INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    ENVIRONMENTAL HEALTH CRITERIA 124

    LINDANE

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

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    First draft prepared by Dr M. Herbst, International Centre
    for the Study of Lindane, Lyon, France and
    Dr G.J. Van Esch, Bilthoven, The Netherlands

    World Health Orgnization
    Geneva, 1991

         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 objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping 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

    Lindane.

        (Environmental health criteria ; 124)

        1.Benzene hexachloride - adverse effects  2.Benzene hexachloride
          - toxicity 3.Environmental exposure  4.Environmental poluutants 
        I.Series

        ISBN 92 4 157124 1        (NLM Classification: WA 240)
        ISSN 0250-863X

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    CONTENTS

    1. SUMMARY AND EVALUATION; CONCLUSIONS; RECOMMENDATIONS

         1.1. Summary and evaluation
              1.1.1. General properties
              1.1.2. Environmental transport, distribution and
                     transformation
              1.1.3. Environmental levels and human exposure
              1.1.4. Kinetics and metabolism
              1.1.5. Effects on organisms in the environment
              1.1.6. Effects on experimental animals and  in vitro
              1.1.7. Effects on humans
         1.2. Conclusions
              1.2.1. General population
              1.2.2. Subpopulations at special risk
              1.2.3. Occupational exposure
              1.2.4. Environmental effects
         1.3. Recommendations

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES,  ANALYTICAL
         METHODS

         2.1. Identity
              2.1.1. Primary constituent
              2.1.2. Technical product
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. Sampling
              2.4.2. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Man-made sources
              3.2.1. Production levels and processes
                     3.2.1.1  Manufacturing process
                     3.2.1.2  World-wide production figures
              3.2.2. Emissions
              3.2.3. Uses
              3.2.4. Extent of use
              3.2.5. Formulations

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Transport and distribution between media
              4.1.1. Volatilization
              4.1.2. Precipitation
              4.1.3. Movement in soils
              4.1.4. Uptake and translocation in plants

         4.2. Biotransformation
              4.2.1. Degradation
                     4.2.1.2  Degradation under humid conditions
                     4.2.1.2  Degradation under submerged conditions
              4.2.2. Degradation under field conditions
              4.2.3. Hydrolytic degradation
              4.2.4. Photolytic degradation (laboratory studies)
              4.2.5. Biodegradation in water
              4.2.6. Microbial degradation (field studies)
              4.2.7. Bioaccumulation/Biomagnification
                     4.2.7.1   n-Octanol/water partition coefficient
                     4.2.7.2  Aquatic environment
                     4.2.7.3  Terrestrial environment
                     4.2.7.4  Bioconcentration in humans
                     4.2.7.5  Field studies

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
                     5.1.2.1  Rain and snow
                     5.1.2.2  Fresh water
                     5.1.2.3  Sea water
              5.1.3. Soil
                     5.1.3.1  Sediment
                     5.1.3.2  Dumping grounds and sewage sludge
              5.1.4. Drinking-water, food and feed
                     5.1.4.1  Drinking-water
                     5.1.4.2  Cereals, fruits, pulses, vegetables,
                              and vegetable oil
                     5.1.4.3  Meat, fat, milk, and eggs
                     5.1.4.4  Animal feed
                     5.1.4.5  Miscellaneous products
              5.1.5. Terrestrial and aquatic organisms
                     5.1.5.1  Plants
                     5.1.5.2  Aquatic organisms
                     5.1.5.3  Terrestrial organisms
         5.2. Exposure of the general population
              5.2.1. Total-diet studies
              5.2.2. Intake with drinking-water and air
              5.2.3. Concentrations in human samples
                     5.2.3.1  Blood
                     5.2.3.2  Adipose tissue
                     5.2.3.3  Breast milk

    6. KINETICS AND METABOLISM

         6.1. Absorption
              6.1.1. Oral administration - experimental animals

              6.1.2. Dermal application - experimental animals
              6.1.3. Other routes - experimental animals
         6.2. Distribution
              6.2.1. Oral administration - experimental animals
              6.2.2. Inhalation - experimental animals
              6.2.3. Other routes
         6.3. Metabolic transformation
              6.3.1. Enzymatic involvement
              6.3.2. Identification of metabolites
              6.3.3. Metabolites identified in humans
         6.4. Elimination and excretion in expired air, faeces, and
              urine
              6.4.1. Oral administration
                     6.4.1.1  Rat
                     6.4.1.2  Rabbit
              6.4.2. Other routes
                     6.4.2.1  Mouse
                     6.4.2.2  Rat
                     6.4.2.3  Human
         6.5. Retention and turnover (experimental animals)
         6.6. Biotransformation
              6.6.1. Plants
              6.6.2. Microorganisms
                     6.6.2.1  Anaerobic conditions
                     6.6.2.2  Aerobic conditions
         6.7. Isomerization

    7. EFFECTS ON LABORATORY MAMMALS AND IN IN-VITRO TEST SYSTEMS

         7.1. Single exposure
              7.1.1. Oral
              7.1.2. Intraperitoneal and intramuscular
              7.1.3. Inhalation
              7.1.4. Dermal
         7.2. Short-term exposure
              7.2.1. Oral
                     7.2.1.1  Mouse
                     7.2.1.2  Rat
                     7.2.1.3  Dog
                     7.2.1.4  Pig
              7.2.2. Inhalation
                     7.2.2.1  Mouse
                     7.2.2.2  Rat
              7.2.3. Dermal
         7.3. Skin and eye irritation; sensitization
              7.3.1. Primary skin irritation
              7.3.2. Primary eye irritation
              7.3.3. Sensitization
         7.4. Long-term exposure
              7.4.1. Oral
              7.4.2. Appraisal of acute and short- and long-term
                     studies

         7.5. Reproduction, embryotoxicity, and teratogenicity
              7.5.1. Reproduction
              7.5.2. Embryotoxicity and teratogenicity
                     7.5.2.1  Oral administration
                     7.5.2.2  Subcutaneous injection
              7.5.3. Reproductive behaviour
              7.5.4. Appraisal of reproductive toxicology
         7.6. Mutagenicity and related end-points
              7.6.1. DNA damage
              7.6.2. Mutation
              7.6.3. Chromosomal effects
              7.6.4. Miscellaneous tests
              7.6.5. Appraisal of mutagenicity and related end-
                     points
         7.7. Carcinogenicity
              7.7.1. Mouse
              7.7.2. Rat
              7.7.3. Initiationpromotion
              7.7.4. Mode of action
              7.7.5. Appraisal of carcinogenicity
         7.8. Special studies
              7.8.1. Immunosuppression
              7.8.2. Behavioural studies
              7.8.3. Neurotoxicity
                     7.8.3.1  Dose-response studies using intact
                              animals
                     7.8.3.2  Studies on mechanism
                     7.8.3.3  Summary
         7.9. Factors that modify toxicity; toxicity of metabolites

    8. EFFECTS ON HUMANS

         8.1. Exposure of the general population
              8.1.1. Acute toxicity, poisoning incidents
              8.1.2. Effects of short- and long-term exposures -
                     controlled human studies
                     8.1.2.1  Oral administration
                     8.1.2.2  Dermal application
              8.1.3. Epidemiological studies (general population)
         8.2. Occupational exposure
              8.2.1. Toxic effects
              8.2.2. Irritation and sensitization

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
              9.1.1. Bacteria
              9.1.2. Algae
                     9.1.2.1  Blue-green algae
                     9.1.2.2  Freshwater algae
                     9.1.2.3  Marine algae

              9.1.3. Dinoflagellates, flagellates, and ciliates
         9.2. Aquatic organisms
              9.2.1. Invertebrates
                     9.2.1.1  Crustacea
                     9.2.1.2  Aquatic arthropods
                     9.2.1.3  Molluscs
              9.2.2. Fish
                     9.2.2.1  Acute toxicity
                     9.2.2.2  Short- and long-term toxicity
                     9.2.2.3  Reproduction
              9.2.3. Amphibia
                     9.2.3.1  Acute toxicity
                     9.2.3.2  Effects on hatching and larval
                              development
         9.3. Terrestrial organisms
              9.3.1. Honey-bees
              9.3.2. Birds
                     9.3.2.1  Acute toxicity
                     9.3.2.2  Short-term toxicity
                     9.3.2.3  Reproduction
              9.3.3. Mammals
         9.4. Appraisal

    10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    APPENDIX I

    REFERENCES

    RESUMÉ

    RESUMEN

    WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR LINDANE

     Members

    Dr S. Dobson, Pollution and Ecotoxicology Section, Institute of
         Terrestrial Ecology, Monkswood Experimental Station, Abbots
         Ripton, Huntingdon, United Kingdom

    Dr G.J. van Esch, Bilthoven, the Netherlands  (Joint Rapporteur)

    Dr M. Herbst, Biological Research, ASTA Pharma AG, Frankfurt,
         Germany  (Joint Rapporteur)

    Professor J.S. Kagan, Department of General Toxicology and
         Experimental Pathology, All-Union Scientific Research Instiute
         of Hygiene and Toxicology of Pesticides, Polymers, and
         Plastics, Kiev, USSR  (Vice-Chairman)

    Dr S.G.A. Magwood, Pesticides Division, Environmental Health Centre,
         Health and Welfare Canada, Tunney's Pasture, Ottawa, Ontario,
         Canada

    Professor W.-O. Phoon, National Institute of Occupational Health and
         Safety, University of Sydney, Sydney, Australia  (Chairman)

    Dr J.F. Risher, US Environmental Protection Agency, Environmental
         Criteria and Assessment Office, Cincinnati, Ohio, USA

    Dr Y. Saito, Division of Foods, National Institute of Hygienic
         Sciences, Setagaya-ku, Tokyo, Japan

    Dr V. Turusov, Laboratory of Carcinogenic Substances, All-Union
         Cancer Research Centre, Moscow, USSR

    Representatives of Non-Governmental Organizations

    Dr P.G. Pontal, International Group of National Associations of
         Manufacturers of Agrochemical Products (GIFAP), Brussels,
         Belgium

     Observers

    Dr A.V. Bolotny, All-Union Scientific Research Institute of Hygiene
         and Toxicology of Pesticides, Polymers, and Plastics, Kiev,
         USSR

    Dr D. Demozay, International Centre for the Study of Lindane (CIEL),
         Rhône-Poulenc Agrochimie, Lyon, Franch.

     Secretariat

    Dr G.J. Burin, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

    Dr K.W. Jager, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland  (Secretary)

    Dr V.A. Rezepov, Centre for International Projects, USSR State
         Committee for Environmental Protection, Moscow, USSR

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

         Every effort has been made to present information in the
    criteria documents as accurately as possible without unduly delaying
    their publication. In the interest of all users of the environmental
    health criteria documents, readers are kindly requested to
    communicate any errors that may have occurred to the Manager of the
    International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland, in order that they may be
    included in corrigenda, which will appear in subsequent volumes.

                                  *   *   *

         A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Palais
    des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
    7985850)

                                  *   *   *

         The proprietary information contained in this document cannot
    replace documentation for registration purposes, because the latter
    has to be closely linked to the source, the manufacturing route, and
    the purity/impurities of the substance to be registered. The data
    should be used in accordance with paragraphs 82-84 and
    recommendations paragraph 90 of the Second FAO Government
    Consultation (1982).

    ENVIRONMENTAL HEALTH CRITERIA FOR LINDANE

         The WHO Task Group on environmental health criteria for lindane
    met in Moscow, USSR, on 20-24 November 1989. The meeting was
    convened with the financial assistance of the United Nations
    Environment Programme (UNEP) and was hosted by the Centre for
    International Projects (CIP), USSR State Committee for Environmental
    Protection. On behalf of the CIP, Dr V.A. Rezepov opened the meeting
    and welcomed the participants. Dr K.W. Jager welcomed the
    participants on behalf of the three cooperating organizations of the
    IPCS (UNEP, ILO, WHO). The Task Group reviewed and revised the draft
    document and made an evaluation of the risks to human health and the
    environment from exposure to lindane.

         The first drafts of this monograph were prepared by Dr M.
    Herbst (on behalf of the International Centre for the Study of
    Lindane (CIEL)) and Dr G.J. van Esch (on behalf of the IPCS). The
    second draft was prepared by Dr G.J. van Esch, incorporating
    comments received following circulation of the first draft to the
    IPCS contact points for Environmental Health Criteria publications.

         The help of the CIEL in making available their proprietary
    toxicological information on lindane to the IPCS and the Task Group
    is gratefully acknowledged. This enabled the Task Group to make its
    evaluation on the basis of more complete data than would otherwise
    have been possible.

         The efforts of all who helped in the preparation and
    finalization of the document are also gratefully acknowledged. Dr
    K.W. Jager of the IPCS Central Unit was responsible for the
    technical development of this monograph and Mrs E. Heseltine of St
    Léon-sur-Vézère, France, for the editing.

    1.  SUMMARY AND EVALUATION; CONCLUSIONS; RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  General properties

         Technical-grade hexachlorocyclohexane (HCH) consists of 65-70%
    alpha-HCH, 7-10% beta-HCH, 14-15% gamma-HCH, and approximately 10%
    of other isomers and compounds. Lindane contains > 99% gamma-HCH.
    It is a solid, with a low vapour pressure, and is poorly soluble in
    water but very soluble in organic solvents, such as acetone, and in
    aromatic and chlorinated solvents. The  n-octanol/water partition
    coefficient (log Pow) is 3.2-3.7.

         Lindane can be determined separately from the other isomers of
    HCH after extraction by liquid/liquid partition, column
    chromatography and detection by gas chromatography with electron
    capture. As these analytical methods are highly sensitive, residues
    of lindane can be identified at a level of nanograms per kilogram or
    per litre.

         Lindane has been used as a broad-spectrum insecticide since the
    early 1950s for agricultural and nonagricultural purposes, which
    include treatment of seeds and soil, application on trees, timber
    and stored materials, treatment of animals against ectoparasites and
    in public health.

    1.1.2  Environmental transport, distribution and transformation

         Lindane is strongly adsorbed on soils that contain a large
    amount of organic matter; furthermore, it can move downward through
    the soil with water from rainfall or artificial irrigation.
    Volatilization appears to be an important route of its dissipation
    under the high-temperature conditions of tropical regions.

         Lindane undergoes rapid degradation (dechlorination) in the
    presence of ultra-violet irradiation, to form
    pentachlorocyclohexenes (PCCHs) and tetrachlorocyclohexenes (TCCHs).
    When lindane undergoes environmental degradation under humid or
    submerged conditions and in field conditions, its half-time varies
    from a few days to three years, depending on type of soil, climate,
    depth of application and other factors. In agricultural soils common
    in Europe, its half-time is 40-70 days. The biodegradation of
    lindane is much faster in unsterilized than in sterilized soils.
    Anaerobic conditions are the most favourable for its microbial
    metabolization. Lindane present in water is degraded mostly by
    microorganisms in sediments to form the same degradation products.

         Limited amounts of lindane and gamma-PCCHs are taken up by and
    translocated into plants, especially in soils with a high content of
    organic matter. Residues are found mainly in the roots of plants,

    and little, if any, is translocated into stems, leaves or fruits.
    Rapid bioconcentration takes place in microorganisms, invertebrates,
    fish, birds and humans, but biotransformation and elimination are
    relatively rapid when exposure is discontinued. In aquatic
    organisms, uptake from water is more important than uptake from
    food. The bioconcentration factors in aquatic organisms under
    laboratory conditions ranged from approximately 10 up to 6000; under
    field conditions, the bioconcentration factors ranged from 10 to
    2600.

    1.1.3  Environmental levels and human exposure

         Lindane has been found in the air above the oceans at
    concentrations of 0.039-0.68 ng/m3 and has been measured at up to
    11 ng/m3 in the air in some countries. The estimated
    concentrations in surface water in a number of European countries
    were mainly below 0.1 µg/litre. The concentration in the River Rhine
    and its tributaries in 1969-74 varied between 0.01 and 0.4 µg/litre;
    after 1974, it was below 0.1 µg/litre. Levels of 0.001-0.02 µg/litre
    have been reported in seawater. The concentrations of lindane in
    soil are generally low - in the range 0.001-0.01 mg/kg, except in
    areas where waste is disposed of.

         Fish and shellfish have been found to contain gamma-HCH at
    concentrations ranging from none detected up to 2.5 mg/kg on a fat
    basis, depending on whether they live in fresh or seawater and
    whether they have a low or high fat content. Levels of about 330 and
    440 µg/kg (wet weight) were found in adipose tissue of polar bears
    in 1982 and 1984, respectively. The concentration of lindane in the
    livers of birds of prey varied between 0.01 and 0.1 mg/kg. Eggs of
    sparrow-hawks collected in 1972-73 in the Federal Republic of
    Germany contained levels of 0.6 up to 11.1 mg/kg (on a fat basis).

         The concentration of lindane in the livers of predatory birds
    varied between 0.01 and 0.1 mg/kg. Eggs of sparrow- hawks collected
    in 1972-73 in the Federal Republic of Germany contained levels of
    0.6 up to 11.1 mg/kg (on a fat basis). The concentrations of lindane
    in drinking-water are generally below 0.001 µg/litre, and in
    industrialized countries more than 90% of human intake of lindane
    originates from food. Over the last 25 years, selected food items
    have been analysed for lindane in a large number of countries. The
    concentrations found in cereals, fruits, vegetables, pulses, and
    vegetable oils ranged from not detected up to 0.5 mg/kg product, and
    those in milk, fat, meat, and eggs from not detected up to 1.0 mg/kg
    product (on a fat basis). In only a few instances were higher
    concentrations found. The concentrations in fish were generally far
    lower than 0.05 mg/kg product (on a fat basis). In total-diet and
    market-basket studies to estimate daily human intake of lindane, a
    clear difference was observed with time: intake in the period around
    1970 was up to 0.05 µg/kg body weight per day, whereas by 1980
    intake had decreased to 0.003 µg/kg body weight per day or lower. In

    the USA, the daily intake of gamma-HCH between 1976 and 1979
    decreased from 0.005 to 0.001 µg/kg body weight per day for infants
    and from 0.01 to 0.006 µg/kg body weight per day for toddlers.

         Determinations of the lindane content in body tissues in the
    general population have been made in a number of countries. The
    content in blood in the Netherlands was in the order of < 0.1-0.2
    µg/litre, but much higher concentrations were found in several
    countries where technical-grade HCH was used. The mean
    concentrations in human adipose tissue in various countries ranged
    from < 0.01 up to 0.2 mg/kg on a fat basis. The concentrations of
    lindane in human milk are generally rather low, at average
    concentrations of < 0.001 up to 0.1 mg/kg on a fat basis; however,
    there has been a clear decrease over time.

         Lindane is thus distributed all over the world and can be
    detected in air, water, soil, sediment, aquatic and terrestrial
    organisms, and food, although the concentrations in these different
    compartments are generally low and are gradually decreasing. Humans
    are exposed daily via food, and lindane has been found in blood,
    adipose tissue, and breast milk; the levels of intake, however, are
    also decreasing.

    1.1.4  Kinetics and metabolism

         In rats, lindane is absorbed rapidly from the gastrointestinal
    tract and distributed to all organs and tissues within a few hours.
    The highest concentrations are found in adipose tissues and skin; in
    various studies, the fat:blood ratio was about 150-200, the
    liver:blood ratio, 5.3-9.6 and the brain:blood ratio, 4-6.5. The
    same fat:blood ratio was found in rats exposed by inhalation. These
    ratios vary with sex, being higher in females. Uptake of lindane
    through the skin after dermal application is slow and occurs to a
    very limited extent; this may explain the low toxicity of lindane
    after dermal exposure.

         Lindane is metabolized mainly in the liver by four enzymatic
    reactions: dehydrogenation to gamma-HCH, dehydrochlorination to
    gamma-PCCH, dechlorination to gamma-TCCH and hydroxylation to
    hexachlorocyclohexanol. The end-products of biotransformation are
    di-, tri-, tetra-, penta-, and hexachloro- compounds. These
    metabolites are excreted mainly via the urine in the free form or
    conjugated with glucuronic acid, sulfuric acid or  N-acetylcystein.
    The elimination is relatively fast, with half-times in rats of 3-4
    days. Bacteria and fungi metabolize lindane to TCCH and PCCH. The
    rate of metabolic transformation in plants is low, and the main
    degradation pathway proceeds via PCCH to tri- and tetrachlorophenol
    and conjugates with beta-glucose and other, unknown compounds. There
    is no evidence that lindane is isomerized to alpha-HCH.

    1.1.5  Effects on organisms in the environment

         Lindane is not very toxic for bacteria, algae, or protozoa: 1
    mg/litre was generally the no-observed effect level (NOEL). Its
    action on fungi is variable, with NOELs varying from 1 to 30
    mg/litre depending on the species. It is moderately toxic for
    invertebrates and fish, the L(E)C50 values for these organisms being
    20-90 µg/litre. In short-term and long-term studies with three
    species of fish, the NOEL was 9 µg/litre; no effect on reproduction
    was seen with levels of 2.1-23.4 µg/litre. The LC50 values for both
    freshwater and marine crustacea varied between 1 and 1100 µg/litre.
    Reproduction in  Daphnia magna was depressed in a dose-dependent
    fashion; the NOEL was in the range 11-19 µg/litre. Reproduction of
    molluscs was not adversely effected by a dose of 1 mg/litre.

         The LD50 for honey-bees was 0.56 µg/bee.

         Acute oral LD50 values for a number of bird species were
    between 100 and 1000 mg/kg body weight. In short-term studies with
    birds, doses of 4-10 mg/kg diet had no effect, even on egg-shell
    quality. Laying ducks treated with doses of lindane up to 20 mg/kg
    body weight, however, had decreased egg production.

         Bats exposed to wood shavings that initially contained 10-866
    mg/m2 lindane, resulting from application at the recommended rate,
    all died within 17 days. No effect on mortality or reproductive
    success was seen in small field mammals given 20 mg/kg diet (the
    highest dose tested). No data were available on effects on
    populations and ecosystems.

    1.1.6  Effects on experimental animals and in vitro

         The acute oral toxicity of lindane is moderate: the LD50 for
    mice and rats is in the range 60-250 mg/kg body weight, depending on
    the vehicle used. The dermal LD50 for rats is approximately 900
    mg/kg body weight. Toxicity was manifested by signs of central
    nervous system stimulation.

         Lindane does not irritate or sensitize the skin; it is slightly
    irritating to the eye.

         In a 90-day study in rats, the NOEL was 10 mg/kg diet
    (equivalent to 0.5 mg/kg body weight). At 50 and 250 mg/kg diet, the
    weights of the liver, kidneys, and thyroid were increased; at 250
    mg/kg diet, an increase was seen in liver enzyme activity. This
    increase in enzyme activity accelerates the breakdown of both
    lindane and other compounds. In another 90-day study in rats, 4
    mg/kg diet (equivalent to 0.2 mg/kg body weight) was considered to
    be the no-adverse-effect level (NOAEL); renal and hepatic toxicity
    were observed at concentrations of 20 mg/kg diet and higher. No
    neurological effect was observed in a 30-day feeding study in rats

    with 240 mg/kg diet (equivalent to 12 mg/kg body weight); however,
    when this dose was given by gavage, neurological effects were seen.
    A short-term toxicity study in mice was considered to be inadequate
    to establish a NOEL.

         Administration of lindane to dogs at 15 mg/kg in the diet
    (equivalent to 0.6 mg/kg body weight) for 63 weeks had no toxic
    effect. In a two-year study of the toxicity of this compound in
    dogs, in which a large number of parameters were measured, no
    treatment-related abnormality was apparent at doses of 50 mg/kg diet
    (equivalent to 2 mg/kg body weight) and lower. In the group given
    100 mg/kg diet, however, levels of alkaline phosphatase were
    increased; and with 200 mg/kg diet, abnormalities in
    electroencephalogram tracings indicative of non-specific neuronal
    irritation were observed.

         In rats exposed by inhalation to lindane at 0.02-4.54 mg/m3
    for 6 h/day for 3 months, the highest dose induced increases in
    hepatic cytochrome P450 values; the NOAEL was found to be 0.6
    mg/m3. In two long-term studies in rats, carried out many years
    ago, doses of 10-1600 mg/kg diet were tested. In one of these
    studies, 50 mg/kg diet (equivalent to 2.5 mg/kg body weight) was
    found to be the NOAEL. At 100 mg/kg diet, an increase in liver
    weight, hepatocellular hypertrophy, fatty degeneration, and necrosis
    were found. In the other study, 25 mg/kg diet (equivalent to 1.25
    mg/kg body weight) had no effect, but hepatocellular hypertrophy and
    fatty degeneration were seen with 50 mg/kg diet.

         Lindane has been investigated for its effects on all aspects of
    reproduction (in rats over three generations) and for its
    embryotoxicity and teratogenicity after oral, subcutaneous and
    intraperitoneal administration in mice, rats, dogs, and pigs. It had
    no teratogenic effect after oral or parenteral administration (extra
    ribs were regarded as variations). Fetotoxic and/or maternal toxic
    effects were observed with doses of 10 mg/kg body weight and above
    given by oral gavage; 5 mg/kg body weight is considered to be the
    NOAEL. Lindane had no effect on reproduction or maturation in the
    three-generation study in rats at doses of up to 100 mg/kg diet; but
    with 50 mg/kg diet, morphological changes in the liver indicating
    enzyme induction occurred in the offspring of the third generation.
    The NOEL in this test was 25 mg/kg diet (equivalent to 1.25 mg/kg
    body weight).

         The NOEL for neurotoxicity in a 22-day study in rats was 2.5
    mg/kg body weight.

         The mutagenicity of lindane has been studied adequately. In
    extensive investigations of its ability to induce gene mutations in
    bacteria and in mammalian cells, and for its capacity to induce
    sex-linked recessive lethal mutations in  Drosophila melanogaster,
    negative results were obtained consistently. Lindane also gave

    negative results in tests for chromosomal damage and sister
    chromatid exchange in mammalian cells  in vitro and  in vivo . The
    results of assays for DNA damage in bacteria and for covalent
    binding to DNA in the liver of rats and mice  in vivo following
    oral administration were also negative. In the very few studies in
    which positive results were obtained, either the study design was
    invalid or the purity of the compound tested was not reported.
    Overall, however, lindane appears to have no mutagenic potential.

         Studies to define the carcinogenic potential of lindane have
    been carried out in mice and rats using dose levels of up to 600
    mg/kg diet in mice and up to 1600 mg/kg diet in rats. Hyperplastic
    nodules and/or hepatocellular adenomas were found in mice given
    doses of 160 mg/kg diet or more; in some studies, the dose levels
    exceeded the maximum tolerated dose. Two studies in mice with dose
    levels of up to 160 mg/kg diet and one in rats with 640 mg/kg diet
    showed no increase in the incidence of tumours.

         The results of studies on initiation-promotion of
    carcinogenicity, on the mode of action, and on mutagenicity indicate
    that the tumorigenic response observed with gamma-HCH in mice is
    mediated by a nongenetic mechanism.

    1.1.7  Effects on humans

         Several cases of fatal poisoning and of non-fatal illness
    caused by lindane have been reported, which were either accidental,
    intentional (suicide), or due to gross neglect of safety precautions
    or improper uses of medical products containing lindane. Symptoms
    included nausea, restlessness, headache, vomiting, tremor, ataxia,
    and tonic-clonic convulsions and/or changes in the
    electroencephalographic pattern. These effects were reversible after
    discontinuation of exposure or symptomatic treatment.

         Notwithstanding extensive use over 40 years, very few cases of
    poisoning in the occupational setting have been reported. In workers
    exposed for long periods during either manufacture or application of
    lindane, the only sign found was increased activity of drug
    metabolizing enzymes in the liver. There is no evidence for the
    relationship suggested in some publications between exposure to
    lindane and the occurrence of blood dyscrasias. A few acute and
    short-term studies in humans indicate that a dose of approximately
    1.0 mg/kg body weight does not induce poisoning; however, a dose of
    15-17 mg/kg body weight resulted in severe toxic symptoms.

         Approximately 10% of a dermally applied dose is absorbed,
    although more passes through damaged skin.

    1.2  Conclusions

    1.2.1  General population

         Lindane is circulating in the environment and is present in
    food chains, so that humans will continue to be exposed. The daily
    intake and total exposure of the general population are decreasing
    gradually, however; they are clearly below the advised acceptable
    daily intake and are of no concern to public health.

    1.2.2  Subpopulations at special risk

         The presence of lindane in breast milk results in exposure of
    breast-fed babies to levels that are generally below the acceptable
    daily intake and therefore of no concern to health. Although lower
    levels of exposure would be preferred, the present levels are not a
    limiting factor for the practice of natural breast-feeding.

         Prescriptions should be followed strictly with regard to the
    therapeutic use of lindane against scabies and to control body lice.

    1.2.3  Occupational exposure

         As long as the recommended precautions to minimize exposure are
    observed, lindane can be handled safely.

    1.2.4  Environmental effects

         Lindane is toxic to bats that roost in close contact with wood
    treated according to the recommended conditions of application.
    Apart from the results of studies of spills into the aquatic
    environment, there is no evidence to suggest that the presence of
    lindane in the environment poses a significant hazard to populations
    of other organisms.

    1.3  Recommendations

    1.   In order to minimize environmental pollution by other isomers
         of HCH, lindane (> 99% gamma-HCH) must be used instead of
         technical-grade HCH.

    2.   In order to avoid environmental pollution, by-products of and
         effluents from the manufacture of lindane should be disposed of
         in an appropriate way.

    3.   In disposing of lindane, care should be taken to avoid
         contamination of natural waters and soil.

    4.   As for other pesticides, proper instructions about application
         procedures and safety precautions should be given to people who
         handle lindane.

    5.   Long-term carcinogenicity tests conducted according to
         present-day standards should be conducted.

    6.   Monitoring of the daily intake of lindane by the general
         population should continue.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL
           METHODS

    2.1  Identity

    2.1.1  Primary constituent

    Common name:             Lindane

    Chemical structure:1

    Fig. 1.  Chemical structure of lindane

    Chemical formula:            C6H6Cl6

    Relative molecular mass:     290.8 (290.9)

    CAS chemical name:           1alpha,2alpha,3ß,5alpha,6ß-
                                 hexachlorocyclohexane

    CAS registry number:         58-89-9

    RTECS registry number:       GV4900000

    Synonym:                     Hexachlorocyclohexane (gamma-isomer)

         According to IUPAC rules, the designation 'benzene
    hexachloride' is incorrect; nevertheless, it is still widely used,
    especially in the form of its abbreviation, BHC. This is therefore
    another common name approved by the ISO. The compound is called
    gamma-HCH by the WHO, but gamma-BHC by the FAO (FAO, 1973). The
    synonym hexachlorocyclohexane (gamma isomer) is used by the
    Environmental Protection Agency and the American Conference of
    Governmental Industrial Hygienists in the USA. The definitions of
    these different appellations are given in Table 1.

    1 See Appendix I

        Table 1.  Definitions of appellations of lindane
                                                                                    
    Name           Definition                     Remarks
                                                                                    
    Lindane        product containing not less    ISO-AFNOR name for a product
                     than 99% gamma-HCH             (not yet recognized by BSI)

    Lindane        = gamma-HCH                    Common name used for
                                                    gamma-HCH in the USSR only

    gamma-HCH      gamma isomer of 1,2,3,4,5,6-   ISO-AFNOR common name
                     hexachlorocyclohexane

    gamma-BHC      gamma isomer of 1,2,3,4,5,6-   ISO BSI common name in
                     benzene hexachloride           English-speaking countries
                                                    (recognized by ISO as
                                                    synonym of gamma-HCH)

    2.1.2  Technical product

    Common trade names: A great number of products containing lindane
                        are on the market; no attempt has been made to
                        list the hundreds of trade names here (see
                        Hudson et al., 1984; Hill & Camardese, 1986;
                        International Register for Potentially Toxic
                        Chemicals, 1989).

    Purity:             The FAO (1973) requires that lindane "... shall
                        consist, essentially, of gamma-BHC as white or
                        nearly white granules, flakes or powder, free
                        from extraneous impurities or added modifying
                        agents and with not more than a faint odour."
                        The FAO further requires that it contain not
                        less than 99.0% gamma-HCH and that the
                        melting-point be at least 112 °C, which is not
                        depressed when the sample is mixed with an equal
                        amount of pure gamma-HCH.

