0.25)e                    1987          Nair & Pillai (1989)

    Israel                        100        0.00256                             -            Weisenberg et al. (1985)

    Italy                         56         0.058d                              -            Franchi & Focardi (1991)

    Italy                         64         0.006 (0.004-0.009)                1987          Larsen et al. (1994)

    Netherlands                   202        0.036a,c                           1972-1973     Greve & Van Zoonen (1990)
                                  278        0.008a,c                           1983

    New Zealand                   38         0.0011                             1988          Bates et al. (1994)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    B.  Breast milkb (contd)

    Norway                        28         0.0007                             1991          Johansen et al. (1994)

    Spain                         240        0.089(0.039-0.21)c                 1984-1987     Conde et al. (1993)
                                  358        0.048(0.037-0.073)c                1990-1991

    Sweden                        20         0.0042 (0.002-0.009)c              1978          Norén (1983a)

    Sweden                        2          0.0007-0.004c                       -            Norén (1983b)

    Sweden                        227        0.003 (0.002-0.004)c               1972          Norén (1988)
                                  245        0.003 (0.003-0.004)c               1976
                                  340        0.003 (0.003-0.004)c               1980
                                  102        0.001 (0.0008-0.001)c              1984-1985

    Sweden                        140        0.0012c                            1989          Norén (1993)

    Sweden                        40         0.0017c                            1986-1987     Vaz et al. (1993)

    Thailand                      3          0.0003c                            1985-1987     Schecter et al. (1989a)

    Turkey                        51         0.0035c                            1988          Üstünbas et al. (1994)

    Turkey                        56         0.021c                             20-30 years   Gocmen et al. (1989)
                                                                                post-exposure
                                                                                during
                                                                                1955-1959
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    B.  Breast milkb (contd)

    United Kingdom                193        0.001 (<0.001-0.005)               1989-1991     MAFF (1992)

    USA                           40         0.00052                            1979          Bush et al. (1985)

    USA                           8          0.0007-0.0008c                     1985-1987     Schecter et al. (1989a)

    Viet Nam                      12         <0.00017c                          1985-1987     Schecter et al. (1989a)

    Yugoslavia                    10         0.006 (0.002-0.017)                1978          Kodric-Smit et al. (1980)

    C.  Serum

    Canada                        25         0.25                               1993          Jarrel et al. (1993)
                                  29         0.21
                                  20         0.35

    Croatia                       15         1a  (<0.5-4)                       1985          Krauthacker (1993)
                                  24         0.9a (<0.5-3)                      1987-1988
                                  26         1a (<0.5-7)                        1989-1990
                                  32         <0.5a (<0.5-4)                     1990

    Germany                       6          1.23 (0.33-2.66)f                    -           van der Ven et al. (1992)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    C.  Serum (contd)

    Spain (near                   21         26 (7.5-69)                        1992          Grimalt et al. (1994)
    organochlorine
    compounds
    factory)

    Spain (hospital               13         4.8 (1.5-15)                       1992          Grimalt et al. (1994)
    in Barcelona)

    Spain                         100        11.09 (1.60-94.2)                  1986          To-Figueras et al. (1995)
                                             4.13 (0.70-19.7)                   1993-1994

    United Republic               11         0.01 (0-0.03)f                       -           van der Ven et al. (1992)
    of Tanzania

    USA                           370        0.189a (0.05-3.21)                   -           Needham et al. (1990)

    D.  Whole blood

    Slovakia                      50         25.2 (6.1-43.2)                    1992          Koœan et al. (1994)
                                                                                                                             

    Table 8 contd.

                                                                                                                             

    Country                       Sample     Mean tissue concentration          Year          Reference
                                  size                (range)
                                                                                                                             

    E.  Follicular fluid

    Canada                        25         0.11                               1993          Jarrell et al. (1993b)
                                  29         0.14
                                  20         0.20

    Federal Republic              15         2.59 (1.1-5.7)                       -           Trapp et al. (1984)
    of Germany
                                                                                                                             

    a    Median value.
    b    The most recent data were used for calculation of intakes via breast milk (section 5.2.4).
    c    Originally expressed as mg/kg milk fat and subsequently converted to a wet weight basis using either the % fat reported,
         or if not given, using 4.2% fat (NHW, 1987).
    d    Number of positive samples
    e    Originally expressed on a dry weight basis and subsequently converted to wet weight using 88% moisture for conversion
         (NHW, 1987).
    f    Values reported in µg/kg.

             HCB is present in a wide range of other tissues and fluids from
    humans, but at lower levels than in adipose tissue and breast milk.
    For example, concentrations of HCB in serum of 370 subjects from the
    general population in the USA studied by Needham et al. (1990)
    averaged 0.189 µg/litre, compared to concentrations of 39 ng/g lipid
    in 287 adipose tissue samples. Schechter et al. (1989b) reported HCB
    levels in various organs in autopsy tissue from three American
    patients. HCB levels in adipose tissue ranged from 15 to 24 ng/g wet
    tissue, while kidney, muscle, lung, spleen and testis contained 1 ng/g
    or less, and adrenals, bone marrow and liver contained intermediate
    concentrations.

         Median blood serum levels of HCB ranged from <0.5 to
    1.0 µg/litre in four population groups (total of 97 samples) from
    Zagreb, Croatia (Krauthacker, 1993). The groups included workers
    employed in the distribution and packing of seeds treated with
    different pesticides, who were expected to have absorbed
    organochlorine compounds at levels greater than the general
    population. However, levels of HCB in the blood of these workers were
    not elevated. Van der Ven et al. (1992) reported the HCB levels in
    maternal serum of 6 and 11 full-term pregnant women in Germany and
    Tanzania, respectively. Levels in Germany averaged 1.23 µg/kg (0.33-
    2.66 µg/kg), whereas those in Tanzania were 0.01 µg/kg (0-0.03 µg/kg).
    Analysis of blood plasma samples from a human organ specimen bank in
    Germany revealed that median annual concentrations of HCB between 1983
    and 1989 ranged between 3.1 and 5.4 µg/litre (Kemper, 1993). Serum and
    ovarian follicular fluid have been shown to contain HCB in patients
    receiving  in vitro fertilization (Jarrell et al., 1993b). Of 72
    patients, HCB was detected in the serum of 60 and follicular fluid of
    49. There was a significant geographical variation among three major
    cities in Canada (Jarrell et al., 1993b). Follicular fluid from
    similarly treated patients in Germany has been shown to contain HCB
    (Trapp et al., 1994). In some studies, workers exposed to chlorinated
    solvents or chlorinated pesticides had elevated levels of HCB in blood
    (section 5.2.7).

    5.2.2  Intake from ambient air

         Based on a daily inhalation volume for adults of 22 m3, a mean
    body weight for males and females of 64 kg (IPCS, 1994), and the range
    of mean levels of HCB measured in ambient air in cities from around
    the world of approximately 0.1 to 0.6 ng/m3 (Table 4), mean intake of
    HCB from ambient air for the general population is estimated to range
    from 3.4 × 10-5 to 2.1 × 10-4  µg/kg body weight per day. Since no
    data on levels of HCB in indoor air were found, it has been assumed
    that levels indoors are the same as those outdoors. The intake of HCB
    via air may be greater in populations residing in the vicinity of
    point sources, but this exposure is considered to be too site-specific
    to estimate reliably.

    5.2.3  Intake from drinking-water

         Based on a daily volume of ingestion for adults of 1.4 litres, a
    mean body weight for males and females of 64 kg (IPCS, 1994), and the
    range of mean concentrations of HCB detected in drinking-water from
    cities of approximately 0.1 to 2 ng/litre (Table 5), the estimated
    mean daily intake of HCB from drinking water for the general
    population ranges from approximately 2.2 × 10-6 to 4.4 × 10-5 µg/kg
    body weight per day.

    5.2.4  Intake from foods

         Based on the average daily consumption of various foodstuffs by
    adults from around the worlda, a mean body weight for males and
    females of 64 kg (IPCS, 1994), and the mean level of HCB detected in
    various foods in the 1990-1991 US FDA Total Diet Study (Table 7), the
    estimated daily intake of HCB from food ranges from  approximately
    0.0004 to 0.0028 µg/kg body weight per day (this range was generated
    by assuming, for food groups in which HCB was not detected, that non-
    detectable values were zero with the detection limit being 0.1 µg/kg.
    These estimates overlap the range of dietary estimates (between 0.001
    and 0.027 µg/kg body weight per day) that have been reported for
    various countries (Canada, USA., Germany, Finland, Viet Nam, Thailand,
    India, Japan, Australia, the Netherlands) (Gartrell et al., 1986; De
    Walle et al., 1995; Fujita & Morikawa, 1992; Kannan et al., 1992a,b;
    Government of Canada, 1993; Kannan et al., 1994). Intakes via food may
    be substantially higher in selected European and Asian countries,
    where the content of HCB in a sampling of a limited range of foods was
    relatively high (Table 7), or in indigenous populations consuming
    large quantities of some wildlife species, such as marine mammals,
    that are known to accumulate relatively high tissue levels of
    lipophilic contaminants (Government of Canada, 1993; Ayotte et al.,
    1995; Kuhnlein et al., 1995).

              

    a    Dietary intakes (g/person/day) consist of: cereals, 323, starchy
         roots, 225; sugar (excludes syrups and honey), 72; pulses and
         nuts, 33; vegetables and fruits, 325; meat, 125; eggs, 19; fish,
         23; milk products (excludes butter), 360; fats and oils (includes
         butter), 31 (all intakes from IPCS, 1994).

         Dietary intakes may also be greater in infants during breast-
    feeding, owing to the accumulation of HCB in the mothers' milk. The
    mean concentrations of HCB in the most recent surveys found for
    various countries range from <0.17 to 48 µg HCB/litre whole milk
    (Table 8). Assuming that infants are exclusively breast fed for the
    first 6 months, during which they consume an average of 0.75 litres of
    breast milk per day and have an average body weight of 7 kg (Health
    Canada, 1994), the estimated mean intakes of HCB from breast milk in
    various countries range from <0.018 to 5.1 µg/kg body weight per day.
    Daily intakes of HCB by breast-feeding infants of Inuit mothers in
    northern Quebec, Canada (a population that consumes substantial
    quantities of marine organisms that accumulate lipophilic
    contaminants) was estimated at 0.45 µg/kg body weight per day, a value
    that was several times greater than for a more southerly population in
    the same province (Ayotte et al., 1995).

    5.2.5  Apportionment of intakes

         Total intake of HCB from ambient air, drinking-water and foods is
    estimated to range from approximately 0.0004 to 0.003 µg/kg body
    weight per day for the general population, the principal route of
    exposure being through the diet (92%). The estimated contributions
    from air and drinking-water are much smaller (7% and 1%,
    respectively). (The contribution from each environmental medium was
    calculated based on the mid-point of the intakes estimated in the
    previous sections.)

    5.2.6  Trends in exposure of the general population over time

         The results of most studies of the levels of HCB in foods and
    human tissues over time indicate that exposure of the general
    population to HCB declined from the 1970s to the mid-1990s in many
    locations. However, this trend has not been evident during the last
    decade in some other locations.

         Routine monitoring of foods in some countries indicates that
    exposure to HCB is decreasing. For example, mean concentrations in
    grab samples of milk, bovine fat, poultry fat and egg fat collected
    from suppliers in Ontario, Canada, decreased by an order of magnitude
    or more between the early 1970s and the mid-1980s (Frank et al., 1983,
    1985a, 1985b; Frank & Ripley, 1990). Brown et al. (1986) reported that
    the frequency of detectable (> 10 ng/g in fat samples, wet weight)
    levels of HCB in the USA meat and poultry supply increased
    dramatically from 1972 to 1977-1978, but had fallen off sharply up to
    1984. More recent data collected through the US FDA Total Diet Study
    indicate that this trend had continued. Between 1982-1984 and 1991,
    the most recent year for which data are available, both the frequency
    of detection of HCB and the estimated average daily intake for people
    of various ages decreased by roughly 80% (US FDA 1990, 1991, 1992). A
    decline in HCB levels in fish from the Baltic and the Swedish West
    Coast was found in the National Swedish Monitoring Programme over the
    period 1988 to 1994 (Bignert, 1995). The annual decrease in levels in

    herring muscle from different places in the Baltic was 12 to 15% and
    in cod liver from the Baltic 21%; from the West Coast it was 12% in
    herring muscle, 23% in cod liver and 23% in dab liver. The trend with
    higher concentrations in samples from the Baltic as compared to the
    West Coast is still seen in the samples.

         The results of most studies of temporal trends of HCB levels in
    human adipose tissue or milk (summarized in Table 8) indicate that
    general population exposures have declined since the 1970s. In routine
    monitoring of breast milk contaminants in German mothers, mean
    concentrations of HCB declined by more than 50% between 1984 and 1991
    (Fürst et al., 1994), and by about 80% between 1979 and 1990 (BUA
    1994). The median HCB content in samples of plasma from a human
    specimen bank in Germany decreased from 4.8 µg/litre in 1983 to
    3.1 µg/litre in 1989, a period of increasing restrictions on indoor
    applications of pentachlorophenol, which contains HCB as a contaminant
    (Kemper, 1993). Mes (1990) reported that concentrations of HCB in
    human adipose tissue from Canadian surveys were significantly lower in
    1985 than in 1972; this decrease occurred in all age classes over this
    period. An increase in the HCB content of human adipose tissue and
    milk was observed in the early 1970s in the Netherlands, and was
    attributed to an increase in the HCB concentration in products of
    animal origin (Greve & Van Zoonen, 1990). Once measures were taken to
    avoid contamination of such products, a gradual decrease in HCB levels
    was observed. Johansen et al. (1994) reported that the concentration
    of HCB in routine monitoring of milk from Norwegian mothers declined
    by 65% between 1982 and 1991. In contrast, in the most extensive study
    of levels of HCB in adipose tissues, the US National Human Adipose
    Tissue Survey (Robinson et al., 1990), in which data on residues were
    collected from a nationally representative sample of 6081 autopsies
    and surgical patients from 1974-1983, there was little change in
    residue concentrations over the study period, with the national median
    level remaining near 30 to 40 ng/g.

    5.2.7  Occupational exposure during manufacture, formulation, or use

         Workers may be exposed to higher concentrations of HCB than the
    general population, particularly in the manufacture of chlorinated
    solvents, and in the manufacture and application of pesticides
    contaminated with HCB.

         In a survey of production industries (perchloroethylene,
    trichloroethylene, carbon tetrachloride, chlorine, triazine herbicides
    and pentachloronitrobenzene), the highest HCB concentrations were
    associated with the production of perchloroethylene and
    trichloroethylene (Spigarelli et al., 1986). The highest level of HCB
    determined in the air on plant property was 24 µg/m3 at a plant
    producing perchloroethylene, carbon tetrachloride and chlorine.
    Relatively high HCB levels (maximum concentration of 2.2 µg/m3 in
    air) were also detected in samples from the pentachloronitrobenzene
    production plant. Lower levels of HCB were measured at triazine
    herbicide production plants (ND - 0.02 µg/m3), and, in the one plant

    that produced only carbon tetrachloride, HCB was not detected (MDL not
    reported). It is not known how representative the data from these
    studies are, as the generation and release of HCB would be minimized
    in plants using appropriate modern technology and waste management
    practices.

         Personal breathing-zone samples (54 in all) from workers in a
    pentachlorophenol production plant contained HCB concentrations
    ranging from <0.1 to 120 µg/m3 (Marlow, 1986), while levels in 112
    area samples throughout the plant ranged from <0.1 to 630 µg/m3.

         HCB concentrations in the blood of workers in a factory producing
    chlorinated solvents ranged from 14 to 233 µg/litre (Burns & Miller,
    1975); this compared with a range <1 to 310 µg/litre in the blood of
    vegetable spraymen (Burns et al., 1974). Mean levels of HCB in the
    blood plasma of workers in a chlorinated solvents plant in the USA
    were 311 µg/litre in 1974, and 312 µg/litre in 1975, and levels in
    whole blood were 160 µg/litre in 1976, and 170 µg/litre in 1977
    (Currier et al., 1980). Concentrations of HCB in blood were positively
    correlated with the number of years worked in the plant, but were not
    associated with airborne levels of HCB or job-category-based exposure
    estimates. Pesticide-exposed vineyard workers in Germany tended to
    have higher HCB whole blood levels (median 7 µg/litre, maximum
    30 µg/litre) than reference controls (median 3 µg/litre, maximum
    17 µg/litre) (Kemper, 1993). Angerer et al. (1992) reported that the
    mean plasma level of HCB in 53 workers at a municipal waste
    incinerator was 5.0 µg/litre, compared with 4.69 µg/litre in 64
    subjects with no known occupational contact.

    6.  KINETICS AND METABOLISM

    6.1  Aquatic and terrestrial biota

         Terrestrial plants such as barley, cress and wheat, and algae
    such as  Oedogonium cardiacum slowly metabolize HCB to polar
    metabolites and non-extractable residues (Lu & Metcalf, 1975;
    Scheunert et al., 1983, 1985; Topp et al., 1989). For example, of the
    total radiolabelled HCB in barley after uptake from soil over one
    growing season, 14% was present as polar metabolites, 20% as plant-
    bound residues and the remainder as the parent compound (Topp et al.,
    1989). In the only available study on HCB depuration rates in plants,
    the aquatic macrophyte  Myriophyllum spicatum eliminated 95% of HCB
    during the first 28 days after exposure ceased (Gobas et al., 1991).

         Invertebrates slowly metabolize HCB to compounds such as
    pentachlorothioanisole, pentachlorophenol and other polar metabolites
    (Lu & Metcalf, 1975; Bauer et al., 1989). In an aquatic model
    ecosystem treated with 14C-HCB for 24 h, unchanged HCB accounted for
    84% of the total radioactivity in snails ( Physa sp.), 67% in water
    fleas ( Daphnia magna) and 65% in mosquito larvae ( Culex pipiens)
    (Lu & Metcalf, 1975). Half-lives for the elimination of HCB by
    invertebrates were less than 5 days for filter-feeding bivalves
    ( Elliptio complanata and  Mytilus edulis) (Bro-Rasmussen, 1986;
    Russell & Gobas, 1989), 16 days for deposit-feeding clams ( Macoma
     nasuta) (Boese et al., 1990), and 27 days for oligochaete worms
    ( Tubifex tubifex and  Limnodrilus hoffmeisteri) (Oliver, 1987).