         In some processes for manufacturing lindane, low levels of
    dioxin may be formed (US Environmental Protection Agency, 1985).
    Under appropriate manufacturing conditions, however, no
    2,3,7,8-tetrachlorodibenzodioxin or 2,3,7,8-tetrachlorodibenzofuran
    is detected in HCH, lindane, trichlorobenzene, industrial liquid or
    gaseous effluents at the analytical limit of detection of 1 µg/kg
    letter from D. Demosay, Rhône-Poulenc, to IPCS dated 17 November
    1989.

    2.2  Physical and chemical properties

         Lindane is a colourless, crystalline solid with either a faint
    or no smell (the characteristic smell of technical-grade HCH is
    attributed to impurities, particularly heptachlorocyclohexane).

    Melting-point:      112.8 °C

    Boiling-point:      288 °C

    Vapour pressure:    0.434 x 10-5 kPa (3.26 x 10-5 mmHg) at 20 °C
                        60.6 x 10-5 kPa (45.6 x 10-5 mmHg) at 40 °C

    Density:            1.85

    Solubility:         nearly insoluble in water at 20 °C (10
                        mg/litre); moderately soluble in ethanol (6.7%);
                        slightly soluble in mineral oils;
                        soluble in acetone and in aromatic and
                        chlorinated solvents

    Stability:          stable to light, air, heat, carbon dioxide, and
                        strong acids; dehydrochlorinates in the presence
                        of alkali or on prolonged exposure to heat with
                        the formation of trichlorobenzenes, phosgene,
                        and hydrochloric acid. It is incompatible with
                        strong bases and powdered metals, such as iron,
                        zinc, and aluminium, and with oxidizing agents;
                        can undergo oxidation when in contact with
                        ozone.

    Corrosivity:        corrosive to aluminium

    Inflammability:     not inflammable

     n-Octanol/water       3.2-3.7 (see section 4.2.7.1) (Demozay &
    partition           Marechal, 1972; Dutch Chemical Industry
    coefficient         Association 1980; American Conference of
    (log Pow):            Governmental Industrial Hygienists, 1986;
                        Rhône-Poulenc Agrochimie, 1986)

    2.3  Conversion factors

         1 ppm = 12.1 mg/m3
         1 mg/m3 = 0.083 ppm

    2.4  Analytical methods

    2.4.1  Sampling

         Sampling procedures and methods for preparing samples of
    formulations and for analysing residues have been described by
    Mestres (1974), the Deutsche Forschungsgemeinschaft (1979), the
    Association of Official Analytical Chemists (1980), and Hildebrandt
    et al. (1986).

    2.4.2  Analytical methods

         Products are analysed by a cryoscopic method (Raw, 1970; FAO,
    1973; WHO, 1985). Formulated products can be analysed by determining
    hydrolysable chlorine (Raw, 1970; FAO, 1973). Since the latter
    method is not specific, other methods, such as gas chromatography,
    are used to obtain sufficient separation of the HCH isomers.

         Residues in food and in soil can be determined after adequate
    clean-up by gas chromatography and other chromatographic methods
    (Nash et al., 1973; Eichler, 1977; Association of Official
    Analytical Chemists, 1980; DeutscheForschungsgemeinschaft, 1983).
    The principle of the method is extraction of a sample with organic
    solvents (acetonitrile, hexane/acetone, acetone, and others). Fat is
    extracted from fatty foods and partitioned between petroleum ether
    and acetonitrile by extracting aliquots or an entire solution of
    acetonitrile into petroleum ether. Residues are purified by
    chromatography on a Florisil colum, and eluted with a mixture of
    petroleum ether and ethylether. Concentrated residues are measured
    by gas chromatography with electron capture detection.

         The method described by the Deutsche Forschungsgemeinschaft
    (1979) for fruits and vegetables is based on extraction of samples
    with acetone and extraction of the aliquot with dichloromethane. The
    residue obtained after evaporation of the solvent is cleaned by
    co-distillation, and the distillate is analysed by gas
    chromatography with electron capture detection. The limit of
    determination depends on the method, the substrate and the sample
    size; the lower limit of determination is 0.001-0.01 mg/kg.

         Palmer & Kolmodin-Hedman (1972) analysed air samples by gas
    chromatography with electron capture detection, and alpha-, beta-,
    and gamma-HCH were determined in serum by gas chromatography after a
    deproteinization extraction step (Palmer & Kolmodin-Hedman, 1972;
    Angerer & Barchet, 1983).

         Wittlinger & Ballschmiter (1987) provided an extensive
    description of analytical methods for HCHs in air, involving
    sampling by adsorption, extraction and preseparation, and
    determination by high-resolution gas chromatography. Sampling was
    performed by pumping air through a glass-fibre filter and then

    through a silica-gel layer, using an internal standard. The sample
    was extracted with dichloromethane and the extract evaporated. The
    preseparation was done on silica gel, and the aliquot was eluted in
    a mixture of hexane and dichloromethane. High-resolution capillary
    gas chromatography, electron capture detection and a mass selective
    detector were used for determination.

         Eder et al. (1987) described three analytical methods for the
    determination of HCHs in sediments: moist samples are extracted with
    a solvent or a mixture of solvents, concentrated or fractionated and
    determined by gas chromatography and electron capture detection.

         Greve (1972) described a method for the determination of
    organochlorine pesticides in water based on gas chromatography of a
    petroleum ether extract after clean-up over Florisil or silica gel.
    The limit of detection for lindane is 0.01 µg/litre.

         Methods used for the determination of lindane in samples of
    soil, animal, and vegetable products in the USSR are described by
    Izmerov (1983). These methods are based on extraction with organic
    solvents, purification and concentration of the extracts and
    determination by gas-liquid chromatography with electron-capture
    detection.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Lindane is not known to occur as a natural product.

    3.2  Man-made sources

    3.2.1  Production levels and processes

    3.2.1.1  Manufacturing process

         HCH was discovered in 1825, but its insecticidal properties
    were first patented only in the 1940s. It has been produced
    commercially since 1949.

         Technical-grade HCH is synthesized from benzene and chlorine in
    the presence of ultra-violet light and comprises 65-70% alpha-HCH,
    7-10% beta-HCH, 14-15% lindane (gamma-HCH), approximately 7%
    delta-HCH, 1-2% epsilon-HCH, and 1-2% other components. By-products
    can be minimized by careful control of the reaction conditions.
    Lindane (> 99% gamma-HCH) can be purified by multiple extractions
    with methanol.

         The extraction of lindane from HCH produces 85%
    non-insecticidal HCH isomers, which can be used as intermediates in
    the production of trichlorobenzene and hydrochloric acid after
    cracking in an integrated installation. Trichlorobenzene is used in
    the synthesis of other chemicals (van Velsen, 1986; Rhône-Poulenc
    Agrochimie, 1986).

    3.2.1.2  World-wide production figures

         Lindane is produced in Austria, France, and Spain and in China,
    India, Turkey, and the USSR. Before 1984, lindane was also
    manufactured in the German Democratic Republic, Poland, Yugoslavia,
    Romania, and Hungary; since then, all production has been stopped in
    Germany, Japan, the Netherlands, the United Kingdom, and the USA.

         Although in most developed countries use of technical-grade HCH
    has been prohibited, it is still used elsewhere on a large scale:
    total consumption of technical-grade HCH in India in 1986-87 was
    approximately 27 000 tonnes (International Atomic Energy Agency,
    1988).

    3.2.2  Emissions

         According to De Bruijn (1979), approximately 0.1% of the
    lindane processed reaches the waste-water of a formulating plant.
    Treatment of the waste-water, however, leads to solid waste, which
    should be incinerated. In the past, it was often dumped in the

    environment and could be dispersed from (open) chemical dumping
    grounds to more remote soils by the wind.

         Lindane enters the environment following application of
    lindane-containing pesticides. Emissions can cross national
    boundaries in water and air. For instance, the total trans-frontier
    flux of lindane into the Netherlands via the surface water of the
    River Rhine was approximately 1.8 tonnes per year (average for
    1980-83) and that via the River Meuse, 0.2 tonnes per year (Slooff &
    Matthijsen, 1988).

    3.2.3  Uses

         Lindane is a broad-spectrum insecticide, which has been used
    since 1949 for agricultural as well as non-agricultural purposes.
    Approximately 80% of the total production is used in agriculture
    (Demozay & Marechal, 1972), mostly for seed and soil treatment. Wood
    and timber protection is the major non-agricultural use. Lindane is
    also used against ectoparasites in veterinary and pharmaceutical
    products (Rhône-Poulenc Agrochimie, 1986).

    3.2.4  Extent of use

         Lindane is used worldwide, with the major exception of Japan,
    where all uses of HCH were cancelled in 1971 mainly because of
    environmental pollution with alpha- and beta-HCH resulting from
    extensive use of technical-grade HCH. At that time, no clear
    difference was made between the risks presented by the individual
    HCH isomers, and lindane was banned as well. In almost all other
    countries, lindane is registered for one or more applications,
    although the use pattern differs from one country to another.

         In 1979, the US Department of Agriculture and the Environmental
    Protection Agency summarized the percentage uses of lindane in the
    USA as follows: seed treatment 48%, hardwood lumber 23%, livestock
    16%, pets 3%, pecans 3%, pineapples 2%, ornamentals 2%, household
    1%, cucurbits 1%, forestry 0.5%, and structures 1%. In France and
    Germany, 70-80% of all lindane used agriculturally is for soil
    treatment, to protect maize and sugar beets, and 15-20% is used for
    seed treatment. De Bruijn (1979) reported an estimate of the pattern
    of use of lindane in the European Economic Community.

    3.2.5  Formulations

         Formulation facilities exist in many countries. Lindane is made
    in numerous forms, the most important of which are: wettable powders
    (up to 90% active ingredient); emulsifiable concentrates (not more
    than 20% active ingredient); flowable suspensions (in water);
    solutions in organic solvents (up to 50% active ingredient); dusts
    and powders (0.5-2% active ingredient); granules and coarse dusts
    (3-4% active ingredient); ready-for-use baits; aerosols; and special

    formulations for use in human and veterinary medicine (Demozay &
    Marechal, 1972).

         Lindane dissolved in organic solvents may be used in 'thermal
    foggers' in glasshouses or atomized in open areas; such solutions
    are appropriate for aerial application (5-10 litres/ha of
    formulations containing 5-10% active ingredient). Concentrated
    solutions containing an anti-vaporization component have been
    applied using an ultra-low volume method at 0.5-1 litre/ha. Various
    fumigation preparations for indoor use have been sold, including
    fumigation strips, tablets, and smoke generators. These contained
    virtually pure lindane to which a small quantity of binding material
    was added. Because of its versatility and relatively low acute
    toxicity, lindane is often used in mixed formulations with other
    insecticides and fungicides (Demozay & Marechal, 1972).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Volatilization

         Some of the active ingredient of lindane volatilizes after it
    has been applied to control insect pests, especially on leaves.
    Starr & Johnson (1968) demonstrated that 20% of an applied dose had
    evaporated 96 h after bean plants had been sprayed with lindane at
    16 °C. The evaporation was dependent on temperature and on the
    humidity of the air. 

         Some of the lindane that reaches the soil may also vaporize as 
    degradation products. Cliath & Spencer (1972) showed the presence of 
    vapours of the metabolite PCCH, which has a vapour pressure 
    approximately 14 times higher than that of lindane.

         In a model test, four soil types, ranging from a loamy sand to
    a clay, were treated with 14C-lindane to give a concentration of
    10 mg/kg soil; water was then added to the samples, they were
    air-dried at 33 °C and at 55 °C, and volatilization was measured by
    trapping the vapours. Three cycles of about 14 days each were
    followed. Lindane volatilized from the soils only with water, and no
    further volatilization occurred after the soils had reached the dry
    state. The four soil types were associated with different
    volatilization rates: the highest occurred in loamy sand. In the
    analysis of vaporized material, unchanged lindane and its
    degradation products were not differentiated; however, considerable
    degradation of lindane was found in the soils, and PCCH was
    identified as a metabolite. At least some of the vaporized material
    may therefore have consisted of degradation products (Guenzi &
    Beard, 1970).

    4.1.2  Precipitation

         Evaporation and adsorption to solid particles are important
    processes in the distribution of lindane. Reverse processes such as
    deposition from the air and remobilization from silt and sediment
    also play a part. Buscher et al. (1964) demonstrated that aeration
    of aqueous solutions of lindane resulted in a loss of 10% over three
    days, which was ascribed to a co-distillation process as it was
    greater than could be explained by evaporation alone. MacKay &
    Walkoff (1973) confirmed that evaporation is an important process in
    the loss of HCH. Lichtenstein & Schulz (1970) found that 16.5% HCH
    was lost from a non-aerated aqueous solution in 24 h at 30 °C.

         The amount of lindane that is distributed by dry deposition
    depends on the nature of the surface above which the organic
    components are present. The half-time for dry deposition of HCHs
    (height of mixing layer, 1000 m) in the Netherlands was calculated

    to be 2-8 days. On this basis, a rough estimate of the annual flux
    to soil and water in that country would be 0.5-1.5 tonnes from an
    outdoor air concentration of 0.4 ng/m3 (Slooff & Matthijsen,
    1988).

    4.1.3  Movement in soils

         Movement of a substance through the soil profile depends on its
    adsorption-desorption characteristics in soil/water systems and, to
    some extent, on its volatility in the soil pores and its diffusion.
    The adsorption-desorption characteristics of lindane have been the
    object of a number of studies (Kay & Elrick, 1967; Mills & Biggar,
    1969; Baluja et al., 1975; Portmann, 1979; Wahid & Sethunathan,
    1979, 1980; Wirth, 1985), all of which showed that lindane is
    strongly adsorbed to organic soil material and weakly adsorbed to
    inorganic matter. In the absence of organic matter, the clay content
    and free iron oxide are implicated in the sorption of lindane (Wahid
    & Sethunathan, 1979). It can be concluded that the mobility of
    lindane is very low in soils with a high content of organic matter
    but might be higher in soils containing little organic matter.

         No consensus has been reached in the literature about the
    possibility that lindane can be remobilized by desorption from
    polluted soil. Generally, HCH isomers are strongly adsorbed. Under
    certain conditions - high concentrations of lindane in highly
    permeable soils with a low organic carbon content (< 0.1%) - a
    small percentage of the compound may be washed out and reach the
    groundwater. Nevertheless, the low rate of transport of lindane
    makes the probability that it will reach groundwater low or very low
    (Slooff & Matthijsen, 1988).

         The diffusion of lindane through soil was investigated by
    Ehlers et al. (1969a,b) and by Shearer et al. (1973). Diffusion was
    strongly influenced by the water content of the soil, by the bulk
    density and by temperature. The diffusion coefficient is nearly zero
    in soil containing 1% water, but with a water content of 3%, lindane
    is displaced from the adsorbing surface so that the diffusion
    coefficient becomes maximal; a further increase in water content
    reduces the diffusion coefficient. The diffusion of lindane in soils
    can thus vary between a 'vapour' and a 'non-vapour' phase, depending
    on the concentration of lindane, the length of time and the water
    content of the soil.

         Leaching of three formulations of lindane was investigated in a
    series of model studies by Heupt (1974) in different soil types. The
    test system consisted of 30-cm columns filled with soil to which
    lindane formulations were applied at application rates corresponding
    to 6 kg of active ingredient per hectare. Rainfall was simulated at
    a rate of 200 mm within two days. No lindane was found in the eluate
    at the limit of detection of 1 µg/litre. In field tests by Cliath &
    Spencer (1971, 1972), lindane was worked into topsoil of two plots

    of sandy loam and two of silty clay to a depth of 0-7.5 or 7.5-15
    cm, corresponding to an application rate of 21 kg/ha. One of the
    plots of each soil type received additional irrigation. Almost no
    movement of lindane was found in the dry plots at the end of the
    two-year observation period. In the irrigated plots, a broadening of
    the lindane-containing zone and downward movement to a depth of 60
    cm were observed, especially in sandy loam; in clay soil, lindane
    had almost no mobility.

         In a series of dissipation studies with 14C-labelled lindane
    in soils, coordinated by FAO and the International Atomic Energy
    Agency, it was demonstrated that persistent pesticides such as
    lindane dissipate much faster in the tropics than in temperate
    climates, probably owing to a large extent to volatilization
    (International Atomic Energy Agency, 1988), as had been found by
    Edwards (1973a,b, 1977). Table 2 summarizes the results of these
    studies.

        Table 2.  Field half-times of gamma-HCH in soils (0-10-cm depth)a

    Country                   Half-time (days)b           Time required for
                                                          initial loss of 50%
               Overall        First phase  Second phase   of radioactivity (days)
                                                                                 
    India      138 (124-147)  41 (30-50)   188 (83-362)   30-45

    Ecuador    150-171        54-60        120-160        40-50

    Kenya       5-8               -              -        3-4

    a Adapted from International Atomic Energy Agency (1988)
    b In temperate soils, the mean half-time was 438 (401-1022) days
      (Edwards, 1973a, b)

    4.1.4  Uptake and translocation in plants

         One of the first investigations on the absorption of lindane by
    various seeds was reported by Bradbury & Whitaker (1956). Lindane
    was taken up from a nutrient solution by the roots of wheat
    seedlings at a rate of up to 100 mg/kg (fresh weight) within seven
    days. Subsequent investigations demonstrated that uptake by plants
    is dependent on a variety of factors.

         The influence of  soil type was investigated by Bradbury
    (1963). Seedlings grown from seed dressed with lindane and planted
    in sand had residue levels about two-fold higher than those of

    plants grown in compost. A further study was reported of the fate of
    14C-lindane in loam and sandy soil and in oat plants grown in
    these soils for 13 days. The loam soil was treated with about 7.3
    mg/kg active ingredient and the sandy soil with about 3 mg/kg.
    Residues were found to be more persistent in loam (53.5% of
    radiolabel) than in sandy soil (33.8%), but oats grown in sandy soil
    took up more residues than those grown in loam (loam soil: roots,
    0.5%; tops, 0.3%; sandy soil: roots, 2.5%; tops, 1.2%).
    14C-Lindane was the major constituent of the soil residues soluble
    in organic solvents. A major metabolite, which was probably
    gamma-PCCH, represented 11% of the organic-soluble radiolabelled
    residues in loam soil; 2,4,5-trichlorophenol accounted for 2.7% of
    these residues. The authors concluded that the three major factors
    that determine the environmental fate of 14C-lindane and other
    insecticides are the insecticide itself, its solubility in water and
    the type of soil to which it is applied. Compounds with greater
    aqueous solubility are more mobile, are taken up by plants to a
    greater extent, and appear to be more susceptible to degradation
    than compounds less soluble in water. In soils with little organic
    matter, insecticide residues are more mobile and hence more
    susceptible to volatilization, uptake by plants, and degradation
    than in more adsorbent soils such as loam (Fuhremann & Lichtenstein,
    1980).

         The  rate of application to soil was found to be a further
    important factor in determining residue levels. Transfer of lindane
    from soil into rice plants was almost proportional to the level of
    contamination of the soil (Kawahara, 1972), but only at low levels
    of contamination. Charnetski & Lichtenstein (1973) reported a good
    correlation between the content of 14C-lindane in sand (at up to 6
    mg/kg, which is about 12 times the concentration expected after
    normal application) and that in pea plants grown for six days; at
    concentrations greater than 10 mg/kg of soil, there was no further
    increase in the residue levels.

         Uptake of lindane after  application to leaves is lower than
    that resulting from application to soil. In lettuce and endives
    treated with 14C-lindane and grown for 21 and 37 days,
    respectively, only 4.5-13.9% of the applied radioactivity was found
    at the time of harvest, and most of the lindane had evaporated into
    the atmosphere (Kohli et al., 1976a).

         Differences in residue levels are also dependent on the plant
    species. Of a series of edible crops grown in soil containing
    lindane at an initial concentration of 5 mg/kg (about 10 times the
    normal application rate), carrots had higher levels than beans,
    tomatoes, or potatoes (San Antonio, 1959). More lindane was absorbed
    from soil with an initial concentration of 2.6 mg/kg by radishes,
    turnips, and spinach than by Chinese cabbage (Kawahara et al.,
    1971). The amounts of residues of HCH isomers in turnips were
    proportional to the initial concentrations of the isomers in the

    soil (0.05, 0.1, 0.5, 1, 5, 10, or 50 mg/kg soil). The soil:plant
    residue ratios were in the range 10-20:1 (Kawahara & Nakamura,
    1972).

         The translocation of lindane and its metabolites in plants has
    also been investigated in detail (San Antonio, 1959; Bradbury, 1963;
    Itokawa et al., 1970; Kawahara, 1972; Kawahara & Nakamura, 1972;
    Charnetski & Lichtenstein, 1973; Balba & Saha, 1974; Eichler, 1980;
    Korte, 1980). Neither lindane taken up from soil nor its metabolites
    were evenly distributed within the plants: Comparatively high
    residue levels were always detected in the roots, whereas only small
    amounts were translocated into stems, leaves, and fruits. Paasivirta
    et al. (1988) showed that in water-plants, lindane concentrations
    are similar in roots and leaves.

    4.2  Biotransformation

    4.2.1  Degradation

    4.2.1.1  Degradation under humid conditions

         The half-times of lindane found by different investigators vary
    considerably, depending on the type of soil to which it is applied
    and, possibly, temperature. Lindane incubated in a sandy-loam soil
    with a water capacity of 28% and 60% saturation at room temperature
    had a half-time of approximately 40 days (Heeschen et al., 1980).
    The half-times of lindane in model tests were 4-6 weeks in humid
    sand with a high content of organic matter and 30 weeks in sandy
    loam (Heupt, 1979). The half-times in aerobic and anaerobic
    conditions ranged from 12 to 174 days and 100 to 720 days,
    respectively; in aerobic field conditions, the half-time was 88-1146
    days (Edwards, 1966; Kohnen et al., 1975; Kampe, 1980; Rao &
    Davidson, 1982; MacRae et al., 1984).

         Assuming that lindane is not washed out below the level of
    ploughed furrows (approximately 20 cm), a half-life of 350 days will
    result in persistence of 50% of a dose one year after application
    (Slooff & Matthijsen, 1988). One month after double treatment of
    potato, beet, and maize crops with lindane, the gamma-HCH content in
    sandy loam soil was 0.32 mg/kg in the field occupied by maize and
    0.68-0.70 mg/kg in the fields with potatoes and beet. After nine
    months, the lindane content in the beet fields had decreased 14
    times and that in the maize fields by only 1.3 times (Kovaleva &
    Talanov, 1973; see Izmerov, 1983).

    4.2.1.2  Degradation under submerged conditions

         Half-time values for lindane of a few to about 120 h were
    determined after incubation in various submerged soil samples. More
    rapid degradation occurred in soils with a high amino acid content,
    and the rate also clearly depended on the number of degrading

    microorganisms present (Ohisa & Yamaguchi, 1979). The rapidity with
    which lindane was degraded under flooded conditions varied in soil
    samples from different locations in Japan. Enrichment of the soils
    with peptone and exclusion of oxygen increased the degradation rate
    (Ohisa & Yamaguchi, 1978a).

         Half-time values of 10-30 days were observed in a comparison of
    four Philippine rice soils under flooded conditions at a temperature
    of 30 °C. Lindane was degraded faster at higher temperatures
    (Yoshida & Castro, 1970). In a similar study with five Indian rice
    soils at 28 °C, 14C-labelled lindane was degraded at half-times of
    between 10 days and more than 41 days. Addition of rice straw
    enhanced the degradation (Siddaramappa & Sethunathan, 1975).

         Tsukano (1973) found a half-time for lindane of 10-14 days in
    soil samples mixed with water. The degradation was almost completely
    inhibited after addition of sodium azide to the soils, indicating
    that the degradation observed in non-sterilized soils was due to
    microbial activity.

    4.2.2  Degradation under field conditions

         Nash (1983) used a microagroecosystem in which moist fallow
    sandy loam was placed in a glass chamber at a depth of 15 cm, plants
    were grown in the chamber and lindane was applied to the surface. A
    half-time of 1-4 days was found for dissipation of lindane in the
    soil.

         In April 1954, formulations containing lindane were applied to
    a sandy loam soil at rates of 2.25 and 4.5 kg/ha on field plots in
    the Rhine valley, and loss of active ingredient was followed during
    the subsequent 1.5 years using a biological test method. The
    insecticidal activity disappeared rapidly during the following
    vegetation period but remained almost constant in winter; further
    degradation was observed during the second vegetation period. At the
    end of the observation period, 3.5-5.5% of the lindane applied at
    2.25 kg/ha remained, and 17-19.5% of that applied at 4.5 kg/ha: the
    speed of degradation was therefore greater at the lower application
    rate. Degradation was virtually identical when the lindane was
    worked into the soil to a depth of 1-2 cm and when it was introduced
    to a depth of 10 cm (Schmitt, 1956).

         In a field test in Miami, Florida, USA, on silt loam and muck
    soils, lindane was applied at the extremely high rates of 11.2 or
    112.1 kg/ha. The initial half-time at the lower rate was 15.5 months
    in muck soil and 4.75 months in loam soil. Degradation was slower at
    the higher rate: the initial half-times were 28.8 months in muck
    soil and 11.1 months in loam soil (Lichtenstein & Schulz, 1958a). In
    an earlier study on the same field plots with the same application
    rates, however, Lichtenstein & Schulz (1958b) found that most of the
    material detected chemically was inactive in the bioassay and

    therefore did not represent lindane. They concluded that the
    breakdown of lindane is faster than it appeared to be using their
    analytical method.

         In an extensive study, sandy loam, silt loam, and muck soils on
    plots in three midwestern states of the USA were treated with
    lindane in 1954 at application rates of 1.1, 11.2, and 112.1 kg/ha
    to a depth of 15.2 cm. After a 4.5-year follow-up, no lindane was
    detected on plots treated with 1.1 kg/ha; but after application at
    the higher rates (far in excess of normal rates), about 36% of the
    applied dose remained. Two major factors that affect the persistence
    of lindane in soils appear to be the amount of organic matter in the
    soil and the climatic conditions of the area (Lichtenstein et al.,
    1960).

         The rates of loss of lindane were calculated by Wheatley (1965)
    in 10 long-term field studies in the United Kingdom. When lindane
    was applied to the soil surface, there was a 50% loss within 4-6
    weeks and a 90% loss within 30-40 weeks. When the lindane was mixed
    into the soil, a 50% loss was observed after 15-20 weeks and 90%
    within 2-3 years. No lindane was recovered 13 years after the last
    application of lindane to a loam soil in Nova Scotia at a rate of
    0.84-1.7 kg/ha (Stewart & Fox, 1971). Cliath & Spencer (1971)
    treated two test plots in California, USA, with 21 kg/ha, which is
    an application rate about 20 times above normal. A half-time of 8
    months was found in sandy loam and 10 months in silty clay.

         After application of lindane on three test plots of light sandy
    soil in the Netherlands for 15 years, to give total amounts of 6.5,
    13.0, and 24.3 kg/ha, only 3, 4, and 8% of the applied amount,
    respectively, was recovered in layers to a depth of 20 cm (Voerman &
    Besemer, 1970). A further follow-up of these plots for four years
    showed rapid disappearance on the two locations with the lower
    application rates; slower degradation was seen on the plot that had
    received the highest application, where lindane was found to a depth
    of 40 cm (Voerman & Besemer, 1975). Admixture of a 5% lindane dust
    to the top 15-cm layer of a test plot at a rate of 10 kg of active
    ingredient per hectare in India led to an initial concentration of
    3.2 mg/kg soil. After an observation period of 180 days, 97.7% of
    the applied lindane had disappeared. The initial half-time of
    lindane in this study was about 30 days (Agnihotri et al., 1977).

         The degradation of gamma-HCH was also determined in a variety
    of studies in which technical-grade HCH was applied to soils. In
    most of these investigations, the application rates were extremely
    high, and in some, applications were made once a year for several
    years (Lichtenstein & Polivka, 1959; Stewart & Chisholm, 1971;
    Shiota & Kanda, 1972; Nash et al., 1973; Jackson et al., 1974;
    Suzuki et al., 1975). Under these conditions, gamma-HCH disappeared
    slowly from the soils and sometimes persisted for long periods.

         The distribution of HCHs was studied in soil treated with
    BHC-20 (containing 70% alpha-HCH, 6.5% beta-HCH, 13.5% gamma-HCH,
    and 5% delta-HCH) in an agricultural area. The concentrations
    changed with time after application; the mean value for gamma-HCH
    was 16 µg/kg. The organic carbon content of the soil appeared to be
    of primary importance, and the significant decrease in isomer
    concentration observed with greater soil moisture was attributed to
    microbial degradation, which is favoured by these conditions
    (Chessells et al., 1988).

         Kathpal et al. (1988) studied the behaviour of a formulation
    consisting of a mixture of five HCH isomers in paddy soils under
    subtropical conditions in India. The recommended application rate of
    2.5 kg active ingredient per hectare and a rate of 5.0 kg/ha were
    used. Gamma-HCH had dissipated by 50-63% within three months under
    paddy, and average residues in soil at harvest were 0.3-0.34 mg/kg.
    Dissipation after nine months (two crop seasons) was 98%. The
    persistence under paddy in this study was fairly high, probably
    owing to the anerobic conditions, which slow microbial degradation.
    The paddy plants absorbed gamma-HCH from the soil: the residues at
    harvest were about 1.0 mg/kg in plants and 0.03-0.06 mg/kg in seeds.

    4.2.3  Hydrolytic degradation

         Determination of the hydrolytic stability of a substance
    provides an indication of whether this process can contribute to the
    disappearance of the substance from the aquatic environment and, to
    a certain extent, from soil. In a model experiment, the half-time of
    lindane at 22 °C was 47.9 h at pH 9 and 100.7 h at pH 7; no
    measurable hydrolysis occurred at pH 5 (Heupt, 1983).

    4.2.4  Photolytic degradation (laboratory studies)

         As lindane has measurable volatility and can be found at low
    levels in air, its degradation in sunlight has been studied.

         Carbon dioxide was formed after 14C-lindane was adsorbed onto
    silica-gel plates at a concentration of 33 µg/kg and irradiated with
    artificial sunlight (> 290 nm) in the presence of air; 6.4% of the
    carbon was oxidized within 17 h. This photo-induced oxidation was
    enhanced when the lindane was exposed to pure oxygen during
    irradiation (Kotzias et al., 1981). No measurable degradation (less
    than 0.5%) was observed 2000 h after exposure of lindane to the
    light of a Xenon lamp in a Xenotest 150 on the wall of a quartz
    vessel (solid phase). When the irradiation was performed in aqueous
    solution, about 4% of the applied lindane was degraded after 2000 h.
    The main degradation product was PCCH (Gardais & Scherrer, 1979).

         Irradiation of lindane with ultra-violet light (254 nm) is
    obviously more effective for degradation of the compound than
    irradiation with light of longer wavelengths. Hamada et al. (1981,

    1982) found rapid degradation of lindane in both the crystalline
    state and in solution with 2-propanol under these conditions, with
    PCCHs and TCCHs as reaction products. Eichler (1977) also found
    rapid degradation of lindane in the solid or gaseous form and in
    aqueous solution in the presence of ultra-violet irradiation, with
    half-times of 12-24 h for the first two phases and 1-2 days for the
    latter two.

    4.2.5  Biodegradation in water

         In a study of the degradation of lindane in a biological
    purification plant, 75% of the compound was degraded within 6 h
    (Eichler et al., 1976).

         Newland et al. (1969) investigated the degradation of gamma-HCH
    in simulated lake impoundments. Sediments from Lake Tomahawk,
    Wisconsin, USA, were added to solutions of 5 mg/litre 14C-labelled
    lindane and equilibrated for 18 h, and aerobic and anaerobic tests
    were run for approximately 88 days. Initially, about 45% of the
    applied lindane was adsorbed to the sediment (200 g per 3-litre
    solution). Under aerobic conditions, about 16% of the added lindane
    was degraded by the end of the observation period, whereas more than
    97% was degraded under anaerobic conditions. When lindane
    degradation was tested in samples of surface water from two
    different regions for periods of 3, 6, or 12 weeks, decreases of up
    to 90% of the initial concentration were found. Most of the lindane
    was metabolized by microorganisms in the sediments: In samples of
    sediment and water autoclaved prior to treatment and incubation, up
    to 95% of the applied lindane was still present (Oloffs et al.,
    1973).

         In a field test in rice fields in the Camargue, France, a
    formulation containing lindane was applied at a rate that resulted
    in an initial concentration in water of 54.8 mg/m3. Rapid
    disappearance was observed, for a half-time of about 1.5 days, and
    within 10 days the concentration had dropped to the background value
    of 0.08 mg/m3 (Podlejski & Dervieux, 1978).

         The degradation of lindane was also tested in the water of a
    drainage canal in the Holland Marsh, Ontario, Canada, in distilled
    water, and in both water types after sterilization. The half-time of
    lindane in the natural water was about six weeks, but a very low
    disappearance rate was seen in the distilled and sterilized water,
    indicating the importance of microbial action for degradation of
    lindane in water (Sharom et al., 1980).

         An aquatic model ecosystem, with pond water, sludge, aquatic
    plants, and fish, was used to study the decomposition and migration
    of lindane. In water without hydrobionts, the half-time was 50 days.
    When sludge and aquatic plants were present, the half-time was 34

    days, and that in the presence of fish was 2 days (Vrochinsky, 1973;
    see Izmerov, 1983).

    4.2.6  Microbial degradation

         A variety of experiments on the degradation of lindane was
    performed with mixed populations of the microorganisms that occur in
    different types of soil, in aquatic sediments (Newland et al., 1969;
    Benezet & Matsumura, 1973), and in other types of soil under
    aerated, submerged, and strictly anaerobic conditions (Macrae et
    al., 1967; Yule et al., 1967; Kohnen et al., 1975; Mathur & Saha,
    1975, 1977; Tu, 1975; Haider, 1979). The fact that lindane was
    removed faster from non-sterile than from autoclaved soil
    demonstrated that its degradation in soil is due to microbial
    activity (Macrae et al., 1967; Kohnen et al., 1975).

         The microorganisms shown by screening experiments to be capable
    of metabolizing and degrading lindane are as follows (Tu, 1976;
    Jagnow et al., 1977):

    Bacteria                Fungi              Algae

    Arthrobacter sp.        Penicillium sp.    Chlamydomonas sp.
    Bacillus sp.            Rhizopus sp.       Chlorella sp.
    Citrobacter sp.
    Clostridium sp.
    Enterobacter sp.
    Micromonospora sp.
    Pseudomonas sp.
    Thermoactinomycetes sp

    In addition, lindane was metabolized in cell-free preparations of 
     Clostridium sp.  in vitro (Heritage & Macrae, 1977a; Ohisa et
    al., 1980).

         Lindane is degraded by soil microorganisms under aerobic as
    well as under anaerobic conditions, but anaerobic conditions are the
    most favourable for its metabolism (Newland et al., 1969; Haider &
    Jagnow, 1975; Vonk & Quirijns, 1979). In an anaerobically grown
    culture of  Clostridium sphenoides supplemented with lindane at 5
    mg/litre, none was found, even after 2 h (Heritage & Macrae, 1979).
    Several species of soil bacteria that have been shown to degrade
    lindane effectively are described in detail in section 6.6.2.

         In field studies in which gamma-HCH was applied at excessive
    doses, it was degraded more slowly than at doses closer to those
    used for normal agricultural applications. Introduction of HCH at up
    to 224 kg/ha, corresponding to 33.6 kg gamma-HCH per hectare,
    exceeded the degradation capacity of soil microorganisms for a long
    period (Nash et al., 1973). In addition, the analytical methods used

    might have resulted in an overestimation of the actual gamma-HCH
    concentration, as concluded by Lichtenstein & Schulz (1958b).
    Therefore, studies in which technical-grade HCH is applied,
    especially at excessive rates, cannot be used to evaluate the
    degradability of lindane in soil.

    4.2.7  Bioaccumulation/Biomagnification

    4.2.7.1   n-Octanol/water partition coefficient

         The  n-octanol/water partition coefficient (Pow) of lindane
    was determined in several studies, with good agreement, covering the
    narrow range of log Pow = 3.29-3.72 (Kurihara et al., 1973;
    Platford, 1981; Darskus, 1982; Geyer et al., 1982; Hermens &
    Leeuwangh, 1982; Geyer et al., 1984). These values indicate that
    lindane can become enriched in lipid-containing biological
    compartments.

    4.2.7.2  Aquatic environment

         The bioconcentration factor for lindane was found to be
    dependent on the concentration to which the organisms, such as
    algae, crustaceae, and fish, were exposed (Bauer, 1972; Ernst, 1975;
    Schimmel et al., 1977; Trautmann & Streit, 1979; Marcelle & Thome,
    1983): The highest bioconcentration factors were seen with the
    lowest exposure concentrations. For example, Marcelle & Thome (1983)
    determined the residues of lindane in brain, liver, and muscle of
    the gudgeon  (Gobio gobio) after exposure to concentrations of
    0.22-142 µg/litre lindane in water. At the lowest concentration, the
    bioconcentration factors in brain, liver, and muscle were about 600,
    200, and 100, respectively, but they decreased to values of less
    than 50 at higher concentrations.

         Mouvet (1985) transplanted the freshwater aquatic moss
     Cinclidotus danubicus from an uncontaminated area to a river that
    received the effluent from an insecticide factory and determined
    gamma-HCH concentrations in water and moss 13, 24, and 51 days after
    the transplant. A three-fold increase in the gamma-HCH level was
    found, with a bioconcentration factor of 294.

         In a variety of aquatic organisms exposed to contaminated
    water, the bioconcentration factor for lindane ranged from 13 to
    1000 on a wet weight basis (Table 3).

    
    Table 3.  Bioconcentration factors of lindane in laboratory
              experiments; test organisms were exposed to contaminated
              water for the specified time
                                                                                                   
    System                     Exposure   Exposure           Bioconcentration  Reference
                               time       concentration      factora
                                          (µg/litre)
                                                                                                    
    Algae
       Cladophora sp.          up to      80.0               180 (d)           Bauer (1972)
                               48 h       3.9                341 (d)

       Nitzschia               24 h       6.1                1500-4700 (v)     Trautmann  & Streit
       actinastroides                                        4400-12 400 (d)     (1979)

    Molluscs
       Aplysia punctata        3-6 days   9000               201-436 (w)       Chabert & Vicente
                                                                                 (1978)

       Mya arenaria            5 days     5                  40                Butler (1971)
       Mercenaria              5 days                        13
         mercenaria

      Mytilus edulis           ns         2.61               74 (w)            Ernst (1975)
                               0.02       242 (w)

      Mytilus edulis           ns         2-5                139 (w)           Ernst (1979)

      Venerupis japonica       3 days     1                  121 (ns)          Yamato et al. 
                                                                                 (1983)

    Annelidae
      Lanice conchilega        ns         2-5                1240 (w)          Ernst (1979)

    Crustacea
      Penaeus duorarum         96 h       0.23               143 (ns)          Schimmel et al.
      Palaemonetes pugio       96 h       1.0                80 (ns)             (1977)

    Table 3 (contd)
                                                                                                   
    System                     Exposure   Exposure           Bioconcentration  Reference
                               time       concentration      factora
                                          (µg/litre)
                                                                                                    
    Insects
      Sigara striata and       1 day      10                 70-100            Kopf & Schwoerbel
      Sigara lateralis                                                           (1980)

    Fish
      Lagodon                  96 h       23.0               287 (ns)          Schimmel et al.
        rhomboides                                                               (1977)
      Cyprinodon               96 h       108.7              727 (ns)
        variegatus

      Leuciscus idus           ns         10-500             765 (ns)          Sugiura et al.
      Cyprinus carpio                                        281 (ns)            (1979)
      Salmo truttafario                                      442 (ns)
      Poecilia                                               938 (ns)
        reticulata

      Poecilia                 4 days     1                  697 (ns)          Yamato et al.
        reticulata                                                               (1983)

      Salmo gairdneri          27 days    30-290             319               Ramamoorthy
                                                                                 (1985)

    a Calculated on the basis of: wet weight (w), dry weight (d), volume (v); ns, not specified

    
         Another approach to the study of the bioconcentration of
    lindane is the use of systems that simulate natural conditions,
    taking into account sedimentary absorption processes and the
    influence of contaminated food. The bioconcentration factors for
    brine shrimp, mosquito larvae, and the brook silverside
     (Haludesthes sicculus sicculus) exposed to lindane applied to the
    sand of a test aquarium were 95, 220-383, and 600-1613,
    respectively, depending on the food chains used (Matsumura &
    Benezet, 1973). Marcelle & Thome (1984) investigated the
    bioconcentration of lindane in the gudgeon  (Gobio gobio) in
    relation to the route of exposure. Fish were exposed either to
    contaminated water alone or additionally to contaminated food. After
    18 days, the group fed contaminated food had a 2.5-fold higher level
    of lindane residues in liver than the group exposed to contaminated
    water alone. Within three days after cessation of exposure, 98.4% of
    the lindane residues had been excreted.

         The uptake, transport, and bioconcentration of lindane were
    also studied in a freshwater food chain, which consisted of
     Chlorella sp.,  Daphnia magna, and  Gasterosteus aculeatus
    (algae-crustacea-fish). Uptake from water was more rapid than uptake
    from food and depended on the duration of the experiment and the
    feeding rate. The increase in lindane residues in the last link of
    the food chain (fish) was not directly proportional to the
    concentration found in the primary links (Hansen, 1980).

    4.2.7.3  Terrestrial environment

         The bioconcentration of lindane was investigated in a
    terrestrial food chain, which consisted of soil, barley,
    caterpillar, and quail. Doses up to 400 times the standard
    agricultural dose (50 and 200 mg/kg soil) were applied to the soil.
    Although lindane was found in all of the links of the food chain,
    the concentrations decreased progressively (Dugast, 1980).

         Feeding hens diets containing lindane at 0.05, 0.15, or 0.45
    mg/kg for 20 weeks resulted in constant values of 0.01, 0.03, and
    0.09 mg/kg of eggs, demonstrating a dose-related accumulation of
    lindane (Cummings et al., 1966).

         Several studies are available on the bioconcentration of
    lindane in rats. After seven rats had received daily doses of 2 or 4
    mg/kg body weight for up to 12 weeks, gamma-HCH was found at a
    concentration of about 8 mg/kg in adipose tissues of the group that
    had recived the high dose (Jacobs et al., 1974). In another
    experiment, four generations of rats were fed a diet containing 20%
    fat and a mixture of insecticides including lindane at levels of
    0.07-0.8 mg/kg. Even in the F3 generation, the levels of gamma-HCH
    residues in adipose tissues were of the same order of magnitude
    (< 0.05-0.56 mg/kg) as those of lindane in the diet (Adams et al.,

    1974). No accumulation occurred, even in four consecutive
    generations.

         Accumulation factors have been determined from feeding studies
    in rats (Fitzhugh et al., 1950; Oshiba, 1972; Baron et al., 1975;
    Suter et al., 1983). In comparison to the concentration of lindane
    in the diet, the highest reported bioconcentration factor was about
    2 for adipose tissue. The average bioconcentration factor for
    adipose tissues in rats derived from all these studies is 1; the
    bioconcentration factors for other tissues are considerably lower.

    4.2.7.4  Bioconcentration in humans

         Geyer et al. (1986) examined data on environmental chemicals
    detectable in adipose tissue and/or breast milk of
    non-occupationally exposed humans and concluded that, in
    industrialized countries, more than 90% of human exposure to HCHs
    originates from food. Mean concentrations of gamma-HCH in human
    adipose tissue in Czechoslovakia, the Federal Republic of Germany,
    and the Netherlands were 0.086, 0.024-0.061, and 0.01-0.02 mg/kg,
    respectively, on a fat basis. The mean bioconcentration factor,
    calculated on the basis of the concentration in the diet (2.3, 5.0,
    and 0.62-0.9 µg/kg, respectively) and levels in adipose tissue, was
    18.6 ± 9 on a lipid basis (range, 10.4-32.5). Greve & Wegman (1985)
    found an accumulation factor (adipose tissue/blood) of 70 for
    gamma-HCH in humans.

    4.2.7.5  Field studies

         The bioconcentration of lindane was investigated by
    environmental monitoring in aquatic ecosystems. The residue levels
    found in different organisms were related to the environmental
    background levels, and these data were used to calculate the
    bioconcentration factors.

         The bioconcentration factor for gamma-HCH in sea water and
    bladder wrack  (Fucus vesiculosus) in the Husum estuary and the
    adjacent North Friesian Wadden Sea in the Netherlands was about 150
    (Herrmann et al., 1984). On the basis of the data given in section
    5.1.5.2 on the occurrence of gamma-HCH in muscle and fat of bream
    collected in the River Elbe, a bioconcentration factor of 10 000 to
    50 000 was calculated (Arbeitgemeinschaft für die Reinhaltung der
    Elbe, 1982).

         Frisque et al. (1983) studied the accumulation of lindane by
    bryophytes  (Cinclidotus danubicus and  C. nigricans) in the Meuse
    River and found a concentration factor of 300-350. The average level
    in the river was 0.067 µg/litre. Hartley & Johnston (1983) found a
    bioconcentration factor for the freshwater clam  Corbicula
     manilensis of 2610 on a lipid basis; and Cosson Mannevy & Marchand

    (1980) found a mean factor of 26 198 (on a dry-weight basis) in
     Mytilus edulis.

         On the basis of the concentrations of gamma-HCH in sea water,
    sediments, and fish from the Mediterranean Sea, El-Dib & Badawy
    (1985) calculated a bioconcentration factor of about 1000 (on a
    lipid basis). Tanabe et al. (1984) reported bioconcentration factors
    for total HCHs in a trophic chain in the western North Pacific. As
    the contribution of gamma-HCH to the residue levels was determined,
    the bioconcentration factors for this isomer can be estimated to be
    about 40, 40, 100, and 1850 for zooplankton, myctophid, squid, and
    dolphin, respectively.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         An average of 0.23 ng/m3 (0.039-0.68 ng/m3) gamma-HCH was
    found in 24 samples of air taken from over the western Pacific, the
    eastern Indian Ocean, and the Antarctic Ocean (Tanabe et al., 1982).

         Levels of gamma-HCH in the air of various regions of the USA
    were within a similar range (US Environmental Protection Agency,
    1976). The levels were below 1 ng/m3 in most samples, and values
    up to 16.2 ng/m3 were found in only two regions.

         Gamma-HCH was found at an average concentration of 0.14 ng/m3
    in the air of unpolluted areas in the Federal Republic of Germany in
    1972; in polluted areas (the Ruhr), a level of 0.8 ng/m3 was found
    in 1976/77 (Deutsche Forschungsgemeinschaft, 1983; Hildebrandt et
    al., 1986). It occurred at 0.52-11 ng/m3 in a location with heavy
    traffic near Ulm in the Federal Republic of Germany and at 0.18-1.1
    ng/m3 in a rural area. The authors concluded that the
    concentrations in the lower troposphere under different
    meteorological conditions reflect regional input and long-range
    transport (Wittlinger & Ballschmiter, 1987).

         The average concentration of gamma-HCH in 55 air samples taken
    near Delft, the Netherlands, in 1979-80 was 0.36 ng/m3 (maximum,
    3.4 ng/m3); in three other locations in the Netherlands, average
    levels of 0.2-0.9 ng/m3 were found. In six houses built on former
    dumping grounds, the average concentration of gamma-HCH was 6
    ng/m3 (range, 1-14 ng/m3), whereas in the space beneath the
    floor the level was below the detection limit (1 ng/m3). Outdoor
    concentrations in this area were 0.3-0.4 ng/m3. In another study,
    the concentrations of gamma-HCH in the space beneath the floor of
    houses were 90 ng/m3. Much higher levels were found in houses
    treated with lindane-containing products for the control of woodworm
    or of long-horned beetle. Peak levels of 51-61 µg/m3 were found
    four weeks after application; these decreased gradually to 8-24
    µg/m3 after 10 weeks. After indoor application of lindane for wood
    preservation, levels of 50 µg/m3 were common, with peak levels of
    up to 100 mg/m3 (Sloof & Matthijsen, 1988).

    5.1.2  Water

    5.1.2.1  Rain and snow

         Levels of 0.001-0.005 µg/litre were found in rain-water
    analysed in the Federal Republic of Germany in 1970-72 (Mestres,
    1974); in 1983, gamma-HCH was found at an average of 0.06 (range,

    0.01-0.18) µg/litre in rain-water near de Bilt, the Netherlands
    (Slooff & Matthijsen, 1988).

         Strachan et al. (1980) found traces of gamma-HCH in 17 samples
    of snow collected from the Canadian side of the Great Lakes in 1976
    and 5-12 ng/litre in 81 samples of rain-water collected in 1976 and
    1977.

    5.1.2.2  Fresh water

         Water samples from selected rivers in Yorkshire, United
    Kingdom, analysed for gamma-BHC in 1966 contained levels of
    0.001-0.18 µg/litre; in 1968, however, the highest value was 0.622
    µg/litre. Water samples from six other rivers, also analysed in
    1968, contained mean values of 0.011-0.030 µg/litre, and the highest
    levels found were 0.020-0.098 µg/litre (Lowden et al., 1969).

         River water samples analysed in 1969-72 in Belgium, France, the
    Federal Republic of Germany, the Netherlands, and Italy contained
    less than 0.1 µg/litre and usually less than 0.05 µg/litre. In 1826
    water samples taken at 99 sites in the Netherlands in 1966-77, the
    highest concentrations of gamma-HCH were found in those from the
    River Rhine and its tributaries. The concentrations of gamma-HCH
    over the period 1969-74 varied between 0.01 and 0.4 µg/litre, but in
    1974-77, the concentrations were all below 0.1 µg/litre (Mestres,
    1974). Gamma-HCH concentrations have been measured in the Rivers
    Rhine, Meuse, and West-Scheldt and in other surface waters in the
    Netherlands since 1969. Since 1974-75, the levels have been below
    0.05 µg/litre in the Rhine and about 0.05 µg/litre in the
    West-Scheldt; in the Meuse, the concentrations were more variable
    and ranged from 0.01 to 1.0 µg/litre. In agricultural and
    horticultural areas, the levels were 0.01-1.0 µg/litre, with
    incidental peaks up to 0.5 µg/litre, probably due to use of lindane.
    The average concentration of dissolved gamma-HCH in the Meuse-Rhine
    estuary in 1974 was 20 ng/litre and that of suspended gamma-HCH
    between 1 and 20 ng/litre. In coastal waters of the Netherlands, the
    concentration of dissolved gamma-HCH was 0.9-4.6 ng/litre and that
    of bound gamma-HCH, 3.1-8.7 ng/litre (Sloof & Matthijsen, 1988).

         A sampling trip along the River Rhine, from Rheinfelden in
    Switzerland to Rotterdam in the Netherlands, proved that the source
    of alpha-, beta-, and gamma-HCH was located in the upper reaches of
    the River. In the Meuse, lindane levels in 1969-77 were all below
    0.1 µg/litre (Wegman & Greve, 1980). In an extensive programme in
    1982 to determine pollution in Dutch surface waters at 45 locations,
    gamma-HCH concentrations were generally between 0.01 and 0.1
    µg/litre (Wammes et al., 1983).

         The mean concentration of gamma-HCH in the River Elbe, from
    Schnackenburg to the North Sea, in 1981-82 was 0.021
    (< 0.001-0.051) µg/litre; during February-November 1988, the

    concentrations were 0.005-0.044 µg/litre (Arbeitsgemeinschaft für
    die Reinhaltung der Elbe, 1988). More figures for Germany are given
    by Wirth (1985). Gamma-HCH was found at three locations in the River
    Rhine at 0.02 µg/litre and in six side-rivers at 0.01-0.06 µg/litre.
    These levels had decreased markedly since 1975 (Landesamt für Wasser
    und Abfall, 1988).

    5.1.2.3  Sea water

         Atlas & Giam (1981), Bidleman & Leonard (1982), Oehme & Stray
    (1982), and Oehme & Mano (1984) analysed water from such widely
    differing areas as the Eniwetok Atoll in the North Pacific, the
    Arabian Sea, the Persian Gulf, the Red Sea, Lillestrøm, Norway, Bear
    Island, and Spitzbergen in the Arctic Ocean. The gamma-HCH
    concentrations were in the range 0.01-0.05 ng/litre, except in the
    Arabian Sea, the Persian Gulf, and at Lillestrøm, where levels up to
    0.67 ng/litre were found (Slooff & Matthijsen, 1988). Levels of
    0.0001-0.004 µg/litre gamma-HCH were measured in the Western
    Pacific, the Eastern Indian, and Antarctic Oceans (Tanabe et al.,
    1982). No gamma-HCH was found in 60 water samples from the Japan Sea
    and Pacific Ocean (detection limit, 0.1 µg/litre) (A. Hamada, letter
    to M. Mercier, dated 28 July 1989; T. Onishi, letter to M. Mercier,
    dated 24 July 1989). The levels detected in water from the North Sea
    and the Arctic Sea are of the order of 0.001-0.02 µg/litre (Deutsche
    Forschungsgemeinschaft, 1983). The maximal level of gamma-HCH in
    North Sea water in 1972 was 0.028 µg/litre; 5-10% of the samples
    contained gamma-HCH (Mestres, 1974). The level of gamma-HCH in
    surface-water of the North Sea in June-July 1986 ranged from 1.0 to
    4.0 ng/litre. The highest concentrations were found close to the
    coast (Umweltbundesamt, 1988-89).

    5.1.3  Soil

         Traces of gamma-HCH are transmitted to soil by precipitation;
    the resulting contamination is generally below the limit of
    detection (0.0001-0.001 mg/kg). Application of lindane in
    agricultural areas can result in higher concentrations: levels in
    some German districts were mainly in the range 0.001-0.01 mg/kg, but
    in certain fields up to 0.6 mg/kg was found (Fricke, 1972).

         Edelman (1984) analysed 96 samples of the upper 10 cm of soil
    from 38 natural reserves in the Netherlands for gamma-HCH: 59
    samples contained < 1 µg/kg, 21 contained 1-10, 9 had 10-20, and 7
    had 20-80 µg/kg (Slooff & Matthijsen, 1988). In the National Soils
    Monitoring Program of the US Environmental Protection Agency (Carey
    et al., 1979), several thousand samples from cropland sites were
    analysed for residues; no gamma-HCH residues were detected in more
    than 99% of the samples. In the Ukraine, however, 36 of 136 soil
    samples taken at various locations contained lindane at levels of
    0.1-5 mg/kg (Talanov, 1977; see Izmerov, 1983).

         In a study on the application of lindane dust by aircraft on
    mosquito breeding sites at 1.3 kg/ha, the gamma-HCH content of the
    soil was 1 mg/kg; after one year, the level was 0.01 mg/kg
    (Vroschinsky, 1973; see Izmerov, 1983).

    5.1.3.1  Sediment

         Gamma-HCH was present in three of six samples of sediment taken
    from Nyumba Ya Mungu Lake in the United Republic of Tanzania in
    1986, at a concentration of 1-4 µg/kg dry weight (Paasivirta et al.,
    1988).

         Martin & Hartmann (1985) found gamma-HCH at levels above the
    detection limit (5 µg/litre) in less than 4% of 117 samples of
    sediment taken in 1980-82 from riverine and pothole wetlands in
    north-central USA. In less than 4% of the samples, gamma-HCH was
    present at above the detection level of 5 µg/kg.

         In Japan, gamma-HCH was found in 9 out of 60 samples of
    sediment at a concentration of 10 µg/kg in 1974 (A. Hamada,letter to
    M. Mercier, dated 28 July 1989; T. Onoshi, letter to M. Mercier,
    dated 24 July 1989).

         The median levels of gamma-HCH in sediments from eight rivers,
    harbours, and sites close to dumping places in the Netherlands were
    15-342 µg/kg dry matter (Slooff & Matthijsen, 1988).

    5.1.3.2  Dumping grounds and sewage sludge

         The soil at various locations in the Netherlands is polluted
    with HCHs as a result of spillage during production, storage, and
    handling of this chemical during the 1950s. The concentrations found
    range up to a few thousand milligrams of HCHs per kilogram of dry
    soil. Further pollution has been caused by the dumping of chemical
    waste, sometimes in order to level the ground; this waste can be
    dispersed from dumping areas by leaching or wind erosion. In certain
    polluted areas, high concentrations of HCHs (mainly alpha- and
    beta-HCHs) were found at depths of more than 2 m below ground level.
    In 18 locations in the Netherlands, the average concentrations of
    gamma-HCH in sewage sludge in 1981 were 8-50 µg/kg dry matter.
    Groundwater was also found to be polluted, but this was restricted
    to the vicinity of the production areas; horizontal transportation
    of HCHs in groundwater appeared to be limited (Slooff & Matthijsen,
    1988).

         Fieggen (1983) found gamma-HCH in sewage sludge at mean values
    of 25 µg/kg dry matter in 1975, 43 µg/kg in 1978, and 12 µg/kg in
    1981.

    5.1.4  Drinking-water, food and feed

         Although in most countries nowadays only lindane is used,
    residues of alpha- and beta-HCH can still be found in crops and
    animal products originating from regions where technical-grade HCH
    (containing all of the HCH isomers) is still in use.

    5.1.4.1  Drinking-water

         Gamma-HCH was found at 0.0001-0.001 µg/litre in water from 19
    lakes in Germany and at levels below 0.001 µg/litre (0.0001-0.0008
    µg/litre) in the drinking-water derived from them (Bernhardt &
    Ziemons, 1974). In the USA, only 3% of drinking-water samples
    examined contained gamma-HCH, in a range of 0.001 to about 0.1
    µg/litre (US Environmental Protection Agency, 1976). In Ottawa,
    Canada, drinking-water samples collected in 1976 contained 0.4-11
    ng/litre (Williams et al., 1978).

    5.1.4.2  Cereals, fruits, pulses, vegetables, and vegetable oil

         The large body of information on gamma-HCH residue levels in
    crops grown and treated with this chemical according to Good
    Agricultural Practice has been reviewed comprehensively by the
    FAO/WHO Joint Meeting on Pesticide Residues and summarized in
    published monographs (FAO/WHO, 1967, 1968, 1969, 1970, 1974, 1975,
    1976, 1978, 1980).

         In samples of ready-to-eat foods collected from 30 markets in
    27 US cities in 1966-67, gamma-HCH levels were 0.003-0.009
    (occasionally 0.06) mg/kg in grains and cereals, 0.002-0.027 mg/kg
    in garden fruits, 0.001-0.005 mg/kg in potatoes, 0.002-0.007 mg/kg
    in leafy vegetables, and 0.004-0.012 mg/kg product in oils, fat, and
    shortening (Martin & Duggan, 1968). In 1967-68, residues of
    gamma-HCH were found at 0.002-0.006 in leafy and root vegetables, at
    0.002-0.003 in garden fruits, and at 0.029-0.085 mg/kg product in
    oils, fat, and shortening (Corneliussen, 1969).

         In monitoring studies carried out on grain in the Federal
    Republic of Germany at one-year intervals since 1975, gamma-HCH
    residues in wheat and barley were 0.001 mg/kg or less (Ocker, 1983).
    More than 800 samples of cereal and cereal products analysed in
    Germany in 1975-78 and 1979-83 contained mean concentrations of
    0.0009-0.04, but cereal products had up to 0.11 mg/kg. The mean
    concentration of gamma-HCH in 200 samples of wheat and rye collected
    in 1986 and 1987 was 0.06 mg/kg, with a maximum of 0.3 mg/kg
    (Umweltbundesamt, 1988-89).

         Of 281 samples of wheat analysed for the presence of gamma-HCH
    in the United Kingdom between October 1978 and April 1979, 71
    contained levels in the range 0.002-0.04 mg/kg. Gamma-HCH was also
    found in one sample of polished rice from Spain, at a concentration

    of 0.008 mg/kg (Steering Group on Food Surveillance, 1982).
    Gamma-HCH was found in 16% of samples of imported maize in the
    United Kingdom in the range none detected to 0.007 mg/kg, and in 28
    samples of different types of pulses at none detected to 0.05 mg/kg.
    Of retail cereal products, only bran and wheat contained detectable
    levels (0.01 mg/kg product) of gamma-HCH in 1982 (Steering Group on
    Food Surveillance, 1986). In 1986-87, 31 of 142 samples of pulses
    contained residues; in nine, levels of < 0.01-0.4 mg/kg were found.
    Peanut butter and vegetable oils contained 0.01 mg/kg (Steering
    Group on Food Surveillance, 1989).

         About 80-90% of samples of fruit, potatoes, and other
    vegetables analysed in the Federal Republic of Germany contained no
    detectable residues of gamma-HCH (Weigert et al., 1983). The
    remaining 10-20% had mean levels up to 0.01 mg/kg, with no
    significant difference between 360 samples originating from
    conventional agriculture and 360 samples from 'alternative'
    agriculture (Vetter et al., 1983). In 1976-78 and 1980, the mean
    concentrations of gamma-HCH were < 0.001-0.002 mg/kg product in
    more than 400 samples of fruit, potatoes, and other vegetables. In
    the Netherlands, residues in fruit and vegetables were generally in
    the range 0-0.1 mg/kg, although some leafy crops, such as endive,
    lettuce, celery, and leek, contained levels up to 5 mg/kg. Samples
    of wheat contained only 0-0.05 mg/kg, with a few measurements up to
    0.2 mg/kg (FAO/WHO, 1978). In France, gamma-HCH residues were found
    in wheat at 0.01-0.02 mg/kg, and at low levels in other commodities,
    such as carrots and endives (Laugel, 1981). Engst et al. (1967)
    found that the gamma-HCH content of carrots grown from seed treated
    with this compound decreased continuously during the first 120 days.
    At normal harvesting time, the early varieties contained 3-6 mg/kg
    product, the mid-season varieties about 2 mg, and the late
    varieties, 0.4 mg/kg. When the carrots were harvested after 200
    days, 0.3-0.7 mg/kg was present (independently of variety). Even
    after 6 months' storage, low residues were still present.

    5.1.4.3  Meat, fat, milk, and eggs

         Martin & Duggan (1968) found gamma-HCH at levels of 0.09 mg/kg
    in dairy products and at 0.01-0.03 mg/kg (with a peak of 0.374
    mg/kg) in samples of meat, fish, and poultry collected from 30
    markets in 27 cities in the USA in 1966-67. Residue levels in
    samples of meat, fish, and poultry in 1967-68 were 0.003-0.026 mg/kg
    (Corneliussen, 1969). No gamma-HCH or levels of 0.01-0.1 mg/kg were
    found in 99% of samples of cow's milk and manufactured milk products
    from Illinois (USA) (Wedberg et al., 1978). In milk samples
    collected during Spring 1983 from 359 bulk transporters,
    representing 16 municipalities of Ontario, Canada, gamma-HCH was
    found in 68% of the samples at a mean concentration of 4.0 µg/kg

    butter fat (Frank et al., 1985). Six samples of cow's milk from six
    locations in Switzerland contained 3.0-5.1 mg/kg on a fat basis
    (Rappe et al., 1987).

         In about 25% of 976 samples of meat and poultry products
    (including eggs) collected in the United Kingdom in 1984-86,
    gamma-HCH was present at a mean concentration of 0.01-0.02 mg/kg.
    The highest level, 3.7 mg/kg, was found in lamb. Processed meat and
    poultry products (631 samples collected in 1985-87) contained mean
    concentrations of 0.01-0.06 mg/kg product. About half of 849 samples
    of retail milk and dairy products collected in 1984-87 contained
    gamma-HCH at concentrations of 0.01-0.03 mg/kg; the highest level,
    0.7 mg/kg, was found in milk (Steering Group on Food Surveillance,
    1989). Imported meat products were also analysed in the United
    Kingdom for the presence of alpha-, beta-, and gamma-HCH. No
    detectable residue of gamma-HCH was found in beef or pork products:
    processed pork contained none detectable to 0.03 mg/kg. Processed
    poultry contained none detectable to 0.04 mg/kg (Steering Group on
    Food Surveillance, 1986). In 1967-70, in the Ukraine, gamma-HCH was
    found in cows' milk at an average concentration of 0.6 mg/litre
    (Medvedev & Perepechkina, 1973; see Izmerov, 1983). In the USSR, the
    following concentrations were found: milk and milk products, 0.055 ±
    0.005 mg/kg; poultry and fish, 0.068 ± 0.021 mg/kg; butter, 0.003 ±
    0.002 mg/kg; vegetables and fruits, 0.008 ± 0.003 mg/kg; groats and
    flour, 0.005 ± 0.002 mg/kg (Sizova & Bogomolova, 1976; see Izmerov,
    1983).