         Sanborn et al. (1977) detected pentachlorophenol and at least
    four unidentified polar metabolites in green sunfish ( Lepomis
     cyanellus) after 28 days of ingesting HCB-contaminated food.
    Pentachlorophenol has also been detected in the excreta and tissues of
    rainbow trout ( Oncorhynchus mykiss) following an intraperitoneal
    dose with HCB (Koss & Koransky, 1978; Koss et al., 1978). Zebra fish
    ( Brachydanio rerio) did not metabolize HCB after a 48-h exposure in
    water (Kasokat et al., 1989). Elimination half-lives of HCB ranged
    from 7-21 days for fathead minnows ( Pimephales promelas) after a
    waterborne exposure (Kosian et al., 1981) to up to 210 days for
    rainbow trout ( Oncorhynchus mykiss) after ingestion of HCB in food
    (Niimi & Cho, 1981).

         Clark et al. (1987) reported that 63% of the total HCB eliminated
    in herring gulls ( Larus argentatus) was found in the egg yolk.
    Breslin et al. (1983) found that 50% of total HCB eliminated from
    laying bobwhite quail ( Colinus virginianus), a species that lays
    many eggs, was accounted for in egg yolk. For most wild species, egg
    laying will account for a relatively small loss of HCB, while
    depletion of stored fat during energetically costly activities such as
    migration and moulting may result in a significant reduction in body
    burdens. The half-life for elimination of HCB in birds ranged from

    24-35 days for domesticated chickens ( Gallus gallus domesticus) fed
    HCB-contaminated diets (Kan & Tuinstra, 1976; Hansen et al., 1978) to
    211 days in intraperitoneally dosed juvenile herring gulls (Clark et
    al., 1987).

    6.2  Mammals

         There are few data on the absorption of HCB by humans. By
    comparing intake and faecal excretion of HCB in a single breast-fed
    infant, Abraham et al (1994) estimated that absorption was virtually
    complete (greater than 99.7% at one month of age and greater than 97%
    at 5 months). The concentrations of HCB in the diet and faeces of a
    single formula-fed infant were too low for reliable estimation of
    absorption (Abraham et al., 1994). The results of animal studies
    indicate that 80% or more of an oral dose of HCB (between 10 and 180
    mg/kg body weight) is absorbed if administered in an oil vehicle
    (Albro & Thomas, 1974; Koss & Koransky, 1975; Ingebritsen et al.,
    1981; Bleavins et al., 1982). In female rats treated with 14C-HCB in
    oil, peak values of radioactivity were reached in 2 to 5 days. The
    absorption was poor (2-20%, depending on the dose) when the substance
    was given as an aqueous suspension (Koss & Koransky, 1975). Little
    information was identified on dermal absorption, although it appears
    to be lower. Koizumi (1991) observed that after dermal application of
    approximately 2.5 mg 14C-HCB in tetrachloroethylene to Fisher-344
    rats for 72 h, only 9.7% of the administered dose was absorbed. No
    information on absorption via the lungs has been reported.

         There are no experimental studies of tissue distribution of HCB
    in humans, although in a small autopsy study of members of the general
    population (Schechter et al., 1989b), the highest levels were found in
    (in order) adipose tissue, adrenals, bone marrow and liver. Laboratory
    studies in a number of animal species also indicate that the highest
    concentrations of HCB are accumulated in tissues with a high lipid
    content, such as the adipose tissue, adrenal cortex, bone marrow, skin
    and some endocrine tissues (thyroid, adrenal and ovary) following
    ingestion or injection of HCB (Koss & Koransky, 1975; Yang et al.,
    1978; Courtney, 1979; Sundlof et al., 1982; Ingebritsen, 1986; Smith
    et al., 1987, 1994; Goldey et al., 1990; Foster et al., 1993; Jarrell
    et al., 1993a). No information was found on the tissue distribution
    following inhalation or dermal exposure. HCB crosses the placenta, and
    is eliminated via the mothers' milk in both animals and humans
    (Villeneuve et al., 1974; Mendoza et al., 1975; Courtney & Andrews,
    1979, 1985; Courtney et al., 1979; Bailey et al., 1980; Bleavins et
    al., 1982; Goldey et al., 1990; section 5.2.1).

         Metabolic transformation is not extensive in the wide range of
    species examined. The pathways of biotransformation of HCB have been
    reviewed by Debets & Strik (1979) and by Renner (1988). The metabolism
    of HCB operates via three distinct pathways. These are oxidative
    pathways, which give rise to phenolic metabolites including
    pentachlorophenol, tetrachlorohydroquinone and tetrachloro-
    benzoquinone; a glutathione-conjugation pathway leading to penta-

    chlorothiophenol, pentachlorothioanisoles, and several other sulfur-
    containing metabolites; and a minor pathway that yields lower
    chlorinated benzenes through reductive dechlorination. Metabolism
    occurs primarily in the liver, although dechlorination of HCB has also
    been demonstrated  in vitro in enzyme preparations from the lung,
    kidney and small intestine (Mehendale et al., 1975).

         The metabolism of HCB has been studied in the rat and guinea-pig
    (Mehendale et al., 1975; Rozman et al., 1975; Koss & Koransky, 1976;
    Koss et al., 1978; Koss & Koransky, 1978; Courtney, 1979), and in the
    monkey (Rozman et al., 1975; Courtney, 1979). Dosing routes included
    gastric intubation and the intraperitoneal route, while dosing
    vehicles included oil and aqueous media. The monitoring for metabolic
    products of HCB has included excretory products and/or tissue residues
    for periods ranging from 28 to 40 days post-dosing. Findings were
    quite dissimilar among the studies. The most common finding was that
    less than 40% of the administered dose was recovered in the excretory
    products and a majority of the recovered dose was unchanged HCB.

         The major metabolites found in the urine of rats, mice and
    guinea-pigs exposed to HCB by various routes in most studies are
    pentachlorophenol (PCP), tetrachlorohydroquinone and
    pentachlorothiophenol (PCTP) (Koss & Koransky, 1978; Koss et al.,
    1978). (There is some question as to whether most of the latter
    compound detected in some studies was an analytical artefact from
    alkaline hydrolysis of the  n-acetyl cysteine conjugate.) Other
    metabolites include tetra- and pentachlorobenzenes and thioanisoles,
    and tri- and tetrachlorophenols, both in free and conjugated forms. It
    has been reported that, after dietary exposure of male and female
    Wistar rats to HCB for 13 weeks,  N-acetyl- S-(pentachloro-
    phenyl)cysteine was the most abundant metabolite via the conjugation
    pathway (89-92% of the total urinary metabolites collected over 24 h,
    after one week of treatment). Mercaptotetrachlorothioanisole was also
    present, excreted as a glucuronide (den Besten et al., 1994). The
    excreta from male Wistar rats given 125 mg/kg body weight on day 1 and
    6 were collected for 12 days (Jansson & Bergman, 1978). Faeces and/or
    urine contained HCB (about 4% of the total does), pentachlorobenzene,
    pentachlorophenol, pentachlorobenzenethiol (both as such and as
    conjugates), methylthiopentachlorobenzene, tetrachlorobenzenedithiol
    and/or methylthiotetrachlorobenzenethiol (both as such and as
    conjugates), dichlorotetrakis(methylthio)benzene (trace amounts),
    hexakis(methylthio)benzene (trace amounts), bis(methylthio)-
    tetrachlorobenzene, tetrachlorobenzenethiol (trace amounts) and
    methylthiotetrachlorobenzene (trace amounts). Compounds found
    accumulated in adipose tissue were hexachlorobenzene,
    pentachlorobenzene, pentachlorobenzenethiol, bis(methylthio)-
    tetrachlorobenzene and pentachloroanisole.

         Rizzardini & Smith (1982) administered 50 µmoles of HCB/kg body
    weight to male and female rats by gavage in arachis oil for 103 days.
    Three urinary metabolites were identified, i.e., pentachlorophenol,
    2,3,5,6-tetrachlorobenzene, 1,4-diol and pentachlorothiophenol
    (derived from mercapturate). The authors reported that female rats
    excreted several times more HCB metabolites than males.

         PCP and PCTP have been detected in the urine of humans from the
    general population of Spain with high body burdens of HCB (To-Figueras
    et al., 1992).

         No reliable information on the elimination half-life of HCB in
    humans was found. Excretion of HCB by laboratory animals occurs mainly
    through the faeces regardless of the route of administration (US EPA,
    1985a; ATSDR, 1990). Both biliary excretion and non-biliary intestinal
    transfer contribute to faecal excretion (Rozman et al., 1981;
    Ingebritsen et al., 1981; Richter & Schäfer, 1981; Sundlof et al.,
    1982). Reported half-lives for the elimination of an oral dose of HCB
    (doses were 3 mg/kg body weight or less in these studies) are
    approximately one month in rats and rabbits, 10-18 weeks in sheep,
    pigs and dogs, and 2.5 to 3 years in rhesus monkeys (Avrahami &
    Steele, 1972; Avrahami, 1975; Rozman et al., 1981; Sundlof et al.,
    1982; Scheufler & Rozman, 1984; Yamaguchi et al., 1986). HCB has been
    detected in the milk of several species, including humans, and the
    results of experiments with mice and ferrets indicate that the
    majority of the maternal body burden can be eliminated via the
    mother's milk during lactation (Bleavins et al., 1982; Courtney &
    Andrews, 1985).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         This section summarizes the extensive literature on the toxicity
    of HCB to laboratory mammals, with emphasis on those studies reporting
    the lowest-observed-effect levels. Information on the dosage with
    respect to body weight was obtained from the original papers, wherever
    possible. When doses were not expressed in this way by the
    investigators and could not be calculated from the data provided,
    approximate doses (given in parentheses) have been estimated based on
    the reference values given in NIOSH (1985).

    7.1  Single exposure

         The acute toxicity of HCB in experimental animals is low;
    reported oral LD50 values for various species range from 1700 mg/kg
    body weight for the cat to between 3500 and > 10 000 mg/kg body
    weight for the rat, with intermediate values for the mouse, rabbit and
    guinea-pig. Reported LC50 values for inhalation exposure range from
    1600 mg/m3 for the cat to 4000 mg/m3 for the mouse, with
    intermediate values reported for the rat and rabbit (IARC, 1979;
    Strik, 1986; Lewis, 1992). Acute lethal doses elicit convulsions,
    tremors, weakness, ataxia, paralysis and pathological changes in
    organs. Strik (1986) reported that HCB has a low skin irritation
    score, is not irritating to the eye and does not sensitize the guinea-
    pig, although no details were provided. In several studies, single
    oral doses of 100-1000 mg/kg body weight produced increases in the
    activities of various liver enzymes in rats within 24 h (Strik, 1986).

    7.2  Short-term and subchronic exposure

         The effects of short-term, repeated exposure to HCB are primarily
    hepatotoxic and neurological. In a number of studies, the effects of
    HCB on rats exposed to oral doses in the range of 30-250 mg/kg body
    weight per day included altered body weight, cutaneous lesions,
    tremors and other neurological signs, hepatomegaly, liver damage and,
    in some cases, early alterations in porphyrin or haem metabolism
    (Courtney, 1979; US EPA, 1985a; Strik, 1986). Short-term exposure
     in vivo induced a variety of enzymes, including glutathione- S-
    transferases and isozymes of cytochrome P-450, identified as
    cytochromes P-450IA1 (CYPIA1), P-450IA2 (CYPIA2) and P-450IIB (CYPIIB)
    (Wada et al., 1968; Courtney, 1979; Denomme et al., 1983; US EPA,
    1985a; Linko et al., 1986; Strik, 1986; Hahn et al., 1988, 1989; Vos
    et al., 1988; Green et al., 1989; Rizzardini et al., 1990; D'Amour &
    Charbonneau, 1992; Smith et al., 1993; Goerz et al., 1994). This means
    that HCB is a mixed-type cytochrome-P-450-inducing compound, with
    phenobarbital-inducible and 3-methylcholanthrene-inducible properties.
    Enzyme induction has been observed at relatively low doses in some
    studies. For instance, in Wistar rats fed HCB in the diet for 14 days,
    the low-effect level for induction of microsomal liver enzyme was
    50 mg HCB/kg feed (approximately 2.5 mg/kg body weight per day), and
    the no-effect level was 20 mg HCB/kg feed (approximately 1 mg/kg body
    weight per day) (den Tonkelaar & van Esch, 1974).

         The effects produced by subchronic exposure to HCB are similar to
    those observed in short-term studies, but are generally evident at
    lower doses (Courtney, 1979; US EPA, 1985a; ATSDR, 1990, 1994). At
    relatively high doses (32 mg/kg body weight per day or more for
    periods from several weeks to 90 days), reported effects have included
    death, skin lesions, behavioural and neurological changes, reduced
    body weight gain, increased organ weights, and altered thyroid
    function and serum levels of thyroid hormones (the latter effect is
    discussed later in this section). At lower doses, hepatotoxic effects
    have been commonly reported, including histological alterations, the
    induction of a variety of hepatic microsomal enzymes and porphyria.

         The porphyrinogenic effects of exposure to HCB have been
    extensively studied since the seminal reports of Ockner & Schmid
    (1961) and De Matteis et al. (1961). These and subsequent earlier
    works, many of them conducted at relatively high doses, have been
    summarized by Courtney (1979), and much of this research is not
    discussed in this report. Porphyria has been observed in several
    species of laboratory mammals, most often manifested as increased
    levels of porphyrins and/or porphyrin precursors in the liver, other
    tissues and excreta. This disturbance in haem synthesis is associated
    with the inhibition of uroporphyrinogen decarboxylase activity (this
    enzyme converts uroporphyrinogen III to coproporphyrinogen III),
    leading to the accumulation of uroporphyrin and other highly
    carboxylated porphyrins, and with the induction of ALA synthetase (the
    enzyme controlling the rate of haem synthesis) (ATSDR, 1994). There is
    a delay before exposed rats become porphyric, which appears to reflect
    the time for the animals to receive a sufficient cumulative dose of
    HCB (Krishnan et al., 1991, 1992), as well as the time needed for the
    porphyrins to accumulate to the level of overt porphyria (Kennedy et
    al., 1986; Kennedy & Wigfield, 1990). Although in most studies
    porphyria has been associated with longer-term exposure to HCB, rats
    exposed to doses of 25-50 mg HCB/kg body weight per day for as little
    as several days had increased levels of hepatic and urinary porphyrins
    (Krishnan et al., 1991, 1992). In another study, hepatic levels of
    highly carboxylated porphyrins were elevated by a single exposure to
    50 mg HCB/kg body weight, although the latter result was not
    accompanied by clinical porphyria (Kennedy & Wigfield, 1990).

         HCB-induced porphyria has been extensively studied in rats, in
    which dietary or gavage exposure of various strains to between 2.5 and
    15 mg HCB/kg body weight per day for periods of 8 to 15 weeks has
    caused hepatic porphyria, and, in some studies, increased levels of
    porphyrins in the kidney and spleen (Grant et al., 1975; Kuiper-
    Goodman et al., 1977; Goldstein et al., 1978; Mendoza et al., 1979;
    Rizzardini & Smith, 1982; Teschke et al., 1983; Smith et al., 1985b;
    Green et al., 1989; Van Ommen et al., 1989; Kennedy & Wigfield, 1990;
    Smith et al., 1990; Den Besten et al., 1993). A no-observed-effect-
    level (NOEL) for HCB-induced porphyria was not determined in these
    studies. Although the data on other species are limited, levels of
    hepatic or urinary porphyrins were increased in mice of various
    strains fed diets containing 200 mg HCB/kg feed (yielding approximate

    doses of 24 mg HCB/kg body weight per day) for periods of 7 to 15
    weeks in some studies (Smith & Francis, 1983; Rizzardini et al., 1988;
    Vincent et al., 1989), and porphyria was induced in Japanese quail
    following short-term oral and intraperitoneal exposure to 500 mg
    HCB/kg body weight per day (section 9.1.2).

         The lowest doses producing porphyrinogenic and other effects on
    the liver in a subchronic study were reported by den Tonkelaar et al.
    (1978). Groups of five pigs exposed for 90 days to doses of 0.5 mg/kg
    body weight per day or more in the diet had increased urinary levels
    of coproporphyrin and alterations in liver histology and microsomal
    enzyme activities, but no effects were observed at 0.05 mg/kg body
    weight per day. However, marked excretion of coproporphyrin alone is
    not a characteristic of the inhibition of uroporphyrinogen
    decarboxylase in animal systems.

         Female rats are more sensitive than males to the porphyrinogenic
    effects of exposure to HCB. In various strains of rats exposed to
    doses of 5 to 10 mg HCB/kg body weight per day in the diet or by
    gavage, for periods of between 3 months or more, females developed a
    marked porphyria which was absent or much reduced in males (Grant et
    al., 1975; Kuiper-Goodman et al., 1977; Rizzardini & Smith, 1982;
    Smith et al., 1985b). In a number of studies, the basis for the
    susceptibility to HCB-induced porphyria of female rats compared to
    males has been examined. Grant et al. (1975) reported that ovariectomy
    decreased, and castration increased, the accumulation of porphyrins in
    the livers of female and male Sprague-Dawley rats with subchronic
    exposure to HCB, suggesting a role for steroid hormones in the
    development of porphyria in this species. In another study, female
    Fischer-344 rats with HCB-induced porphyria had higher levels of
    cytochrome P-450IA isoenzymes and ethoxyresorufin- O-deethylase
    activity than males, whereas males had higher levels of total
    cytochrome P-450 and activities of microsomal monooxygenases
    associated with cytochrome P-450IIB1 (Smith et al., 1990). In Fischer-
    344 rats with HCB-induced porphyria, sex-related differences in
    urinary and hepatic porphyrin levels were paralleled by differences in
    the excretion of phenolic metabolites, particularly
    pentachlorothiophenol (Rizzardini & Smith, 1982). These findings were
    further investigated in a short-term study by D'Amour & Charbonneau
    (1992), which indicated that male rats may be more resistant to HCB-
    induced porphyria than females because hepatic conjugation of HCB with
    glutathione is more important in males. Male Sprague-Dawley rats
    receiving a porphyrinogenic dose of HCB (100 mg HCB/kg body weight per
    day by gavage for 5 days) had significantly lower hepatic gluthione
    concentration and higher glutathione transferase activity (to 3,4-
    dichloronitrobenzene) than controls, whereas no significant
    differences were observed in females. Biliary excretion of PCTP (a
    metabolite of glutathione conjugation) and the rate of elimination of
    HCB from the liver were greater in males than in females.