         Concentrations of gamma-HCH were measured in 1250 samples of
    milk and other dairy products in France in 1970-77 and in 1981. In
    the first period, the gamma-HCH concentration was < 0.1 mg/kg of
    fat; by 1981, the levels had declined to < 0.03 mg/kg of fat
    (Laugel, 1981; Rhône-Poulenc Agrochimie, 1986). Higher levels (mean,
    0.85 mg/kg) were found in animal fat, but meat and eggs generally
    contained no detectable residue (Laugel, 1981). The mean levels of
    gamma-HCH found in a large number of samples of various food items
    in Germany (Hildebrandt et al., 1986) are shown in Table 4.

         The levels of gamma-HCH in food items analysed in France were
    0.006-0.01 mg/kg in 113 samples of vegetables, 0.005-0.04 mg/kg in
    192 samples of fish and seafood, 0.005-0.041 mg/kg in 154 samples of
    preserved meat, 0.007-0.017 mg/kg in 104 samples of cereal products,
    0.007-0.034 mg/kg in 120 samples of butter and cheese,  0.005-0.059
    mg/kg in 25 samples of oil and fat, and 0.006-0.021 mg/kg in 26
    samples of fruit (Rhône-Poulenc Agrochimie, 1986).

        Table 4.  Levels of gamma-HCH (mg/kg) in food items in Germany
                                                                             
    Food item                 1973-78          1979-83            1973-83

    Meata                                                         0.004-0.04

    Meat productsa                             0.006-0.055
                                               (maximum, 0.52)

    Animal fata                                                   0.007-0.09
                                                                  (maximum, 0.5)

    Gamea                                                         0.042-4.072

    Poultrya                  0.01-0.05        0.004-0.046
                                               (maximum, 0.471)

    Chicken eggs                                                  < 0.001-0.01
    Chicken eggsa,c           0.001-0.02
                              (maximum, 1.9)

    Milk and milk productsa   0.05             0.01-0.02

    Cow's milka,b             0.03             0.01

    Vegetable oil and         0.01-0.02
    margarinea 

    Oil seeds, nuts, pulses                    0.001-0.127

    Fish and fish products    0.01-0.02        0.002-0.009

    Shell-fish and molluscs                    < 0.001-0.020

    a From Hildebrandt et al. (1986); on fat basis
    b From Anon. (1984)
    c From Koelling (1978)
    
         Skaftason & Johannesson (1979) found a mean value of 13 µg/kg
    in 35 samples of butter from Iceland in 1968-70. Of 32 samples
    analysed in 1974-78, only five contained gamma-HCH, at a mean value
    of 7 ± 2 µg/kg. The mean concentration in meat, poultry and eggs in
    the Netherlands in 1976-78 was 0.002 mg/kg (range, 0.001-0.004
    mg/kg) (De Vos et al., 1984); the levels in dairy products were
    similar.

         Fifteen of 105 chicken eggs from seven areas in Kenya had a
    median concentration of 0.01 mg/kg (range, 0.01-0.04 mg/kg) (Kahunyo
    et al., 1988). Ten samples each from two lots of lamb and beef were
    collected randomly from markets in Bagdad, Iraq, in 1983 and
    analysed for the presence of gamma-HCH. An average concentration of
    0.225 (0.004-1.611) mg/kg was found in lamb, and 0.116 (0.005-0.83)
    mg/kg was found in beef (Al-Omar et al., 1985).

    5.1.4.4  Animal feed

         Of 114 samples of animal feed analysed in the United Kingdom in
    1982-85, 49 contained gamma-HCH at concentrations up to 2.3 mg/kg
    product (Steering Group on Food Surveillance, 1986).

    5.1.4.5  Miscellaneous products

         Lanolin produced from crude wool grease may contain gamma-HCH:
    a level of 1.2 mg/kg was found in the USA (Anon. 1989); and Meemken
    et al. (1982) found average levels of 2.4 and 2.1 mg/kg in 1976 and
    1981, respectively, in Germany. Concentrations of 0.001-0.23 mg/kg
    were found in cosmetic creams made from the lanolin.

    5.1.5  Terrestrial and aquatic organisms

    5.1.5.1  Plants

         Gamma-HCH was present in most of 13 samples of three types of
    moss and four types of lichen collected on the Antarctic Peninsula
    (Graham Land) in 1985 at a mean concentration of 0.84 mg/kg (range,
    0.4-1.7 µg/kg) (Bacci et al., 1986).

         In 1984, near Florence and Siena, Italy, far from primary
    sources of pollution, leaves from ten species of tree and two
    species of lichen were found to contain average levels of 8.2
    (range, 2-14) and 10 (9-11) µg/kg dry weight, respectively.
    Gamma-HCH levels in plant species collected in 14 countries ranged
    from 0.2 to 700 µg/kg dry weight (Gaggi et al., 1986).

    5.1.5.2  Aquatic organisms

         Freshwater mussels  (Anodonta piscinalis) were used to monitor
    bioaccumulation of pollutants at 17 sampling sites in a river basin

    in Finland between 1984 and 1987. One to three mussels were used per
    sampling site. Gamma-HCH was found in concentrations varying from
    none detected to 553 µg/kg on a fat basis; however, a clear decrease
    was seen over the period of study (Herve et al., 1988).

         Cowan (1981) studied the extent of pollution by HCHs of
    Scottish coastal waters using  Mytilus edulis as the biological
    indicator. The gamma-HCH levels at 118 sites were < 6-53 µg/kg dry
    weight, which are similar to those found in Germany, the
    Netherlands, Spain, and the United Kingdom. The fish and shellfish
    sampling programme of the Ministry of Agriculture, Fisheries, and
    Food in the United Kingdom in 1977-84 was implemented mainly in
    areas around the coasts of England and Wales. The range found for
    gamma-HCH was < 0.001 (none detected) to 0.075 mg/kg wet weight;
    the level in fish muscle was < 0.001 mg/kg wet weight (Franklin,
    1987).

         The average concentration of gamma-HCH was measured in 10
    marine organisms collected along the Mediterranean coast of Spain
    during 1985.  Mytilus galloprovincialis, Venus gallina,  Sardina
     pilchardus, and  Mullus surmuletus contained 0.1-1.7 µg/kg fresh
    weight (maximum, 16 µg/kg) (Pastor et al., 1988).

         Bream collected in rivers and lakes at 15 locations in Germany
    contained average gamma-HCH concentrations of 106-696 µg/kg on a fat
    basis (Umweltbundesamt, 1988-89), while bream collected in the River
    Elbe, between Schnackenburg and the North Sea, contained average
    concentrations up to 0.031 mg/kg in muscle and up to 2.6 mg/kg in
    adipose tissue (Arbeitgemeinschaft für die Reinhaltung der Elbe,
    1982). In 1970-72, different types of fish, mussels, and shrimps
    were analysed for gamma-HCH. Fish with a low fat content, collected
    in the Atlantic Ocean and the North Sea, contained 0.004-0.008 mg/kg
    fresh weight, and fat fish contained 0.01 (0.01-0.026) mg/kg fresh
    weight. Fat fish caught in the Baltic contained higher levels - up to
    0.2 mg/kg fresh weight. Mussels and shrimp caught in the North Sea
    contained none to 0.009 mg/kg fresh weight; mussels from the Baltic
    coast contained 0.009-0.011 mg/kg. In 1973-76, similar values were
    found, except that the fat fish had lower levels. Marine organisms
    from the Baltic Sea generally contained higher levels of gamma-HCH
    than those from the North Sea. Freshwater fish from industrially
    contaminated areas contained higher levels (Hildebrandt et al.,
    1986). Gamma-HCH was detected at levels up to 7.0 µg/kg (mean, 2.5
    µg/kg) in the muscle of flounders collected off the coast of the
    North Sea in Germany in 1986 (Umweltbundesamt, 1988-89).

    5.1.5.3  Terrestrial organisms

          Earthworms: Gamma-HCH was found in the soil of ten arable and
    two orchard sites in the United Kingdom at 0.01 and 0.08 mg/kg soil,

    respectively, and in worms living in the two soils at 0.05 and 0.3
    mg/kg (Advisory Committee on Pesticides and Other Toxic Chemicals,
    1969).

          Birds: Bednarek et al. (1975) determined total HCH isomers at
    levels of 0.03-0.63 mg/kg total egg (or 0.6-11.1 mg/kg on a fat
    basis) in eggs of birds of prey, such as the sparrowhawk  (Accipiter
     nisus), in two areas of Germany in 1972-73. Eggs of sandwich terns
    collected in the Elbe estuary contained arithmetic means (10 eggs)
    of 0.006 mg/kg fresh weight in 1981, 0.002 in 1985, 0.003 in 1986,
    and 0.028 in 1987 (Umweltbundesamt, 1988-89). The concentrations
    found in the livers of avian predators in the United Kingdom are
    shown in Table 5.

         The mean levels of gamma-HCH detected in 23 barn owls  (Tyto
     alba Scop.) obtained in Leon, Spain, were 0.03 (0.003-0.083) mg/kg
    wet weight in muscle, 0.036 (0.002-0.208) in liver, 0.051
    (0.009-0.144) in fat, 0.012 (0.002-0.031) in brain, and 0.081
    (0.005-0.343) in kidneys (Sierra & Santiago, 1987).

    Table 5.  Residues of gamma-HCH in livers of avian predators in the
    United Kingdoma
                                                                 
    Bird                      Date        No. of      gamma-HCH
                                          samples     (mg/kg)
                                                                 
    Sparrowhawk               1963        11          0.01

    Kestrel                   1963        20          0.04
                              1964        28          0.1
                              1965        60          0.03

    Tawny owl                 1964        14          0.01

    Heron (adults)            1964        17          0.005

    Great crested grebe       1963/66     15          0.03

    a From Advisory Committee on Pesticides and Other Toxic Chemicals
      (1969)

         Faladysz & Szefer (1982) examined adipose tissue from seven
    species of diving ducks at their winter quarters in the southern
    Baltic. Residues of gamma-HCH were detected in only 4 of 129 samples
    from three species of duck examined (range, 0.001-0.51 mg/kg on a
    fat basis).

           Mammals: No gamma-HCH (< 0.01 mg/kg) was found in muscle
    tissue from 51 North American wolves captured in 1969-71 in sparsely

    populated forest regions (Schneeweis et al., 1974). Norstrom et al.
    (1988) determined the contamination of the marine ecosystem of the
    Canadian Arctic and sub-Arctic by organochlorine compounds by
    analysing adipose tissue and liver from 6-20 polar bears  (Ursus
     maritimus) per zone collected from 12 zones between 1982 and 1984.
    The levels were 0.30-0.87 mg/kg on a fat basis; the highest levels
    were found in zones receiving continental run-off.

         Mean concentrations of gamma-HCH in 86 samples of kidney fat
    from roe-deer  (Capreolus capreolus) collected in five locations in
    Germany in 1985-86 were 8-12 µg/kg, with a maximum of 1020 µg/kg
    (Umweltbundesamt, 1988-89).

    5.2  Exposure of the general population

         The data presented above demonstrate that the main source of
    exposure of the general population is food.

    5.2.1  Total-diet studies

         In total-diet studies carried out in the United Kingdom between
    1966 and 1985, 22-25 samples of foods in 20-24 groups were purchased
    in 21 towns throughout the country and prepared by cooking. The
    calculated mean levels of gamma-HCH residues in the total diet were
    0.004 mg/kg in 1966-67, 0.0035 in 1970-71, 0.003 in 1974-75, 0.0025
    in 1975-77, 0.002 in 1979-80, 0.0015 in 1981, and 0.0005 in 1984-85,
    resulting in dietary intakes of 6.6, 5.5, 4.4, 3.9, 3.0, 2.0, and
    0.5 µg/person per day (Egan & Hubbard, 1975; Steering Group on Food
    Surveillance, 1982, 1986, 1989).

         The average daily intake of gamma-HCH in the USA was estimated
    on the basis of residues found in 30 market-basket composites
    collected in 30 cities over the period 1964-80, as shown in Table 6.

         Infant foods collected in the United Kingdom in 1985-87
    generally contained very low levels of gamma-HCH (range, < 0.002 to
    < 0.01 mg/kg product) (Steering Group on Food Surveillance, 1989).
    Residues of gamma-HCH were also measured in food composites from 10
    cities of the USA in 1974-75 (Johnson et al., 1979). Levels of
    0.008-0.012 mg/kg food were found in diets of six-month-old infants,
    and 0.001-0.007 mg/kg in the diets of two-year-old toddlers. Similar
    samples collected in 1976-79 in 10 cities consisted of about 50
    items of infant food and 110 items of food for toddlers. The daily
    intake of gamma-HCH was 0.005 µg/kg body weight for infants and 0.01
    for toddlers in 1976, 0.006 and 0.008 in 1977, 0.003 and 0.005 in
    1978, and 0.001 and 0.006 in 1979 (Gartrell et al., 1985b).

    Table 6.  Average daily intake of gamma-HCH in the USA, 1964-80a
                                                                 
    Year                          gamma-HCH intake (µ/kg
                                  body weight per day)
                                                                 
    1964-69                       0.05
    1965-70                       0.02-0.07b
    1973                          0.0032
    1974                          0.0084
    1975                          0.0031
    1976                          0.0025
    1977                          0.0039
    1978                          0.0024
    1979                          0.0038
    1980                          0.0028

    a From Johnson & Manske, 1976; US Environmental Protection
      Agency, 1980; Gartrell et al., 1985a
    b From Duggan & Corneliussen (1972)

         Total-diet studies conducted by the US Food and Drug
    Administration before 1982 were based on a 'composite sample
    approach', regardless of the diet involved. Later studies were based
    on dietary information obtained through surveys, so that the 'total
    diet' of the US population could be represented by a relatively
    small number of food items for a large number of age-sex groups
    (Gunderson, 1988). The average intake of gamma-HCH in the diet of
    14-16-year-old boys (mean body weight, 60 kg), estimated using the
    more recent methods, is shown in Table 7 (S. I. Shibko, letter to
    IPCS, dated 29 June1989). The daily intakes in 1982-84 in different
    age groups were 0.0019 µg/kg body weight per day for 6-11-month-old
    children, 0.0079 for two-year-old children, 0.0031 for
    14-16-year-old girls, 0.0034 for 14-16-year-old boys, 0.0020 for
    25-30-year-old women, 0.0025 for 25-30-year-old men, 0.0016 for
    60-65-year-old women, and 0.0018 for 60-65-year-old men (Gunderson,
    1988). The concentrations for these eight groups in 1984-86, 1987,
    and 1988 were < 0.01 µg/day for 6-11-month-old infants, < 0.04 for
    two-year-old children, and < 0.1 for the other six groups (S. I.
    Shibko, letter to IPCS, dated 29 June 1989).

    Table 7.  Average daily intake of gamma-HCH in 14-16 year-old boys
              in the USAa
                                                                  
              Year             Intake                             
                               µg/day            µg/kg body weight
                                                 per day
                                                                  
              1982-84          0.204             0.0034
              1984-86          0.078             0.0013
              1987             0.108             0.0018
              1988             0.084             0.0014

    a From S.I. Shibko, letter to IPCS, dated 29 June 1989

         In total-diet studies in Germany, fruit, potatoes, and other
    vegetables ready for consumption contained 0.001 mg/kg product
    (Kampe & Andre, 1980). In 17 food groups in Spain, the gamma-HCH
    concentration ranged from none detected to 0.019 mg/kg product; the
    level in fat was up to 0.268 mg/kg. The daily intake amounted to
    0.0138 mg/person in 1971-72 (Carrasco et al., 1976). In a total-diet
    study in the Netherlands in 1977, the average concentration of
    gamma-HCH in 100 samples was 0.03 mg/kg on a fat basis; the highest
    level was 0.14 mg/kg (Greve & van Hulst, 1977). In another study in
    the Netherlands, a mean daily intake of 0.002 mg/person was
    determined for 1976-78 (De Vos et al., 1984).

         Data from Canada, Guatemala, Japan, the United Kingdom, and the
    USA indicate a very low daily intake of gamma-HCH over the years
    1971-84. The median values ranged from 0.01 to 0.05 µg/kg body
    weight (Gorchev & Jelinek, 1985). The daily intake of lindane in the
    USSR was calculated from a market-basket survey to be about 0.005
    mg/day. Cooking reduced this level by a factor of 4.3 (Sizova &
    Bogomolova, 1976; see Izmerov, 1983).

    5.2.2  Intake with drinking-water and air

         Edwards (1981) calculated the daily intake of gamma-HCH with
    drinking-water to be 0.4 ng per person, assuming a daily consumption
    of 2 litre of water; the median daily intake via air was also
    calculated to be 17 ng per person, indicating that only small
    quantities of gamma-HCH are ingested with water and air.

         Guicherit & Schulting (1985) measured the concentration of
    gamma-HCH in the atmosphere and calculated that the daily average
    intake of a 70-kg Dutch person by inhalation would be 7.2 ng.
    Another calculation of the average human intake with air, on the
    basis of ambient concentrations, was 12 ng/day, which represents
    about 1% of the total daily intake by all routes. The daily intake
    of gamma-HCH in the USA was estimated to be 0.002 µg/kg body weight
    by air and 0.07 µg/kg by the oral route (Hildebrandt et al., 1986).

    5.2.3  Concentrations in human samples

         The concentrations of gamma-HCH in human samples are a good
    indication of the total exposure of the general population.

    5.2.3.1  Blood

         Gamma-HCH was detected at a geometric mean of 0.4 µg/litre
    (range, 0.1-4.1 µg/litre) in the blood of 49 of 62 people in
    Louisiana, USA (Selby et al., 1969). In a follow-up study, a
    geometric mean of 0.4 µg/litre (range, 0.1-6.0 µg/litre was found in
    47 out of 53 blood samples from pregnant women. Polishuk et al.
    (1970) found a mean concentration of 0.4 ± 0.8 µg/litre in the blood
    of 24 pregnant women and 0.3 ± 0.6 µg/litre in the blood of 23
    infants living in Israel. Wassermann et al. (1982) found a mean of
    4.3 ± 4.8 µg/litre in serum of 10 women in Israel with a normal
    pregnancy. In a group of 17 women with an abnormal pregnancy
    (premature birth), a mean concentration of 15.0 ± 7.2 µg/litre was
    detected. Bercovici et al. (1983) found a concentration of 8.0 ± 4.5
    µg/litre in the serum of seven Israeli women with a normal pregnancy
    and a mean concentration of 8.5 ± 7.8 µg/litre in 17 women with a
    'missed abortion'.

         Reiner et al. (1977) found a mean concentration of 4.1 ± 0.6
    µg/litre (range, 0.5-15.0) in 23 of 147 serum/plasma samples from
    people living in a town in Yugoslavia. Similar levels were found in
    other parts of the country (Krauthacker et al., 1980).

         Siddique et al. (1981) found gamma-HCH at a mean concentration
    of 25.0 ± 16.0 µg/litre (range, 8.0-47.0) in the blood of 15 people
    in India, and Saxena et al. (1981) found a mean concentration of
    19.0 ± 12.4 µg/litre (range, 2.4-135.0) in the blood of 100 pregnant
    women, aged 18-34 years, in the Indian countryside. Nonvegetarian
    women had higher blood levels than vegetarian women. Kaphalia & Seth
    (1983) found blood levels of 12.0 (none detected to 71.0) µg/litre
    in 48 men (aged 20-40 years), 12.00 (range, 5.0-24.0) µg/litre in 16
    women (aged 10-30 years) and 16.0 (range, 3.0-64.0) µg/litre in 16
    children (< 10 years) in India.

         Eckenhausen et al. (1981) found a geometric mean of 0.9
    µg/litre of gamma-HCH (range, < 0.4-3.8) in 28 out of 48 pregnant
    women in the Netherlands. After delivery, a geometric mean of 0.5
    (range, 0.2-19.0) µg/litre was measured in 24 out of 66 women, and a
    mean of 0.5 (range, < 0.3-34) µg/litre in 33 out of 86 babies.

         Blood samples from Dutch citizens were analysed in 1978 (70
    samples), 1980 (48 samples), 1981 (127 samples), and 1982 (54
    samples); the concentration of gamma-HCH was in the range < 0.1-0.2
    µg/litre blood (Greve & van Harten, 1983; Greve & Wegman, 1985).
    Blok et al. (1984) measured the levels of gamma-HCH in the blood of
    65 healthy volunteers (34 women and 31 men) in the Netherlands and
    found residues in approximately two-thirds of the people studied.

    The median concentration in both men and women was 0.2 µg/litre
    (range, none detected to 0.6 µg/litre). Bertram et al. (1980) found
    a median concentration of 1.18 µg/litre (range, none detected to
    2.94) in 118 whole-blood samples in Germany.

         In 8 of 35 serum samples from mothers in Norway and in 6 of 35
    corresponding samples of umbilical cord serum, the levels of
    gamma-HCH ranged from 0.2 to 27 µg/kg wet weight. In serum samples
    from immigrant mothers and in 5 of 7 corresponding umbilical cord
    serum samples, the levels were 0.1-3.4 µg/kg wet weight (Skaare et
    al., 1988).

    5.2.3.2  Adipose tissu

         Mes et al. (1982) analysed 99 samples of adipose tissue from
    autopsied accident victims in different areas of Canada and found an
    average concentration of gamma-HCH of 0.003 mg/kg (wet weight)
    (range, 0.001-0.03 mg/kg). Nearly all of the samples (90%) contained
    gamma-HCH.

         In 567 samples of adipose tissues from Dutch citizens analysed
    for the presence of gamma-HCH in 1968-83, the concentration varied
    from < 0.01 to 0.04 mg/kg; the highest levels were found for
    1968-76 (Greve & van Harten, 1983; Greve & Wegman, 1985). Bertram et
    al. (1980) found a median concentration of 0.05 mg/kg (range, none
    detected to 0.44) in 72 samples of adipose tissue from people in
    Germany. In specimens of subcutaneous fat taken in 1982-83 from 48
    children (34 < 1 year; 14 aged 2 years), the concentration of
    gamma-HCH was 0.04 mg/kg fat (range, 0.01-0.21 mg/kg). The average
    concentration was highest in infants aged 0-6 weeks, at 0.07 mg/kg
    fat (range, 0.02-0.21 mg/kg) (Niessen et al., 1984). The results of
    nine studies carried out in Germany in 1969-83 (598 samples) gave a
    mean concentration for gamma-HCH of 0.01-0.34 mg/kg on a fat basis
    (Hildebrandt et al., 1986).

         Twenty-nine samples of adipose tissue were taken at necropsy
    and 24 at surgery in the Poznan district in Poland and compared with
    100 samples from residents of the Warsaw region. The mean
    concentration of gamma-HCH in Poznan was 0.020 ± 0.018 and that in
    Warsaw, 0.022 ± 0.003 mg/kg (Szymczynski et al., 1986).

         The mean concentration of gamma-HCH in 360 samples of adipose
    tissue collected in eight regions of Japan in 1974 was 0.035 mg/kg
    (Takabatake, 1978).

    5.2.3.3  Breast milk

         Breast milk is a major route of elimination of organochlorine
    pesticides and polychlorinated biphenyls in women.

         In a Swedish study, the levels of gamma-HCH in mothers' milk
    were found to be related to their dietary habits: levels in
    lacto-vegetarians were lower than those in subjects who ate a mixed
    diet, and these were lower than those found in mothers who ate a
    mixed diet which regularly included fatty fish from the Baltic Sea
    (Noren, 1983).

         A significant correlation was found between the concentration
    of gamma-HCH in breast milk and the amounts of meat products and
    animal fat in the diet. In addition, concentrations of gamma-HCH in
    breast milk appeared to be higher in rural areas than in urban areas
    (Cetinkaya et al., 1984).

         Variations in residue levels in human milk during a lactation
    period of up to 9 months were investigated in five women aged 23-36
    years in Germany: gamma-HCH concentrations were 0.004-0.022 mg/kg on
    a fat basis, and no essential change in residue level occurred over
    the lactation period (Fooken & Butte, 1987).

         More than 7100 samples of breast milk were analysed in Germany
    between 1969 and 1984 by 20 authors, and the results were summarized
    by Hildebrandt et al. (1986). The mean concentration of gamma-HCH
    was 0.01-0.11 mg/kg on a fat basis, but a mean concentration of 0.45
    mg/kg was found for a group of 137 samples. A slow decrease in the
    mean concentration was observed between 1978 and 1984. The average
    concentration in human milk (2709 samples) in Germany in 1979-81 was
    0.06 mg/kg on a fat basis (Fooken & Butte, 1987); in 1981-83, the
    average level in 132 samples of breast milk was 0.032 mg/kg milk fat
    (Cetinkaya et al., 1984). The results of other studies were
    summarized by the Deutsche Forschunsgemeinschaft (1978, 1983). The
    results for other countries are comparable to those for Germany,
    although higher levels (mean, 0.33 mg/kg) were measured in
    Czechoslovakia in 1971-73 (Deutsche Forschungsgemeinschaft, 1983).
    Average concentrations in human milk in France between 1970 and 1975
    were in the order of 0.06-0.07 mg/kg (fat basis) (Rhône-Poulenc
    Agrochimie, 1986).

         Tuinstra (1971) analysed 40 breast milk samples from young
    mothers (18-32 years of age) in the Netherlands and found a median
    concentration of 0.01 mg/kg on a fat basis (range, none detected to
    0.04 mg/kg on a fat basis). The median concentration of gamma-HCH in
    278 samples of human milk collected in 11 maternity centres in the
    Netherlands was < 0.01 mg/kg on a fat basis; the highest value
    found was 0.08 mg/kg (Greve & Wegman, 1985).

         Mes et al. (1986) studied 210 breast milk samples from five
    regions across Canada and found gamma-HCH at a mean concentration of
    5 µg/kg (on a fat basis). Davies & Mes (1987) studied 18 breast milk
    samples from Canadian, Indian, and Inuit mothers in Canada whose
    fish consumption was comparable to the national rate. The level of
    gamma-HCH was 7 µg/kg in milk fat of the indigenous population, in
    comparison with 5 µg/kg in a national survey.

         Vukavic et al. (1986) measured gamma-HCH in 59 samples of
    colostrum collected in Autumn 1982 (26 samples) and Spring 1983 (33
    samples) in Yugoslavia from healthy nursing mothers on the third day
    after delivery. The concentrations of gamma-HCH were significantly
    higher in Autumn (1.71 ± 0.44 µg/litre) than in Spring (0.67 ± 0.12
    µg/litre).

         Breast milk samples from four women in Iraq, examined once a
    week for 20 weeks, contained average levels of 0.009, 0.005, 0.134,
    and 0.005 mg/kg whole milk. Gamma-HCH levels in placental tissue
    from these four donors were 0.004, 0.011, 0.013, and 0.006 mg/kg,
    respectively. Fluctuations in the residue levels were seen to be due
    to variations in the daily dietary intake and variations in the fat
    content of the breast milk (Al-Omar et al., 1986).

    6.  KINETICS AND METABOLISM

    6.1  Absorption

    6.1.1  Oral administration - experimental animals

         The uptake of lindane by rats or mice has been studied after
    oral administration. Direct information on the velocity of uptake
    from the gastrointestinal tract is available, which can be
    supplemented by information from studies in which excretion of
    orally administered radioactive lindane was followed.

         Lindane taken up from the intestines is transferred almost
    exclusively to the blood. No significant amount was found in the
    lymph of rats after injection of 0.05 or 0.1 µmol into the loops of
    the small intestines  in vivo. Absorption was rapid: 29-53% of the
    injected material was absorbed from the intestinal loops within the
    first 30 min (Turner & Shanks, 1980). Uptake of lindane from the
    intestines of rats given 12.5 mg in oil during five days was less
    effective in animals depleted of their intestinal microorganisms by
    maintenance under aseptic conditions than that in conventional rats.
    The asepticized rats also excreted more unchanged lindane in the
    faeces than conventional animals (Macholz et al., 1983).

    6.1.2  Dermal application - experimental animals

         Hawkins & Reifenrath (1984) developed an apparatus to determine
    the evaporation and percutaneous penetration of
    hexachloro-[U-14C]-cyclohexane (lindane)  in vitro, applying a
    dose of 4 µg/cm2 on pig skin. Evaporation accounted for 26 ± 5%;
    skin oxidation for 43 ± 17%; and percutaneous penetration for only
    0.7 ± 0.3% of the applied radiolabel. Reifenrath et al. (1984) also
    evaluated models consisting of human or pig skin grafted onto the
    congenitally athymic nude mouse, hairless dogs and weanling
    Yorkshire pigs for predicting skin penetration in humans. A
    radioactive dose of 0.05 µCi of [U-14C]-labelled lindane (98%) was
    applied topically to 1.27 cm2 (4 µg/cm2) of each model, and
    radiolabel (percentage of applied dose) was measured in urine and
    faeces, skin scrub, application site, and carcass. Incomplete
    excretion of the label following topical application was corrected
    for by parental (subcutaneous) administration of 2 µCi in propylene
    glycol. The results showed significant correlations between the
    values for human skin and those for human skin grafted on athymic
    mice and for weanling Yorkshire pigs, but no correlation was found
    between the values for humans and those for the hairless dog or for
    pig skin grafted on athymic nude mice.

         Dermal absorption has also been investigated in rats and
    rabbits. Groups of 24 male Charles-River Crl:CD(SD)BR rats and male
    Hra:(NZW)SPF rabbits were given a single dermal application of
    lindane (20% emulsifiable concentrate to which 14C-lindane had

    been added) on clipped skin at doses of 0.1, 1, or 10 mg/rat and
    0.5, 5, and 50 mg/rabbit, corresponding to 0.02, 0.2, and 2
    mg/cm2, respectively. Urine and faeces were collected 0.5, 1, 2,
    4, 10, or 24 h after application from four animals per dose level;
    and four animals per group were bled and sacrificed 0.5, 2, 4, 10,
    and 24 h after application of the test material. The ratio between
    the quantity absorbed at a dose of 1 mg and that absorbed at 10 mg,
    as well as that between 0.2 and 1 mg/rat at equal exposure duration,
    decreased with increasing exposure time and concentration. On a
    group basis, the total recoveries were 75-85% for rats and 75-82%
    for rabbits. A significant fraction of the applied dose was found in
    the urine: 16, 15, and 12%, respectively, at application levels of
    0.1, 1, and 10 mg/rat. The corresponding values for rabbits were 46,
    29, and 41% for doses of 0.5, 5, and 50 mg/rabbit. Much lower levels
    were found in the faeces. Total adsorption (24 h) increased in rats
    from 5% of the applied amount at the highest dose to 28% at the
    lowest exposure. For rabbits, penetration was more rapid, and
    adsorption at 24 h ranged from 17 to 56% of the applied dose. The
    applied doses per unit surface area were approximately the same,
    permitting a comparison of penetration rates. The average
    penetration rates after 24 h for rats were 0.2, 2, and 4 µg/cm2
    per hour for groups treated with 0.02, 0.2, and 2 mg/cm2. The
    penetration rates after 24 h for rabbits were 0.5, 3, and 14
    µg/cm2 per hour for the groups treated with 0.02, 0.2, and 2
    mg/cm2. These studies indicate that appreciable absorption of
    lindane takes place after dermal applicatioon (Bosch, 1987, 1987b).

    6.1.3  Other routes - experimental animals

         When doses of 40 or 80 mg/kg body weight of a mixture of 14C-
    and 36Cl-gamma-HCH in rapeseed oil were injected intraperitoneally
    into rats, 25% was absorbed within 1 h and at least 90% after 1 day.
    Four days after the injection, only traces of lindane were left in
    the abdominal cavity. One day after the injection, about 40% of the
    applied dose was found in the organs and tissues (Koransky et al.,
    1963).

    6.2  Distribution

    6.2.1  Oral administration - experimental animals

         After uptake, lindane is distributed to all organs and tissues
    in the body of laboratory animals, at measurable concentrations
    within a few hours.

         When lindane was administered orally to rats at doses of 1, 10,
    or 100 mg/kg diet for up to 56 days, the highest concentrations were
    found in adipose tissue. The fat:blood ratio in this study was very
    close to 150 at all times, whereas the liver:blood ratio was
    3.4-3.5. Lindane concentrations in organs reached a maximum after

    2-3 weeks and slowly decreased thereafter. The authors did not
    differentiate between males and females (Oshiba, 1972).

         Twenty-four hours after oral administration of 14C-labelled
    lindane at 8 mg/kg body weight in sunflower oil to rats for 10 days,
    more than 35% of the administered activity was deposited in fat.
    Muscle and kidneys contained 3.5 and 3.7%, respectively, and all
    other organs that were analysed contained less than 1%; 17.4% was
    found in urine and 13.8% in faeces. In total, only 78.7% was
    recovered; however, skin was not analysed in this study. (Other
    studies have demonstrated that a significant amount of lindane
    administered to rats and mice is deposited in the skin, so that some
    of the missing 21.3% of the total applied dose could have been
    there.) A fter an additional 48 h, the concentrations in all organs
    were reduced to about one-half of the values seen after 24 h,
    showing that no single organ retained lindane significantly longer
    than the others. Urine contained 24.5% and faeces, 20.9% (Seidler et
    al., 1975).

         After single oral doses to rats, the fat:blood ratio ranged
    between 145 and 206 and the brain:blood ratio between 4 and 6.5
    (Vohland et al., 1981).

         After continuous dietary administration of lindane at doses of
    0.2, 0.8, 4.0, 20, or 100 mg/kg diet for 13 weeks to Wistar KFM-Han
    rats, the highest concentrations were reached in the fatty tissue.
    At the highest dose, the fat:blood ratio was 44 in males and 69 in
    females and the liver:blood ratio was 5.3 in males and 9.6 in
    females. After six weeks with no further administration, lindane
    concentrations in organs were close to the control values (Suter et
    al., 1983).

         The distribution of lindane in brain after oral administration
    at 30 mg/kg or intravenous administration at 0.3 mg/kg was studied
    using autoradiography-imaging analysis and dissection-liquid
    scintillation counting techniques. The two routes of administration
    gave similar results. A heterogeneous distribution of label in brain
    regions was observed: the radiolabel concentration in the white
    matter was higher than that in thalamus, mid-brain, pons and medulla
    at different times relative to the mean value for whole brain. The
    affinity of lindane for white matter and myelinated structures was
    related to its lipophilic behaviour (Sanfeliu et al., 1988).

         Mosha et al. (1986) studied the distribution and elimination of
    gamma-HCH in adult female goats. Eight goats were administered a
    daily dose of 6 mg/kg body weight by gavage for five consecutive
    days. Blood and milk were collected before exposure and during 10-60
    days after exposure, and organs and tissues were collected and
    analysed. One goat was used as a control. The blood concentration of
    gamma-HCH was approximately 0.1 mg/litre during the dosing period
    and decreased gradually thereafter; none was detectable after day

    20. The concentrations in milk were about eight times higher than
    those in blood but decreased in parallel. The concentration in fat
    samples on day 7 was 1.4 mg/kg, but those in other tissues were
    about 0.1 mg/kg.

    6.2.2  Inhalation - experimental animals

         After rats were exposed to lindane at doses of 0.02, 0.1, 0.5,
    or 5 mg/m3 for 90 days by inhalation, the highest concentrations
    were found in fatty tissues. At 5 mg/m3, the fat:serum ratio was
    150 in males and 464 in females; at 0.5 mg/kg, it was 161 in males
    and 245 in males; at 0.1 mg/kg, 137 in males and 429 in males; and
    at 0.02 mg/kg, 92 in males and 377 in females. At the 5 mg/m3
    exposure level, the liver:blood ratios were 1.9 in males and 4.2 in
    females and the brain:serum ratios were 9 in males and 23 in
    females. These values suggest that higher concentrations are reached
    in fat after inhalation than after oral administration, whereas
    liver appear to be somewhat lower after inhalation. After a recovery
    period of four weeks, concentrations in all organs had decreased to
    the control values (Oldiges et al., 1983).

    6.2.3  Other routes

         One day after intraperitoneal injection to rats of a mixture of
    14C- and 36Cl-lindane in rapeseed oil, the highest contents were
    those of skin and fat - 15.7% and 10.7%, respectively. Less than 1%
    was found in all other organs, including the central nervous system
    (Koransky et al., 1963). When lindane or deuterated lindane was
    administered intraperitoneally to rats at doses of 10 mg/kg body
    weight, about 40 mg/kg fat were found after one day in both males
    and females. At that time, the blood concentration in males was 0.2
    mg/litre; 1-2 mg/kg were present in brain and 0.7 mg/kg in skeletal
    muscle. Deuterated lindane was found at 110 mg/kg in depot fat of
    males, and the levels in brain and muscle were about twice those of
    undeuterated lindane (Stein et al., 1980).

         Mottram et al. (1983) studied the metabolic fate of lindane in
    three groups of two white female pigs. The pigs were sprayed once
    with either 5.6 g or 1.4 g of an anti-louse spray, which represented
    16 and 4 times, respectively, the normal dose of 350 mg/pig. Five
    animals served as controls. Rapid accumulation of lindane occurred,
    and several metabolites were found in adipose tissue. The main
    metabolite was 1,2,4-trichlorobenzene. The residues were eliminated
    rapidly from adipose tissue, so that 30 days after treatment, the
    residual concentration in pigs sprayed with a dose 16 times the
    recommended rate was no greater than that in the untreated controls.

         Residue levels were also investigated in four lactating goats
    following oral and topical application of labelled lindane (Wilkes
    et al., 1987a,b). Two Alpine goats were housed in metabolic cages
    and administered lindane (purity not stated) spiked with

    14C-lindane in the diet at doses of 1 and 10 mg/kg twice daily for
    four days; they were sacrificed 12-14 h after the last dose. One
    Alpine goat received two topical applications at a seven-day
    interval of a lindane solution (purity unspecified) containing 11.0
    mg/ml to a shaved area that represented about 25% of the body
    surface area, to simulate total body spray; it was sacrificed 48 h
    after the last application. A Nubian goat was not only shaved over
    the same extent but also had its remaining hair clipped to
    approximately 3 cm, and the whole surface of the animal was treated
    with lindane, to simulate dip treatment; this animal was sacrificed
    24 h later. After sacrifice, radiolabel was measured in tissues and
    in the intestinal contents; radiolabel in exhaled carbon dioxide was
    measured on one occasion.

         Total recovery of radiolabel was low: approximately 50% in the
    study by oral administration and 16-30% in the study by dermal
    application. To determine the reason for the losses after oral
    administration, the fate of labelled lindane in rumen fluid at 37 °C
    was investigated  in vitro. About 55% of the radiolabel was
    recovered as 14CO2, and 38% remained in the rumen fluid. The
    authors stated that their results "clearly show that volatile
    14C-labelled organics were evolved from 14C-lindane fortified
    rumen fluid," and "that the losses in the  in vivo studies were due
    to volatile 14C-lindane metabolites." Attempts to trap the
    labelled volatile compounds, however, proved unsuccessful.

         From 35 to 46% of the radiolabel administered orally was
    excreted in the urine over a period of 4 days, and 10-12% of the
    dermily applied dose was found in urine over 8-9 days. Much lower
    activities were found in faeces, and insignificant amounts in
    expired air. The amount of radiolabel in whole milk after oral
    administration reached a plateau after 2-3 days, corresponding to a
    total concentration of 0.4 ppm (6-8 ppm in the fat) at the lower
    dose (2 mg/kg per day) and 3 ppm (about 50 ppm in the fat) at the
    higher exposure level (20 mg/kg per day). Significant activity was
    also found in the milk after dermal administration, corresponding to
    levels of 0.1-0.7 ppm in whole milk.

    6.3  Metabolic transformation

         The metabolism of lindane is initiated by one of four possible
    reactions:

         - Dehydrogenation leads to the formation of gamma-HCH;
         - Dehydrochlorination leads to the formation of gamma-PCCH;
         - Dechlorination leads to the formation of gamma-
           tetrachlorohexene;
         - Hydroxylation leads to the formation of
           hexachlorocyclohexanol.

    These compounds must be considered as intermediates, and the initial
    reactions are followed by a series of further dehydrogenating,
    dechlorinating, dehydrochlorinating, and hydroxylating steps.

         A large number of metabolites and end-products occur during the
    metabolism of lindane (see section 6.3.2). Detailed descriptions and
    schemes of the metabolic pathway of lindane leading to the various
    isomeric metabolites have been proposed (Engst et al., 1970, 1977,
    1978a, 1979a; Kurihara & Nakajima, 1980). These pathways involve
    metabolites that have not as yet been detected. These missing
    metabolites may be very unstable compounds which are rapidly
    transformed to other intermediates and thus escape detection.
    Another possibility is that conjugates are formed which are tightly
    bound to proteins  via sulfur, and these could be detected only
    after the complex is hydrolysed.

         The essential steps in the metabolism of lindane are known, and
    these are shown, with the main metabolites, in Figure 2 and are
    discussed below.

    6.3.1  Enzymatic involvement

         Lindane is converted by enzymatic reactions, mainly in the
    liver. One group of enzymes involved in the biotransformation of
    lindane are microsomal, e.g., cytochrome P-450-dependent
    monoxygenases. Five groups of male Wistar rats were injected
    intraperitoneally with gamma-HCH at 25 mg/kg body weight on four
    consecutive days to investigate the induction of cytochrome P-450 in
    liver microsomes. gamma-HCH was found to be a 'mixed type' inducer
    which mediates the induction of cytochrome P-450 b/e, c and d forms
    (Kumar & Dwivedi, 1988). These enzymes are involved in
    hydroxylation, dehydrogenation, and dechlorination. Other hepatic
    cytosolic enzymes are involved in the dehydrochlorination reaction.
    The intermediate metabolites or end-products of the
    biotransformation may result as a consequence of the four enzymatic
    reactions listed above.

         A cytochrome P-450-dependent dehydrogenation reaction was
    described in rat liver microsomes  in vitro. Incubation of lindane
    with rat liver homogenates resulted in the formation of
    hexachlorocyclohex-1-ene, and the authors proposed that this
    dehydrogenation is an important initial step in the metabolism
    leading to the detoxication of lindane (Chadwick et al., 1975).

         Stein et al. (1977) found that at least two independent
    pathways were involved in the metabolism of lindane. The first is
    the possible formation of unstable intermediates, such as
    hexachlorocyclohexanol, after an initial hydroxylation leading to
    the main metabolite, 2,4,6-trichlorophenol (2,4,6-TCP), and
    involving cytochrome P-450. The second pathway includes
    dehydrogenation of lindane to 1,2,3,4,5,6-HCCH, subsequent

    hydroxylation and dehydrochlorination to 2,3,4,6-tetrachlorophenol.
    TCP and tetrachlorophenol are formed  in vitro in a ratio of about
    2:1.

         In the presence of oxygen and NADPH  in vitro, rat liver
    microsomes metabolize lindane mainly to 2,4,6-TCP (Tanaka et al.,
    1977, 1979). 3,4,5,6-Tetrachlorocyclohexene was identified as an
    intermediate after lindane was incubated under N2 with liver
    preparations (Chadwick et al., 1978; Kurihara et al., 1979).
    Experiments with rat liver preparations  in vitro demonstrated the
    importance of glutathione in the metabolism of lindane. Glutathione
    enhanced the conversion of lindane to dichlorophenol (DCP) by a
    factor of 3-4, but conjugates were formed only in the presence of
    liver cytosol protein as a source of glutathione transferase. The
    initial step appears to be dehydrochlorination to 1,3,4,5,6-PCCH,
    followed by conjugation and further dehydrochlorination to DCP -
    mainly 2,4-DCP. The DCPs found in the urine of rats are a mixture of
    different isomers. The rate of formation of  S-(dichlorophenyl)
    glutathione from HCH in rat liver cytosol apparently depends on
    gradual monodehydrochlorination, and the enzymatic transfer of
    reduced L-glutathione (GSH) onto PCCH is not preceded by a second
    dehydrochlorination (Stein et al., 1977; Portig et al., 1979; Tanaka
    et al., 1979).

         When a 1:1 mixture of lindane and the corresponding
    hexadeuterated compound was fed to Wistar rats, the ratio of MCP,
    DCP, and TCP, excreted as mercapturic acids, showed an isotopic
    effect. The rate-limiting step for the formation of DCP and TCP is
    either a dehydrochlorination or a dehydrogenation of lindane,
    whereas formation of MCP must be initiated by dechlorination to
    tetrachlorocyclohexane, followed by conjugation with glutathione
    (Kurihara et al., 1980).

         Lindane was converted mainly to gamma-HCCH by rat liver
    microsomes, and significant amounts of 2,4,6-TCP and
    2,3,4,6-tetrachlorophenol were detected. Human liver microsomes
    converted lindane into four major metabolites:
    gamma-1,2,3,4,5,6-hexachlorocyclohex-1-ene; gamma-1,3,4,5,6-PCCH;
    beta-1,3,4,5,6-PCCH, and 2,4,6-TCP. Smaller amounts of
    2,3,4,6-tetrachlorophenol and pentachlorobenzene were found
    (Fitzloff et al., 1982).

         Human and rat liver microsomes converted the lindane
    metabolites gamma-PCCH and 3,4,6/5-PCCH to 1,2,4-tetrachlorobenzene,
    1,2,3,4-tetrachlorobenzene, 2,4,5-TCP, 3,4,5/6-pentachloro-2-
    cyclohexen-1-ol and beta-PCCH-oxide or 3,4,6/5-PCCH-oxide. The
    identity of the beta-PCCH-oxide was confirmed by column
    chromatography and gas-liquid chromatography-mass spectrometry. It
    is stable to hydrolysis by microsomal epoxide hydrolase
    (E.C.3.3.2.3.) and under various aqueous acid conditions. Its
    toxicological role is still unknown. Although this compound is
    structurally related to epichlorhydrin and epoxides, it was not
    mutagenic to  Salmonella typhimurium strain TM 677 (Fitzloff & Pan,
    1984).

         Two groups have reported the formation of trace amounts of
    chlorinated benzenes from lindane in rats. Hexachlorobenzene was
    found in faeces (Gopalaswamy & Aiyar, 1984) and pentachlorobenzene
    in brain (Vohland et al., 1981). The two studies are consistent in
    so far as the identified amounts of chlorobenzenes are extremely low
    and near the detection limit; however, they are also contradictory,
    because hexachlorobenzene was found exclusively in the first study
    and pentachlorobenzene in the second. It is impossible to clarify
    whether artefacts were measured in these studies, e.g., enrichment
    of impurities in the starting material. If indeed chlorinated
    benzenes are formed from lindane, the amounts obtained are
    insignificant compared to those of other metabolites.

    6.3.2  Identification of metabolites

         Metabolites of lindane have been identified in a large number
    of studies,  in vivo in body fluids, urine, faeces, organs, and
    tissues, and  in vitro. Most of the  in-vivo studies were carried
    out with rats, but similar results were obtained in other animal
    species.

         The following metabolites have been identified:

          Cycloalkenes: 1,2,3,4,5,6-hexachlorocyclohexene (HCCH);
    1,3,4,5,6-pentachlorocyclohexene (PCCH); 3,4,5,6-
    tetrachlorocyclohexene; 2,3,4,5,6-pentachloro-2-cyclohexen-1-ol; and
    2,3,4,6- and 2,4,5,6-tetrachloro-2-cyclohexene-1-ol (Chadwick &
    Freal, 1972a; Freal & Chadwick, 1973; Chadwick et al., 1975; Engst
    et al., 1976; Kujawa et al., 1977; Tanaka et al., 1977; Chadwick et
    al., 1978; Engst et al., 1978b; Kurihara et al., 1979; Vohland et
    al., 1981; Fitzloff et al., 1982; Mottram et al., 1983; Sanfeliu et
    al., 1988).

          Chlorobenzenes: 1,2,3,4,5,6-hexachlorobenzene, 1,2,3,4,5-
    pentachlorobenzene and 1,2,3,5-, 1,2,4,5-, and 1,2,3,4-
    tetrachlorobenzene (Aiyar, 1980; Voh land et al., 1981; Gopalaswamy
    & Aiyar, 1984; Artigas et al., 1988). Mono-, di-, tri-, and
    tetrachlorobenzenes have been reported in pigs (Mottram et al.,
    1983).

          Chlorophenols: 2,3,4,5,6-pentachlorophenol; 2,3,4,5-,
    2,3,4,6-, and 2,3,5,6-tetrachlorophenol; 2,3,5-, 2,4,5-, and
    2,4,6-trichlorophenol (TCP); and 2,4- and 3,4-dichlorophenol (DCP)
    (Grover & Sims, 1965; Chadwick & Freal, 1972a,b; Freal & Chadwick,
    1973; Kurihara & Nakajima, 1974; Chadwick et al., 1975; Engst et
    al., 1976; Kujawa et al., 1977; Stein et al., 1977; Tanaka et al.,
    1977; Engst et al., 1978b; Tanaka et al., 1979; Aiyar, 1980;
    Fitzloff et al., 1982).

          Conjugates of these compounds:

       - 2,3- and 2,6-dichlorophenol were conjugated with  glutathione
         (Portig et al., 1979);

       - 2,4-DCP; 2,3,5-, 2,4,5-, and 2,4,6-TCP; 2,3,4,5-, 2,3,4,6-, and
         2,3,5,6-tetrachlorophenol; 2,3,4,5,6-PCP and
         tetrachloro-2-cyclohexene-1-ol were conjugated with  glucuronic
          acid (Grover & Sims, 1965; Kurihara & Nakajima, 1974; Engst
         et al., 1976; Chadwick et al., 1981);

       - 2,3,5-, 2,4,5-, and 2,4,6-TCP; 2,3,4,5- and 2,3,4,6-
         tetrachlorophenol; 2,3,4,6- tetrachloro-2-cyclohexene-1-ol; and
         2,3,4,5,6-pentachloro-2-cyclohexen-1-ol were conjugated with
         sulfate (Grover & Sims, 1965; Kurihara & Nakajima, 1974;
         Chadwick et al., 1981); and

       - 4-monochlorophenol; 2,4- and 3,4-DCP and 2,3,5- and 2,4,5-TCP
         were conjugated with mercapturic acids (Grover & Sims, 1965;
         Kurihara et al., 1979, 1980).

    6.3.3  Metabolites identified in humans

         Engst et al. (1978b) analysed urine from workers apparently
    exposed to technical-grade HCH (during manufacture?) and found
    alpha-, beta-, gamma-, and delta-HCH, traces of hexa- and
    pentachlorobenzene, gamma- and delta-PCCH, pentachlorophenol,
    2,3,4,5-, 2,3,4,6-, and 2,3,5,6-tetrachlorophenol, several
    trichlorophenols, as well as glucuronides of some of these
    metabolites. The PCCHs, tetrachlorophenol, hexachlorobenzene, and
    pentachlorophenol were also identified in blood.

         The urine of 21 men working in the production of gamma-HCH with
    a purity of 99.8% from technical-grade HCH (16% alpha-, 7% beta-,
    and 45% gamma-HCH) was examined for the presence of chlorinated
    phenols. External and internal exposure was estimated from
    measurements of the concentrations of HCH isomers in the air of the
    workroom and in serum samples. The men had been employed for periods
    ranging from a few months up to 30 years (mean, 10.6 years,) and
    they were aged 24-62 years (mean, 46 years). Fourteen mono-, di-,
    tri-, and tetrachlorophenols and seven dihydroxychlorobenzenes of
    unknown configuration were identified in urine. The main metabolites
    were 2,4,6-, 2,3,5-, and 2,4,5-trichlorophenol, which were excreted
    in nearly equal quantities. The mean concentrations of alpha-,
    beta-, and gamma-HCH in the serum of exposed workers were 49 (range,
    11-138), 82 (17-434) and 52 (9-188) µg/litre; the levels in controls
    were < 1.0 µg/litre. The air concentrations of alpha-, beta-, and
    gamma-HCH were 2-4, 1-3, and 23-63 µg/m3 (Angerer et al., 1983).

    6.4  Elimination and excretion in expired air, faeces, and urine

    6.4.1  Oral administration

         In mammals, including human beings, lindane is excreted very
    rapidly in urine and faeces after metabolic degradation; only small
    quantities are eliminated unchanged (Seidler et al., 1975). As
    lindane is subjected to four types of reaction -
    dehydrochlorination, dechlorination, dehydrogenation, and oxidation
    - many intermediate metabolites are found, the nature of which
    depends on the initial reactions. Nevertheless, the excreted
    metabolites are all various isomers of dichloro-, trichloro-, and
    tetrachlorophenols, which are excreted either free or in a
    conjugated form with glucuronic or sulfuric acid or
     N-acetylcysteine (Rhône-Poulenc Agrochimie, 1986).

    6.4.1.1  Rat

         Sprague-Dawley rats were fed diets containing lindane at 400
    mg/kg diet for 5 weeks. Within 24 h, mainly 2,3,4,6- and
    2,3,4,5-tetrachlorophenols, 2,3,5-, 2,4,5-, and
    2,4,6-trichlorophenols and 3,4-dichlorophenol were found in the free
    form in urine and faeces, at 27.1%, 4.3%, 8.4%, 14.7%, and 51.1%,
    respectively (Chadwick & Freal, 1972a; Chadwick et al., 1975).

         After 14C-lindane was administered orally to rats at 8 mg/kg
    body weight for 10 days, 23% of the metabolites in faeces and urine
    were in the free form, and 77% in conjugated form, partly as
    glucuronides (Seidler et al., 1975).

         Metabolites were extracted from the urine of male Wistar rats
    that had received 19 daily oral doses of 8 mg/kg body weight. After
    hydrolysis of conjugates, the metabolites found were 2,4,6-TCP,
    2,3,4,6- and 2,3,5,6-tetrachlorophenol, tetrachlorocyclohexenol,
    pentachlorocyclohexenol, and pentachlorophenol (Engst et al., 1976).
    Formation of 2,4,5,6- and 2,3,4,6-tetrachlorocyclohexenol was
    confirmed by Chadwick et al. (1978) in a study with Sprague-Dawley
    rats fed diets containing lindane at 400 mg/kg diet for one month.

    6.4.1.2  Rabbit

         Five rabbits fed gelatin capsules containing 14C-lindane at
    3-12 mg/animal twice weekly for 26 weeks excreted 54% of the
    radiolabel in urine and 13% in faeces. About 56% of the urinary
    metabolites were soluble; those that were identified were 2,3,5-,
    2,4,5-, and 2,4,6-trichlorophenol, 2,3,4,6- tetrachlorophenol, 2,3-
    and 2,4-dichlorophenol and 2,3,4,5- tetrachlorophenol. The presence

    of seven chlorophenols and six chlorobenzenes was indicated
    (Karapally et al., 1973).

    6.4.2  Other routes

    6.4.2.1  Mouse

         Lindane metabolites were analysed in the urine of mice after a
    single intraperitoneal injection of 14C-lindane at 16 or 21
    µg/mouse. Within three days, 57% of the total radiolabel had been
    excreted in urine, mainly as conjugates with glucuronic or sulfuric
    acid. About 25% of the excreted conversion products were 2,4,6-TCP,
    and 4-6% was 2,4-DCP; ; 41-46% of the chlorophenols were conjugated
    and 3% in the free form (Kurihara & Nakajima, 1974).

    6.4.2.2  Rat

         Intraperitoneal administration to rats of lindane in arachis
    oil at daily doses of 40 mg/kg body weight (total, 4 g) was followed
    by urinary excretion of 2,3,5- and 2,4,5-TCP, either in free form or
    as sulfuric and glucuronic acid conjugates (Grover & Sims, 1965).

         One day after intraperitoneal injection of a mixture of 14C-
    and 36Cl-labelled lindane to rats, 18.97% of the radiolabel was
    found in the excreta; 7.39% was still not absorbed, indicating again
    that elimination of lindane begins during the absorption phase.
    After 4 days, 52% of the total activity was found in the excreta.
    The resulting half-time was about 4 days (Koransky et al., 1963). An
    even shorter half-time of 1-2 days was seen in depot fat in another
    study after intraperitoneal injection of 10 mg/kg to rats (Stein et
    al., 1980).

         After intraperitoneal administration of 40 mg/kg body weight to
    rats, 20% of the total dose left the body  via the faeces and 80%
     via the urine (Koransky et al., 1963, 1964). In another study,
    however, the amounts of radiolabel excreted by rats in urine and
    faeces were about equal (Seidler et al., 1975). Only traces of
    unchanged lindane were found in faeces and urine. of the chlorine
    derived from lindane that is excreted in the urine, about 60% is
    inorganic and 40% is organic (Koransky et al., 1964).

         Mono-, di-, and trichlorophenyl mercapturic acids were found to
    be the main metabolites after intraperitoneal administration of
    lindane at 17.2 and 34.4 µmol to male Wistar rats, accounting for
    more than 60% of the urinary metabolites (Kurihara et al., 1979).

    6.4.2.3  Human

         The urinary excretion of radiolabel after intravenous
    administration of 14C-labelled lindane to six human subjects at 1
    µCi in propylene glycol was 24.6% ± 6.1 of the administered dose
    within five days. About 80% was excreted in first 24 h. The
    half-time was 26 h (Feldmann & Maibach, 1974).

    6.5  Retention and turnover (experimental animals)

         The highest concentrations of gamma-HCH in the bodies of mice
    were found 3 h after oral administration of a single dose of 1.2
    mg/mouse. After 72 h, 270 µg of the original 1200 µg/animal
    remained. A half-time of 2-3 days can be deduced from these results
    (van Asperen, 1958).

         When lindane was fed to rats for 56 days at doses of 1, 10, or
    100 mg/kg diet, organ contents increased to a maximum within 2-3
    weeks, depending on the dose. From that time on, the concentrations
    in all organs decreased slowly, and equilibria were approached by
    the end of the administration period. The concentration ratios
    between different organs and blood remained constant throughout the
    time of administration, and when treatment was stopped the
    concentrations in all organs, including adipose tissue, decreased
    rapidly. Similar results were seen after starvation for 6 days,
    whereas diets rich in fat or protein accelerated the reduction of
    the lindane content in organs and tissues. The kinetics of excretion
    indicate a half-time of 3-4 days for oral administration of a single
    dose of 14C-lindane (Oshiba, 1972).

         After continuous feeding of lindane in corn oil at 50 mg/kg
    diet for 60 days to Osborne-Mendel rats, a constant equilibrium
    concentration of about 50 mg/kg was reached in adipose tissue within
    9 days. After cessation of lindane administration, the concentration
    dropped to values between 2.5 and 11.5 mg/kg tissue within 9 days
    (Baron et al., 1975). One-half of an applied dose was excreted from
    the bodies of rats within 3-4 days (Seidler et al., 1975).

         After oral administration of gamma-HCH as a single dose of 60
    mg/kg to rats, a maximal concentration of 8.8 ± 1.1 mg/kg tissue was
    reached in the brain after 12-24 h. This concentration decreased
    with a half-time of 1.5 days (Vohland et al., 1981). Oral
    administration of lindane in the diet for 13 weeks at doses up to
    100 mg/kg diet resulted in concentrations in fat that were lower
    than those administered in the diet. The difference was more
    pronounced at higher doses. After administration of 100 mg/kg diet,
    11.4 mg/kg were found in fat (Suter et al., 1983).

         All studies in which lindane was fed continuously to rats
    showed that this compound does not accumulate in significant amounts
    in the body. The highest accumulation factor found for fatty tissues
    was about 2, and an average accumulation factor for fatty tissues of
    about 1 can be deduced from the published data. The corresponding
    factors for other tissues are considerably lower.

    6.6  Biotransformation

    6.6.1  Plants

         In order to study the metabolism of lindane in wheat, plants
    were grown from seed containing 480 mg/kg of 14C-lindane. In
    seedlings, 35.5% of the radiolabel was associated with unmetabolized
    lindane, 29.1% with the group of chlorobenzenes and 26.3% with
    chlorophenols. In mature plants, the extractable residues consisted
    of 5.4% lindane in roots and 21.4%in straw, up to 13.9%
    chlorobenzenes and up to 53% chlorophenols. The chlorobenzenes
    extracted from wheat roots were mostly tri- and tetrachlorobenzenes.
    The concentrations of di- and pentachlorobenzene and of gamma-PCCH
    were low (Balba & Saha, 1974).

         Lindane and possible metabolites were determined in white
    cabbage after leaf application and in carrots grown in treated soil.
    In cabbage, a maximum of 0.04 mg/kg of lindane residues could be
    detected at the time of harvest. In the carrots, residue levels of
    0.4-1.0 mg/kg were found. In the second year after treatment,
    residue levels were < 0.005 mg/kg. Up to 0.05 mg/kg of gamma-PCCH
    and traces of 1,2,4-tri- and 1,2,3,4- tetrachlorobenzene were found.
    Hexachlorobenzene was not detected in any of the samples (Eichler,
    1975, 1980).

         Itokawa et al. (1970) investigated the fate of 14C-lindane in
    spinach and carrots grown in treated soil: 30-70% of the total
    residues in the different plant parts were lindane. Five metabolites
    were identified but not further characterized.

         Lindane was converted to 36% soluble and 30% unextractable
    residues under outdoor conditions after foliar application to
    endives and lettuce. About 97% of the soluble fraction was found to
    consist of chlorophenols in free or conjugated form. Minor
    quantities of various chlorobenzenes were found. The conversion to
    unextractable residues was dependent on weather conditions; the
    composition of the unextractable residues was not analysed in detail
    (Kohli et al., 1976a).

         After lettuce plants were grown in nutrient solution containing
    14C-lindane at 1.45 mg/kg for 4 weeks, the radiolabel extracted
    from the plants consisted of about 77% lindane and 20% polar and 3%
    non-polar residues. 2,3,4,6-Tetrachlorophenol, conjugated tetra- and
    pentachlorophenol, and unidentified metabolites were found in the
    polar fraction. The non-polar fraction contained tri- and
    pentachlorobenzene as well as gamma-PCCH and HCCH (Kohli et al.,
    1976b).

         The metabolism of lindane was investigated in a variety of
    plant-cell tissue cultures with high metabolic activity and in
    lettuce plants grown in nutrient solution (Stöckigt, 1976; Stöckigt
    & Ries, 1976). Tobacco tissue cultures were found to produce trace
    amounts of 1,2,4-trichlorobenzene, while in carrot cultures,
    1,2,3,4-tetrachlorobenzene and several isomers of trichlorophenol
    conjugated with beta-glucose were found. This investigation also
    demonstrated that intact lettuce plants cannot produce
    pentachlorophenol or chlorobenzenes. Metabolism of lindane to carbon
    dioxide was not detected.

         Moza et al. (1974) applied gamma-PCCH, a plausible metabolic
    intermediate of lindane, to young maize and pea plants in nutrient
    solution. Various chlorobenzenes and chlorophenols were formed. The
    most abundant metabolites in maize were 1,2,4,5-tetrachlorobenzene
    and 2,3,5- and 2,4,5-trichlorophenol, and the most abundant in pea
    plants was 1,2,4,5-tetrachlorobenzene.

         Pea plants were grown under laboratory conditions in nutrient
    solution containing 14C-lindane. After transfer into lindane-free
    medium, either lindane or its metabolites were released from roots,
    and to a lesser extent from other parts of the plant, within one day
    (Charnetski & Lichtenstein, 1973).

         The results described above are reflected in Figure 3, which
    does not, however, include the conversion of lindane to traces of
    hexachlorobenzene or pentachlorophenol or to the corresponding
    alpha- and beta-HCH isomers (Kohli et al., 1976a,b; Steinwandter,
    1976).

          Appraisal

         Lindane is not absorbed by the leaves of plants, and its poor
    absorption by roots rapidly reaches a plateau. Most of the lindane
    applied to plants is removed by evaporation or leaching. The rate of
    metabolic transformation is low. The main degradation pathway
    proceeds  via formation of gamma-PCCH to tri- and tetrachlorophenol
    in free or conjugated form. Other metabolites that have been
    described occasionally, such as hexachlorocyclohexene and
    chlorobenzenes, are present in only negligible quantities.

    6.6.2  Microorganisms

         The metabolism of lindane has also been investigated in
    bacteria, fungi, and algae. Chlorocycloalkenes, chlorobenzenes, and
    chlorophenols were found to be metabolic intermediates, and carbon
    dioxide to be the end-product. Volatile, chlorine-free hydrocarbons
    were also found (Haider & Jagnow, 1975; Haider et al., 1975).