         Other mechanistic studies have suggested the involvement of
    oxidative metabolism of HCB in the development of porphyria, although
    the mechanism remains to be elucidated. In female Wistar rats 
    co-treated with 300 mg HCB/kg in the diet (approximately 15 mg HCB/kg
    body weight per day) and triacetyloleandomycin (TAO) (to selectively
    inhibit cytochrome P-450IIIA1/2 and thereby prevent the oxidative
    biotransformation of HCB) for 10-13 weeks, both the excretion of PCP
    and TCHQ (tetrachlorohydroquinone, the reduced analogue of the
    reactive tetrachlorobenzoquinone) and the extent of hepatic porphyria
    and urinary porphyrin excretion were greatly diminished (Van Ommen et
    al., 1989; Den Besten et al., 1993). In 13-week feeding studies on
    female Wistar rats exposed to 300 mg HCB/kg diet (approximately 15 mg
    HCB/kg body weight per day) in the presence or absence of TAO, the
    degree of porphyria was better correlated with excretion of PCP than
    TCHQ, and in comparative studies pentachlorobenzene (which is
    metabolized to PCP by a different mechanism than for HCB) was not
    porphyrinogenic (Den Besten et al., 1993).

         In addition, it has been suggested that the aryl hydrocarbon
    receptor (Ah receptor) may be involved in the accumulation of hepatic
    porphyrins in mice (Linko et al., 1986; Hahn et al., 1988, 1989). Ah-
    responsive strains of inbred mice were more sensitive to hepatic
    porphyrin accumulation after HCB exposure than non-responsive mice
    (Smith & Francis, 1983; Hahn et al., 1988), and HCB has been shown to
    be a weak agonist for the Ah receptor (Hahn et al., 1989).

         Full discussion of the evidence for a unifying hypothesis of
    porphyria induced by HCB and other chemicals that act in a similar
    way, as well as for human sporadic porphyria cutanea tarda, is beyond
    the scope of this document. There is however, substantial experimental
    and human evidence implicating a complex interaction between
    hepatocellular iron and oxidative processes leading to the oxidation
    of unstable uroporphyrinogen to uroporphyrin, possibly mediated by
    induced cytochrome P-450 isozymes (reviewed by Smith & De Matteis,
    1990). There is evidence that inhibition of uroporphyrinogen
    decarboxylase may occur through formation of an inhibitor of the
    enzyme during the oxidation of uroporphyrinogen (Rios de Molina et
    al., 1980; Smith & De Matteis, 1990). HCB may act partly through
    induction and uncoupling of the cytochrome P-450 system to form
    reactive oxygen species, especially in the presence of an increased
    available iron pool (Smith & De Matteis, 1990; Den Besten et al.,
    1993).

         Subchronic exposure to low doses of HCB has also caused changes
    in calcium homoeostasis and bone morphometry. Male Fischer-344 rats
    administered HCB by gavage in corn oil had elevated serum levels of
    1,25-dihydroxy-vitamin-D3 and reduced calcium excretion after 5
    weeks, and increased femur density, weight and strength after 15
    weeks. These effects were evident at 0.7 mg/kg body weight per day but
    not at 0.07 mg/kg body weight per day (Andrews et al., 1989, 1990).

         While technical HCB is known to be contaminated with chlorinated
    dibenzo- p-dioxins, dibenzofurans and biphenyls (Villanueva et al.,
    1974; Goldstein et al., 1978), the effects (primarily hepatic) of
    subchronic dietary exposure of rats to either pure or technical HCB
    were virtually identical, indicating that the effects observed in this
    study were due to the parent compound (Goldstein et al., 1978).

         In a number of studies on various strains of rats, short-term or
    subchronic exposure to HCB affected the thyroid, as indicated by
    decreased serum levels of total and free thyroxine (T4) and often, to
    a lesser extent, triiodothyronine (T3). In some instances, these are
    accompanied by compensatory increases in thyroid weight, circulating
    levels of thyroid-stimulating hormone or iodine uptake by the thyroid
    (Rozman et al., 1986; Kleiman de Pisarev et al., 1989, 1990; Van Raaij
    et al., 1991a, 1993a, 1993b; Foster et al., 1993; Den Besten et al.,
    1993; Sopena de Krakoff et al., 1994). Den Besten et al. (1993)
    reported such effects in rats exposed to as little as 9.5 mg/kg body
    weight per day following dietary exposures for 13 weeks, although
    effect levels were somewhat higher in other studies, which involved
    exposure for a shorter duration and/or employed an aqueous vehicle.
    Somewhat different effects (decreased levels of T3 in serum and no
    change in T4, accompanied by increased uptake of iodine by the
    thyroid) were observed in hamsters exposed to 100-200 mg HCB/kg feed
    (approximately 12-24 mg/kg body weight per day) for 18-28 weeks (Smith
    et al., 1987).

         The mechanisms that have been advanced to account for the effects
    of HCB on the thyroid include accelerated metabolism of thyroid
    hormones by HCB-induced enzymes or accelerated deiodination of
    thyroxine, in conjunction with increased biliary excretion (Kleiman de
    Pisarev, 1989; Van Raaij et al., 1993b), and interference with plasma
    transport of thyroid hormones through displacement of T4 from binding
    sites on proteins (Van Raaij et al., 1991a, 1993a). Van Raaij et al.
    (1991b, 1993a) reported that intraperitoneal injection of
    pentachlorophenol and tetrachlorohydroquinone, but not HCB itself,
    decreased serum thyroxine levels in rats, indicating that these
    metabolites may be involved in the effects of HCB on the thyroid.
    These authors reported that PCP was a more effective competitor for
    thyroxine-binding sites of serum carriers  in vitro, and more
    effective at occupying carrier sites in  ex vivo experiments, than
    HCB (van Raaij et al., 1991a), and demonstrated that T4 binding sites
    were partially occupied in the serum of rats exposed to HCB (Van Raaij
    et al., 1993a). In the latter study, it was estimated that competition
    for thyroid hormone binding sites, by PCP metabolized from HCB, could
    account for almost half of the observed reduction in serum levels of
    T4.

    7.3  Long-term toxicity and carcinogenicity

         A range of non-neoplastic effects from long-term exposure to HCB,
    which are primarily hepatotoxic, have been observed at relatively low
    doses. In a two-generation study with Sprague-Dawley rats, liver and

    heart weights were increased in Fo males exposed to TWA doses of 0.29
    and 1.50 mg/kg body weight per day in the diet for 3 months, and
    histopathological changes in the liver were observed in F1 animals of
    both sexes exposed to maternal doses of 0.29-0.38 and 1.50-1.90 mg
    HCB/kg body weight per day in diet  in utero, through nursing, and
    then continued on the same diet as their parents for their lifetimes.
    The no-effect level in this study was 0.06-0.07 mg/kg body weight per
    day (Arnold et al., 1985; Arnold & Krewski, 1988). Dietary exposures
    of Sprague-Dawley rats to 10 mg/kg and above (approximately 0.5-0.6
    mg/kg body weight per day) for 9-10 months induced  in vivo mixed-
    function oxidase activity, as indicated by reductions in drug-induced
    sleeping times (Grant et al., 1974). Exposure of Sprague-Dawley rats
    to 5 mg HCB/kg in diet (approximately 0.25-0.30 mg/kg body weight per
    day) for 3-12 months caused proliferation of smooth endoplasmic
    reticulum, altered mitochondria and increased numbers of storage
    vesicles in liver, but these effects were not evident at 1 mg/kg in
    diet (approximately 0.05-0.06 mg/kg body weight per day) (Mollenhauer
    et al., 1975; 1976). In a study by Böger et al. (1979), oral
    administration of 2, 8 or 32 mg HCB to female Wistar rats twice weekly
    for 203 days (0.57, 2.3 or 9.1 mg HCB/kg body weight per day) resulted
    in hepatocellular enlargement, proliferated smooth endoplasmic
    reticulum, increased glycogen and porphyrin deposits, and enlarged
    mitochondria, but these effects were not seen at a lower dose (0.5 mg
    HCB/kg body weight twice weekly, or 0.14 mg HCB/kg body weight per
    day). Bleavins et al. (1984a) reported that exposure of female mink to
    a dietary concentration of 1 mg/kg (estimated to yield a dose of
    0.16 mg/kg body weight per day) for 47 weeks significantly increased
    serotonin concentrations in the hypothalamus of dams, and depressed
    hypothalamic dopamine concentrations in kits exposed  in utero and
    through nursing.

         As in subchronic studies, female rats were more sensitive than
    males to porphyria induced by chronic exposure to HCB. Grant et al.
    (1974) reported that in Sprague-Dawley rats fed diets containing HCB
    for 9-10 months, reduced weight gain and porphyria were observed in
    females, but not males, receiving 80 or 160 mg HCB/kg feed
    (approximately 4 or 8 mg HCB/kg body weight per day). A dose-related
    increase in relative liver weights and in the hepatic content of HCB
    was noted in both sexes. Hepatic enzyme activities and cytochrome
    P-450 activities were increased in males administered 40 mg HCB/kg
    feed or more. Exposure to 10 mg HCB/kg feed (approximately 0.5-0.6 mg
    HCB/kg body weight per day) induced  in vivo mixed-function oxidase
    activity, as indicated by reductions in sleeping time for
    pentobarbital and zoxazolamine exposure.

         The carcinogenicity of HCB has been assessed in several bioassays
    in rats, mice and hamsters. The following discussion is limited
    principally to the four studies in which adequate numbers of animals
    of both sexes were exposed for a sufficient length of time to more
    than one dose level.

         Cabral et al. (1977) and Cabral & Shubik (1986) reported a
    statistically significant increase of liver cell tumours (hepatomas)
    in groups of 30-60 male and female Syrian golden hamsters fed 50, 100
    or 200 mg HCB/kg (4, 8 or 16 mg/kg body weight per day) HCB in their
    diets for life. The incidence of "haemangioendotheliomas" of the liver
    was significantly increased in both sexes at 200 mg/kg and in males at
    100 mg/kg, and of alveolar adenomas of the thyroid in males at
    200 mg/kg. (The latter finding is interesting in the light of reports
    of excesses of thyroid neoplasms, or of enlargement of the thyroid, in
    human populations with elevated exposures to HCB (section 8.1.))  The
    authors reported that three of the hepatic "haemangioendotheliomas"
    (which are non-invasive by definition) metastasized. It seems likely,
    therefore, that these tumours were malignant, though misclassified.

         In another study, HCB was administered in the diet to groups of
    30 or 50 outbred male and female Swiss mice at concentrations of 0,
    50, 100 and 200 mg/kg (0, 6, 12 and 24 mg/kg body weight per day) for
    120 weeks (Cabral et al., 1979; Cabral & Shubik, 1986). In females
    exposed to 200 mg/kg, a statistically significant increase in the
    incidence of "liver cell tumours (hepatomas)" was noted. "Hepatomas"
    were also elevated, though not significantly, in males at this dose
    and in both sexes at 100 mg/kg. The number of tumour-bearing animals,
    the latent period, and the multiplicity and size of tumours increased
    with dose.

         Arnold et al. (1985) and Arnold & Krewski (1988) investigated the
    potential carcinogenicity to rats of combined  in utero, lactational
    and oral exposure to analytical grade HCB. Groups of 40 or more
    weanling male and female Sprague-Dawley rats were fed diets containing
    0, 0.32, 1.6, 8 or 40 mg HCB/kg. (Based on data supplied by the
    author, mean doses for males were 0, 0.01, 0.06, 0.29 and 1.50 mg/kg
    body weight per day and for females 0, 0.01, 0.07, 0.38 and 1.90 mg/kg
    body weight per day). After 3 months, the F0 rats were bred, and 50
    F1 pups of each sex were randomly selected from each group. From
    weaning, the F1 animals were continued on the same diet for their
    lifetimes (up to 130 weeks). In exposed F1 females, increased
    incidences of neoplastic liver nodules and adrenal phaeochromocytomas
    were noted at the highest dose. A significantly increased incidence of
    parathyroid adenomas was noted in males receiving 40 mg HCB/kg in
    their diet.

         In a study by Lambrecht et al. (1983a,b; Ertürk et al., 1986),
    groups of 94 weanling Sprague-Dawley rats were fed diets containing 0,
    75 or 150 mg/kg (4 and 8 mg/kg body weight per day for males and 5 and
    9 mg/kg body weight per day for females, respectively) for up to 2
    years. Statistically significant increases in the incidence of
    hepatomas/haemangiomas and of renal cell adenomas were noted at both
    doses in animals of both sexes surviving beyond 12 months. Incidences
    of hepatocellular carcinomas and bile duct adenomas/carcinomas were
    also elevated in females at both doses. In female rats, significant
    increases in the incidences of adrenal cortical adenomas at 75 mg/kg
    and phaeochromocytomas at both doses were reported. Lambrecht et al.

    (1983b) reported a leukaemia involving the thymus, spleen, liver and
    kidney in rats exposed to HCB in this study, but did not present any
    quantitative data. The results of this study were only reported in
    summary form, with few details of the study protocol and results. In
    addition, HCB was incorporated into the diet as a powder in this
    study, raising the possibility that some of the effects observed may
    have been in part attributable to the inhalation of aerosolized HCB.

         High incidences of liver tumours have also been reported in some
    more limited studies in which single dietary concentrations (100 or
    200 mg/kg) were administered to small groups (i.e., between 4 and 15)
    of females of three strains of rats (Smith & Cabral, 1980; Smith et
    al., 1985b); in one strain (Fischer-344), hepatocellular carcinomas
    were observed (Smith et al., 1985b). HCB has not, however, been
    carcinogenic in several other studies in various strains of mice
    (Theiss et al., 1977; Shirai et al., 1978; Smith et al., 1989),
    perhaps as a result of the low doses, short durations of exposure
    and/or small group sizes employed. Results were also negative in a
    second study by Arnold et al. (1985), in which groups of 50 male
    Sprague-Dawley rats were fed diets containing 40 mg HCB/kg in
    conjunction with various levels of vitamin A for 119 weeks, indicating
    the probable higher sensitivity of the two-generation carcinogenesis
    bioassay.

         Ertürk et al. (1982, 1986; Lambrecht et al., 1982a,b) examined
    the tumorigenic activity of subchronic exposure to HCB in both sexes
    of Swiss mice, Syrian golden hamsters and Sprague-Dawley rats at
    dietary levels of 0, 100 and 200 mg/kg (mice) and 0, 200 and 400 mg/kg
    (hamsters and rats) for 90 days. At day 91, 25 of 50 animals in each
    group were sacrificed for histological examination, with the remainder
    being sacrificed at 6-week intervals (up to 341, 361 and 424 days for
    mice, hamsters and rats, respectively). The results of these studies
    were reported in summary form only, and much of the quantitative data
    were not presented. The authors reported that, as the experiment
    progressed, treated animals developed hepatomas, bile duct adenomas,
    renal adenomas and carcinomas, and lymphosarcomas of the thymus,
    spleen, and lymph nodes. However, the only tumour and species for
    which they presented clear evidence of a treatment-related increase in
    incidence was for lymphatic tumours in mice (Ertürk et al., 1982).
    Lymphatic and renal neoplasms were observed as early as the end of the
    90-day period. It is not clear from these reports which tumours each
    species developed or the dietary levels associated with the observed
    effects, as well as other experimental details.

         Results from a number of studies have indicated that HCB is a
    co-carcinogen or promoter of cancer. Concomitant exposure to 50 mg
    HCB/kg in diet (approximately 6 mg HCB/kg body weight per day)
    enhanced the induction of liver tumours by polychlorinated terphenyl
    (at 250 mg/kg diet) in male ICR mice (Shirai et al., 1978). Exposure
    to HCB (100-200 mg/kg in diet (approximately 5-10 mg HCB/kg body
    weight per day) or 1 mmole/kg i.p. at 1 and 5 weeks) promoted the
    development of hepatocellular carcinomas and/or hepatic gamma-
    glutamyltranspeptidase-positive foci initiated by diethylnitrosamine
    in various strains of rats (Pereira et al., 1982; Herren-Freund &
    Pereira, 1986; Stewart et al., 1989).

         In some recent studies, the possible mechanisms by which HCB
    induces tumours in animals have been investigated.

         Bouthillier et al. (1991) presented the results of studies of
    Sprague-Dawley rats exposed to 100 mg HCB/kg by gavage for periods of
    several weeks, which indicated that the observed increase in renal
    tumours in male Sprague-Dawley rats following exposure to HCB
    (Lambrecht et al., 1983b; Ertürk et al., 1986) is related to protein
    droplet nephropathy. The mechanism by which structurally diverse
    hydrocarbons induce hyaline droplet nephropathy in male rats has been
    well documented and involves accumulation of alpha-2u-globulin,
    resulting in necrosis, regeneration and, in some cases, tumours. This
    response is sex- and species-specific, and hence is unlikely to be
    relevant to humans. This mechanism does not, however, explain the
    increased (but lower) incidence of renal tumours in females also
    reported by Lambrecht et al. (1983b).

         Carthew & Smith (1994) hypothesized that some HCB-induced hepatic
    tumours in rats may be produced by a non-genotoxic mechanism. They
    noted that hepatotoxicity of HCB in rodents gives rise to peliosis and
    necrosis with haemosiderosis, indicating that vascular damage has
    occurred, and confirmed the presence of such damage in the liver of
    chronically HCB-exposed rats by the identification of widespread
    fibrin deposits, using an antibody to rat fibrin. These deposits
    occurred in association with abundant haemosiderosis in hepatocytes
    and areas of widened hepatic sinusoids. On this basis, it was
    suggested that the formation of hepatomas and haemangiomas with
    elements of peliosis could be the result of compensatory hyperplastic
    responses to hepatocellular necrosis and the simultaneous loss of
    hepatocellular cords, perhaps potentiated by the accumulation of iron
    in the liver.

         Mechanistic studies that address the relevance to humans of the
    remaining tumour types induced in rodents by HCB have not been
    identified.

    7.4  Mutagenicity and related end-points

         HCB has not been found to be genotoxic in most studies conducted
    to date. HCB did not cause either frameshift or base pair substitution
    mutations in  Salmonella  typhimurium at doses of as much as 10
    mg/plate with or without metabolic activation, with both rat and
    hamster liver activation systems, pre-incubation and plate
    incorporation methods, and technical and 99.9% pure HCB (Haworth et
    al., 1983; Górski et al., 1986; Siekel et al., 1991). A weak positive
    response in  S. typhimurium strain TA98 at 50 and 100 µg/plate was
    reported by Gopalaswamy & Aiyar (1986) and Gopalaswamy & Nair (1992).
    However, the authors also reported mutagenic activity for lindane, in
    contrast to the results of other studies (e.g., Haworth et al., 1983).

    Doses of up to 1000 µg/plate of HCB did not induce tryptophan
    reversion or DNA damage in  Escherichia coli strains WP2 and WP2uvrA
    with or without metabolic activation (Siekel et al., 1991).