         Mixed populations of bacteria metabolize lindane to gamma-PCCH,
    alpha-, beta-, or gamma-3,4,5,6-tetrachloro-1- cyclohexene (TCCH),
    pentachlorobenzene, 1,2,3,4-, 1,2,3,5-, or
    1,2,4,5-tetrachlorobenzene, 1,2,4- or 1,3,5-trichlorobenzene, 1,2-
    and 1,4- dichlorobenzene, as well as carbon dioxide (Yule et al.,
    1967; Haider et al., 1974; Kohnen et al., 1975; Mathur & Saha, 1975;
    Tu, 1975; Haider et al., 1976; Jagnow et al., 1977; Mathur & Saha,
    1977; Vonk & Quirijns, 1979).

         Metabolites of lindane were identified as PCCH and TCCH in
    populations of  Escherichia coli (Francis et al., 1975; Vonk &
    Quirijns, 1979); PCCH, tetrachloro-1-cyclohexene, 1,2,3,4-
    tetrachlorobenzene, and carbon dioxide in  Pseudomonas sp. (Benezet
    & Matsumura, 1973; Matsumura et al., 1976; Engst et al., 1979a); and
    TCCH, 1,2,4-trichlorobenzene, and 1,4-dichlorobenzene in
     Clostridium sp. (Heritage & MacRae, 1977a,b; Ohisa & Yamaguchi,
    1978b; Heritage & MacRae, 1979; Ohisa et al., 1980, 1982).

         Quantitative data on the metabolism of lindane in bacteria are
    given by MacRae et al. (1967), Benezet & Matsumura (1973), Haider et
    al. (1974), Haider & Jagnow (1975), Kohnen et al. (1975), Mathur &
    Saha (1975, 1977), and Haider (1979). The most abundant metabolites
    are PCCH and TCCH (up to 45.8% and 21.7%, respectively, of the
    initial dose of lindane). Chlorobenzenes may occur in only small or
    trace amounts. Carbon dioxide is formed under aerobic or submerged
    incubation conditions, and up to 20% of an initial dose of lindane
    was converted to carbon dioxide within 140 days (Kohnen et al.,
    1975). Strictly anaerobic conditions resulted in rapid release of
    chloride from lindane and in its conversion to volatile chlorine-
    free metabolites. Within 5 days, up to 90% of the applied dose had
    been released as volatile, chlorine-free hydrocarbons (Haider &
    Jagnow, 1975).

         Lindane was shown to be effectively metabolized in the algae
     Chlorella and  Chlamydomonas (Sweeney, 1969; Elsner et al.,
    1972); 1,3,4,5,6-PCCH was reported to occur as a metabolite, but no
    quantitative data are available.

         Depending on the availability of oxygen, lindane may follow
    various metabolic pathways in bacteria (Fig. 4).

         Unspecified fungi were also able to metabolize lindane,
    although at a lower rate than bacteria. The following metabolites
    were identified: gamma-PCCH; hexachlorobenzene; pentachlorobenzene;
    TCCH; 1,2,3,4-, 1,2,3,5-, and 1,2,4,5- tetrachlorobenzene; 1,2,3-,
    1,2,4-, and 1,3,5-trichlorobenzene; 1,2- and 1,4- dichlorobenzene;
    pentachlorophenol; 2,3,4,5-, 2,3,4,6-, and
    2,3,5,6-tetrachlorophenol; 2,3,4- and 2,4,6-trichlorophenol, and
    carbon dioxide. Metabolic intermediates such as PCCH were found at
    up to 1% of the initial dose of lindane. About 1% of the intial dose
    was converted to carbon dioxide after an incubation period of 52
    days (Engst et al., 1974; Kujawa et al., 1976; Engst et al., 1977).

    6.6.2.1  Anaerobic conditions

         The influence of growth conditions on the metabolic route of
    lindane in bacteria was demonstrated in the facultative anaerobe  E.
     coli as well as with mixed populations of soil microorganisms
    (Mathur & Saha, 1977; Vonk & Quirijns, 1979). These reports and
    others demonstrate the predominant formation of gamma-TCCH under
    anaerobic growth conditions. Anaerobic metabolism consists of a
    series of dechlorinating steps, leading to rapid formation of
    chlorine-free, volatile hydrocarbons and chloride (Haider & Jagnow,
    1975; Jagnow et al., 1977). Carbon dioxide is not formed under
    anaerobic conditions.

         A possible metabolic pathway under anaerobic conditions was
    proposed by Ohisa et al. (1980). Lindane is dechlorinated by a
    cytochrome P-450-dependent reaction to TCCH, followed by
    dechlorination to the unstable dichlorocyclohexadiene and
    dehydrochlorination to monochlorobenzene. The degradation of lindane
    serves as an energy source for the cells (Ohisa et al., 1982). A
    relationship between the metabolization of lindane and the Stickland
    reaction (a coupled oxidation-reduction reaction between pairs of
    amino acids) has been discussed (Ohisa & Yamaguchi, 1979; Ohisa et
    al., 1980, 1982). The ability to degrade lindane is linked to a
    bacterial enzyme system that catalyses the evolution of hydrogen
    during fermentation (Jagnow et al., 1977).

    6.6.2.2  Aerobic conditions

         Under aerobic conditions, the metabolism of lindane in bacteria
    is initiated predominantly by dehydrochlorination to gamma-PCCH
    (Vonk & Quirijns, 1979). Further intermediates are chlorobenzenes,
    and the end-product is carbon dioxide. No phenolic intermediate was
    observed under submerged conditions (Mathur & Saha, 1975).

    6.7  Isomerization

         The detection of beta-HCH in the tissues of rats fed gamma-HCH
    led to the conclusion that isomerization of lindane had occurred
    (Kamada, 1971); however, the purity of the gamma-HCH used was not

    given in this report, and it is possible that impurities were
    measured.

         Studies in rats by Copeland & Chadwick (1979) and Eichler et
    al. (1983) demonstrated that lindane did not undergo
    bioisomerization. Gopalaswamy & Aiyar (1984) reported
    biotransformation of gamma-HCH to hexachlorobenzene in male rats.
    The results of a study by Chadwick & Copeland (1985), however, using
    six young female Fischer 344 rats administered lindane in arachis
    oil at 20 mg/kg body weight daily for six days (control animals
    received the vehicle only), indicated that no significant
    biotransformation of lindane to hexachlorobenzene occurred in these
    animals. The gamma-HCH contents of adipose tissue on a fat basis
    were 0.04 ± 0.003 mg/kg in controls and 129 ± 6 mg/kg in
    lindane-treated rats.

         The possibility of isomerization of lindane to alpha- and
    beta-HCH was also investigated in mixed populations of soil
    microorganisms and other defined bacterial strains.

         Newland et al. (1969) studied the degradation of lindane in
    simulated lake impoundments and found traces of alpha-HCH under
    anaerobic incubation conditions. Benezet & Matsumura (1973)
    described the formation of small amounts of alpha-HCH from lindane
    incubated either with aquatic sediments or with suspension cultures
    of  Pseudomonas putida supplemented with NAD. Matsumura et al.
    (1976) described an NAD-dependent pathway in  P. putida leading to
    the formation of alpha-HCH under anaerobic conditions. Three percent
    of the initial radioactivity of 14C-lindane was found at a
    location with the same Rf value as alpha-HCH after separation of the
    metabolites by thin-layer chromatography.

         Engst et al. (1979b) indicated isomerization of lindane to
    alpha- and beta-HCH in anaerobically grown cultures of  P.
     aeruginosa, in a study in which metabolites were analysed by gas
    chromatography. Lindane was not reported to be isomerized to alpha-
    or beta-HCH in fungi (Engst et al., 1977).

         Vonk & Quirijns (1979) found a conversion rate of lindane to
    alpha-HCH of 0.2% after anaerobic incubation of lindane for 4 or 8
    weeks with either sandy or silt loam soil samples and  E. coli. No
    alpha-HCH was formed in control experiments in which sterile
    nutrient medium was incubated with gamma-HCH for 28 days. Growing
    mycelium of  Aspergillus niger produced no alpha-HCH. In this
    study, metabolites were identified by gas-liquid chromatography and
    verified by mass spectrometry.

         Haider (1979, 1983) tested anaerobic, semi-anaerobic, and
    aerobic incubation of radioactive labelled lindane with
     Citrobacter, Serratia, Clostridium, Klebsiella, Pseudomonas, and
     E. coli. Incubation did not increase the level of alpha-HCH. The

    results of the experiment with  Pseudomonas under anaerobic
    conditions were not reported.

         Deo et al. (1981) studied the interconversion of gamma-HCH in a
    sterile aquatic solution over periods of 1 day up to 4 weeks.
    Gas-liquid chromatography indicated a slow interconversion of
    gamma-HCH with time. Solvent extracts were tested for their toxicity
    by topical application onto 2-day-old  Drosophila melanogaster. The
    observed decrease in toxicity of the gamma-HCH solution with time
    may have been due to both degradation and isomerization to less
    toxic isomers, such as alpha-HCH.

         Taken together, the results of tests conducted under anaerobic
    conditions show that only a very small amount of lindane, if any, is
    converted to alpha-HCH, and there is no conclusive indication of
    isomerization to beta-HCH.

    7.  EFFECTS ON LABORATORY MAMMALS AND IN IN-VITRO TEST SYSTEMS

         Lindane has been tested for acute and for short- and long-term
    toxicity in a number of animal species. Some of the earlier studies
    were undertaken using material of unspecified purity; and in some
    others, technical-grade HCH was used that contained various
    quantities of alpha- and beta-HCH, in addition to lindane. Those
    studies that are relevant to this review have been included.

    7.1  Single exposure

         The acute toxicity of lindane has been investigated in numerous
    studies in a variety of species and strains of laboratory animals
    via several routes of application. The reported LD50 values for
    lindane given by different routes of administration are of the same
    order of magnitude in the various species, and no sex-dependent
    difference was seen. A marked difference in acute oral toxicity
    results from the type of vehicle used: oily solutions of lindane
    were more toxic than suspensions in water, and when mineral oils
    were used as carriers fewer toxic effects were seen than with
    vegetable oils (Muralidhara et al., 1979). Young animals were
    generally more sensitive than adults. Lindane was more toxic to
    animals suffering from protein deficiency than to rats with a normal
    protein supply (Chen, 1968).

    7.1.1  Oral

         The LD50 values for the mouse, rat, guinea-pig, and rabbit
    are summarized in Table 8.

         The choice of vehicle used for administering lindane in studies
    of its acute oral toxicity is important: the LD50 after
    administration in an oily solution or of an emulsifiable concentrate
    was 88 mg/kg body weight, but that for wettable powders, granules,
    flowable concentrations and aqueous suspensions was in the order of
    170 mg/kg or even higher.

         Single oral doses of 40 mg/kg body weight dissolved in oil were
    lethal to dogs; dogs that received 30 mg/kg survived but had
    convulsions (Barke, 1950). McNamara and Krop (1948) found that a
    dose of 100 mg/kg body weight was lethal to all of three treated
    dogs, and 50 mg/kg caused death in four out of seven animals. These
    data indicate that the lethal dose for dogs of lindane administered
    as an oily solution is about 40-50 mg/kg body weight.

    Table 8.  Reported oral LD50 values for g-HCH in experimental
              animals

    Species                   LD50(mg/kg)   References

    Rats (male, female, or    90-270      Slade (1945); Woodard &
    males and females)                    Hagan (1947);
                                          Riemshneider (1949);
                                          Antonovic (1958); Gaines
                                          (1960); Edson et al.
                                          (1966); Muacevic (1966,
                                          1970, 1971a,b); Chen
                                          (1968); Schafer (1972);
                                          Frohberg et al. (1972b)

    Mice (different strains)  55-250      Woodard & Hagan (1947);
                                          Graeve & Herrnring
                                          (1951); Nurmatov (1965);
                                          Frohberg et al. (1972a);
                                          Paul et al. (1980);
                                          Wolfe & Ralph (1980)

    Guinea-pig                100         Cameron (1945)

    Rabbit                    90-200      Cameron (1945); Nurmatov
                                          (1965)

         In an incident in which eight cows ingested a powder containing
    19.1% gamma-HCH, those that ate 112 g or more of the powder died,
    while those given 70 g survived. These findings indicate that, for
    cows, the fatal dose was between 70 and 112 g or 140-225 mg/kg body
    weight of the powder (equivalent to 28-45 mg/kg body weight
    (McParland et al., 1973).

    7.1.2  Intraperitoneal and intramuscular

         Mice of the NMRI-EMD strain (SPF) were administered lindane as
    a 0.5% suspension in 0.5% carboxymethylcellulose solution and were
    observed for 14 days. The intraperitoneal and intramuscular LD50
    values were found to be 97 and 152 mg/kg body weight, respectively
    (Frohberg et al., 1972a). In rats, only the intraperitoneal LD50
    has been determined: it was found to be 69 mg/kg body weight in
    Wistar-AF/HAN-EMD administered the compound in
    carboxymethylcellulose (Frohberg et al., 1972b).

    7.1.3  Inhalation

         Wistar (HAN/Boe) rats were exposed by whole-body exposure to
    lindane at (analytical) concentrations of 0, 273, or 603 mg/m3 for
    4 h. The average particle size was 0.4 µm, and the animals were
    observed for 14 days. Neither deaths nor abnormalities were found
    (Oldiges et al., 1980). The

         The 4-h acute LC50 for a lindane (99.6%) aerosol was determined
    by exposing four groups of five males and five female KFM-HAN Wistar
    rats by inhalation to aerosols containing lindane at 0.1, 0.38,
    0.64, or 2.1 mg/litre; 50% or more of the particles had a diameter
    of less than 7 µm. The observation time was 22 days. At toxic doses,
    signs of neurotoxicity (curved body posture, paddling movements and
    spasms) were observed. The acute 4-h LC50 was found to be about
    1600 mg/m3 for animals of each sex (Ullman et al., 1986d).

    7.1.4  Dermal

         The acute dermal toxicity for rabbits was 200-300 mg/kg
    (Medvedev, 1974; see International Register for Potentially Toxic
    Chemicals, 1983).

         Sherman strain rats were given one dermal application of
    lindane (99%) dissolved in xylene, and no attempt was made to remove
    the compound during the observation time of 14 days. The LD50 was
    1000 mg/kg body weight for males and 900 mg/kg body weight for
    females (Gaines, 1960).

         Male New Zealand rabbits, both young adult (2-3 kg) and just
    weaned (1 kg) were shaved only, shaved and depilated or shaved,
    depilated and 'stripped', and a commercial preparation of 1% lindane
    and 99% inert material was applied once to the entire body except
    the head, limbs, and perineal surface at a dose of 6 ml/kg body
    weight (equivalent to a dose of lindane of 60 mg/kg body weight, a
    dose reportedly used in infants). The lindane was allowed to remain
    on the skin during the experiment. Two of four adult rabbits that
    were treated after having been shaved, depilated, and 'stripped'
    exhibited excitement after about 24 h. Adult rabbits that had been
    shaved only showed no effect. Weanling rabbits exhibited severe
    anorexia and convulsions, and death occurred in some cases. The
    effects were more pronounced in weanlings with inflamed or damaged
    skin. The concentrations of lindane in whole blood of weanlings when
    convulsions occurred (about 24 h after treatment) were 0.7-2.5 µg/ml
    (Hanig et al., 1976).

    7.2  Short-term exposure

    7.2.1  Oral

    7.2.1.1  Mouse

         In young dd mice fed diets containing lindane at 0, 2, 4, or 10
    mg/kg diet for three months, no effect on growth and no
    histopathological change in the main organs were seen at any dose
    level (Chen & Liang, 1956). Similarly, Kitamura et al. (1970) saw no
    difference in behaviour, food consumption or body weight gain from
    that in controls in ICR mice fed diets containing lindane at 0.1, 1,
    10, and 100 mg/kg diet for 36 days. No histopathological examination
    was carried out.

    7.2.1.2  Rat

         Short-term studies carried out by Slade (1945) and Laug (1948)
    were more or less inadequate for an evaluation.

         Doisy & Bocklage (1949, 1950) fed lindane-containing diets to
    weanling rats for four weeks; doses of 400, 600, and 800 mg/kg diet
    caused high mortality rates. Food intake and weight gain were
    markedly reduced, especially in the group receiving 800 mg/kg diet.
    The animals showed irritability, hyperactivity, and convulsions. A
    dose of 200 mg/kg diet was without effect. Young rats were more
    susceptible than adults.

         In a three-month toxicity study, groups of 15 male and 15
    female Wistar KFM-Han (outbred) SPF rats were fed diets containing
    lindane (99.85%) at 0, 0.2, 0.8, 4, 20, or 100 mg/kg diet. After 12
    weeks of treatment, most of the animals were sacrificed; the
    remaining rats were placed on a control diet for six weeks and then
    sacrificed. Lindane had no effect on mortality, food consumption,
    haematological parameters, the results of urinalysis, or clinical
    symptoms, although rats fed 100 mg/kg diet gained 8.4-14.9% less
    weight than controls. Liver cytochrome P-450 levels were increased
    in females given diets containing lindane at 0.8 mg/kg diet or more
    and in high-dose males at the termination of dosing; these values
    returned to the control levels during the recovery period. Such
    increases in cytochrome P-450 activity are regarded as an adaptation
    phenomenon due to induction of the microsomal detoxifying enzymes.
    Slight, dose-related, reversible increases in absolute and/or
    relative weights of livers and kidneys were observed in male and
    female rats fed lindane at 20 or 100 mg/kg diet, and
    histopathological examination revealed changes in these animals.
    Those in the liver included dose-dependent, minimal-to-slight
    centrilobular hepatocellular hypertrophy at the end of the
    application period. After the recovery period, liver weights were
    found to be normal, and no centrilobular hypertrophy was seen. In
    the kidneys, minimal-to-slight, unicellular and multicellular

    necrosis of epithelial cells was observed in proximal convoluted
    tubules, and basophilic tubules, interstitial nephritis and hyaline
    droplets were seen in epithelial cells of the convoluted tubules.
    After the recovery period, the tubular degeneration was no longer
    present, but the nephritis and basophilic tubules were still present
    in the animals that had received 100 mg/kg. No effects were observed
    with doses of 4 mg/kg diet (equivalent to 0.3 mg/kg body weight) and
    below (Suter et al., 1983).

         In a 12-week study with groups of 10 male and 10 female Wistar
    RIV:TOX (C-S) rats, four weeks old at the beginning of the
    experiment, lindane (99.8%) was administered in the diet at
    concentrations of 0, 2, 10, 50, and 250 mg/kg. At the highest dose,
    increases were seen in the induction of enzymes, such as
    aminopyrine- N-demethylase and ethoxyresorufine- O-deethylase, but
    cytochrome P-450 and aryl hydroxylase activity were not increased.
    At the two highest dose levels, the weights of livers, kidneys, and
    thyroid were increased. The no-effect level of lindane in this study
    was 10 mg/kg diet (equivalent to 0.75 mg/kg body weight) (van Velsen
    et al., 1984).

         Young male Wistar rats were fed gamma-HCH at a dose of 0 (five
    rats) or 800 mg/kg diet (eight rats) for two weeks, and urinary
    excretion of body constituents that reflect renal function was
    measured. Glucosuria and increased excretion of creatinine and urea
    were found, and hypertrophy and degeneration of the renal tubular
    epithelia were observed histologically (Srinivasan et al., 1984). In
    young male Wistar rats administered gamma-HCH at 800 mg/kg diet for
    two weeks, liver weights were increased, but no difference was found
    in moisture, nitrogen, protein, or glycogen levels. The fat and DNA
    content of the liver were found to be increased, but the DNA content
    per unit issue was decreased. The predominant change in the liver
    was hypertrophy. Testicular weight was no different from that in
    control animals, but the protein content was higher, and the DNA
    content was lower. The histological changes observed were tubular
    atrophy and spermatogenic arrest; the interstitial space was found
    to be oedematous (Srinivasan et al., 1988).

         Liver function was studied in male Wistar rats fed a control
    diet (6-8 rats) or gamma-HCH at 800 mg/kg diet (8-12 rats).
    Gamma-HCH produced noticeable hepatocellular effects, as indicated
    by increased activity of serum aminotransferases, hepatic
    glucose-6-phosphate dehydrogenase and aldolase and decreased
    activity of liver glucose-6-phosphatase. Liver mitochondrial
    dinitrophenol/Mg++/Ca++-activated ATPase activity was decreased,
    and levels of microsomal Na+, K+-ATPases were lower in treated
    than control animals (Srinivasan & Radhakrishnamurty, 1988).

         In a preliminary study, 24 Fischer-344 weanling, female rats,
    received daily oral doses of either arachis oil or lindane at 0.069
    mmol/kg body weight for 189 days. Lindane induced a significant

    increase in body weight after 112 days of treatment. In a subsequent
    dose-response study, female Fischer-344 rats, 21 days of age, were
    gavaged daily with arachis oil (six rats) or lindane at 5 (six
    rats), 10(eight rats), 20 (12 rats), or 40 mg/kg body weight (12
    rats). At 20 mg/kg, lindane induced an increase in body weight after
    10 weeks of treatment. At 40 mg/kg, 7 out of the 12 rats died; the
    other animals had increased body weight gain. Greater food
    consumption was observed, and obesity was induced, as indicated by
    the Lee index. In addition, lindane caused delay in vaginal opening,
    disrupted oestrous cycling, reduced pituitary and uterine weights
    and elevated food consumption during pro-oestrous. This response
    suggests that, by inducing alterations in the reproductive function
    of female rats and by interfering with hormonal regulation of the
    energy balance, lindane may be anti-oestrogenic rather than
    oestrogenic as previously proposed (Chadwick et al., 1988).

    7.2.1.3  Dog

         Lehman (1952) found a high mortality rate in dogs given lindane
    at daily doses of 10 or 15 mg/kg body weight on five days per week
    over a period of 2 to 221 days. (No details available). Lehman
    (1965) reported a study initially conducted by Fitzhugh et al., in
    which dogs (two males and two females per group) were exposed to
    lindane at 0 or 15 ppm (equivalent to approximately 0.6 mg/kg body
    weight) in the diet for a total of 63 weeks. No effect was observed
    on mortality, organ weights, body weight gain, haematological
    parameters, or histological appearance.

         During a two-year toxicity study, groups of four male and four
    female beagle dogs were fed lindane (99%) at 0, 25, 50, or 100 mg/kg
    diet. The amounts of lindane that were actually ingested were 0.83,
    1.60, and 2.92 mg/kg body weight per day. Convulsions seen
    occasionally in control and low-dose animals were not related to the
    treatment. No treatment-related change was observed in body weight,
    food or water consumption, ophthalmological parameters,
    electroencephalographic traces, results of haematological
    examinations, urinalysis, and liver function tests, or organ
    weights. At autopsy, somewhat darker colouration and a brittle
    consistency of the liver were seen at 100 mg/kg. In addition,
    alkaline phosphatase activity was increased in the highest dose
    group. No treatment-related abnormality was apparent with 25 or 50
    mg/kg diet.

         A supplementary group of four male and four female dogs was
    administered lindane at 200 mg/kg diet for 32 weeks. High-voltage
    slow-wave activity changes, possibly indicative of nonspecific
    neuronal irritation, were recorded in electroencephalographic
    tracings at this dose level. No such effect was observed in the
    two-year study at 100 mg/kg diet (Rivett et al., 1978).

    7.2.1.4  Pig

         Schnell (1965) fed diets containing lindane (99.5%) at 0, 5,
    10, 20, 40, or 80 mg/kg diet to groups of five pigs over a period of
    nine months. No clinical symptom was seen in any animal during the
    test period. Food and water intake remained normal, and
    haematological investigations and histopathological examination of
    the liver, spleen, kidneys, adrenals, heart, and brain revealed no
    substance-related change, even at the highest dose level tested.

    7.2.2  Inhalation

    7.2.2.1  Mouse

         Balaschow (1964) exposed mice for 6 h/day to a lindane aerosol
    containing a nominal concentration of 1 mg/m3 for 2.5 months.
    During the first two weeks, white blood cell counts showed the
    presence of leukocytosis, with a shift to the left; from the end of
    the first month, leukopenia with a shift to the right was observed,
    and toxic granulations and vacuoles appeared in the nuclei and
    cytoplasm of some leukocytes. Later, a reduced mitotic rate was
    observed. The relationship between the different cell types in the
    bone marrow was undisturbed.

         Four groups of 45 male and 45 female CD-1 (Charles River) mice
    were exposed by whole-body inhalation to aerosols (geometric mean
    particle diameter, about 3 µm) containing lindane (purity at least
    99.6%) at 0, 0.3, 1.0, or 5-10 g/m3 for 6 h/day, on five days per
    week for 14 weeks. The test dose levels were selected on the basis
    of a preliminary range-finding study, which showed that males did
    not develop major signs of toxicity after five exposures for 6 h/day
    to lindane at 1.0 and 10.0 mg/m3. During the main study, however,
    an unexpectedly high mortality rate was seen in females exposed to
    10 mg/m3; after the first five exposures, therefore, the
    concentration for the high-dose group was lowered to 5 mg/m3.
    Subgroups of 15 mice of each sex in each group were sacrificed after
    7, 14, and 20 weeks. The group sacrificed at 20 weeks was a recovery
    group, which was not exposed to lindane after exposure week 14. Ten
    of the 15 mice in each subset were used for pathological evaluation,
    and the remaining five were examined for serum lindane levels. The
    lindane aerosol was highly toxic to female mice at 5 mg/m3, and
    probably also at 1 mg/m3. The no-observed-effect level was
    concluded to be 0.3 mg/m3 (Klonne & Kintigh, 1988).

    7.2.2.2  Rat

         Groups of 12 male and 12 female Wistar Han/Boe SPF rats were
    exposed by whole-body inhalation to lindane (99.9%) at nominal
    concentrations of 0, 0.02, 0.12, 0.6, or 4.5 mg/m3 (average
    particle size, 0.92 µm) for 6 h/day for three months. The two groups
    that received 0 or 4.54 mg/m3 were used to investigate recovery.

    Slight diarrhoea and ruffled fur were observed temporarily in the
    high-dose animals only. Measurements of body and organ weights and
    of food and water intake, clinical chemistry, and histopathology
    showed no treatment-related change. Hepatic cytochrome P-450 values
    were increased at the end of the exposure period in animals at the
    highest dose, but all values returned to that of the control during
    the six-week recovery period. Increased kidney weights and cloudy
    swelling of the tubular epithelium were observed especially in males
    at the two highest dose levels, but, again, all values were
    comparable with those in controls at the end of the recovery period.
    The no-effect-level was probably 0.6 mg/m3 (Oldiges et al., 1983).

    7.2.3  Dermal

         Four groups of 49 male and 49 female Charles River rats (Crt:
    (WI)BR strain) were exposed dermally to lindane (purity at least
    99.5%) at dose levels of 0, 10, 60, or 400 mg/kg per day, selected
    on the basis of a preliminary range-finding study, on five
    consecutive days per week. The test substance was applied as a
    suspension in aqueous carboxymethyl cellulose at a constant volume
    of 4 ml/kg to a clipped area of the skin on the dorsal area and was
    retained for 6 h with a dressing consisting of a gauze pad
    heat-welded to plastic-backed aluminium foil. In the main phase of
    the study, 23 animals of each sex in each group were treated for 13
    weeks before sacrifice; one group of 13 animals/sex were sacrificed
    after 6 weeks of treatment; a third (recovery phase) group,
    consisting of 13 animals of each sex, was retained in the study for
    an additional six weeks. At sacrifice, three animals in each group
    were selected for determination of tissue levels of lindane (Brown,
    1988).

         The toxic effects induced by subchronic dermal exposure to 60
    and 400 mg/kg consisted of pathological lesions of the kidneys in
    males (increased organ weight, hyaline droplet formation, tubular
    degeneration with necrosis, basophilic tubules, casts) and
    hypertrophy of the liver in males and females. Whereas the effects
    on the liver were reversible, some of the histopathological changes
    in the kidneys persisted (tubular degeneration with necrosis,
    granular casts) after the recovery period. Although there was
    evidence of increased intensity of hyaline droplet formation at the
    lowest dose tested (10 mg/kg per day), this effect was very slight;
    that level could therefore be considered to be the
    no-observed-effect level. The use in this study of semi-quantitative
    methods for determination of blood levels, protein, and turbidity
    makes it difficult to come to any definite conclusion; however, the
    results of the urinalysis did not provide evidence that lindane
    adversely affects kidney function.

    7.3  Skin and eye irritation; sensitization

    7.3.1  Primary skin irritation

         Application of 0.5 g of lindane to the intact skin of New
    Zealand white rabbits, in a study performed in compliance with the
    guidelines of the Organization for Economic Co-operation and
    Development and the US Environmental Protection Agency, did not
    cause irritation (Ullmann et al., 1986a).

    7.3.2  Primary eye irritation

         Lindane placed in the conjunctival sac of the left eye of New
    Zealand white rabbits at 0.1 g was slightly irritating (Ullmann et
    al., 1986b).

    7.3.3  Sensitization

         The allergic potential of lindane was tested in a
    Magnusson-Kligman maximization test (according to the guidelines of
    the Organization for Economic Co-operation and Development) on
    Durkin-Hartley albino guinea-pigs. Ten males and ten females
    received lindane (99.6%) and five males and five females received
    the vehicle, ethanol. No difference was seen between the test group
    and the controls after the first and second challenge application 24
    and 48 h later, and it was concluded that lindane has no skin
    sensitizing (contact allergenic) potential in these guinea-pigs
    (Ullmann et al., 1986b).

         Ullmann et al. (1987a) conducted a further maximization test
    (following the guidelines of the Organization for Economic
    Co-operation and Development) with Dunkin-Hartley albino guinea-pigs
    to test the contact hypersensitization potential of a lindane
    formulation. Ten males and ten females received intradermal
    injections of 5% 'Nexit fluessig' (containing 25.9% lindane) in
    saline, and five males and five females received the saline vehicle.
    No sensitization reaction was observed after the first and second
    challenge application, 24 and 48 h later.

         Comparable experiments were carried out with two other
    formulations, 'Nexit stark', a powder containing 78.9% lindane
    (Ullmann et al., 1987b), and 'Agronex Saatgutpuder', a powder
    containing 20.1% (Ullmann et al., 1987c). Each was administered as
    intradermal injections of 0.1% in saline. No sensitization reaction
    was observed after two challenge reactions 24 and 48 h later.

    7.4  Long-term exposure

    7.4.1  Oral

         In two long-term studies, lindane powder was mixed into the
    diet of Wistar rats (10 males and 10 females) at 10, 100, or 800
    mg/kg diet and as an oily solution at 5, 10, 50, 100, 400, 800, or
    1600 mg/kg diet, either as the gamma isomer or as technical HCH
    (containing only 13% of the gamma isomer). Two control groups were
    used. At 100 mg/kg diet, liver weight was increased, and
    histopathological examination revealed hepatocellular hypertrophy,
    fatty degeneration and necrosis as well as nephritic reactions
    (granular degeneration and calcification in male rats). These
    findings were more pronounced at the 400, 800, and 1600 mg/kg
    dietary levels. At these concentrations, the life span of animals in
    groups treated with the oily solution was shortened by 20-40%. The
    no-effect level in this experiment was 50 mg/kg diet (Fitzhugh et
    al., 1950; Lehman, 1952).

         Similar results were obtained in another lifetime study, in
    which groups of 10 male and 10 female rats received lindane at 25,
    50, or 100 mg/kg diet. The dose of 25 mg/kg had no effect on the
    liver, but hepatocellular hypertrophy was observed with 50 mg/kg and
    slight fatty liver-cell degeneration was described in the group
    receiving 100 mg/kg diet (Truhaut, 1954).

    7.4.2  Appraisal of acute and short- and long-term studies

         The acute oral toxicity (LD50) of lindane in different
    species, depending on the vehicle used, ranges from 56 to 480 mg/kg
    body weight. Preparations in oil were more toxic than aqueous
    solutions or suspensions. The ranges for rats and mice were similar
    (88-270 and 56-246 mg/kg, respectively). The dermal LD50 for rats
    is approximately 900 mg/kg body weight, but smaller amounts (60
    mg/kg as a 1% cream) caused convulsions, anorexia, and deaths in
    weanling rabbits. No skin irritation or sensitization was observed,
    and eye irritation was slight.