         There have been reports of mutagenic activity for HCB in
    eukaryotic cells  in vitro, although these studies have limitations.
    Guerzoni et al. (1976) reported a positive finding for methionine
    reversion in  Saccharomyces  cerevisiae strain 632/4 exposed to HCB,
    but Brusick (1986) did not consider the observed increase to meet
    current standards of a positive response. In addition, only a single
    dose level was used in that study, and there was no exogenous
    metabolic activation. Kuroda (1986) reported that in cultured Chinese
    hamster lung cells (V79), HCB did not induce OUAr mutations, but did
    induce 8AGr mutations. However, both the magnitude of the increase
    (which was small, roughly 1/105 survivors at the two highest doses)
    and uncertain dose-response indicate that this response is open to
    question.

         Oral administration of as much as 221 mg HCB/kg body weight per
    day to male rats for 5 or 10 days failed to induce dominant lethal
    effects in two different studies (Khera, 1974; Simon et al., 1979),
    although Simon et al. (1979) did observe a slight reduction in male
    reproductive performance (numbers of females inseminated and
    impregnated). Rumsby et al. (1992) reported that liver neoplasms that
    developed in iron-overloaded C57Bl/10ScSn mice exposed for 18 months
    to 0.01% HCB in the diet were not associated with a high frequency of
    mutations in the Ha-ras proto-oncogene at codon 61. Only two mutations
    were observed at different sites, from 23 preneoplastic and neoplastic
    lesions examined, indicating that activation of the Ha-ras gene is not
    an important event in the hepatocarcinogenicity of HCB in this test
    system.

         HCB has not been found to be clastogenic in the few available
    studies in which this end-point has been examined. The compound did
    not increase the frequency of sister chromatid exchanges in the bone
    marrow of male mice given as much as 400 mg/kg body weight (by an
    unspecified route), although the lack of detail in reporting the test
    protocol and results limits the interpretation of this study (Górski
    et al., 1986). HCB did not induce chromosomal aberrations  in vitro
    in cultured Chinese hamster fibroblast cells at concentrations as high
    as 12 mg/ml, with or without metabolic activation (Ishidate, 1988), or
    in human peripheral blood lymphocytes exposed to up to 0.1 mmol/litre
    (Siekel et al., 1991). Treatment of rats with 1000 mg HCB/kg diet for
    15 days was hepatotoxic, but did not cause early diploidization in
    hepatocytes as measured by flow cytometry (Rizzardini et al., 1990).

         The results of less specific assays also indicate that HCB does
    not interact strongly with DNA, although there are two reports that
    the compound binds, at low levels, to DNA. After incubating
    hepatocytes isolated from phenobarbital-treated rats with 14C-HCB
    (5 µM) for 20 h, Stewart & Smith (1987) reported the maximum amount of
    radioactivity associated with DNA was < 9.9 × 10-5% of the substrate

    added, and was only marginally above that of hepatocytes held at 4°C;
    the authors considered this to be significantly lower than expected
    for hepatocarcinogens. Gopalaswamy & Nair (1992) also reported a low
    order of binding of HCB to DNA from the livers of rats exposed to
    25 mg HCB/kg. Short-term exposure (<1 day) of rats to oral doses of
    700 or 1400 mg/kg body weight (Kitchin & Brown, 1989) or to as much at
    300 mg/kg body weight i.p. (Górski et al., 1986) did not cause hepatic
    DNA damage, as measured by alkaline elution.

    7.5  Reproductive and developmental toxicity

         Relatively low doses of HCB have been found to affect some
    reproductive tissues in female monkeys. Oral exposure of cynomolgus
    monkeys to 0.1 mg/kg body weight per day in gelatin capsules for 90
    days caused stratification of the ovarian germinal epithelium
    (Babineau et al., 1991; Jarrell et al., 1993a). Higher dosages (1.0
    and 10.0 mg/kg body weight per day) were associated with cellular
    degeneration of this surface epithelium. The low dosage was associated
    with ultrastructural as well as light microscopic changes in surface
    epithelium (Babineau et al., 1991; Sims et al., 1991).

         In ovarian follicles the low dose was associated with an
    increased number of lysosomal elements in germ cells (Singh et al.,
    1990a). The basal lamina was thickened. Higher dosages were associated
    with greater degenerative changes in their cells and granulosa cells
    (Singh et al., 1991, 1990b).

         These studies demonstrated changes in ovarian tissues with no
    other evidence of toxicity. In particular, the induction of
    superovulation with human menopausal gondotrophin (HMG) in these
    animals was associated with a normal estradiol response, oocyte
    recovery, oocyte maturation,  in vitro fertilization and early embryo
    development (Jarrell et al., 1993a). These studies confirm the
    findings of Iatropoulous et al. (1976) in which the administration of
    8 to 128 mg/kg body weight (by gavage in 1% methylcellulose) for 60
    days induced severe follicular degeneration in primordial germ cells,
    pseudostratification of the ovarian surface epithelium, hepatic
    degeneration and severe systemic toxicity in Rhesus monkeys.

         In subsequent studies of similarly treated animals, the higher
    doses were associated with reduced luteal phase progesterone and
    blunted estradiol responses to HMG (Foster et al., 1992a,b). Reduction
    in adrenal steroidogenesis occurred in ovariectomized rats in response
    to exposure to HCB at concentrations of 1, 10 and 100 mg/kg body
    weight for 30 days (Foster et al., 1995).

         In contrast, the results of studies on a variety of species have
    indicated that repeated exposure to HCB can affect male reproduction,
    but only at relatively high doses. Mice exposed to 250 mg HCB per kg
    feed (approximately 30 mg HCB/kg body weight per day) for 21 days had
    reduced serum testosterone levels; based on the results of  in vitro
    tests, it was suggested that this was due to increased metabolism by 

    hepatic microsomal enzymes induced by HCB (Elissalde & Clark, 1979).
    Histological changes in the testes (retarded sexual maturation) were
    noted in pigs fed a diet yielding a dose of 50 mg HCB/kg body weight
    per day for 90 days (den Tonkelaar et al., 1978). The mating index for
    male rats receiving five consecutive daily gavage doses of 221 mg
    HCB/kg body weight in corn oil was decreased compared to those
    receiving 0 or 70 mg/kg body weight However, the fertility index for
    the mated female rats (sperm positive smears) was not affected (Simon
    et al., 1979).

         As discussed in the following paragraphs, placental and
    lactational transfer of HCB, demonstrated in a number of species, can
    adversely affect both the fetus and nursing offspring. The lactational
    route appears to be more important than placental transfer. Adverse
    effects on suckling infants are generally observed more frequently,
    and at lower doses, than are embryotoxic or fetotoxic effects.

         Grant et al. (1977) conducted a four-generation study on female
    (20/dose level) and male (10/dose level) weanling Sprague-Dawley rats
    fed diets containing 0, 10, 20, 40, 80, 160, 320 or 640 mg HCB/kg
    feed. The two highest doses caused some deaths in the F0 dams before
    first whelping, and reduced the fertility index. Dietary levels of 160
    mg/kg or more reduced litter sizes, increased the number of
    stillbirths, and adversely affected pup survival. Similar effects were
    seen at 80 mg/kg after the first two generations, while 40 mg/kg was
    hepatotoxic to the F1a and F3a pups. A dietary level of 20 mg/kg
    (approximately 1-1.2 mg/kg body weight per day) was designated as the
    no-observed-effect level.

         Arnold et al. (1985) fed groups of male and female Sprague-Dawley
    rats from weaning on diets containing up to 40 mg HCB/kg. The rats
    were then bred at 3 months, and the F1 pups were continued on the
    same diet for their lifetimes. HCB had no effect on fertility, but pup
    survival was significantly reduced in the 40 mg/kg group (calculated
    doses of 1.50 and 1.90 mg/kg body weight per day for males and
    females, respectively).

         In other studies, maternal doses in the range from 1.4 to 4 mg/kg
    given to rats and cats have been found to be hepatotoxic and/or
    affected the survival or growth of nursing offspring. In some cases,
    these or higher doses reduced litter sizes and/or increased numbers of
    stillbirths (Mendoza et al., 1977, 1978, 1979; Hansen et al., 1979;
    Kitchin et al., 1982).

         Mink are particularly sensitive to the effects of prenatal and
    perinatal exposure to HCB; the offspring of mink fed diets containing
    concentrations as low as 1 mg/kg (approximately 0.16 mg/kg body weight
    per day) for 47 weeks (prior to mating and throughout gestation and
    nursing) had reduced birth weights and increased mortality (Rush et
    al., 1983; Bleavins et al., 1984b).

         The available data on the developmental toxicity of HCB are
    limited. CD-1 mice administered 100 mg/kg body weight by gavage on
    days 7-16 of gestation had a significantly increased incidence of
    abnormal fetuses per litter, and one case of renal agenesis was
    reported. Some cleft palates were produced, but they all occurred in
    one litter. This dose also increased maternal liver-to-body weight
    ratios and decreased fetal body weights (Courtney et al., 1976). In a
    series of studies reported by Andrews & Courtney (1986), combined
     in utero and lactational exposure of CD-1 mice and CD rats (strain
    unclear, probably Sprague-Dawley) to HCB (mouse dams received 10 or 
    50 mg/kg body weight per day, and rats 10 mg/kg body weight per day, 
    by gavage during gestation) resulted in increases in body weight and
    kidney weights of pups of both species, along with enlarged kidneys
    and a few cases of hydronephrosis. Increased liver weights were
    observed in rat pups, and the occurrence of abnormal kidneys was
    sporadic, with no dose-response relationship in studies with mice.
    Khera (1974) reported a significant increase in the incidence of
    unilateral or bilateral 14th rib in litters of Wistar rats receiving
    doses of 80 and 120 mg HCB/kg body weight during gestation, but
    maternal toxicity (loss of body weight and neurological effects) and
    reduced fetal weights were noted in animals in these groups. (It
    should be noted that, based on the biological half-lives reported for
    HCB in mammals (section 6.2), the concentration of HCB in the dams in
    these studies would not have reached the maximum that might occur as a
    result of intake over a longer period).

         Neurobehavioural development was affected in the offspring of
    rats exposed to 2.5 or 25 mg/kg body weight per day by gavage 2 weeks
    prior to breeding. Pups in both treated groups were hyperactive (based
    on tests of negative geotaxic reflex, olfactory discrimination, and
    exploratory locomotor activity) at 6-20 days of age. Pups from the
    high treatment groups showed reduced acoustic startle response at 23
    days of age, but a significantly increased response at 90 days. These
    doses did not affect learning (swim T-maze) or motor activity in older
    offspring, nor maternal or fetal body weights, length of gestation,
    number of pups/litter at birth, or number of days to eye opening
    (Goldey & Taylor, 1992).

         Lilienthal et al. (1996) recently reported HCB-induced effects on
    neurobehavioural development of rat pups exposed both maternally and
    through the diet (dams were exposed to 0, 8 or 16 mg HCB/kg diet for
    90 days prior to mating and throughout gestation and nursing, after
    which the offspring were fed the same levels for 150 days). Exposure
    to HCB did not affect the mean body weight of the pups (except males
    at 150 days of age), or the number of pups/litter, but did increase
    the mean body weight of dam, and their liver-to-body weight ratios.
    Schedule-controlled behaviour was affected at 8 and 16 mg HCB/kg diet
    (0.64 and 1.28 mg/kg body weight per day), as indicated by a dose-
    related decrease in post-reinforcement pause at the end of the
    experiment. Exploratory locomotor activity, open field behaviour at 21
    days of age, and active avoidance learning at 90 days of age were
    unaffected.

    7.6  Immunotoxicity

         The results of a number of studies have indicated that HCB
    affects the immune system, with immunosuppressive effects in mice and
    immunostimulatory effects in rats (summarized by Vos, 1986).

         Balb/C mice exposed to 5 mg HCB/kg diet (approximately 0.6 mg/kg
    body weight per day) for 3 to 18 weeks were more susceptible to
     Leishmania infection (Loose, 1982) and had reductions in resistance
    to a challenge with tumour cells and in the cytotoxic macrophage
    activity of the spleen (Loose et al., 1981). Barnett et al. (1987)
    reported that Balb/C mice exposed to maternal doses of 0.5 or 5 mg
    HCB/kg body weight per day  in utero and through nursing had severe
    depression of the delayed-type hypersensitivity response to a contact
    allergen (oxazolone). In a number of studies, exposure of mice to
    diets containing 167 mg HCB/kg in diet (approximately 20 mg HCB/kg
    body weight per day) for several weeks depressed humoral immunity,
    cell-mediated immunity and host resistance (Vos, 1986; Carthew et al.,
    1990).

         In rats or rhesus monkeys with oral exposure to between 3 and 
    120 mg HCB/kg body weight per day for periods from 3 weeks to 6 months 
    in various studies, proliferative histopathological effects in the
    thymus, spleen, lymph nodes, and/or lymphoid tissues of the lung have
    been observed (Kimbrough & Linder, 1974; Iatropoulos et al., 1976;
    Goldstein et al., 1978; Vos et al., 1979a,b; Kitchin et al., 1982).
    Gralla et al. (1977) observed that long-term exposure to 1 mg HCB/day
    (equivalent to a dose at the start of the experiment of roughly
    0.12 mg/kg body weight per day) caused nodular hyperplasia of the
    gastric lymphoid tissue in beagle dogs.

         In rats, prominent changes following dietary exposure to HCB
    include elevated IgM levels and an increase in the weights of the
    spleen and lymph nodes. Histopathologically, the spleen shows
    hyperplasia of B-lymphocytes in the marginal zone and follicles, while
    lymph nodes show an increase in proportions of high endothelial
    venules, indicative of activation. High endothelial-like venules are
    induced in the lung, as are accumulations of macrophages. Functional
    tests revealed an increase in cell-mediated immunity, as measured by
    DTH reactions, a notable increase in primary and secondary antibody
    response to tetanus toxoid, and decreased NK activity in the lung (Vos
    et al., 1979a,b). Stimulation of humoral and cell-mediated immunity
    occurred even at dietary levels as low as 4 mg HCB/kg (approximately
    0.2 mg HCB/kg body weight per day); at such a dose conventional
    parameters for hepatotoxicity were unaltered (Vos et al., 1983).
    Therefore, the developing immune system of the rat seems to be
    particularly vulnerable to the immunotoxic action of HCB.

         More recent studies indicate that HCB may cause autoimmune-like
    effects in the rat. Wistar rats treated with HCB had elevated levels
    of IgM, but not IgG, against the autoantigens single-stranded DNA,
    native DNA, rat IgG (representing rheumatoid factor), and bromelain-

    treated mouse erythrocytes (that expose phosphatidylcholine as a major
    autoantigen). It has been suggested that HCB activates a recently
    described B cell subset committed to the production of these
    antibodies (Schielen et al., 1993). The role of these autoantibodies
    is still a matter of controversy. Increased levels have been
    associated with various systemic autoimmune diseases, but a protective
    role of these autoantibodies against development of autoimmune disease
    has been postulated as well. Interesting in this respect are the
    observations that HCB had quite opposite effects in two different
    models of autoimmune disease in the Lewis rat. HCB treatment severely
    potentiates allergic encephalitis elicited by immunization with myelin
    in complete Freund's adjuvant, while it strongly inhibits the
    development of arthritic lesions elicited by complete Freund's
    adjuvant as such (Van Loveren et al., 1990).

         A possible relation between the immunomodulatory properties of
    HCB and HCB-induced skin lesions, attributed in the literature to the
    porphyrinogenic action of HCB, was recently indicated. In rats treated
    with a combination of HCB and triacetyloleandomycin (TAO, a selective
    inhibitor of cytochrome P-450IIIa), porphyria was greatly reduced.
    Remarkably, combined treatment with HCB and TAO did not substantially
    affect the incidence and severity of skin lesions. In addition, TAO
    did not influence the immunomodulatory effect of HCB, including the
    formation of antibodies. From these findings it has been suggested
    that an immunological component underlies, at least in part, the
    HCB-induced skin lesions in the rat (Schielen et al., 1995).

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

         Numerous reviews have been published of an accidental poisoning
    incident in Turkey that occurred in 1955-1959 as a result of
    HCB-treated wheat grain (distributed by the Turkish government for
    planting purposes) being ground into flour and made into bread
    (Schmid, 1960; Cam & Nigogosyan, 1963; Dogramaci, 1964; Peters, 1976;
    Courtney, 1979; Peters et al., 1982; US EPA, 1985a; Gocmen et al.,
    1989). In this incident, more than 600 cases of porphyria cutanea
    tarda (PCT) were clinically identified, and it was estimated that as
    many as 3000-5000 persons were affected, with a mortality of 10%. The
    condition developed primarily in children 4-14 years of age (roughly
    80% of cases), occurring infrequently in adults and rarely in children
    under 4 years of age. In a number of reports, it has been suggested
    that males developed the condition in higher proportion than females.
    However, Dogramaci et al. (1962) demonstrated that the sex ratio was
    skewed in favour of males in both the affected and unaffected
    populations. In addition to disturbances in porphyrin metabolism
    (excretion of porphyrins and porphyrin precursors was greatly
    increased), clinical manifestations included skin lesions (erythema,
    bullae), ulcerations and resultant scarring, friable skin,
    hyperpigmentation, hypertrichosis, enlarged liver, weight loss,
    enlargement of the thyroid gland and lymph nodes, neurological
    effects, and a characteristic port wine colour of the urine (from
    increased excretion of porphyrins). In roughly half the cases,
    osteoporosis of extremities, deformation of the fingers or arthritis
    was also noted. The dermatological lesions, which occurred on the
    exposed parts of the body, particularly the face and hands, were often
    precipitated by sunlight. They tended to remit in winter and relapse
    during the spring and summer (Peters, 1976; Peters et al., 1982). The
    estimated dose was 50-200 mg/day for a number of months before
    manifestations of the disease became apparent (Cam & Nigogosyan,
    1963); the basis for this estimate was not presented, however, making
    exposure calculations unreliable for this population. In 20- to 30-
    year follow-ups of exposed individuals, neurological, dermatological
    and orthopaedic abnormalities persisted, and there were elevated
    levels of porphyrins in excreta of some individuals (Peters et al.,
    1982; Peters et al., 1986; Gocmen et al., 1989).

         In this incident, a disorder called "pembe yara" or "pink sore"
    was described in infants of mothers who either had PCT or had eaten
    HCB-contaminated bread. These infants developed characteristic pink
    cutaneous lesions, and often had fevers, diarrhea, vomiting, weakness,
    convulsions, enlarged livers and progressive wasting. It is noteworthy
    that PCT was not observed in these children (Cam, 1960; Peters et al.,
    1982). At least 95% of these children died within a year of birth, and
    in many villages no children between the ages of 2-5 years survived
    during the period 1955-1960. Elevated concentrations of HCB (levels
    were not quantified at the time, but the average concentration in milk

    from 56 porphyric mothers, 20-30 years after the incident, was
    510 ng/g on a fat basis) were found in the mothers' milk and cessation
    of breast-feeding slowed the deterioration of infants with this
    disorder (Peters et al., 1966; Gocmen et al., 1989).

         No adequate epidemiological studies of cancer in populations
    exposed to HCB in the environment were found in the literature. In
    long-term follow-up of the Turkish poisoning victims with porphyria
    (Peters et al., 1982; Cripps et al., 1984; Gocmen et al., 1989) there
    was no evidence of increased cancer incidence, although these studies
    were not designed to evaluate this end-point, and only a small
    fraction of the exposed people was followed up. There was a high
    frequency of enlarged thyroids in the Turkish poisoning victims (27%
    of men and 60% of women, compared to an average of 5% in the area
    (Peters et al., 1982)), but Gocmen et al. (1989) reported that they
    observed no malignant tumours of the liver or thyroid in 252 of the
    poisoning victims. In three patients who underwent thyroidectomy,
    histopathological examination indicated that the enlargement was due
    to colloidal goitre.

         Grimalt et al. (1994) reported a small ecological study of cancer
    incidence (129 cases in all) in the inhabitants of a village in Spain
    located near a chlorinated solvents factory. There were statistically
    significant excesses of thyroid neoplasms and soft-tissue sarcomas in
    males, compared with the province as a whole, although these were
    based on only 2 and 3 cases, respectively. The exposures experienced
    by this population were somewhat unclear. Levels of HCB in ambient air
    and in the sera of volunteers were much higher in the village than in
    Barcelona (means of 35 ng/m3 versus 0.3 ng/m3 and 26 µg/litre versus
    4.8 µg/litre, respectively), but the authors presented evidence that
    historical exposures had been much higher and indicated that all of
    the males with cancer for whom there were occupational histories had
    worked in the factory. Ambient air monitoring revealed that there were
    exposures to a variety of other compounds, including polychlorinated
    biphenyls, p,p'DDE, chloroform, carbon tetrachloride,
    trichloroethylene and tetrachloroethylene, but at similar or lower
    levels than in the reference community.

    8.2  Occupational exposure

         There have been case reports of workers developing PCT as a
    result of direct contact with HCB (Courtney, 1979; Currier et al.,
    1980), although there was no association between exposure to HCB and
    PCT in three cross-sectional studies of very small populations of
    exposed workers (Morley et al., 1973; Burns et al., 1974; Currier et
    al., 1980). There was no evidence of cutaneous porphyria in a cross-
    sectional study of the general population in Louisiana, USA, exposed
    to HCB through the improper transport and disposal of hex waste;
    however, plasma concentrations of HCB were significantly correlated
    with levels of coproporphyrin in urine and of lactic dehydrogenase in
    blood (Burns & Miller, 1975).

         Available epidemiological studies on the carcinogenicity of HCB
    in occupationally exposed humans are restricted to one study of a
    cohort of 2391 magnesium metal production workers in Norway. Although
    the incidence of lung cancer was significantly elevated compared to
    that of the general population, workers were exposed to numerous other
    agents in addition to HCB, including coal tar, asbestos and dust of
    metal oxides and chlorides (Heldaas et al., 1989). Selden et al.
    (1989) reported a case of hepatocellular carcinoma in a 65-year-old
    man who had been employed for 26 years in an aluminum smelting plant,
    where he had potential exposure to a range of substances, including
    HCB, other chlorobenzenes, chlorophenols, dioxins and furans.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Data on the acute and chronic ecotoxicity of HCB are available
    for species from a number of trophic levels, including protozoans,
    algae, invertebrates and fish, for both the freshwater and marine
    environments. With reference to terrestrial organisms, toxicity data
    are available only for birds and mammals (the results of studies in
    mammals are summarized in chapter 7). Since HCB is nearly insoluble in
    water, and tends to partition from water to the atmosphere, the
    substance is lost rapidly from open-test solutions. Hence, it is
    difficult to maintain test concentrations for a sufficient time to
    establish concentration-effects profiles for aquatic organisms.
    Furthermore, HCB tends to bind to suspended solids in the water column
    and thus may not be bioavailable to test organisms. This discussion of
    the toxicity of HCB to aquatic organisms will therefore focus on tests
    conducted under flow-through conditions, static renewal conditions, or
    using closed vessels with minimal headspace. In addition, no
    consideration has been given to tests in which concentrations of HCB
    were well above its solubility in water (5 µg/litre at 25°C).

    9.1  Short-term exposure

    9.1.1  Aquatic biota

         Of four freshwater algal species tested, only one,  Chlorella
     pyrenoidosa, was affected by concentrations of HCB in water at or
    below its limit of aqueous solubility. Reduced production of
    chlorophyll, dry matter, carbohydrate and nitrogen was observed for
     C. pyrenoidosa after exposure to a nominal concentration of
    1 µg/litre HCB for 46 h in a static-closed system (Geike & Parasher,
    1976a). A no-observed-effect concentration (NOEC) was not determined
    in this study.

         At concentrations equal to its aqueous solubility in water
    (5 µg/litre), HCB was not lethal to the freshwater water flea
     Daphnia magna in a flow-through test in which concentrations of HCB
    were measured (Nebecker et al., 1989). In 96-h flow-through tests on
    marine invertebrates, exposure to HCB caused 13% mortality in pink
    shrimp ( Penaeus duorarum) at a measured concentration of 7 µg
    HCB/litre, and 10% mortality in grass shrimp ( Palaemonetes pugio) at
    17 µg/litre. The NOEC values in these species were 2.3 µg/litre and
    6.1 µg/litre, respectively (Parrish et al., 1974). In a static-closed
    system, there was a 10% reduction in reproduction of the ciliate
    protozoan  Euplotes vannus after exposure to a nominal concentration
    of 10 µg/litre HCB for 48 h (Persoone & Uyttersprot, 1975).

         The available data on freshwater fish species indicated no
    harmful effects at concentrations at or near the limit of solubility
    of HCB in water during acute exposure (Call et al., 1983; Ahmad et
    al., 1984). In the only available study for marine fish species, there
    were no effects on mortality in sheepshead minnow ( Cyprinodon
     variegatus) after flow-through exposure to a measured concentration
    of 13 µg/litre HCB for 96 h (Parrish et al., 1974).

         Limited data are available concerning the toxic effects of HCB in
    sediment on freshwater and marine biota. In a 96-h sediment toxicity
    test on the marine shrimp,  Crangon septemspinosa, no mortality was
    observed at the highest concentration of HCB tested, 300 µg/litre
    (McLeese & Metcalfe, 1980).

         Several studies have confirmed that there is a relatively
    constant body residue associated with acute lethality in freshwater
    fish, invertebrates and algae exposed to mono-to-pentachlorobenzenes
    (McCarty et al., 1992a; Ikemoto et al., 1992). The acute LC50
    critical body residue for chlorobenzenes is 2 µmol/g wet weight, or
    569.6 µg/g wet weight for HCB, assuming that HCB has the same mode of
    action as the other chlorobenzenes (McCarty et al., 1992b).

    9.1.2  Terrestrial biota

         The LD50 for HCB in herring gull ( Larus argentatus) embryos
    injected on day 4 and tallied on day 25 was 4.3 µg/g body weight
    (Boersma et al., 1986). At a dose of 1.5 µg/g body weight, there were
    significant reductions in embryonic weight. Five-day LC50 values
    (i.e., 5 days of HCB-containing diet followed by 3 days of untreated
    diet) were 617 µg/g diet for 10-day-old ring-necked pheasants
    ( Phasianus colchicus) and > 5000 µg/g diet for 5-day-old mallards
    ( Anas platyrhynchos) (Hill et al., 1975). Induction of porphyria has
    been observed in studies of Japanese quail following administration of
    500 µg HCB/g body weight per day for between 5 and 10 days either in
    food or via intraperitoneal injection (Buhler & Carpenter, 1986;
    Lambrecht et al., 1988).

    9.2  Long-term exposure

    9.2.1  Aquatic biota

         Growth of cultures of the alga  Chlorella  pyrenoidosa was
    increased by exposure for 3 months to a nominal concentration of 1 µg
    HCB/litre (Geike & Parasher, 1976b), while that of the protozoan
     Tetrahymena pyriformis was decreased after a 10-day exposure to the
    same concentration (Geike & Parasher, 1976b).

         After exposure to 5 µg HCB/litre for 10 days in a static-renewal
    system, crayfish ( Procambarus clarki) experienced damage to the
    hepatopancreas (Laseter et al., 1976). The fertility of  Daphnia
     magna was reduced by 50% after exposure for 14 days to a measured
    concentration of 16 µg/litre HCB in a static-closed system (Calamari
    et al., 1983). Significantly increased mortality was observed in
    amphipods,  Gammarus lacustris, exposed to a measured concentration
    of 3.3 µg HCB/litre for 28 days under flow-through conditions
    (Nebecker et al., 1989). However, the results of this study indicated
    a weak-dose response relationship. In two other flow-through studies,
    there were no effects on survival, growth or reproduction of the
    amphipod  Hyallela azteca and the worm  Lumbriculus variegatus at a
    measured concentration of 4.7 µg HCB/litre (Nebecker et al., 1989).

         In several studies, fathead minnows ( Pimephales promelas) and
    rainbow trout ( Oncorhynchus mykiss) experienced no mortality or
    effects on growth after exposure to levels of HCB approaching its
    aqueous solubility (Ahmad et al., 1984; Carlson & Kosian, 1987; US
    EPA, 1988; Nebecker et al., 1989). However, Laseter et al. (1976)
    reported liver necrosis in large-mouth bass ( Micropterus salmoides)
    after an exposure for 10 days to 3.5 µg HCB/litre under flow-through
    conditions.

         Guidelines for the protection and management of aquatic sediment
    quality in Ontario, Canada (Persaud et al., 1991) have given a no-
    observed-effect level (NOEL), a lowest-observed-effect level and a
    severe-effect level for a variety of contaminants. The values given
    for HCB are 10 ng/g dry weight, 20 ng/g dry weight and 24 000 ng/g
    organic carbon. The partitioning approach was used to determine the
    lowest-observed-effect level, whereas the severe-effect level was more
    dependent on the screening level concentration approach. The
    limitation of both approaches is that they are unable to separate the
    biological effects that are due to a combination of contaminants; thus
    while ecotoxicological effects can be established, these cannot be
    attributed to any one chemical contaminant. This is a very serious
    limitation since virtually all sediments are contaminated with a wide
    variety of pollutants, and there is no indication that HCB was the
    dominant pollutant.

         Quantitative structure-activity relationships (QSAR) were used to
    estimate the narcotic toxicity for 19 species to predict NOELs (Van
    Leeuwen et al., 1992). The NOELs for water, sediment and residues in
    biota were predicted only on the basis of the octanol/water partition
    coefficient and relative molecular mass. The QSAR-derived level for
    HCB in sediments was 5814 ng/g dry weight (20.4 nmol/g in the
    reference) for sediments with 5% total organic carbon content. The
    adjusted value for sediment with 1% total organic carbon content is
    1163 ng/g. There is no experimental verification of these
    calculations. Thus, no firm evidence is available on the critical
    levels of HCB in sediments.

    9.2.2  Terrestrial biota

         In adult Japanese quail ( Coturnix japonica) fed diets
    containing HCB for 90 days, mortality was increased at 100 µg HCB/g 
    in diet, and hatchability of eggs was significantly reduced at 20 µg/g
    (Vos et al., 1971, 1972). At 5 µg/g, increased liver weight, slight
    liver damage and increased faecal excretion of coproporphyrin were
    observed. Eurasian kestrels ( Falco tinnunculus) fed mice containing
    200 µg HCB/g fresh body weight for 65 days had significant weight
    loss, ruffling of feathers, tremors, increased liver weight and
    decreased heart weight (Vos et al., 1972).

         The available long-term toxicity data for mammals are discussed
    in section 7.

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

    10.1  Evaluation of human health risks

    10.1.1  Exposure

         Based on estimates of mean exposure from various media (section
    5.2), the general population is exposed to HCB principally in food
    (mean intakes for adults range from 0.0004 to 0.0028 µg/kg body weight
    per day). Intakes are estimated to be considerably less for ambient
    air (3.4 × 10-5 to 2.1 × 10-4 µg/kg body weight per day) and
    drinking-water (2.2 × 10-6 to 4.4 × 10-5 µg/kg body weight per day).
    Based on these intakes, it is estimated that the total average daily
    intake of HCB from food, air and drinking-water is between 0.0004 and
    0.003 µg/kg body weight per day.

         Data on levels of occupational exposure to HCB are limited but
    indicate that workers in some industries may be exposed to higher
    levels of HCB than the general population, particularly in the
    manufacture of chlorinated solvents, and in the manufacture and
    application of chlorinated pesticides contaminated with HCB. In some
    instances inappropriate manufacturing and waste management practices
    may expose nearby populations to higher levels of HCB than the general
    population. Exposures may also be elevated in some indigenous
    subsistence populations, particularly those that consume large
    quantities of food species near the top of the food chain.

         Owing to the elimination of HCB in breast milk, mean intakes by
    nursing infants are estimated to range from < 0.018 to 5.1 µg/kg body
    weight per day in various countries (see section 5.2.4 and Table 8).

    10.1.2  Health effects

         Available data on the effects of HCB in humans are limited
    principally to those of people exposed in an accidental poisoning
    incident that occurred in Turkey between 1955 and 1959. More than 600
    cases of porphyria cutanea tarda (PCT) were observed, and infants of
    exposed mothers experienced cutaneous lesions, clinical symptoms and
    high mortality. It has been estimated that victims were exposed to an
    estimated dose of 50-200 mg HCB/day for an undetermined, but extended,
    period of time. However, the basis of this estimate was not provided,
    making exposure calculations unreliable for this population. Studies
    of the carcinogenicity of HCB in humans are limited to two small
    epidemiological studies of cancer incidence in populations with poorly
    characterized exposure to HCB as well as to numerous other chemicals.
    No excesses of neoplasms have been reported in long-term follow-up
    studies of the people with porphyria in the incident in Turkey, but
    only a small fraction of the population was followed-up, and these
    studies were not designed specifically to assess neoplastic end-
    points.

         Hence, the available data on humans are inadequate to serve as a
    basis for assessment of effects from exposure to HCB. The remainder of
    this evaluation is, therefore, based on studies in animals.

         Based on the studies reviewed in section 7, the critical effects
    induced by HCB in experimental animals comprise both non-neoplastic
    and neoplastic effects.

         With respect to non-neoplastic effects, repeated exposure to HCB
    has been found to cause a wide range of non-neoplastic effects in
    several species of animals, with similar lowest-observed-effect-levels
    (LOELs) and no-observed-effect-levels (NOELs) for a number of end-
    points (see Table 9). In these studies, effects reported have included
    those on the liver in pigs and rats, on calcium metabolism in rats, on
    ovarian histopathology in monkeys, on immune function in mice and
    rats, on neurotransmitter levels in the hypothalamus of mink, on
    postnatal survival in mink, and on neurobehavioural development in
    rats. The range over which the various effects have been observed is
    quite narrow; the lowest LOELs compiled in Table 9 range from 0.1 to
    0.7 mg/kg body weight per day, while the lowest NOELs range from 0.05
    to 0.07 mg/kg body weight per day.

         Based on the induction of a variety of tumours in hamsters, rats
    and mice exposed by ingestion, there is sufficient evidence that HCB
    is carcinogenic in animals. The available evidence indicates that HCB
    has little or no genotoxic activity and is therefore unlikely to be a
    direct-acting (genotoxic) carcinogen. However, the Task Group noted
    that tumours, some of which were malignant, have been induced in
    multiple species, at multiple sites, in some instances at doses that
    were not overtly toxic in other respects and that are within an order
    of magnitude of those that produce more subtle toxicological effects,
    or following subchronic exposure. Although there is some evidence to
    suggest that HCB may cause cancer by indirect mechanisms, the evidence
    is not definitive at this time and does not address all tumour sites.

        Table 9.  No-observed-effect and lowest-observed-effect levels (NOELs and LOELs) in mammals exposed to HCB

                                                                                                                             

    Species   Effect                                            NOEL               LOEL           Reference
                                                             (mg/kg body        (mg/kg body
                                                           weight per day)    weight per day)
                                                                                                                             

    Mouse     Depressed delayed-type hypersensitivity            -               0.5a           Barnett et al.
              response to oxazolone in mice exposed                                             (1987)
              to HCB in peanut butter in utero
              (throughout gestation) and via nursing
              to 45 days of age (section 7.6)

    Mouse     Increased susceptibility to Leishmania             -               0.6            Loose et al. (1981);
              infection, and reductions in resistance                                           Loose (1982)
              to a challenge with tumour cells and in
              the cytotoxic macrophage activity of the
              spleen in mice with subchronic exposure
              to HCB in diet (section 7.6)

    Rat       Alterations in Ca metabolism (increased      0.07                  0.7            Andrews et al.
              serum 1,25-dihydroxy-vitamin-D3 levels,                                           (1989, 1990)
              reduced Ca excretion, alterations in
              femur density, bone morphometry and
              strength), increased liver weights, with
              subchronic gavage exposure to HCB
              (section 7.2)

    Rat       Increased cell-mediated and humoral                -               0.2a           Vos et al. (1983)
              immune function, intraalveolar
              macrophage accumulation, microsomal
              ethoxyresorufin-O-deethylase activity,
              in rats exposed to HCB in utero, via
              nursing and in the diet to 5 weeks of
              age (section 7.6)
                                                                                                                             

    Table 9 contd.

                                                                                                                             

    Species   Effect                                            NOEL               LOEL           Reference
                                                             (mg/kg body        (mg/kg body
                                                           weight per day)    weight per day)
                                                                                                                             

    Rat       Increased organ weights (heart, brain        0.05-0.07             0.27-0.35      Arnold et al. (1985);
              and liver) in F0 males, compound-                                                 Arnold & Krewski (1988)
              related histological changes in liver
              of both sexes of F1 rats with long-term
              exposure to HCB in diet (section 7.3)

    Rat       Ultrastructural changes in livers            0.05-0.06             0.25-0.30      Mollenhauer et al.
              (proliferation of SER, altered                                                    (1975, 1976)
              mitochrondria, increase in numbers of
              storage vesicles) of rats with long-term
              exposure to HCB in diet (section 7.3)

    Rat       Induction of in vivo mixed-function              -                 0.5-0.6        Grant et al. (1974)
              oxidase activity in rats with long-term
              exposure to HCB in diet (section 7.3)

    Rat       Dose-related decrease in the post-               -                 0.64           Lilienthal et al.
              reinforcement pause (PRP) after schedule-                                         (1996)
              controlled operant conditioning of rats
              exposed to HCB in utero, through nursing,
              and up to post-natal day 150

    Mink      Increased serotonin concentrations in            -                 0.16a          Rush et al. (1983);
              hypothalamus of mink dams with long-term                                          Bleavins et al. (1984a,b)
              dietary exposure to HCB, decreased
              dopamine levels in hypothalamus, reduced
              birth weights, and increased mortality
              to weaning in mink kits with in utero
              plus lactational exposure to HCB
              (sections 7.3, 7.5)
                                                                                                                             

    Table 9 contd.