         Although older, long-term studies in the rat suggest a
    no-observed-adverse-effect level of 25 mg/kg diet, contemporary
    short-term studies in rats indicate that this level is10 mg/kg diet,
    equivalent to 0.75 mg/kg body weight on the basis of increased
    hepatic, renal, and thyroid weights, increased cytochrome P-450
    activity and histopathological findings in liver and kidneys.

    7.5  Reproduction, embryotoxicity, and teratogenicity

    7.5.1  Reproduction

         Trifonova et al. (1970) found no reduction in the fertilization
    rate of female rats after oral treatment for 90 days with lindane at
    approximately 5 mg/kg body weight. When the dose was doubled over a
    test period of 138 days, the fertilization rate was reduced.
    (Details not given.)

         A three-generation test was carried out in which 10 male and 10
    female CD-rats were administered lindane at concentrations of 25,
    50, or 100 mg/kg diet continuously. The treatment had no influence
    on fertility, litter size, breeding rate, weight of newborn animals,
    lactation, malformation rate, or maturation. The liver weights of
    young animals of the F3b generation were increased, especially
    among females. Histopathological examination of the liver showed
    enlarged hepatocytes and vacuolization in animals treated with 50
    and 100 mg/kg diet (Palmer et al., 1978a).

    7.5.2  Embryotoxicity and teratogenicity

    7.5.2.1  Oral administration

          Mouse: Lindane was administered orally to seven groups of 25
    pregnant NMRI-EMD (SPF) female mice at 0, 12, 30, or 60 mg/kg body
    weight in 0.5% carboxymethyl cellulose, on either days 6-15 or days
    11-12 of pregnancy. In the group receiving the highest dose, fetal
    mortality was increased and fetal weights were decreased. A slight,
    non-dose-related increase in malformation rate was found in the
    mid-dose group (4.2%, as compared to 1.9% in controls). At the
    highest dose, increased maternal mortality (48%) and reduced body
    weight gain were observed. The treatment had no effect on the number
    of implantations per dam, the percentages of early and late
    resorptions, the number of runts or the malformation rate (Frohberg
    & Bauer, 1972b).

          Rat: Groups of 20 female CFY-rats received lindane at 5, 10,
    or 20 mg/kg body weight by gavage during days 6-15 of pregnancy. In
    the groups given 10 and 20 mg/kg, maternal toxicity (reduced food
    intake and reduced weight gain) was observed, and two female rats
    given 20 mg/kg died. At the same dose, there was a dose-related
    increase in the incidence of offspring with extra (14th) ribs, which
    was statistically significant. Other anomalies and litter parameters
    were comparable to those in the controls, and there was no evidence
    of embryo- or fetoxicity (Palmer et al., 1978b).

         Khera et al. (1979) gave female Wistar rats (20 animals per
    group) a lindane formulation (50% in corn oil) at 3.12, 6.25, or
    12.5 mg/kg body weight (expressed as 100% lindane) by intubation on
    days 6-15 of gestation. No effect was seen on the number of living

    fetuses per litter, the number of dead plus resorbed fetuses or mean
    fetal weight at 22 days of gestation. No malformation other than the
    usual range of developmental variants was observed in any group. A
    slight increase in the frequency of anomalies of the ribs and
    reduced cranial ossification were seen in the fetuses exposed to
    6.25 mg/kg; these effects were confined to two litters and were
    probably not dose-related.

         Female rats that received lindane orally at a dose of 25 mg/kg
    body weight daily during pregnancy had higher post-implantation
    embryonal mortality than aontrols, and at 12.5 mg/kg, no mortality
    was found. Neither dose level induced teratological abnormalities
    (Mametkuliev, 1976; see International Register for Potentially Toxic
    Chemicals, 1983).

          Rabbit: Lindane was administered by intragastric intubation
    to New Zealand white rabbits (13 animals per group) on days 6-18 of
    gestation at doses of 5, 10, and 20 mg/kg body weight. All treated
    animals showed slight tachypnoea and lethargy during the treatment
    period, and body weight gain and food intake were reduced.
    Pre-implantation loss was significantly higher in the group given 20
    mg/kg, but, as treatment did not start until day 6 of gestation,
    this effect is unlikely to have been due to lindane.
    Post-implantation loss and the incidence of resorptions were
    increased at 5 and 20 mg/kg. The number of offspring with extra
    (13th) ribs was significantly lower in animals given 5 mg/kg and
    significantly higher in rabbits at 20 mg/kg than in controls. Fetal
    and litter weights were unaffected, and the incidence of other
    anomalies was similar to that in controls (Palmer et al., 1978b).

          Dog: An increased frequency of stillbirths, unrelated to
    dosage or period of administration, was seen in beagle dogs fed
    lindane at 0 (five dogs), 7.5 (13 dogs) or 15 mg/kg body weight (14
    dogs) from day 1 or 5 throughout gestation. No significant
    teratogenic effect was observed. The number of living pups was
    similar in control and test groups (Earl et al., 1973).

          Pig: Groups of six female pigs received lindane at 0, 50, or
    500 mg/kg diet from 30 days prior to mating until day 30 of
    gestation. No treatment-related effect was found on number of
    embryos, embryo weight, or rate of ovulation (Duee et al., 1975).

          Cow: In an accidental poisoning incident, four pregnant cows
    received lindane at 13.4 g (28 mg/kg body weight) 6-17 weeks
    pre-partum. All had convulsions and muscular tremors in the ensuing
    48 h but recovered with veterinary treatment. All calved on time and
    produced normal, healthy calves. Four non-pregnant cows died after
    receiving 21 g of lindane, which suggests that the minimum lethal
    dose is 28-45 mg/kg body weight (McParland et al., 1973).

    7.5.2.2  Subcutaneous injection

          Mouse: Lindane was administered subcutaneously (in a 0.5%
    carboxymethyl cellulose solution) to groups of 25 pregnant NMRI
    miceat 6 mg/kg body weight on either days 11-13 or days 6-15 of
    pregnancy. Except for a slight increase in the frequency of runts in
    the latter group, no effect was seen on the number of implantations
    or of living embryos per dam or on the percentage of absorptions or
    resorptions; no treatment-related malformation was reported
    (Frohberg & Bauer, 1972a).

          Rat: Groups of 20 Sprague-Dawley rats received lindane at
    doses of 0, 5, 15, or 30 mg/kg body weight by subcutaneous injection
    on days 6-15 of gestation. Maternal toxicity was observed in the
    mid- and high-dose groups. No effect attributable to the
    administration of lindane was noted on pregnancy rates, maternal
    gross pathology or reproduction, or offspring viability and
    development. No teratogenic effect was found at necropsy or in
    visceral and skeletal examinations (Reno, 1976a; Hazelton
    Laboratories, 1976a).

          Rabbit: Lindane was injected subcutaneously at 0, 5, 15, 30
    or 45 mg/kg body weight into pregnant rabbits on days 6-18 of
    pregnancy, except that the highest dose was given on days 6-9 and
    then reduced to 30 mg/kg body weight. No embryotoxic or teratogenic
    effect was found in fetuses exposed to the two lower doses. At the
    two higher dose levels, increased maternal toxicity was found. At
    the highest dose, the number of resorptions was increased, and 14
    out of 15 animals died (Reno, 1976b; Hazelton Laboratories, 1976b).

    7.5.3  Reproductive behaviour

         Adult female Fischer (CDF-344) rats were injected
    intraperitoneally on the morning of pro-oestrus with lindane at 25,
    33, 50, or 75 mg/kg body weight in sesame oil, and in the evening,
    they were examined for lordosis behaviour with a sexually
    experienced male. A dose-dependent reduction in sexual receptivity
    was seen with increasing doses of lindane: treated animals required
    a greater number of mounts before the first lordosis response was
    observed, and they may have required more sensory stimulation to
    elicit the lordosis reflex. Most of the females also failed to
    exhibit proceptive behaviour (darting and hopping) during the mating
    test. This inhibition resembles the rapid effects of another
    chlorinated pesticide, chlordecone, and does not appear to depend
    upon disruption by lindane of the inhibition of the central nervous
    system by gamma-aminobutyric acid (GABA). The results substantiate
    previous suggestions that the ability of chlorinated pesticides to
    interfere with intracellular oestradiol receptors cannot explain
    their rapid attenuation of reproductive behaviour (Uphouse, 1987).

    7.5.4  Appraisal of reproductive toxicology

         Lindane was investigated in tests covering all aspects of
    reproduction (three-generation studies in rats) and in tests for
    embryotoxicity and teratogenicity by oral, subcutaneous and
    intraperitoneal administration in mice, rats, dogs, and pigs).

         Lindane did not exhibit teratogenic properties after oral or
    parenteral application (extra ribs were regarded as variations).
    Fetal and/or maternal toxic effects were observed in rats with doses
    of 10 mg/kg body weight and higher given by oral gavage; 5 mg/kg is
    therefore considered to be the NOAEL.

         No effect on reproduction or maturation was seen in the
    three-generation study at doses of lindane up to 100 mg/kg diet, but
    morphological signs suggesting liver enzyme induction occurred with
    doses from 50 mg/kg diet in the third generation. The no-effect
    level in this test was 25 mg/kg diet (equivalent to approximately
    1.25 mg/kg body weight).

    7.6  Mutagenicity and related end-points

         Lindane was tested in mutagenicity tests with a variety of
    end-points. The relevant experiments are summarized in Tables 9, 10,
    and 11. Those studies that were not performed according to protocols
    which comply to the present international standards are considered
    to be of limited relevance; some studies used lindane preparations
    of less than 99% purity or of unknown purity. The results are so
    consistent, however, that the limitations of some studies did not
    vitiate a final assessment.

    7.6.1  DNA damage

         The ability of lindane to damage DNA was tested in  Bacillus
     subtilis and in  Escherichia coli WP2 in the  rec assay, and
    tests for unscheduled DNA synthesis tests were performed in primary
    rat hepatocytes and human fibroblasts. No mutagenic potential was
    detected.

         Sina et al. (1983) developed a sensitive alkaline elution assay
    in non-radiolabelled rat hepatocytes to measure DNA single-strand
    breaks induced by chemicals. This assay is used to predict
    carcinogenic/mutagenic activity. Lindane at doses of 0.03 and 0.3
    mmol/litre induced DNA damage, increasing with dose.

         After oral administration of lindane to rats and mice, a very
    low covalent binding index (0.02-0.01) was calculated, suggesting
    that no significant binding to DNA had occurred.

         The incorporation of orally admini stered radiolabelled
    thymidine into liver DNA was determined in SIV-50-SD-rats 24 h after

    a single oral dose by gavage of 0.01, 0.1, or 1.0 mmol/kg gamma-HCH.
    No effect on liver DNA synthesis was seen (Büsser & Lutz, 1987).

    7.6.2  Mutation

         The ability of lindane to induce gene mutation has been
    investigated extensively in  S. typhimurium and  E. coli, using an
    adequate range of strains to cover both base-pair and frame-shift
    mutations. Most of the tests were performed both with and without
    metabolic activation by 9000 x g preparations from the livers of
    induced rats or mice (Table 9).

         Negative reults were obtained in the host-mediated assay using
    mice and  S. typhimurium or  Serratia marescens. Furthermore, a
    test for point mutations in V79 Chinese hamster cells, the  hprt
    test for forward mutations, indicated no mutagenic effect of
    lindane. A test for sex-linked recessive lethal mutation in
     Drosophila melanogaster also gave a negative result (Table 9).

          D. melanogaster were also used to test for dominant lethal
    mutation. Groups of 25 males and 25 females aged 6-24 h were
    transferred to food containing HCH (Gammexane) at 20 mg/kg food
    medium, and their progeny were raised on this food. Five males and
    five females of the F1 generation (the 'toxic generation') were
    raised on normal food and were allowed to mate with each other and
    lay eggs for 24 h in 10 oviposition jars. From this generation of
    flies, three successive mutation-generations were raised on normal
    food, and the numbers of larvae hatched from eggs laid on each of
    the first 10 days after enclosion were again recorded. The
    percentage of larvae hatched from the total number of eggs laid,
    cumulated over the entire period was significantly decreased in the
    second and third generations. These results suggest that the
    preparation tested is mutagenic (Sinha & Sinha, 1983).

         A test for induction of reverse mutations in  Saccharomyces
     cerevisiae gave inconclusive results.

    7.6.3  Chromosomal effects

         Most of the cytogenetic tests performed with lindane both  in
     vivo and  in vitro did not indicate mutagenic properties of
    lindane. In only une study were there positive findings, but the
    purity of the material tested was not given and the description of
    the test was poor. Lindane therefore apparently does not induce
    chromosomal breakage (Table 10).

    
    Table 9.  Result of mutagenicity tests of gamma-HCH
                                                                                                                                     
    Test system                   Dose                      Type of test   Metabolic   Result      Reference
    (Organisms/Cells)                                                                  activation
                                                                                                                                     
    Bacillus subtilis 
       H17 rec+                   0.02 ml of solution       plate          none            -       Shirasu et al. (1976)
       M45 rec-                     containing 1 mg/ml      plate          none            -
                                    in DMSO

    Escherichia coli 
       WP2 try-                   approx. 1 mg              plate          none            -       Ashwood-Smith et al. (1972)

       WP2                        4 gradient plates,        plate          S9-mix          -       Probst et al. (1981)
       WP2 uvr A-                    covering 10 000-fold   plate          S9-mix          -
                                     concentration range

       WP2 urv A                  6-7 dose levels up to     plate          none            -       Oesch (1980)
                                     5000 µg                S9-mix         -

    Salmonella typhimurium
       TA98, TA100, TA1535,       1-1000 µg                 plate          S9-mix          -       van Dijck & van de Voorde
       TA1537, TA1538,                                                                             (1976)
       TA1950, TA1978

       TA98, TA100,               93, 139, 208 µg           plate          none            -       Röhrborn (1977a)
       TA1535, TA1538

       TA100, TA1535,             6-7 dose levels up to     plate          none            -       Oesch (1980)
       TA1537, TA98                  5000 µg                plate          S9-mix          -

       TA100, TA1535,             8 dose levels, 0 up to    plate          none            -       Haworth et al. (1983)
       TA1537, TA98                  333 µg                                S9-mix          -

    Table 9 (contd)
                                                                                                                                     
    Test system                   Dose                      Type of test   Metabolic   Result      Reference
    (Organisms/Cells)                                                                  activation
                                                                                                                                     
    Salmonella typhimurium contd)

       TA100, TA1535,             4, 20, 100, 500, or       plate          S9              -       Anderson & Styles (1978)
       TA1538, TA98                  2500 µg in DMSO

       G46, TA98, TA100,          concentration gradient    plate          S9-mix          -       Probst et al. (1981)
       TA1537, TA1538,
       C3076, TA1535, D3052

    Host-mediated assay
    Salmonella typhimurium G46    25 mg/kg bw               mouse          nr              -       Buselmaier et al. (1972)
                                  (subcutaneous)            (NMRI)

    Serratia marescens            25 mg/kg bw               mouse          nr              -       Buselmaier et al. (1972)
       a 21. leu-                 (subcutaneous)            (NMRI)

    Mammalian cells
    hprt locus
    V79 Chinese hamster cells     0.5-500 µg/ml             plate          S9-mix          -       Glatt & Oesch (1984);
                                  0.5-250 µg/ml             plate          S9-mix          -       Oesch & Glatt (1984)

    Sex-linked recessive
    lethal test
    Drosophila melanogaster       0.001%                    injected       nr              -       Benes & Sram (1969)
                                  (aqueous sol.)            into
                                                            abdomen
                                                            (0.2 µl)
                                                                                                                                     
    DMSO, dimethyl sulfoxide; nr, not relevant; bw, body weight

    Table 10.  Results of tests for other genetic effects
                                                                                                                                     
    End-point                              Dose                        Effects                    Result       Reference
                                                                                                                                     
    Chromosomal aberrations in vitro
    Chinese hamster fibroblast cell line   2.1 mg/mla (in ethanol)     Chromatid gaps, chromatid  Equivocal    Ishidate & Odashima
      (CHL)                                                              and chromosomal breaks                (1977)

    Lymphocytes from human peripheral      0.1, 0.5, 1.0, 5.0, or      Chromosomal breakage       Equivocal b   Tzoneva-Maneva et al.
      blood (different donors)               10 µg/ml                    only at toxic dosages                 (1971)
                                                                         (5 and 10 µg/ml)

    Chromosomal aberrations in vivo
    Chinese hamster bone-marrow cells      0.125, 1.25, or 12.5 mg/kg  Increase in chromosomal    (-)          Röhrborn (1976, 1977a)
                                             body weight orally for      gaps at highest dose
                                             5 days                      level

    Syrian hamster bone-marrow cells       64, 128, 280, or 640 mg/kg  No chromosomal              -           Dzwonkowska & Hubner
                                             body weight                 aberration                            (1986)

    Rat bone-marrow  cells                 1.5, 7.0, or 15 mg/kg               -                   -           Gencik (1977)
                                             body weight orally for
                                             12 weeks

    Human lymphocytes                      occupational exposure                                   -           Desi (1972)
                                             (no further details)

    Sister chromatid exchange in vivo      
    Mouse bone-marrow cells (strain CF1)   Male/female: 2/1.6, 10/8, or
                                             50/40 mg/kg body weight           -                   -           Guenard et al. (1984a)
                                             as a single oral
                                             application
  
    Mouse bone-marrow cells                Single intraperitoneal              -                   -           Guenard et al. (1984b)
    (strain CF1)                             injection of 1.3, 6.4, or
                                             32.1 mg/kg body weight

    Table 10 (contd)
                                                                                                                                     
    End-point                              Dose                        Effects                    Result       Reference
                                                                                                                                     
    Micronucleus test in vivo
    Mouse erythroblasts (CBA male mice)    75 mg/kg body weight                -                   -           Jenssen & Ramel (1980)

    Dominant lethal test
    Rats (males; strain Chbb = THOM)       1.5, 7.0, or 15 mg/kg body                                          Röhrborn (1977b)
                                             weight daily for 8 weeks
                                             orally (in olive oil)c

    Rat (males; strain Wistar)             1.5, 7.0, or 15 mg/kg body                           Questionable   Cerey et al. (1975)
                                             weight in olive oil                                  positiveb

    Mouse (males; strain ICR/Ha Swiss)     15, 75, 200, or 1000 mg/kg          -                     -         Epstein et al. (1972)
                                             body weight once
                                             intraperitoneally
                                           15 mg/kg body weight                -                  Equivocal    Epstein et al. (1972)
                                             five times, orally

    Mouse (males; strain NMRI-EMD)         Single intraperitoneal              -                     -         Frohberg & Bauer (1972c)
                                             injection of 12.5, 25, or
                                             50 mg/kg body weight

    a Maximal effective dose
    b Inadequate study; protocol does not comply with international standards
    c Males dosed continuously during the whole mating period (8 weeks)

    Table 11.  Results of tests for DNA damage
                                                                                                                                     
    End-point                         Dose                     Type of test       Metabolic    Result       Reference
                                                                                  activation
                                                                                                                                     
    Unscheduled DNA synthesis
      (transformed SV-40) human       1, 1000 µM (in acetone)  Tissue culture     None            -         Ahmed et al. (1977)
      fibroblast (cell-line VA-4)                                fluid                         S9-mix           -

    Unscheduled DNA synthesis and     500 µg/ml                Tissue culture        -         50-70%       Rocchi et al. (1980)
      repair capacity after damage                                                             inhibition
      by UV-rays (human lymphocytes)

    Primary rat hepatocytes           100 nmol/ml              Plate                 -            -         Probst et al. (1981)
                                        (in DMSO)

    Covalent DNA binding
    Male mouse (strain NMRI, CF1      12-13 mg/kg body         Liver DNA          Not relevant    -         Sagelsdorff et al. (1983)
      and C6B3F1)                       weight orally and 8.7                                  (covalent
                                        up to 23 mg/kg body                                    binding
                                        weight orally                                          index,
                                                                                               0.02-0.1)

    
         Lindane was tested for its ability to induce sister chromatid
    exchange  in vivo (in mice by oral and intraperitoneal
    administration) and  in vitro (in Chinese hamster ovary cells); no
    effect was seen. No mutagenic effect was observed in a test for
    micronucleus formation in the bone marrow of mice treated  in vivo,
    and lindane did not induce chromosomal damage  in vivo.

         Two of three tests for induction of dominant lethal mutation in
    rats gave clearly negative results, and the other gave a
    questionably positive response. The significance of the latter test
    must be regarded as low, because the purity of the material tested
    was not given and the test was not performed in compliance with an
    acceptable standard.

    7.6.4  Miscellaneous tests

         Lindane tested in a MO4 cell culture at doses of 1, 10, and
    100 µg/ml induced no multinucleation or major toxicity (de Brabander
    et al., 1976).

         Lindane at a concentration of 101.8 µg/ml did not induce
    6-thioguanine-resistant mutations in Chinese hamster V79 cells.
    Concentrations of 100 and 200 µg/ml were significantly cytotoxic;
    the concentration that allowed 10% survival was 120 µg/ml. At 11.6
    µg/ml, lindane weakly inhibited metabolic cooperation between 6-TGs
    and 6-TGr V79 cells. It was concluded from these studies that
    lindane is not mutagenic in this test system; however, it inhibits
    metabolic cooperation, mimicking the powerful tumour promotor
    12- O-tetradecanoylphorbol 13-acetate in this assay system
    (Tsushimoto et al., 1983).

         The morphology of primary monkey kidney cells was examined 24 h
    after addition of lindane (99.8% in 1% dimethylformamide) to the
    growth medium, and readings were made daily for three days. Lindane
    applied at concentrations above 10 mg/litre induced marked cellular
    damage, and 250 mg/litre had cytotoxic effects (Desi et al., 1977).

    7.6.5  Appraisal of mutagenicity and related end-points

         The mutagenicity of lindane has been adequately studied. This
    compound has been extensively investigated for its ability to induce
    gene mutation in both bacteria and mammalian cells, and for its
    activity in the assay for sex-linked recessive lethal mutation in
     D. melanogaster. Negative results were obtained consistently. Its
    ability to induce chromosomal damage and sister chromatid exchange
    has been investigated in mammalian cells both  in vitro and  in
     vivo, again with negative results. Both assays for DNA damage in
    bacteria and studies  in vivo to investigate covalent binding to
    DNA in the liver of rats and mice following oral administration also
    gave negative results. The few studies in which positive results

    were obtained involved invalid study designs or lindane of unknown
    purity.

         Overall, lindane appears not to have mutagenic potential.

    7.7  Carcinogenicity

    7.7.1  Mouse

         Gamma-HCH was fed to 20 male ICR/JCL mice (five weeks old) at
    300 or 600 mg/kg diet for 26 weeks. Increased liver weights were
    reported in the group receiving the higher dose. Five of 10 mice in
    this dose group had type 0 or type I liver lesions. Type 0 lesions
    were characterized as areas of atypical, small liver cells, uniform
    in size and with a small nucleus, which normally forms round spots
    and is readily distinguishable from the surrounding liver tissue.
    Type I lesions were described as 'benign liver tumours' (Goto et
    al., 1972).

         Groups of 20 male mice (eight weeks old) were fed gamma-HCH at
    100, 250, or 500 mg/kg diet for 24 weeks. The highest dose level
    resulted in increased liver weight. No nodular hyperplasia or
    hepatocellular tumour was observed (Ito et al., 1973b).

         Hanada et al. (1973) treated 10-11 dd mice of each sex with
    lindane at 100, 300, or 600 mg/kg diet for 32 weeks and killed the
    survivors 5-6 weeks after the end of exposure. Hepatomas were found
    in 1/3 females and 3/4 males that ingested 600 mg/kg diet and
    survived for 36-38 weeks; none were found in animals fed 100 or 300
    mg/kg diet. At the two higher doses, most animals had atypical
    proliferations in the liver. alpha-Fetoprotein could not be
    identified in the serum of the animals with hepatomas.

         In an experiment lasting 110 weeks, 30 male and 30 female CF1
    mice were fed lindane (> 99.5%) at 400 mg/kg diet. A group of
    controls comprising 45 male and 44 female mice were fed a standard
    diet. Benign and malignant liver tumours were diagnosed in 24% of
    male controls and 23% of female controls and 93% of treated males
    and 69% of treated females. Significant mortality (15%) occurred
    during the early phase of the study in the treated group (Thorpe &
    Walker, 1973). In a complete reexamination of all slides, the
    reviewer concluded that lindane had not affected the incidence of
    hepatocellular carcinomas inanimals of either sex but had enhanced
    the incidence of hepatocellular adenoma (and hyperplastic nodules)
    in male mice. In this strain, therefore, lindane had a tumorigenic
    effect only in male mice (Vesselinovitch & Carlborg, 1983).

         Herbst et al. (1975) and Weisse & Herbst (1977) studied the
    carcinogenic potential of lindane at 12.5, 25, or 50 mg/kg diet
    administered for 80 weeks to 50 male and 50 female Chbi:NMRI mice (a
    strain with a low (2%) spontaneous rate of hepatomas). The control

    group consisted of 100 males and 100 females. No evidence of
    substance-related tumour formation was seen in animals of either sex
    at any dose level. Electron microscopic examination showed no fine
    structural hepatocellular alterations.

         Groups of 50 B6C3F1 hybrid mice of each sex were fed lindane
    at 80 or 160 mg/kg diet for 80 weeks and were killed 10-11 weeks
    after the end of treatment. Hepatocellular carcinomas were found in
    5/49 pooled male controls, 2/10 matched male controls, 19/49 males
    fed 80 mg/kg diet and 9/46 males fed 160 mg/kg diet, and in 2/47
    pooled female controls, no matched female controls, 2/47 females fed
    80 mg/kg diet, and 3/46 females fed 160 mg/kg diet. Only the
    incidence of hepatocellular carcinomas in the males at the lower
    dose was significantly different from that in controls. It was
    concluded that lindane is not carcinogenic in this test system (US
    National Cancer Institute, 1977). In a reexamination of the slides,
    the reviewer was in full agreement with the conclusions of the
    original authors (Vesselinovitch & Carlborg, 1983).

         Wolff & Morrissey (1986) administered diets containing lindane
    at 160 mg/kg diet for 24 months to three phenotypes of (YS x VY)
    F1 hybrid mice: obese yellow Avy/a, lean pseudoagouti Avy/a, and
    lean black a/a. Hepatocellular adenomas were found in 35% of yellow
    A vy/a mice (9% in controls) and in 12% of pseudoagouti Avy/a mice
    (5% in controls); no increase in the incidence of liver tumours was
    seen in the black a/a mice.

    7.7.2  Rat

         Groups of 10 male and 10 female Wistar rats were fed for life
    on diets containing 10, 100, or 800 mg/kg diet of powdered lindane
    or 5, 10, 50, 100, 400, 800, and 1600 mg/kg diet of lindane in corn
    oil. The life span of the animals was shortened by 20-40% in a
    dose-dependent manner with administration of 400, 800, and 1600
    mg/kg diet, except in those given 800 mg/kg diet of powdered
    lindane. No increase in tumour incidence was reported in the 200
    treated rats (Fitzhugh et al., 1950) (see also section 7.4.1).

         In a lifetime study, groups of 10 rats of each sex received
    lindane at 0, 25, 50, or 100 mg/kg diet. No tumour formation was
    found (Truhaut, 1954). (Details not given.)

         Groups of 18-24 male W rats received lindane (99%) at 500 mg/kg
    diet for 24 or 48 weeks. High mortality was seen; none of the six or
    eight surviving animals had developed a liver tumour by 24 or 48
    weeks, respectively (Ito et al., 1975).

         Groups of 50 Osborne-Mendel rats of each sex were administered
    lindane for 80 weeks and were then transferred to the control diet
    for an additional 28-30 weeks; survivors were killed at 108-110
    weeks. The males received 320 or 640 mg/kg diet for 38 weeks,

    lowered thereafter to 160 and 320 mg/kg diet; the females received
    320 and 640 mg/kg for two weeks, then 160 and 320 mg/kg for 49 weeks
    followed by 80 and 160 mg/kg diet for 29 weeks. Matched controls
    consisted of 10 animals per sex; these were combined for statistical
    evaluation with 45 untreated male and female rats from other
    bioassays. No increase in tumour rate was seen in treated groups of
    either sex (US National Cancer Institute, 1977).

    7.7.3  Initiation-promotion

         The tumour-initiating activity of gamma-HCH was studied by
    observing the appearance of phenotypically altered foci in female
    Wistar rats (Schröter et al., 1987). Groups of 3-8 rats were
    operated to remove the median and right liver lobes; they were then
    administered gamma-HCH at 30 mg/kg body weight daily for two weeks,
    followed by phenobarbital at 50 mg/kg body weight daily for 15
    weeks. Liver foci were identified by means of the
    gamma-glutamyltransferase reaction and morphological alterations. No
    evidence of initiating activity was found.

         Promoting activity was studied by administering
     N-nitrosomorpholine as a single dose of 250 mg/kg body weight by
    gavage, followed by 4, 15, and 20 weeks' administration of gamma-HCH
    at 0.1, 0.5, 2.5, 10.0, or 30.0 mg/kg body weight per day. Both the
    number and the size of altered foci were enhanced by doses of 2-3
    mg/kg. The authors concluded that gamma-HCH could be classified as a
    tumour promotor.

         In an experiment using male dd mice (26-30 per group, eight
    weeks old), administration of Kanechlor-500 at 500 mg/kg diet
    induced nodular hyperplasia and hepatocellular carcinoma in the
    livers of mice after 32 weeks' exposure. Administration of lindane
    (99% pure) at 50, 100, or 250 mg/kg dietwith or without the
    polychlorinated biphenyl at 250 mg/kg diet induced none of those
    lesions after 24 weeks. Lindane was therefore neither tumorigenic a
    promoter in this experiment (Ito et al., 1973a).

    7.7.4  Mode of action

         Considerable work has been done using mice generated
    genetically from (C3H x VY)F1 or (YS x VY)F1 mice. The resulting
    Avy/Avy, Avy/a and A/a crosses contain a genomic locus known as the
    Agouti locus, which has been linked to tumorigenicity in these mice.
    Treatment of Agouti mice with lindane at 160 mg/kg diet has been
    found to saturate the lindane elimination pathways and thereby
    result in an increased burden of lindane and its metabolites. This
    excessive build-up could explain the tumorigenicity of lindane, at
    least when given at 'excessive' levels (Wolff, 1986; Wolff et al.,
    1986).

         The tumour response to lindane has been characterized in (YS x
    VY) F1 hybrid mice (Table 12). Lindane increased the incidence of
    benign tumours only in the Avy/a genotype, while the 'normal' A/a
    mice had no tumours. This finding indicates the existence of a
    genetic predisposing factor, which may be of some importance in
    evaluating the hazard of exposure to lindane. A phenotypic factor is
    apparently involved, as mice of the obese yellow phenotype had a
    greater tumour response in the liver than their isogenic siblings,
    pseudoagouti mice; such factors may themselves result in more
    tumours. Tumour incidence was not increased in normal black mice,
    but the incidence of benign tumours of the liver and lung was
    increased in Y genotype mice. The time of tumour onset was as early
    as 18 months in pseudoagouti mice, but the normal black mice had no
    tumours in the 24-month test period. Avy/a yellow mice thus have a
    proclivity to form hepatocellular adenomas and lung tumours, which
    is augmented (and not caused exclusively) by exposure to lindane.
    The pseudoagouti and normal black mice have a low rate of
    spontaneous tumours in the liver and lung, but only the pseudoagouti
    respond to lindane. Thus, some genetically derived mice form benign
    tumours, but the 'normal' A/a controls do not. Holder & Stöhrer
    (1989) concluded that these findings are of limited applicability to
    the situation in humans.