                                                                                                                             

    Species   Effect                                            NOEL               LOEL           Reference
                                                             (mg/kg body        (mg/kg body
                                                           weight per day)    weight per day)
                                                                                                                             

    Dog       Nodular hyperplasia of gastric lymphoid            -               0.12           Gralla et al.
              tissue in beagles with long-term                                                  (1977)
              exposure to HCB in gelatin capsules
              (section 7.6)

    Pig       Increased urinary coproporphyrin and         0.05                  0.05           Den Tonkelaar et al.
              microsomal liver enzyme activity in                                               (1978)
              pigs with subchronic exposure to HCB
              in diet (section 7.2)
                                                                                                                             

    a    Doses reported are those received by dams
        10.1.3  Approaches to risk assessment

         The following is provided as a potential basis for derivation of
    guidance values. Since ingestion is by far the principal route of
    exposure and since the toxicological data for other routes of
    administration are insufficient for evaluation, only the oral route is
    addressed here, though the ultimate objective should be reduction of
    total exposure from all routes.

         Based on the scientific evaluation of the data for the non-
    neoplastic and neoplastic end-points, two possible approaches to
    develop health-based guidance values were suggested.

    10.1.3.1  Non-neoplastic effects

         The approach for non-neoplastic effects assumes a threshold for
    these effects and is based on the use of the NOAEL or NOEL and an
    uncertainty factor that takes account of interspecies and
    interindividual variation in sensitivity to the substance, as well as
    the quality of the available studies and the severity of effect.

         The available data are sufficient to develop a Tolerable Daily
    Intake (TDI) for HCB. The lowest reported NOELs and LOELs for several
    different types of effects, such as those on the liver in rats and
    pigs, calcium metabolism in rats, ovarian morphology in monkeys,
    immune function in rats and mice, neurobehavioural development in rats
    and perinatal survival in mink, fall within a very small range (Table
    9). Based on the lowest reported NOELs included in the table
    (approximately 0.05 mg/kg body weight per day based primarily on
    hepatic effects observed in a subchronic study in pigs and in chronic
    studies in rats), a TDI of 0.17 µg/kg body weight per day has been
    derived for non-neoplastic effects, by incorporating an uncertainty
    factor of 300 (x 10 for intraspecies variation; × 10 for interspecies
    variation, × 3 for severity of effect). A factor of 3 for severity of
    effects was chosen as HCB causes i) multiple non-neoplastic effects in
    several species, and ii) LOELs for a number of end-points for which
    NOELs have not been determined are very close to the NOEL, from the
    critical studies, of 0.05 mg/kg body weight per day. However, it is
    fully realized that national authorities may choose other end-points
    or uncertainty factors depending upon data evaluation and future
    scientific findings.

    10.1.3.2  Neoplastic effects

         The approach for neoplastic effects is based on the Tumorigenic
    Dose5, or TD5 i.e., the intake or exposure associated with a 5%
    excess incidence of tumours in experimental studies in animals (IPCS,
    1994). This is a benchmark approach in which the TD5 is calculated
    directly from the experimental data rather than using the upper or
    lower confidence limits. Uncertainty factors are then applied to the
    TD5 to obtain a guidance value. The choice of uncertainty factors is
    based on the level and nature of mechanistic data available, the 

    quality of the database, the tumour pattern, the dose-response
    relationship, and the experimental model chosen. The final value will
    reflect the degree of certainty one has with the available
    information.

         For the purpose of indicating the magnitude of risk of HCB, the
    two-generation study in rats has been selected, owing to its relevance
    to the exposure of the general human population, as the design of this
    study involved exposure to relatively low concentrations of HCB in the
    diet (including  in utero and lactational exposure). Moreover, tumour
    pathology was inadequately reported in the available studies in
    hamsters and mice, and there is some concern that in the other
    adequate study in rats, there may also have been exposure by
    inhalation to some HCB that was incorporated in the diet as a powder.

         The TD5 value was calculated from the results of the two-
    generation study in rats using a multistage model (Crump & Howe,
    1982). The tumour incidences in the pups were analysed in the same
    manner as data from a single-generation study, owing to the lack of
    information on individual litters. On this basis, the TD5 values
    range from 0.81 mg/kg body weight per day for neoplastic liver nodules
    in females to 2.01 mg/kg body weight per day for parathyroid adenomas
    in males. The Task Group decided that the most sensitive end-point
    (neoplastic nodules of the liver) would be used in its analysis. In
    calculating the suggested guidance value, it was agreed to use an
    uncertainty factor of 5000, based on consideration of the insufficient
    mechanistic data. The TD5 was divided by this uncertainty factor to
    arrive at the suggested guidance value of 0.16 µg/kg body weight per
    day. However, it is fully realized that national authorities may
    choose other end-points or uncertainty factors depending upon data
    evaluation and future scientific findings.

         Although infants may have a high intake of HCB via breast milk
    for a short time, the TD5 and TDI were considered to be protective of
    the health of this population (unless there are extreme exposures),
    because one of the long-term studies used in deriving these values
    included lactational exposure. However, it should be noted that the
    TD5 and TDI values derived above should not be compared directly with
    intakes from breast milk by nursing infants, since the guidance values
    are based on a lifetime intake, whereas the duration of breast-feeding
    is relatively short.

    10.2  Evaluation of effects on the environment

         HCB is widely distributed in the environment, by virtue of its
    mobility and resistance to degradation, although slow photodegradation
    in air (half-life of approximately 80 days) and microbial degradation
    (half-life of several years) do occur. It has been detected in air,
    water, sediment, soil and biota from around the world. HCB is a
    bioaccumulative substance (BCF values range from 375 to > 35 000),
    and biomagnification of HCB through the food chain has been reported.

         In studies of the acute toxicity of HCB to aquatic organisms,
    exposure to concentrations in the range of 1 to 17 µg/litre reduced
    production of chlorophyll in algae and reproduction in ciliate
    protozoa. In longer-term studies, the growth of sensitive freshwater
    algae and protozoa was affected by a concentration of 1 µg/litre,
    while a concentration of approximately 3 µg/litre caused mortality in
    amphipods and liver necrosis in largemouth bass. The concentrations of
    HCB in surface waters around the world are much lower than these
    effect levels (3 to 5 orders of magnitude lower), except in a few
    extremely contaminated localities.

         Injection studies in eggs have shown that tissue levels of
    1500 ng/g wet weight reduce embryo weights in herring gulls (lowest
    dose tested). No studies were available to establish a NOAEL. For many
    bird species, reduced embryo weights are associated with lower
    survival of chicks. This effect level is within an order of magnitude
    of the levels measured in the eggs of sea birds and raptors from a
    number of locations from around the world, suggesting that present
    levels of HCB in certain locations may harm embryos of bird species.

         Experimental studies on mink indicate that they are sensitive to
    the toxic effects of HCB; long-term ingestion of diets containing 
    1000 ng HCB/g (the lowest dose tested) increased mortality, decreased 
    birth weights of offspring exposed  in utero and via lactation, and 
    altered levels of neurotransmitters in the hypothalamus of dams and 
    their offspring. No studies were available to establish a NOAEL. This
    dietary effect level is only a few times higher than the
    concentrations of HCB measured in various species of fish from a
    number of industrialized locations from around the world, suggesting
    that present levels of HCB in fish species from certain locations may
    adversely affect mink and perhaps other fish-eating mammals.

    11.  RECOMMENDATION FOR PROTECTION OF HUMAN HEALTH AND THE ENVIRONMENT

    a)   Alternatives should be found for any present uses of HCB.

    b)   It is important to reduce the environmental burden of HCB by:

         (i)  identifying remaining sources and quantities of release to
              the environment from these sources, including point source
              emissions, waste disposal sites and production facilities;

         (ii) applying appropriate manufacturing and waste disposal
              practices in order to decrease levels of HCB in the
              environment.

    c)   Human monitoring of HCB in blood and breast milk should be
         undertaken to develop data representing exposure of the general
         population, in order to identify highly exposed populations and
         potential sources, and to enable interpretation of individual
         results.

    d)   In order to gauge the efficacy of control measures it would be
         valuable to monitor environmental levels and effects in locations
         where levels are higher than the global average.

    e)   Neonatal effects in humans and other species have been associated
         with ingestion of high doses of HCB through breast milk. It is
         recommended that techniques be developed to assess appropriately
         the risk to infant health from exposure to HCB and related
         compounds in breast milk.

    12.  FURTHER RESEARCH

    12.1  Environment

    a)   To improve the database available for environmental risk
         assessment, it is considered important to establish a NOEL for
         the serious reproductive effects seen in mink at dietary levels
         approaching those found in certain locations.

    b)   Since HCB is persistent in soil and sediment, it would be
         valuable to perform biodiversity experiments with HCB-treated
         soil and sediment.

    12.2  Human health

    a)   Based on the effects of low doses of HCB on ovarian tissues in
         primates, involving disorders of germ cells and the ovarian
         surface epithelium, the following is recommended:

         (i)  exposed populations should be studied for relevant
              reproductive human outcomes of interest, particularly, fetal
              loss and ovarian cancer;

         (ii) reproductive tissues such as ovarian follicular fluid should
              be included in human monitoring studies on HCB levels and/or
              effects.

    b)   In order to decrease uncertainty in the risk assessment of HCB
         and related compounds, research into the primary mechanism(s) of
         action for tumorigenic, thyroid, reproductive, porphyrigenic,
         neurotoxic and immunological effects of HCB should be undertaken.

    c)   Preliminary evidence suggests that HCB acts, at least in part,
         through Ah receptor-linked mechanisms. This should be evaluated
         more fully and compared to other polyhalogenated aromatic
         chemicals for which a wealth of data are already available.

    d)   Given the toxicity of HCB and the few data for humans,
         multicentre longitudinal studies of highly exposed human
         populations should be undertaken. End-points of interest should
         cover toxicokinetics (e.g., half-life), thyroid function,
         porphyrin metabolism, reproductive outcomes (e.g., fetal losses),
         and cancer. Nursing infants from these populations should be
         followed to assess immunological and neurobehavioural
         development.

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer has classified
    HCB as a Group 2B carcinogen (possibly carcinogenic to humans) based
    on inadequate evidence for carcinogenicity to humans and sufficient
    evidence for carcinogenicity to animals (IARC, 1987).

         A drinking-water guideline of 1 µg/litre was developed for HCB
    based on an evaluation of the production of liver tumours in female
    rats and applying the linearized multistage model to calculate an
    excess life-time cancer risk of 10-5 (WHO, 1993).

         A conditional acceptable daily intake of 0.6 µg HCB/kg body
    weight was developed by the Joint FAO/WHO Joint Meeting on Pesticide
    Residues in Food (FAO/WHO, 1975). This recommendation was withdrawn in
    1978 (FAO/WHO, 1978).

         Regulatory standards established by national bodies in different
    countries and the European Union are summarized in the Legal File of
    the International Register of Potentially Toxic Chemicals (IRPTC,
    1993).

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    RÉSUMÉ ET CONCLUSIONS

    1.  Identité, propriétés chimiques et physiques et méthodes d'analyse

         L'hexachlorobenzène (HCB) est un composé organique chloré
    modérément volatil. Il est pratiquement insoluble dans l'eau, mais
    extrêmement soluble dans les lipides et présente une tendance à la
    bioaccumulation. L'hexachlorobenzène de qualité technique contient
    jusqu'à 2% d'impuretés, dont la principale est le pentachlorobenzène.
    Les autres consistent en dibenzo- p-dioxines, dibenzofuranes et
    biphényles fortement substitués par le chlore. L'analyse des
    échantillons biologiques ou prélevés dans l'environnement comporte
    généralement une extraction préliminaire de la prise d'essai, souvent
    suivie d'une purification, après quoi les extraits organiques sont
    soumis soit à une chromatographie en phase gazeuse couplée à la
    spectrométrie de masse (GC/MS), soit à une chromatographie en phase
    gazeuse avec détection par capture d'électrons (GC/ECD).

    2.  Sources d'exposition humaine et environnementale

         L'hexachlorobenzène a été utilisé un temps comme fongicide pour
    traiter les semences, mais il n'est plus actuellement utilisé à cet
    effet dans la plupart des pays. Il continue néanmoins à être libéré
    dans l'environnement à partir d'un certain nombre de sources,
    notamment lors de l'épandage de pesticides organochlorés, ou encore
    lorsque les sous-produits de la préparation des solvants, composés
    aromatiques ou pesticides chlorés sont rejetés sans précautions,
    incomplètement brûlés ou s'échappent de décharges anciennes.

    3.Transport, distribution et transformation dans l'environnement

         L'hexachlorobenzène est réparti dans tout l'environnement du fait
    de sa mobilité et de sa persistance, même s'il se décompose lentement
    dans l'air sous l'action de la lumière et dans le sol sous l'action
    des microorganismes. Dans la troposphère, il est transporté sur de
    grandes distances et s'élimine de l'air en se déposant sur le sol et
    sur l'eau. On a fait état d'une bioamplification notable le long de la
    chaîne alimentaire.

    4.  Concentrations dans l'environnement et exposition humaine

         Un peu partout dans le monde, l'hexachlorobenzène est présent, à
    distance de ses sources, sous faible concentration dans l'air ambiant
    (quelques ng/m3 ou moins) ainsi que dans l'eau de boisson et les eaux
    de surface (quelques ng/litre tout au plus). Cependant, au voisinage
    des points d'émission, on a pu mesurer des concentrations plus
    élevées. Ce composé s'accumule dans les milieux biologiques et on en a
    décelé la présence chez des invertébrés, des poissons, des reptiles,
    des oiseaux et des mammifères (y compris l'Homme) à distance des
    points d'émission, en particulier dans les tissus adipeux des
    organismes situés aux niveaux trophiques supérieurs. Chez la
    population humaine de divers pays, on en a mesuré dans les tissus

    adipeux des quantités qui vont, en moyenne, de quelques dizaines à
    quelques centaines de ng/g de poids humide. En se fondant sur les
    quantités représentatives d'hexachlorobenzène présentes dans l'air,
    l'eau et les denrées alimentaires, on peut estimer à une valeur
    comprise entre 0,0004 et 0,003 µg/kg de poids corporel, la dose
    absorbée journalièrement par un adulte de la population générale. Cet
    apport se fait principalement par la voie alimentaire. Du fait de la
    présence d'hexachlorobenzène dans le lait maternel, on estime que dans
    les différents pays les enfants nourris au sein en reçoivent
    quotidiennement une quantité comprise entre < 0,018 et 5,1 µg/kg de
    poids corporel. Les études consacrées à l'évolution de la quantité
    d'hexachlorobenzène présente dans l'organisme humain montrent, pour la
    plupart, que l'exposition de la population générale a baissé dans de
    nombreux endroits, entre les années 70 et le milieu de la décennie
    actuelle.

    5.  Cinétique et métabolisme chez l'Homme et les animaux de
        laboratoire

         On manque de données toxicocinétiques chez l'Homme.
    L'hexachlorobenzène est facilement résorbé par la voie orale chez
    l'animal d'expérience, mais il franchit mal la barrière cutanée (on ne
    possède pas de données concernant l'inhalation). Chez l'Homme et
    l'animal, il s'accumule dans les tissus riches en lipides, comme les
    tissus adipeux, le cortex surrénalien, la moelle osseuse, la peau et
    certains tissus endocriniens. En outre, il peut être transmis à la
    progéniture par l'intermédiaire du lait maternel ou en traversant la
    barrière placentaire. La métabolisation de l'hexachlorobenzène est
    limitée et ses principaux métabolites urinaires sont le
    pentachlorophénol, la tétrachlorhydroquinone et le
    pentachlorothiophénol. La demi-vie d'élimination de
    l'hexachlorobenzène va d'environ un mois chez les rats et les lapins à
    2 ou 3 ans chez le singe.

    6.  Effets sur les animaux de laboratoire et dans les épreuves
        in vitro

         L'hexachlorobenzène présente une faible toxicité aiguë pour les
    animaux de laboratoire (1000 à 10 000 mg/kg de poids corporel).
    L'expérimentation animale montre en outre que ce composé n'est pas
    irritant pour la peau ou les yeux et ne provoque pas de
    sensibilisation chez le cobaye.

         Les données dont on dispose au sujet de la toxicité générale de
    l'hexachlorobenzène indiquent que celle-ci s'exerce notamment au
    niveau de la voie de biosynthèse de l'hème. Chez plusieurs espèces de
    mammifères de laboratoire exposés à de l'hexachlorobenzène, on a
    constaté une élévation des concentrations de porphyrines ou de leurs
    précurseurs dans les excréta ainsi que dans divers tissus, notamment
    le tissu hépatique. De nombreuses études ont relevé des cas de
    porphyrie chez des rats exposés de manière chronique ou subchronique à

    de l'hexachlorobenzène administré par voie orale à des doses
    quotidiennes comprises entre 2,5 et 15 mg par kg de poids corporel.
    Chez des porcs à qui on faisait ingérer ce composé en doses
    quotidiennes égales ou supérieures à 0,5 mg par kg de poids corporel,
    on a observé une augmentation de l'excrétion des coproporphyrines
    (aucun effet n'a été observé dans cette étude à la dose de 0,05
    mg/kg). On a également montré que l'exposition à l'hexachlorobenzène
    affectait de nombreux organes ou systèmes (comme le foie, les poumons,
    les reins, la thyroïde, la peau ainsi que le système nerveux et le
    système immunitaire) mais ces effets n'ont pas été aussi souvent
    signalés que la porphyrie.

         L'hexachlorobenzène est un inducteur du cytochrome P-450 de type
    mixte. Il possède des propriétés phénobarbital-inductibles et
    3- méthylcholantrène-inductibles. Il se fixe sur le récepteur Ah.

         Lors d'études longitudinales sur des rats, on a observé à
    plusieurs reprises des effets bénins (modifications
    histopathologiques, induction d'enzymes) chez les animaux recevant des
    doses quotidiennes comprises entre 0,25 et 0,6 mg de composé par kg de
    poids corporel. La dose sans effet observable obtenue dans ces études
    se situait entre 0,05 et 0,07 mg d'hexachlorobenzène par kg de poids
    corporel et par jour. Chez des visons femelles, on a observé une
    modification de la concentration de neurotransmetteurs dans
    l'hypothalamus après administration prolongée du composé par la voie
    alimentaire à la dose quotidienne de 0,16 mg par kg de poids corporel.
    Les mêmes constatations ont été faites dans la progéniture de ces
    animaux, qui avait été exposée pendant les périodes gestationnelle et
    périnatale. Lors d'études subchroniques sur des rats on a constaté une
    modification de l'homéostase calcique et des paramètres
    ostéomorphométriques à la dose quotidienne de 0,7 mg/kg de poids
    corporel, mais pas à celle de 0,07 mg/kg.

         Un certain nombre d'études  in vivo ont été effectuées sur des
    rongeurs afin de mettre en évidence la cancérogénicité éventuelle de
    l'hexachlorobenzène. Chez des hamsters qui avaient reçu une nourriture
    contenant de l'hexachlorobenzène à la dose moyenne de 4, 8 ou 16 mg/kg
    de poids corporel, on a observé chez les deux sexes et à toutes les
    doses un accroissement de l'incidence des carcinomes
    hépatocellulaires. Aux doses de 8 et 16 mg/kg, on constatait la
    présence d'hémangioendothéliomes et à la dose la plus forte,
    d'adénomes de la thyroïde chez les mâles. En exposant pendant 120
    semaines des souris à ce composé par la voie alimentaire aux doses
    quotidiennes respectives de 6, 12 et 24 mg/kg de poids corporel, on a
    provoqué un accroissement de l'incidence des carcinomes
    hépatocellulaires chez les deux sexes aux deux doses les plus élevées,
    mais cet accroissement n'était pas significatif, sauf chez les
    femelles exposées à la dose la plus forte.  In utero, l'exposition de
    rats par la voie orale ou lactationnelle à des doses alimentaires
    quotidiennes d'hexachlorobenzène allant de 0,01 à 1,5 mg/kg de poids
    corporel (mâles) ou de 1,9 mg/kg (femelles) pendant des périodes
    pouvant durer jusqu'à 130 semaines  post utero, c'est-à-dire la durée
    de vie moyenne, a entraîné à la dose la plus forte un accroissement de

    l'incidence des nodules hépatiques néoplasiques et des
    phéochromocytomes surrénaliens chez les femelles et un excès
    d'adénomes parathyroïdiens chez les mâles. Lors d'une autre étude
    chronique effectuée sur des rats, on a exposé les animaux, par la voie
    alimentaire et pendant des durées allant jusqu'à 2 ans, à des doses
    journalières moyennes de 4-5 et 8-9 mg/kg de poids corporel. Les
    effets constatés consistaient en une augmentation de l'incidence des
    hépatomes et des adénomes rénaux aux deux doses et chez les deux
    sexes. Chez les femelles, on observait en outre une augmentation de
    l'incidence des carcinomes hépatocellulaires, des adénomes et des
    carcinomes des voies biliaires, des phéochromocytomes et des adénomes
    du cortex surrénalien. On a également signalé une incidence élevée des
    tumeurs du foie dans un certain nombre d'études plus limitées au cours
    desquelles on avait administré une seule dose d'hexachlorobenzène par
    la voie alimentaire à de petits groupes de rates. Par ailleurs, on a
    observé qu'après exposition subchronique par voie alimentaire à ce
    composé, des souris, des hamsters et des rats avaient présenté des
    tumeurs du foie, des voies biliaires, du rein, du thymus, de la rate
    et des ganglions lymphatiques. Le même type d'exposition favorise
    l'apparition de tumeurs hépatiques chez des souris sous l'action de
    terphényles polychlorés et chez des rats, sous l'action de la
    diéthylnitrosamine.

         Sauf dans le cas des tumeurs rénales chez les rats mâles (qui, du
    moins en partie, semblent résulter d'une dégénérescence hyaline) et
    des hépatomes chez les rats des deux sexes (qui pourraient résulter de
    réactions hyperplasiques à la nécrose hépatocellulaire), on n'a pas pu
    trouver d'études mécanistiques concernant les divers types de tumeurs
    provoquées par l'hexachlorobenzène et le risque encouru à cet égard
    par l'Homme.

         L'hexachlorobenzène n'a guère d'aptitude à provoquer directement
    des mutations géniques, des lésions chromosomiques ou la réparation de
    l'ADN. Il s'est révélé faiblement mutagène lors de quelques-unes des
    études portant sur des bactéries et des levures, mais il convient de
    noter que chacune de ces études comportait des limitations. Il y a
    également des signes d'un faible taux de liaison à l'ADN  in vitro et
     in vivo, mais dans une proportion très inférieure à celle que l'on
    attendrait d'une substance cancérogène génotoxique.

         Lors d'études sur la reproduction, des doses d'hexachlorobenzène
    ne dépassant pas 0,1 mg par kg de poids corporel qu'on avait fait
    ingérer quotidiennement pendant 90 jours à des singes, ont provoqué
    des anomalies dans la structure microscopique et l'ultrastructure de
    l'épithélium germinatif superficiel, structures qui constituent une
    cible inhabituelle pour des toxines ovariennes. Cette dose a également
    endommagé l'ultrastructure des cellules germinales primordiales. Alors
    même que ces sites étaient spécifiquement attaqués et présentaient des
    lésions d'autant plus importantes que la dose était plus forte, le
    développement folliculaire, ovocytaire et embryonnaire restait normal,
    ce qui semble indiquer que l'hexachlorobenzène a un site d'action à
    localisation spécifiquement ovarienne. Chez les mâles, la fonction de
    reproduction n'est affectée qu'à des doses beaucoup plus élevées

    (entre 30 et 221 mg/kg p.c. par jour), comme l'ont montré un certain
    nombre d'études effectuées sur plusieurs espèces n'appartenant pas à
    l'ordre des primates.

         Des rats et des chats exposés par la voie transplacentaire ou
    lactationnelle à des doses quotidiennes d'hexachlorobenzène comprises
    entre 3 et 4 mg/kg p.c. ont présenté des signes d'hépatotoxicité et on
    a également constaté des effets délétères sur la survie et la
    croissance de leur progéniture. Dans certains cas, il y avait à ces
    doses - ou à des doses plus élevées - une réduction de l'effectif des
    portées et un nombre accru de mortinaissances. (En général, les ratons
    et les chatons à la mamelle étaient plus souvent affectés - et à des
    doses plus faibles - que les embryons et les foetus). Chez la
    progéniture de visons qui recevaient une alimentation ne contenant pas
    plus de 1 mg d'hexachlorobenzène par kg de nourriture (soit environ
    0,16 mg/kg p.c. par jour), on a constaté une réduction du poids de
    naissance et un accroissement de la mortalité au sevrage. Quelques
    études ont mis en évidence des anomalies squelettiques ou rénales chez
    les foetus de rats et de souris exposés à de l'hexachlorobenzène
    pendant la gestation, mais les doses qui produisaient ces anomalies
    n'étaient pas toxiques pour les mères. Par ailleurs, le lien de ces
    anomalies avec la prise d'hexachlorobenzène n'a pas été formellement
    établi. Dans deux études, dont l'une comportait une exposition
    transplacentaire et postnatale, on a observé des anomalies du
    développement neurocomportemental des ratons après exposition
     in utero, les mères ayant reçu par voie orale des doses quotidiennes
    d'hexachlorobenzène allant de 0,64 à 2,5 mg/kg de poids corporel.

         Selon un certain nombre d'études, l'hexachlorobenzène aurait des
    effets délétères sur le système immunitaire. Chez des rats et des
    singes exposés à des doses quotidiennes comprises entre 3 et 120 mg
    d'hexachlorobenzène par kg de poids corporel, on a constaté des
    modifications histopathologiques au niveau du thymus, de la rate, des
    ganglions lymphatiques et des tissus lymphoïdes pulmonaires. Chez des
    chiens beagle exposés de façon chronique à des doses quotidiennes
    correspondant à 0,12 mg de composé par kg p.c., on a observé une
    hyperplasie nodulaire du tissu lymphoïde gastrique. Un certain nombre
    d'études menées sur des rats ont montré qu'après plusieurs semaines
    d'exposition à de l'hexachlorobenzène par la voie alimentaire, il y
    avait stimulation de l'immunité humorale, et dans une moindre mesure,
    de l'immunité à médiation cellulaire, sans modification de la fonction
    des macrophages. A des doses quotidiennes ne dépassant pas 4 mg de
    composé par kg de nourriture (environ 0,2 mg par kg p.c.),
    administrées pendant la gestation, pendant le maternage et jusqu'à
    l'âge de 5 semaines, il y a eu augmentation de la réponse immunitaire
    à médiation cellulaire et de la réponse immunitaire humorale ainsi
    qu'une accumulation de macrophages dans le tissu pulmonaire des
    ratons. Par contre, la plupart des études effectuées sur des souris
    ont fait ressortir les propriétés immunosuppressives de
    l'hexachlorobenzène; des doses ne dépassant pas 0,5 à 0,6 mg/kg de
    poids corporel administrées quotidiennement pendant plusieurs semaines
    ont eu les effets suivants: diminution de la résistance à une
    infection leishmanienne ou à une épreuve cancérogène par exposition à 

    des cellules tumorales, réduction de l'activité cytotoxique des
    macrophages spléniques et de l'hypersensibilité retardée chez la
    progéniture après exposition  in utero ou pendant la période de
    maternage. Lors d'un certain nombre d'études portant sur diverses
    souches de rats, on a constaté qu'une exposition de brève durée ou une
    exposition subchronique à de l'hexachlorobenzène modifiait la fonction
    thyroïdienne, comme on pouvait en juger d'après la réduction de la
    thyroxine sérique libre ou totale (T4) et souvent, mais dans une
    moindre mesure, de la triiodothyronine (T3).

    7.  Effets sur l'Homme

         La plupart des données que l'on possède au sujet des effets de
    l'hexachlorobenzène sur l'Homme, proviennent d'intoxications
    accidentelles qui se sont produites en Turquie en 1955-59, avec plus
    de 600 cas répertoriés de porphyrie cutanée tardive. Lors de cet
    accident, on a observé des troubles du métabolisme des porphyrines,
    des lésions cutanées, des hyperpigmentations, des hypertrichoses, des
    hépatomégalies, des hypertrophies de la thyroïde et des ganglions
    lymphatiques, avec, dans environ la moitié des cas, une ostéoporose et
    une arthrite, principalement d'ailleurs, chez les enfants. Les enfants
    nourris au sein dont la mère avait été exposée, présentaient des
    lésions appelées  pembe yara, c'est-à-dire "lésions roses", et la
    plupart d'entre eux sont décédés dans l'année. On dispose de quelques
    données concernant des cas de porphyrie cutanée tardive chez des
    personnes ayant subi une exposition relativement intense à
    l'hexachlorobenzène sur leur lieu de travail ou dans leur
    environnement général.

         Les quelques études épidémiologiques disponibles concernant le
    cancer souffrent d'un certain nombre d'insuffisances: effectif réduit,
    exposition à l'hexachlorobenzène mal caractérisée ou exposition
    simultanée à de nombreux autres agents, et ne permettent pas d'évaluer
    la cancérogénicité de ce composé pour l'Homme.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         Lors d'études sur la toxicité aiguë de l'hexachlorobenzène pour
    les organismes aquatiques, on a constaté que l'exposition à des
    concentrations de l'ordre de 1 à 17 µg/litre réduisait la production
    de chlorophylle chez les algues ainsi que la reproduction chez les
    ciliés, et qu'en outre, elle provoquait la mort des crevettes roses et
    des crevettes américaines du genre  Hippolyte, mais elle n'a pas
    provoqué la mort de poissons d'eau douce ou de mer. Lors d'études à
    plus long terme, on a constaté que la croissance de certaines algues
    et protozoaires dulçaquicoles sensibles étaient affectée à une
    concentration d'hexachlorobenzène de 1 µg/litre et que des
    concentrations d'environ 3 µg/litre provoquaient la mort d'amphipodes
    et de perches appartenant à l'espèce  Micropterus salmoides.

    9.  Evaluation des risques pour la santé humaine et des effets sur
        l'environnement

    9.1  Effets sur la santé

         Le Groupe de travail a conclu que les données disponibles sont
    suffisantes pour que l'on puisse formuler des valeurs-guides relatives
    aux effets cancérogènes et non cancérogènes de l'hexachlorobenzène.

         En ce qui concerne les effets non cancérogènes constatés sur le
    foie à dose élevée chez des porcs et des rats exposés par la voie
    orale et en se basant sur la dose sans effet observable la plus faible
    (0,05 mg/kg de poids corporel par jour), on arrive, compte tenu d'un
    facteur d'incertitude de 300 (10× pour les variations
    interspécifiques, 10x pour les variations intraspécifiques et 3× pour
    la gravité de l'effet), à une TDI de 0,17 µg/kg de poids corporel.

         La méthode utilisée pour déterminer la valeur-guide relative aux
    effets cancérogènes repose sur la dose tumorigène TD5, c'est-à-dire
    la dose ingérée qui provoque une augmentation de 5% de l'incidence
    tumorale chez les animaux de laboratoire. D'après les résultats d'une
    étude de cancérogénicité portant sur deux générations de rats et en
    faisant appel à un modèle multiphasique, on obtient une TD5 de
    0,81 mg/kg de poids corporel par jour, l'effet retenu étant la
    formation de nodules cancéreux hépatiques chez les femelles. Compte
    tenu de l'insuffisance des données mécanistiques, on a appliqué un
    facteur d'incertitude de 5000 pour calculer la valeur-guide chiffrée à
    0,16 µg/kg de poids corporel par jour.

    9.2  Effets sur l'environnement

         Le Groupe de travail a remarqué qu'il existe très peu d'études
    expérimentales à partir desquelles on puisse procéder à une évaluation
    du risque écologique. La concentration d'hexachlorobenzène dans les
    eaux de surface est généralement inférieure de plusieurs ordres de
    grandeur à celle qui pourrait être dangereuse pour les organismes
    aquatiques, sauf dans certains endroits fortement pollués. Toutefois,
    les concentrations d'hexachlorobenzène relevées dans les oeufs
    d'oiseaux de mer et de rapaces en différents lieux du globe sont
    proches de celles qui provoquent une diminution du poids des embryons
    chez la mouette argentée (1500 µg/kg), ce qui incite à penser que le
    composé pourrait être embryotoxique pour certaines espèces sensibles
    d'oiseaux. De même, les concentrations d'hexachlorobenzène dans les
    poissons de divers endroits du monde sont du même ordre de grandeur
    que la dose de 1000 µg/kg qui entraîne une réduction du poids de
    naissance et une augmentation de la mortalité chez la progéniture de
    visons. Cela incite à penser que ce composé pourrait avoir des effets
    indésirables chez les visons et éventuellement chez d'autres
    mammifères piscivores.

    10.  Conclusions

    a)  L'hexachlorobenzène est un composé chimique persistant qui subit
    une bioaccumulation du fait de sa liposolubilité et de sa résistance à
    la décomposition.

    b)  L'expérimentation animale montre que l'hexachlorobenzène provoque
    des cancers et affecte de nombreux organes, tissus et systèmes comme
    le foie, les poumons, les reins, la thyroïde, les tissus des gonades,
    le système nerveux et le système immunitaire.

    c)  En ce qui concerne l'Homme, on a pu observer, à l'occasion d'une
    forte exposition d'origine accidentelle, les manifestations cliniques
    d'une intoxication par l'hexachlorobenzène qui se traduisaient par une
    porphyrie cutanée tardive chez les enfants et les adultes et par la
    mort chez des nourrissons alimentés au sein.

    d)  Il est justifié de prendre diverses mesures pour réduire la
    quantité d'hexachlorobenzène présente dans l'environnement.

    e)  On a proposé les valeurs-guides à visée sanitaire suivantes pour
    la dose totale ingérée quotidiennement (TDI): en ce qui concerne les
    effets non cancérogènes, 0,17 µg/kg de poids corporel par jour ; en ce
    qui concerne les effets cancérogènes, 0,16 µg/kg de poids corporel par
    jour.

    1.  RÉSUMEN Y CONCLUSIONES

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         El hexaclorobenceno (HCB) es un compuesto orgánico clorado de
    volatilidad moderada. Es prácticamente insoluble en el agua, pero es
    muy liposoluble y bioacumulativo. El HCB de calidad técnica contiene
    hasta un 2% de impurezas, en su mayor parte pentaclorobenceno; el
    resto incluye dibenzo- p-dioxinas, dibenzofuranos y bifenilos
    altamente clorados. Para determinar el HCB en el medio ambiente y en
    material biológico se procede por lo general a extraer la muestra
    mediante disolventes orgánicos, a lo que sigue con frecuencia un paso
    de limpieza, a fin de obtener extractos orgánicos analizables mediante
    cromatografía de gases/espectrometría de masas (GC/MS) o cromatografía
    de gases con detección de captura de electrones (GC/ECD).

    2.  Fuentes de exposición humana y ambiental

         Hubo un tiempo en que el HCB se utilizó mucho en la limpieza de
    semillas para prevenir las enfermedades micóticas de los cereales,
    pero ese uso se abandonó en la mayor parte de los países en los años
    setenta. El HCB se sigue liberando en el medio ambiente a partir de
    diversas fuentes, que incluyen el uso de algunos plaguicidas clorados,
    procesos de combustión incompleta y viejos vertederos, así como los
    métodos inapropiados de producción y de eliminación de desechos en la
    fabricación de disolventes clorados, compuestos aromáticos clorados y
    plaguicidas clorados.

    3.  Transporte, distribución y transformación en el medio ambiente

         El HCB se distribuye por todo el medio ambiente porque es móvil y
    persistente, aunque se produce una lenta fotodegradación en el aire y
    una degradación microbiana en el suelo. En la troposfera el HCB es
    transportado a grandes distancias y es eliminado de la fase aérea por
    su depósito en el agua y el suelo. Se ha informado de que se produce
    una importante bioamplificación del HCB a través de la cadena trófica.

    4.  Niveles ambientales y exposición humana

         Se encuentran concentraciones bajas de HCB en el aire ambiental
    (a lo sumo unos pocos ng/m3), en el agua de bebida y en las aguas
    superficiales (a lo sumo unos pocos ng/litro) de zonas alejadas del
    punto emisor en todo el mundo. No obstante, se han hallado
    concentraciones más altas cerca de los puntos emisores. El HCB es
    bioacumulativo y se ha detectado en invertebrados, peces, reptiles,
    aves y mamíferos (incluido el hombre) lejos de los puntos emisores,
    particularmente en el tejido adiposo de organismos de los niveles
    tróficos más altos. Los niveles medios en el tejido adiposo de la
    población humana general en diversos países van de decenas a centenas
    de ng/g de peso en fresco. Considerando los niveles representativos de
    HCB en el aire, el agua y los alimentos, se estima que la ingesta
    total de HCB por los adultos de la población general está comprendida 

    entre 0,0004 y 0,003 mg/kg de peso corporal al día. Esa ingesta se
    realiza principalmente a través de los alimentos. Debido a la
    presencia de HCB en la leche materna, se ha estimado que la ingesta
    media por los lactantes alimentados al pecho en diversos países va de
    < 0,018 a 5,1 mg/kg de peso corporal al día. Los resultados de la
    mayoría de los estudios realizados acerca de las concentraciones de
    HCB en los alimentos y en los tejidos humanos a lo largo del tiempo
    indican que la exposición de la población general al HCB disminuyó
    desde los años setenta hasta mediados de los noventa en muchos
    lugares. Sin embargo, esa tendencia no se ha confirmado con claridad
    durante el último decenio en otros lugares.

    5.  Cinética y metabolismo en animales de laboratorio y en el
        ser humano

         No hay suficientes datos sobre la toxicocinética en el hombre. El
    HCB es absorbido rápidamente por vía oral por los animales de
    experimentación, y escasamente a través de la piel (no existen datos
    sobre la inhalación). En los animales y en los seres humanos, el HCB
    se acumula en los tejidos ricos en lípidos, como el tejido adiposo, la
    corteza suprarrenal, la médula ósea, la piel y algunos tejidos
    endocrinos, y puede transmitirse a la descendencia a través tanto de
    la placenta como de la leche materna. El HCB sufre un metabolismo
    limitado, generando pentaclorofenol, tetraclorohidroquinona y
    pentaclorotiofenol como principales metabolitos en la orina. Las
    semividas de eliminación del HCB están comprendidas entre
    aproximadamente un mes en la rata y el conejo y 2 ó 3 años en el mono.

    6.  Efectos en animales de laboratorio y en las pruebas in vitro

         La toxicidad aguda del HCB en los animales de experimentación es
    baja (1000 × 10 000 mg/kg de peso corporal). En los estudios con
    animales, el HCB no causa irritación cutánea ni ocular y no tiene
    efectos de sensibilización en el cobayo.

         Los datos disponibles acerca de la toxicidad sistémica del HCB
    indican que las vías de la biosíntesis del grupo hemo son una
    importante diana de la toxicidad del hexaclorobenceno. Se han hallado
    niveles elevados de porfirinas o de precursores de la porfirina, o de
    ambas cosas, en el hígado, en otros tejidos y en las excretas de
    varias especies de mamíferos de laboratorio expuestos al HCB. Se ha
    informado de la aparición de porfiria en varios estudios realizados
    con ratas expuestas por vía oral crónica o subcrónica a dosis entre
    2,5 y 15 mg de HCB/kg de peso corporal al día. La excreción de
    coproporfirinas aumentó en cerdos que ingirieron 0,5 mg de HCB/kg de
    peso corporal al día o más (en el último estudio no se observó ningún
    efecto con 0,05 mg de HCB/kg de peso corporal al día). Se ha visto
    también que la exposición repetida al HCB afecta a una amplia gama de
    sistemas orgánicos (entre ellos el hígado, los pulmones, los riñones,
    la tiroides, la piel y los sistemas nervioso e inmunitario), aunque
    las referencias a estos efectos son menos frecuentes que las
    relacionadas con la porfiria.

         El HCB es un inductor de tipo mixto del citocromo P-450, con
    propiedades inducibles por el fenobarbital y por el 3-metilcolantreno.
    Se sabe que se une al receptor Ah.

         Por lo que se refiere a los estudios crónicos, en ratas expuestas
    a dosis de 0,25 a 0,6 mg de HCB/kg peso corporal al día se observaron
    efectos leves en el hígado (cambios histopatológicos, inducción
    enzimática); en dichos estudios los NOEL estaban comprendidos entre
    0,05 y 0,07 mg de HCB/kg de peso corporal al día. Las concentraciones
    de neurotransmisores en el hipotálamo se vieron alteradas en visones
    hembra sometidos a través de los alimentos a una exposición crónica de
    0,16 mg de HCB/kg de peso corporal al día, y en su descendencia
    expuesta a lo largo de la gestación y la lactancia. En estudios
    subcrónicos realizados en ratas la homeostasis del calcio y la
    morfometría ósea se vieron afectadas con 0,7 mg de HCB/kg de peso
    corporal al día, pero no con 0,07 mg/kg de peso corporal al día.

         La carcinogenicidad del HCB ha sido evaluada mediante varios
    bioensayos realizados con roedores. En hámsters mantenidos con
    alimentos con los que ingerían unas dosis medias de 4, 8 ó 16 mg/kg de
    peso corporal al día durante toda la vida, se produjeron aumentos en
    la incidencia de tumores de las células del hígado (hepatomas) en los
    dos sexos y a todas las dosis, hemangioendoteliomas hepáticos a dosis
    de 8-16 mg/kg de peso corporal al día, y adenomas tiroideos de los
    machos a la dosis mayor. La exposición alimentaria de ratones a dosis
    de 6, 12 y 24 mg/kg de peso corporal al día durante 120 semanas dio
    lugar a un aumento de la incidencia de tumores de las células del
    hígado (hepatomas) en ambos sexos a las dos dosis mayores (no
    significativo, excepto para las hembras a la dosis mayor). En ratas,
    la exposición  in útero, durante la lactancia y por vía oral al HCB a
    través de alimentos que proporcionaban a lo largo de su vida dosis
    medias comprendidas entre 0,01 y 1,5 mg/kg de peso corporal al día
    (machos) o 1,9 mg/kg de peso corporal al día (hembras) por espacio de
    hasta 130 semanas  post útero produjo a la mayor de las dosis un
    aumento de la incidencia de nódulos hepáticos neoplásicos y de
    feocromocitomas suprarrenales en las hembras y de adenomas
    paratiroideos en los machos. En otro estudio crónico realizado en la
    rata, la exposición por un periodo de hasta dos años a alimentos que
    proporcionaban dosis medias de HCB de 4-5 y de 8-9 mg/kg de peso
    corporal al día indujo aumentos de la incidencia de hepatomas y de
    adenomas de las células renales a ambas dosis en los dos sexos, y de
    carcinomas hepatocelulares, adenomas y carcinomas de las vías
    biliares, y feocromocitomas suprarrenales y adenomas de la corteza
    suprarrenal en las hembras. Se ha informado también de incidencias
    elevadas de tumores hepáticos en algunos estudios más limitados en los
    que se administraron concentraciones alimentarias únicas a grupos
    reducidos de ratas hembra. Además, se ha informado de que, después de
    una exposición alimentaria subcrónica al HCB, ratones, hámsters y
    ratas desarrollaron tumores en el hígado, las vías biliares, el riñón,
    el timo, el bazo y los ganglios linfáticos. La exposición alimentaria
    al HCB favoreció la inducción de tumores hepáticos por el terfenilo
    policlorado en el ratón y por la dietilnitrosamina en la rata.

         Con excepción de los tumores renales en la rata macho
    (aparentemente debidos, al menos en parte, a una nefropatía por
    acumulación de gotas hialinas) y de los hepatomas en la rata (posible
    resultado de la respuesta hiperplásica a una necrosis hepatocelular),
    no se conocen estudios mecanísticos que hayan determinado el
    significado del tipo de tumores inducidos por el HCB en el caso del
    hombre.

         El HCB tiene una escasa capacidad de inducción directa de
    mutaciones de los genes, lesiones cromosómicas y reparaciones del ADN.
    Mostró una leve actividad mutágena en un reducido número de los
    estudios realizados en bacterias y levaduras, aunque hay que señalar
    que todos esos estudios presentan limitaciones. Existen también
    algunos indicios de un cierto grado de unión al ADN  in vitro e
     in vivo, aunque a niveles muy inferiores a los habituales en los
    carcinógenos genotóxicos.

         En estudios sobre la reproducción, la exposición oral de monos a
    tan sólo 0,1 mg de HCB/kg de peso corporal al día durante 90 días
    afectó a la estructura revelada por microscopia óptica y a la
    ultraestructura del epitelio germinal superficial, una diana poco
    usual para las toxinas que afectan al ovario. Dicha dosis causó
    también daños ultraestructurales en las células germinales
    primordiales. Estos cambios específicos en tejidos-diana, para los que
    dosis mayores son aún más lesivas, se asocian por lo demás a un
    desarrollo normal del folículo, el ovocito y el embrión, lo que indica
    que el HCB tiene una acción específica en el ovario. La reproducción
    masculina sólo se vio afectada a dosis mucho mayores (entre 30 y
    221 mg/kg de peso corporal al día) en estudios realizados en varias
    especies distintas de los primates.

         La exposición de ratas y gatos, a través de la placenta o durante
    la lactancia, a dosis maternas comprendidas entre 3 y 4 mg/kg de peso
    corporal al día tuvo efectos hepatotóxicos o afectó a la supervivencia
    o el crecimiento de la descendencia en período de lactancia. En
    algunos casos, dosis iguales o superiores a ésas redujeron el tamaño
    de las camadas o aumentaron el número de abortos. (Los efectos nocivos
    en los cachorros sin destetar han sido observados más frecuentemente,
    y a dosis menores, que los efectos embriotóxicos o fetotóxicos.) La
    descendencia de visones expuestos crónicamente a sólo 1 mg de HCB/kg
    de alimento (aproximadamente 0,16 mg/kg de peso corporal al día) tuvo
    un peso reducido al nacer y presentó una mayor mortalidad hasta el
    destete. A pesar de que se han observado trastornos esqueléticos y
    renales de los fetos en algunos estudios realizados en ratas y ratones
    expuestos al HCB durante la gestación, dichas alteraciones o bien no
    estaban claramente relacionadas con el tratamiento o bien ocurrieron a
    dosis que eran también tóxicas para las madres. En dos estudios, uno
    de los cuales incluía exposición posnatal y durante la lactancia, el
    desarrollo neurocomportamental de las crías de rata se vio afectado
    por la exposición  in útero a dosis maternas orales de 0,64 a 2,5 mg
    de HCB/kg de peso corporal al día.

         Los resultados de varios estudios indican que el HCB afecta al
    sistema inmunitario. Ratas y monos expuestos a dosis entre 3 y 120 mg
    de HCB/kg de peso corporal al día sufrieron alteraciones
    histopatológicas en el timo, en el bazo y en los ganglios linfáticos o
    los tejidos linfoides del pulmón. La exposición crónica de perros
    sabuesos a 0,12 mg/kg de peso corporal al día produjo una hiperplasia
    nodular del tejido linfoide gástrico. En varios estudios realizados en
    la rata, la inmunidad humoral y, en menor grado, la celular se vieron
    potenciadas tras varias semanas de exposición alimentaria al HCB,
    mientras que la función de los macrófagos no se alteró. Una cantidad
    tan pequeña como 4 mg de HCB/kg de alimento (aproximadamente 0,2 mg/kg
    de peso corporal al día) durante la gestación, a lo largo de la
    lactancia y hasta las 5 semanas de edad incrementó las respuestas
    inmunitarias humoral y celular y provocó la acumulación de macrófagos
    en el tejido pulmonar de crías de rata. Por el contrario, se ha
    observado un efecto inmunodepresor del HCB en la mayor parte de los
    estudios llevados a cabo con ratones; dosis de sólo 0,5-0,6 mg/kg de
    peso corporal al día durante varias semanas redujeron la resistencia a
    la infección por  Leishmania o a una provocación con células
    tumorales, disminuyeron la actividad citotóxica de los macrófagos del
    bazo, y redujeron la respuesta de hipersensibilidad de tipo retardado
    en la descendencia expuesta  in útero y durante la lactancia. En
    varios estudios realizados con diversas cepas de ratas, la exposición
    de breve duración o subcrónica al HCB afectó a la función tiroidea, a
    juzgar por los reducidos niveles séricos de tiroxina total y tiroxina
    libre (T4) y a menudo, en menor grado, de triyodotironina (T3).

    7.  Efectos en el ser humano

         La mayor parte de los datos acerca de los efectos del HCB en el
    ser humano provienen de intoxicaciones accidentales que tuvieron lugar
    en Turquía en los años 1955-1959, entre las que se identificaron más
    de 600 casos de porfiria cutánea tardía (PCT). En esa ocasión se
    observaron alteraciones en el metabolismo de la porfirina, lesiones
    dermatológicas, hiperpigmentación, hipertricosis, aumento del tamaño
    del hígado, de la glándula tiroides y de los ganglios linfáticos; se
    observaron también (aproximadamente en la mitad de los casos)
    osteoporosis o artritis, sobre todo en los niños. Los niños
    amamantados por madres expuestas al HCB como consecuencia de ese
    accidente desarrollaron un trastorno conocido como pembe yara
    (ulceración rosada), y la mayor parte murieron antes de un año.
    Existen también algunos indicios de que la PCT afecta a personas
    sometidas a una exposición relativamente alta al HCB en el lugar de
    trabajo o en el medio ambiente general.

         Los pocos estudios epidemiológicos disponibles acerca de la
    incidencia de cáncer tienen un valor limitado, ya sea por lo reducido
    de la muestra, por la deficiente caracterización de la exposición al
    CHB o por la exposición a otros muchos agentes, y son insuficientes
    para evaluar la carcinogenicidad del HCB para el ser humano.

    8.  Efectos en otros organismos en el laboratorio y sobre el terreno

         En los estudios realizados sobre la toxicidad aguda del HCB para
    los organismos acuáticos, la exposición a concentraciones comprendidas
    entre 1 y 17 mg/litro redujo la producción de clorofila en algas y la
    reproducción de protozoos ciliados, y causó mortalidad en el camarón
    rosado y en las quisquillas, pero no aumentó la mortalidad de peces de
    agua dulce o de mar. En estudios a largo plazo, el crecimiento de
    algas y protozoos vulnerables de agua dulce se vio afectado por una
    concentración de 1 mg/litro, mientras que concentraciones de
    aproximadamente 3 mg/litro provocaron mortalidad en anfípodos y
    necrosis hepática en la perca americana.

    9.  Evaluación de los riesgos para la salud humana y de los efectos
        en el medio ambiente

    9.1  Efectos en la salud

         El Grupo Especial llegó a la conclusión de que los datos
    disponibles son suficientes para establecer valores indicativos
    respecto a los efectos neoplásicos y no neoplásicos del HCB.

         En cuanto a los efectos no neoplásicos, considerando el NOEL más
    bajo notificado (0,05 mg de HCB/kg de peso corporal al día), referido
    sobre todo a los efectos hepáticos observados a dosis mayores en
    estudios realizados en cerdos y ratas expuestos por vía oral, e
    incorporando un factor de incertidumbre de 300 (× 10 en concepto de
    variación interespecíes, × 10 en concepto de variación intraespecie, y
    × 3 en concepto de gravedad del efecto), se ha calculado una IDT de
    0,17 mg/kg de peso corporal al día.

         El criterio seguido en cuanto a los efectos neoplásicos se basa
    en la dosis tumorigénica TD5, es decir, la ingesta asociada a un
    exceso del 5% en la incidencia de tumores detectada en los
    experimentos con animales. Considerando los resultados del bioensayo
    de carcinogenicidad en dos generaciones de ratas, y empleando el
    modelo polietápico, la TD5 es de 0,81 mg/kg de peso corporal al día
    para los nódulos neoplásicos del hígado en las hembras. Habida cuenta
    de la insuficiencia de los datos mecanísticos, se utilizó un factor de
    incertidumbre de 5000 para establecer un valor indicativo, basado en
    criterios de salud, de 0,16 mg/kg de peso corporal al día.

    9.2  Efectos en el medio ambiente

         El Grupo Especial señaló que existen muy pocos estudios
    experimentales con los que llevar a cabo una evaluación de los riesgos
    para el medio ambiente. Los niveles de HCB en las aguas superficiales,
    excepto en unos pocos lugares extremadamente contaminados, son en
    general varios órdenes de magnitud inferiores a los que se supone que
    entrañan riesgos para los organismos acuáticos. No obstante, las
    concentraciones de HCB en los huevos de las aves marinas y las rapaces
    de algunos lugares en distintas zonas del mundo se aproximan a niveles

    que en la gaviota argéntea se asocian a una disminución del peso del
    embrión (1500 mg/kg), lo que parece indicar que el HCB puede dañar los
    embriones de especies de aves vulnerables. Del mismo modo, los niveles
    de HCB observados en peces de diversos lugares del mundo se encuentran
    a un orden de magnitud del nivel alimentario de 1000 mg/kg, asociado a
    una reducción del peso al nacer y a un aumento de la mortalidad de la
    descendencia en los visones. Esto parece indicar que el HCB puede
    tener efectos nocivos en los visones y, tal vez, en otros mamíferos
    que se alimentan de peces.

    10. Conclusiones

    a)  El HCB es un producto químico persistente que se bioacumula debido
    a su liposolubilidad y a su resistencia a la degradación.

    b)  Los estudios realizados con animales han demostrado que el HCB
    produce cáncer y afecta a una amplia gama de sistemas de órganos, con
    inclusión del hígado, los pulmones, los riñones, la tiroides, los
    tejidos reproductivos y los sistemas nervioso e inmunitario.

    c)  En seres humanos sometidos a una alta exposición accidental se ha
    observado toxicidad sintomática, en particular porfiria cutánea tardía
    en niños y en adultos y mortalidad en lactantes.

    d)  Es necesario adoptar diversas medidas para reducir la carga
    ambiental de HCB.

    e)  Se han propuesto los siguientes valores indicativos basados en
    criterios de salud para la ingesta diaria total (IDT) de HCB por el
    ser humano: efectos no cancerígenos, 0,17 µg/kg de peso corporal/día;
    yefectos neoplásicos, 0,16 µ/kg de peso corporal/día.
    


    See Also:
       Toxicological Abbreviations
       Hexachlorobenzene (HSG 107, 1998)
       Hexachlorobenzene (ICSC)
       Hexachlorobenzene (PDS)
       Hexachlorobenzene (PIM 256)
       Hexachlorobenzene (FAO/PL:1969/M/17/1)
       Hexachlorobenzene (WHO Pesticide Residues Series 4)
       Hexachlorobenzene  (IARC Summary & Evaluation, Supplement7, 1987)
       Hexachlorobenzene  (IARC Summary & Evaluation, Volume 20, 1979)
       Hexachlorobenzene  (IARC Summary & Evaluation, Volume 79, 2001)