        Table 12.  Carcinogenic responses in normal (A/a), pseudoagouti (Avy/a), and
               agouti (Avy/a) mice after 24 months of dietary exposure to lindane a 

    Tumour               Phenotypeb     No lindane     160 ppm lindane    p value
                                         No.     %      No.       %
                                                                                     
    Liver adenoma           B           6/96     6     3/96       3       -
                            PS          5/95     5    11/95      12*      0.11
                            Y           8/93     9    33/94      35*      8.2E-06

    Hepatocellular          B           3/96     3     1/96       1       -
       carcinoma            PS          2/95     2     5/95       5       -
                            Y          12/93    13**  16/94      27       -

    Combined liver          B           9/96     9     4/96       4       -
       tumours              PS          7/95     7    16/95      17*      0.036
                            Y          20/93    22**  49/94      52*      1.1E-05

    Hyperplasia of lung     B          10/96    10    79/96      82*      <E-08
       Clara cells          PS         10/95    10    71/94      76*      <E-08
                            Y          14/95    15    68/95      52*      <E-08

    Lung tumourc            B           2/29     2     1/96       3       -
                            PS          2/95     6     5/94      14       0.0692
                            Y          12/95     4    16/95      19*      0.0012

    Table 12 (continued)

    *  Statistically significant dose-related response compared to non-treated
       comparable controls of the same phenotype
    ** Liver response increased in obese yellow (Avy/a) mice compared to A/a black
       controls even in absence of treatment

    a From Holder & Stöhrer (1989)
    b B, black normal controls; PS, pseudoagouti; Y, yellow
    c Not malignant; origin of cells uncertain
    
         Tumour promotion was tested as a mechanism of action for
    lindane in both the yellow and pseudoagouti variants of the (C3H x
    VY) F1 mouse using phenobarbital, which increases the incidence of
    benign tumours in the liver of yellow mice, as the tumour-promoter.
    Lindane at a dose of 160 mg/kg diet may exceed saturation of the
    metabolic mechanisms, especially in yellow mice with the (C3H x
    VY)F1 genotype. Chadwick et al. (1987) found reduced elimination
    of lindane in yellow and pseudoagouti mice and explained their
    findings as follows: The yellow mouse carrying the Avy locus has a
    propensity for tumorigenicity, which is enhanced by the yellow obese
    phenotype. The lungs and livers of these animals therefore are very
    likely to contain cells that are already transformed, whereas in
    normal black mice there may be none or very few transformed cells.
    Hence, Avy strain mice would be expected to respond to a tumour
    promoter, whereas black mice would not; this was also the pattern of
    tumour response observed. The authors concluded that, because
    phenobarbital promotes tumours in this strain of mice, lindane is
    also a promoter.

         Oesch et al. (1982) studied the specific activities in CF1
    and B6C3F1 mice and Osborne-Mendel rats of some of the enzymes
    thought to be involved in lindane metabolism. Lindane was
    administered at 51-360 mg/kg diet for three days or three months. No
    clear change was seen in animals treated for three days, but changes
    in enzyme activity were noted after three months' treatment. In the
    CF1 strain (sensitive to liver tumour induction), a large increase
    in liver weight was observed; this was not the case in B6C3F1
    mice. In the Osborne-Mendel rats, a smaller increase was found.
    Glutathione- S-transferase activity was increased in CF1 mice and
    to a lesser extent in B6C3F1 mice and the rats. Increased
    glutathione- S-transferase activity may lead to rapid conjugation
    of glutathione with reactive metabolites, as, for example, epoxides
    derived from lindane. Rat liver microsomes had more
    UDP-glucuronosyltransferase activity than those from mouse liver.
    This increased activity in rats could also lead to rapid conjugation
    of phenols derived from lindane. The most striking difference,
    however, was that CF1 mice had more monooxygenase activity and
    less epoxide hydroxylase activity than rats; whether either of these
    changes would result in an accumulation of reactive epoxides from
    lindane remains to be elucidated.

         Iverson et al. (1984) studied the ability of 14C-gamma-HCH to
    bind to liver macromolecules of untreated and
    phenobarbital-pretreated male HPB black mice  in vivo and  in
     vitro. There was preferential binding of gamma-HCH to protein but
    not to DNA.

         These studies in mice indicate that lindane does not behave as
    an initiator, in that it does not induce the preneoplastic foci seen
    with known carcinogens, such as  N-nitrosoporpholine and
     N-methyl- N-nitrosourea (Holder & Stöhrer, 1989). Lindane can,
    however, act as a tumour promoter, in that it caused outgrowth of
    foci and increased the areas of the foci, indicative of
    preneoplastic conditions. Whether these foci actually go on to form
    tumours was not determined.

         The notion that lindane has some characteristics in common with
    tumour promoters is corroborated by the finding that it inhibits
    cell-to-cell communication of the low-molecular-weight compound,
    tritiated uridine. Trosko (1982) found that such inhibition occurred
    when cells were pretreated with a variety of free-radical scavengers
    and suggested that the inhibition might involve a free-radical
    generating process. Some tumour promoters have been suggested to act
    by a mechanism involving free radicals (Kensler & Trush, 1984; Rao &
    Reddy, 1987).

         If lindane acts by the tumour promotion mechanism suggested by
    formation of gamma-glutamyltransferase-positive foci in the liver
    and inhibition of cell-to-cell communication, it is likely to be a
    dose-rate-limited process because of its known reversibility. That
    is, the compound must be administered at above a certain amount and
    rate or its carcinogenic effects are reversible and cease to be
    manifested. Such a mechanism would therefore probably result in a
    sigmoid response in models.

         Zeilmaker & Yamasaki (1986) studied the effect of lindane on
    gap-junctional intercellular communication in cultured Chinese
    hamster V79 cells, grown as monolayer using a microinjection/dye
    transfer technique. Intercellular communication via gap junctions is
    thought to play a crucial role in cell proliferation and
    differentiation and in tissue homeostasis, and consequently in
    carcinogenesis. Lindane inhibited junctional communication in a
    dose-response relationship (0-20 µg/ml) after a 60-h exposure, but
    inhibition was seen after 24 h incubation only with the highest dose
    level. In an earlier study, lindane strongly inhibited metabolic
    cooperation between V79 cells at a non-toxic dose of 10 µg/ml
    (Tsushimoto et al., 1983).

         Another explanation for the finding that Avy/a yellow mice have
    a predisposition for tumorigenicity but not necessarily for
    carcinogenicity is their reduced immunocompetence, as evidenced by
    decreased antibody response to T-cell-dependent immunogen tetanus

    toxoid, enhanced antibody response to T-cell-independent immunogen
    type III pneumococcal polysaccharide, decreased rates of carbon
    clearance and increased rates of immunoglobulin A formation. The
    pseudoagouti mice did not have reduced immunocompetence and had
    reactions similar to those of normal black A/a mice in these
    immunological tests (Holder & Stöhrer, 1989).

         The lindane metabolite, 2,4,6-trichlorophenol (TCP),
    constitutes a significant proportion of the urinary metabolites of
    lindane and is considered to be a carcinogen. However, direct
    measurements of comparative potency indicate that TCP contributes
    only a small fraction of the 'lindane cancer potency' and therefore
    may not add significantly to the quantitative impact of lindane. The
    notion that TCP adds quantitatively to the carcinogenicity of
    lindane  per se remains a major element in the evaluation of the
    carcinogenic hazard of lindane to humans (Holder & Stöhrer, 1989).

    7.7.5  Appraisal of carcinogenicity

         Studies to define the carcinogenic potential of lindane have
    been conducted with mice and rats, at doses of up to 600 mg/kg diet
    in mice and up to 1600 mg/kg diet in rats. In some studies, the dose
    levels exceeded the maximum tolerated dose. Hyperplastic nodules
    and/or hepatocellular adenomas were found in studies with mice at
    doses from 160 mg/kg diet. Two studies using mice and one study
    using rats, with dose levels of up to 160 mg/kg diet in mice and 640
    mg/kg diet in rats, showed no increase in the incidence of tumours.
    The results of studies on initiation-promotion, on mode of action,
    and on mutagenicity indicate that the tumorigenic effect of
    gamma-HCH in mice results from non-genetic mechanisms.

    7.8  Special studies

    7.8.1  Immunosuppression

         Desi (1976) and Desi et al. (1978) reported the results of a
    subacute study in which groups of 30-36 male rabbits were treated
    orally, five times per week for 5-6 weeks, with doses of lindane
    representing 0, 1/5, 1/10, 1/20, and 1/40 of the oral LD50, which
    was 60 mg/kg body weight. Once a week, different doses of  S. 
     typhimurium 'Ty 2' vaccine were injected intravenously. The
    humoral immune response was determined by the tube agglutination
    test. A linear regression was found between the dose of lindane and
    reduction in antibody titres, in a time-dependent manner. The lowest
    dose, 1.5 mg/kg body weight (1/40 of the oral LD50) caused no
    immunosuppression.

    7.8.2  Behavioural studies

         The learning rate in a maze and responses to conditioning in a
    Skinner box were studied after feeding lindane at daily doses of

    2.5, 5, 10, or 50 mg/kg body weight to Wistar rats for 40 days. In
    the maze, no effect was seen with 2.5 mg/kg, but at 5 mg/kg there
    was stimulation accompanied by an increased error rate in maze
    running activity; at 10 and 50 mg/kg, the animals became sedated and
    committed more errors than the controls. In the Skinner box,
    stimulation was seen with 2.5 and 5 mg/kg. At 10 mg/kg, no
    difference was seen from the controls, whereas animals treated at 50
    mg/kg were less active than the controls (Desi, 1974).

    7.8.3  Neurotoxicity

         Lindane produces a variety of neurological effects, both
    central and peripheral, in mammals. The induced increase in neuronal
    excitability and the underlying mechanisms of action have been
    investigated both  in vivo and  in vitro.

    7.8.3.1  Dose-response studies using intact animals

         The effects of lindane on body temperature, food intake, and
    body weight were studied in Wistar rats given single or repeated
    non-convulsant oral doses. Groups of eight male and eight female
    rats were given lindane as a single oral dose of 30 mg/kg in olive
    oil. Controls received olive oil alone. Further groups of eight
    males and eight females received 10 mg/kg and two groups of male
    rats received 30 mg/kg once daily for seven days at either
    thermoneutral ambient temperature or cold ambient temperature
    (4 °C). The single dose of 30 mg/kg significantly decreased core
    temperature 5 h later; this lindane-induced hypothermia was strongly
    potentiated by cold stress in rats kept at 4 °C. A decrease in body
    weight gain was also observed. No hypothermic effect was seen with
    10 mg/kg (Camon et al., 1988a).

         The relationship between the brain concentration of lindane and
    its convulsant effect was studied in male Wistar rats administered
    lindane (99.5%) dissolved in olive oil daily by gavage at doses of
    5, 12, or 20 mg/kg body weight for 12 days. The mean plateau
    concentration in brain was achieved within 5-8 days. There was a
    strong correlation between the doses administered and the
    concentration in brain at the plateau. A convulsant response was not
    seen with 5 mg/kg, but tonic convulsions occurred at the two higher
    doses. The rate of response (percentage of rats with convulsions)
    was also correlated with the log of the concentration of lindane in
    brain. The concentration in brain decreased after 12 days of daily
    administration of doses of 5 and 12 mg/kg, but not with 20 mg/kg
    (Tusell et al., 1988).

         Camon et al. (1988b) investigated the effect of convulsant and
    non-convulsant doses of lindane on regional glucose uptake in the
    brain. Male Wistar rats received intraperitoneal injections of
    3H-2-deoxyglucose, and the amount of label in different brain
    structures was assayed by liquid-scintillation counting in 18

    dissected brain regions. Lindane at a single convulsant dose (150
    mg/kg orally) increased 2-deoxyglucose uptake in olfactory
    tubercules, hypothalamus, hippocampus, paraflocculi, and the
    post-medulla. With a single, non-convulsant dose of 30 mg/kg, the
    uptake of 2-deoxyglucose was less affected; after treatment with 10
    mg/kg per day for one week, 2-deoxyglucose uptake was observed in
    superior colliculi but was decreased in the parietal cortex. The
    increased uptake in limbic regions seen at the convulsive dose
    correlates with the experimentally observed association between
    signs of poisoning induced by lindane and damage to the limbic
    system.

         Intraperitoneal injections of gamma-HCH (99.0%) in corn oil at
    80-480 mg/kg body weight increased the accumulation of cerebellar
    cyclic GM in male CD-1 mice. Furthermore, it inhibited the binding
    of 3H-tert-butylbicyclo- ortho-benzoate (a ligand for the
    GABA-A receptor-linked chloride channel) in mouse cerebellum
    (Fishman & Gianutsos, 1987).

         Fishman & Gianutsos (1988) gave male CD-1 mice gamma-HCH at
    single intraperitoneal doses of 80-400 mg/kg body weight in corn
    oil. At the lowest dose, gamma-HCH increased the lethality and the
    frequency of tonic/clonic seizures induced by intraperitoneal
    injection of 50 mg/kg pentylenetetrazole or 20 mg/kg picrotoxin but
    had no effect on locomotor activity.

         Sunol et al. (1988) studied the effect of administering lindane
    by gavage at 150 mg/kg body weight in olive oil on the GABAergic and
    dopaminergic systems, by measuring the concentrations of GABA,
    dopamine and its metabolites in seven brain areas at the onset of
    seizures. All animals suffered tonic convulsions 18.3 ± 1.4 min
    after lindane administration. The concentration of GABA was
    decreased only in the colloculi and not in the other areas. Dopamine
    concentrations were increased in the mesencephalon, and those of its
    metabolite, DOPAC, were also increased in the mesencephalon and the
    striatum (abstract only).

         In studies by Desi (1983), adult female CFY rats were given a
    daily dose of lindane (99.5%) at 2.5 mg/kg body weight. This dose
    level had no functional, neurological, electroencephalographic, or
    psychophysiological effect, used as early signs of disturbances of
    the nervous system. A dose of 5.0 mg/kg body weight altered the
    electrical activity of the brain, as indicated by changes in the
    complex electroencephalograph, the number of changing
    electroencepahlographic bands and the index number. In behavioural
    experiments, running speed and number of errors indicated an
    inhibitory effect of lindane at 5.0 mg/kg body weight on learning
    capacity; this result was not seen with 2.5 mg/kg.

         Müller et al. (1981) studied the electroneurophysiological
    effects of various HCH isomers on groups of 15 male Wistar rats by

    feeding them diets containing each isomer for 30 days. Conduction
    velocity delay was observed in the animals fed the gamma isomer at a
    daily dose of 25.4 mg/kg, but not at 12.3 or 1.3 mg/kg. The greatest
    delay was induced by the lindane metabolite
    gamma-pentachlorocyclohexene (38-783 mg/kg body weight).

         Lindane was reported to lower the threshold for kindled
    seizures (resulting from repetitive stimulation of the limbic system
    within the brain) in rats (Joy et al., 1982, 1983). In these
    experiments, stimulating electrodes were implanted in the amygdala
    and other part of the limbic system, and the animals were stimulated
    with a one-second train of pulses at 60 Hz on each day of the study.
    In this procedure, no response is elicited initially; however, with
    repeated stimulation, the procedure induces increasing levels of
    electrical seizure, with clonic seizures resulting after many
    trials. A developing after-discharge becomes progressively longer,
    and the severity of the accompanying motor signs becomes more
    pronounced, until kindling is completed. The subject then exhibits
    stable convulsive responses for weeks or months afterwards. The
    duration of the electrical seizure and the severity of the
    behavioural response were found to increase much more rapidly when
    lindane was administered at daily oral doses of 1, 3, or 10 mg/kg
    body weight 3 h before each kindling trial. These effects were found
    to be dose-dependent, and a threshold exposure of 0.5 mg/kg per day
    was calculated. Rats administered lindane at this concentration were
    found to develop brain levels of lindane which fluctuated between
    0.2 and 0.4 µg/g.

         Joy & Albertson (1987a,b) demonstrated that lindane alters
    dentate gyrus granule response to perforant path input in the intact
    rat in a manner indistinguishable from picrotoxin or
    pentylenetetrazol, which are known GABA-mediated chloride channel
    antagonists. In this study, 19 male Sprague-Dawley rats were
    anaesthetized with urethane, electrodes for stimulating and
    recording responses from the dentate gyrus of the hippocampus were
    implanted, and the animals were placed in a stereotaxic device.
    Lindane was then administered intraperitoneally in dimethylsulfoxide
    to each animal at sequential doses of 5, 10, 20, and 40 mg/kg body
    weight. Single or paired electrical stimuli were presented at
    different intensities and at different intervals to evaluate the
    effects of lindane on inhibition and facilitation. These studies
    demonstrated a dose-dependent change in perforant path granule cell
    function, manifested as an increase in the excitability of the
    granule cell to other stimuli. Lindane was also found to induce a
    small but statistically significant, dose-dependent increase in
    presynaptic inhibition, as well as a significant increase in
    postsynaptic inhibition. A dose-dependent effect on GABA-mediated
    inhibition was measurable at exposures that were not convulsant in
    unanaesthetized animals. The results of this  in-vivo study
    indicate that inhibition of GABA-mediated chloride channels in the

    brain is probably an important mechanism by which lindane produces
    neuronal hyperexcitability and convulsions.

    7.8.3.2  Studies on mechanism

         Although the precise mechanism by which lindane exerts its
    neurotoxic action is not fully resolved, studies using preparations
    of synaptosomes (pinched-off nerve endings) and of cholinergic
    neuromuscular junctions, as well as studies using intact animals,
    have provided insight into this issue. The results of representative
    studies with each type of preparation are summarized in Table 13.

    
    TABLE 13. Known effects of lindane on central and peripheral nerves or muscle tissue

    Effect                        Species   Type of preparation          Reference

    Inhibition of                 Rat       in vivo                      Joy & Albertson (1987 a,b)
     GABA-mediated chloride
     ion uptake in CNS
                                  Rat       Brain synaptosomes/          Eldefrawi et al. (1985)
                                            neuronal membrane            Matsumura & Tanaka (1984)
                                                                         Abalis et al. (1985, 1986)

                                  Mouse     Brain synaptosomes           Fishman & Gianutsos (1988)

    Increased availability        Rat       Brain synaptosomes           Hawkinson et al. (1989)
     of intracellular Ca++
                                  Rat       Neuroblastoma cells          Joy et al. (1987)

                                  Rat       Neurohybridoma cells         Joy et al. (1988)

                                  Frog      Neuromuscular junction       Joy et al. (1987)
                                                                         Vogel et al. (1985)
                                                                         Publicover & Duncan (1979)

    Decreased conduction          Rat       Tail nerve                   Müller et al. (1981)
     velocity

    Mitochondrial damage          Frog      Skeletal muscle              Publicover et al. (1979)

    Na+-K+-ATPase inhibition      Frog      Skeletal muscle              Pandy et al. (1985)

                                  Rat       Liver mitochondria           Srinivasan &
                                                                         Radhakrishnamurty (1988)

    TABLE 13. (Continued)

    Effect                        Species   Type of preparation          Reference

    Ca++-Mg++-ATPase              Beef      Brain                        Uchida et al. (1974)
     inhibition
                                  Rat       Liver mitochondria           Srinivasen &

                                                                         Radhakrishnamurty (1988)

    
         Lindane was shown to inhibit the uptake of chloride ions at
    inhibitory synapses in the brain (Matsumura et al., 1984; Abalis et
    al., 1985, 1986; Fishman & Gianutsos, 1988), and it is this mode of
    action that is now widely considered to account primarily for the
    convulsant activity of this insecticide. Because of its structural
    similarity to picrotoxinin, lindane has a good geometric fit to the
    picrotoxinin-binding site at the outer end of the chloride channel.
    Once bound, the lindane is believed to block the action of the
    neurotransmitter GABA, which mediates the entry of the Cl- necessary
    for inhibitory neuronal function (Matsumura, 1985). More recent
    studies by Joy & Albertson (1987a,b) provide evidence of such
    inhibition of GABA in rats  in vivo, demonstrating that: (a) this
    mechanism operates at clinically relevant exposure levels (5-40
    mg/kg); (b) the magnitude of this effect is dose-dependent; and (c)
    this effect can be clearly measured at subconvulsant exposure levels
    in unanaesthetized subjects.

         Lindane has also been demonstrated to increase the excitability
    of presynaptic cholinergic neurons at central (Hawkinson et al.,
    1989) and peripheral (Vogel et al., 1985; Publicover & Duncan, 1979)
    synapses. Using a nerve-muscle preparation, a universally accepted
    model for a cholinergic synapse, Publicover & Duncan demonstrated
    that concentrations of lindane as low as 5 x 10-5 mol/litre
    increase the spontaneous release of acetylcholine. Similar results
    were reported by Vogel et al. (1985), who observed increases up to
    100 fold in spontaneous release of neurotransmitter in the presence
    of lindane at 10-4 mol/litre. This increase was found in both
    studies to be somewhat dependent upon the concentration of
    extracellular calcium ions. In the presence of normal (approx. 1-2
    mmol/litre) Ca++, the increase in spontaneous transmitter release
    was 2.5-20 times greater than that measured when the extracellular
    Ca++ level was buffered to 10-7 mol/litre, the homeostatically
    maintained intracellular Ca++ concentration. An expanded report of
    the study of Vogel et al. (1985) was made by Joy et al. (1987), who
    additionally described a similar lindane-induced excitability in
    neuroblastoma cells. Hutchison verified the involvement of Ca++ in
    the enhanced release of acetylcholine using a rat brain synaptosome
    preparation, and he postulated that the increased excitability of
    cholinergic synapses (widely dispersed throughout the brain) may
    contribute to the convulsant effect of lindane.

         Pandy et al. (1985) reported that lindane weakly inhibits
    Na+-K+-ATPase activity in skeletal muscle, and they suggested
    that lindane can inhibit Ca++-Mg++, Ca++-, and mg++-ATPase.
    Uchida et al. (1974) reported decreased Ca++-Mg++-ATPase
    activity in beef brain. Since all of these ATPases are involved in
    the maintenance of intracellular Ca++ concentration and have been
    identified in a neuronal membrane preparation (Yamaguchi et al.,
    1979), it is possible that the disruption of homeostatic calcium
    regulation by lindane contributes to its excitatory action on the
    central nervous system.

    7.8.3.3  Summary

         Chronic exposure to low levels of lindane can result in
    proconvulsant activity, as demonstrated experimentally using the
    kindling model of experimental epilepsy. Lindane has also been shown
    to cause convulsions in rats administered oral doses of 12 mg/kg
    daily for 12 days; a dose of 5 mg/kg body weight did not induce
    convulsions within that period. The convulsive effect has been
    suggested to be associated with inhibition of GABA-mediated chloride
    channels in the brain, as demonstrated experimentally in mammals
    both  in vivo and  in vitro. Changes in the electroencephalogram
    and decrements in a variety of behavioural parameters have been
    observed with lindane at a dose of 5 mg/kg/body weight per day for
    40 days, but not at 2.5 mg/kg for 22 days. A delay in peripheral
    nerve conduction velocity was observed in rats administered a
    dietary concentrations of 25 mg/kg body weight, but not at 12 mg/kg.

    7.9  Factors that modify toxicity; toxicity of metabolites

         Pretreatment of rats with lindane minimized or inhibited the
    convulsive effects of pentazole, picrotoxin, loramine, strychnine,
    mintracol, cyclohexane sulfonamide and electro-shock (Herken,
    1950a,b,c, 1951; Coper et al., 1951; Kewitz et al., 1952; Lange,
    1965). It was demonstrated that premedication for two weeks with
    daily doses of 2 mg lindane not only accelerated the metabolism of
    other chemicals, but also caused an acceleration of its own
    breakdown: in Fischer rats given two oral administrations of lindane
    in oil at 2 mg/kg, there was increased excretion of glucuronic acid
    conjugates (Chadwick et al., 1971).

         The smallest single oral dose of lindane that reduced
    pentobarbital sleeping time in FW-49 rats was 5 mg/kg body weight
    (Schwabe & Wendling, 1967). The smallest single intraperitoneal dose
    of lindane that shortened hexabarbital anaesthesia was 15 mg/kg body
    weight. A similar result was obtained in Sprague-Dawley rats fed a
    diet containing lindane at 0.5 mg/kg; the effect was more distinct
    with a dose of 4 mg/kg diet (Kolmodin-Hedman et al., 1971).

    8.  EFFECTS ON HUMANS

    8.1  Exposure of the general population

    8.1.1  Acute toxicity, poisoning incidents

         Several cases of fatal poisoning and numerous cases of
    non-fatal illness caused by or ascribed to lindane have been
    reported. These incidents were either accidental, intentional
    (suicide) or due to gross neglect of safety precautions. In many of
    these cases, the effects ascribed to lindane were more likely to
    have been due, in total or in part, to other substances. A critical
    review of these cases is provided by Hayes (1982).

         The toxic or lethal dose appears to vary considerably with the
    carrier and/or the degree of homogenization of the product. Under
    certain conditions, 10-20 mg/kg body weight can present a lethal
    hazard to humans, but higher concentrations can be tolerated when
    followed by timely and appropriate medication. Starr & Clifford
    (1972) described a case of acute lindane intoxication in a
    2.5-year-old child who had severe epileptiform convulsions after
    ingesting presumably two 0.78-g pellets containing 95% lindane. The
    child recovered under medical care.

         A suicide attempt was reported by Ohly (1973). The person
    ingested about 100 ml of a 25.5% lindane emulsion concentrate, which
    corresponds to a dose of about 309 mg/kg body weight. No vomiting or
    diarrhoea was seen, but severe convulsions occurred within the first
    24 h after lindane ingestion. Elevated serum levels of
    glutamic-oxaloacetic transaminase, lactic dehydrogenase,
    glutamic-pyruvate transaminase, and creatine phosphokinase activity,
    in conjunction with the results of a liver biopsy, suggested fatty
    degeneration and severe toxic damage to the liver. After five weeks
    of clinical treatment, the patient recovered completely.

         A number of cases of poisoning cases have been described after
    medical treatment or abuse (Davies et al., 1983; Kurt et al., 1986;
    Petring et al., 1986; Berry et al., 1987).

         Clinical signs of intoxication can appear from a few minutes to
    some hours after intake of lindane, depending on the route of
    administration, the formulation, the concentration of lindane, and
    the quantity involved. In mild cases, indisposition, nausea,
    dizziness, restlessness, frontal headaches, and sometimes vomiting
    occur. Muscular fasciculation, disturbances of equilibrium, ataxia,
    and tremor may appear. Pains in the upper abdomen are frequently
    coupled with diarrhoea and uncontrolled micturition. Clonic-tonic
    convulsions of some minutes' duration may occur, and these may recur
    after several hours or even days in response to optical, tactile,
    and acoustic stimuli. In fatal cases, death follows several hours to
    several days after intake. The cause of death is usually central

    respiratory failure or acute circulatory collapse, often after
    convulsions (Hayes, 1982; Jaeger et al., 1984).

    8.1.2  Effects of short- and long-term exposures - controlled human
           studies

    8.1.2.1  Oral administration

         Lindane given orally as a vermicide at a dose of 45 mg to an
    adult patient (26 years old) in poor condition induced convulsions,
    nausea, and vomiting. Recovery took place within 3-4 h. Of 15
    patients in the same trial, who repeatedly received up to 30
    mg/person for up to three days, six complained of nausea; no other
    symptom was reported (Graeve & Herrnring, 1949).

         Severe toxic symptoms were described in healthy volunteers
    after oral intake of 15-17 mg/kg body weight of lindane in a liquid
    carrier (Hofer, 1953; Schmiedeberg & Wasserburger, 1953). Reports of
    toxic effects after administration of lindane against scabies
    indicate that children are more sensitive to lindane than adults,
    and rare cases of aplastic anaemia have been reported (G. Volans,
    National Poison Unit, London, letter to IPCS, 1989).

    8.1.2.2  Dermal application

         Clinical reports after pharmaceutical use of lindane
    cutaneously suggest that exposures somewhat higher than 5 mg/kg body
    weight per day do not usually result in acute neurotoxic symptoms.
    No cause-effect relationship was found between lindane and blood
    dyscrasias (Ginsburg et al., 1977; Kramer et al., 1980; Morgan et
    al., 1980).

         Three groups, each consisting of one male and one female
    volunteer, received an application of 30 g of a 0.3% commercial
    lindane emulsion over the entire body (except the head and the angle
    of the elbow) on three consecutive days. The first group removed the
    emulsion by washing with soap and water 3 h after application; the
    second removed it 10 h after application by washing with water only
    at body temperature, and the third group by washing with soap and
    water 10 h after application. A group of scabies patients were given
    an application of 50 g of the emulsion over the entire body, except
    the angles of the elbows. Blood samples were taken regularly from
    all participants in the trial over a period of 1-144 h. The highest
    average serum concentration found approximately 5.5 h after
    application in the healthy volunteers was slightly less than 5
    µg/litre, while in scabies patients an average of about 200 µg/litre
    was found after 4 h. It was concluded that scabies patients deposit
    greater concentrations of lindane in their bodies than do healthy
    persons; the levels were higher in women than in men (Lange et al.,
    1981; Zesch et al., 1982).

         Feldmann & Maibach (1974) studied the absorption and excretion
    of 14C-labelled lindane dissolved in acetone, applied at 4
    µg/cm2 to the forearms of six human subjects. The usual dose of
    radioactivity was 1, 2, or 5 µCi. Data obtained after intravenous
    dosing was used to correct the results obtained on skin penetration
    for incomplete urinary recovery. Total excretion of 14C after
    topical application was 9.3% ± 3.7 of the dose in five days. Skin
    absorption is incomplete because the chemical is lost from the skin
    surface by washing, evaporation or gradual exfoliation of outer
    layers of the stratum corneum. The amount absorbed into the body
    depends on the relationship between the speed with which it
    penetrates the skin and the speed with which it is lost from the
    skin surface.

         Serum concentrations of gamma-HCH were determined in nine
    children (3.5-18 years old) following application of a 1% gamma-HCH
    shampoo to treat pediculosis capitis (head lice). The shampoo was
    applied vigorously to dry hair in a sufficient amount to saturate
    the hair and scalp thoroughly. After 10 min, small quantities of
    water were added until a lather formed, and shampooing was continued
    for 4 min; thereafter, the hair was rinsed and blown dry. Gamma-HCH
    was present in the serum of all children 2-24 h following the
    application. A maximal concentration of 1.4 µg/litre was found after
    2-4 h; this level decreased within 24 h to 0.41 µg/litre.
    Re-treatment increased the maximal level to 3.6 µg/litre (Ginsburg &
    Lowry, 1983).

         Nitsche et al. (1985) applied emulsions of 0.3 and 1.0%
    14C-lindane to defined areas of 2 cm2 intact or stripped skin.
    They found that the flux of lindane in the skin was time-dependent:
    Generally, the concentration increased with the depth of the layer.
    Increased availability of lindane, induced by absence of the stratum
    corneum and a long application period, resulted in preferential
    accumulation in the epidermis, with none in the subcutaneous fat.
    When intact skin was washed with soap and water 3 h after the
    application, the concentration of lindane in the layer below the
    stratum corneum 7 h later was higher than that in skin that had not
    been washed. Washing of intact skin after a short penetration period
    (3 h) resulted in introduction of lindane; this phenomenon was not
    seen with stripped skin. Lindane could be more effectively removed
    from the stratum corneum with soap and water than with water alone.

    8.1.3  Epidemiological studies (general population)

         The rate of mortality from liver cancer in the USA was related
    to the 'domestic disappearance' of organochlorine pesticides. In
    1962, 18 and 15 years after the introduction of DDT and technical
    HCH, respectively, by which time any increase in the mortality rate
    from primary liver cancer would be manifest, the number of cases of
    primary liver cancer as a percentage of the total number of deaths

    from liver cancer began a gradual, steady decline, from 61.3% in
    1962 to 56.9% in 1972. The death rate (per 100 000 per year) from
    primary liver cancer during this period declined from 3.46 to 3.18
    (Deichmann & MacDonald, 1977).

         A considerable number of case reports have been published in
    which different blood dyscrasias were described in people who had
    been exposed to lindane or to lindane and other chemicals (Mendeloff
    & Smith, 1955; Albahary et al., 1957; Jedlicka et al., 1958;
    Stieglitz et al., 1967; West, 1967; Hoshizaki et al., 1969;
    Vodopick, 1975). The issuance by the US Environmental Protection
    Agency (1977) of a 'rebuttable presumption against registration and
    continued reregistration' of lindane in 1977 was triggered in part
    by the problem of blood dyscrasias. Studies conducted over periods
    of several weeks to several years, however, have given no indication
    that there might be a cause-effect relationship between exposure to
    lindane and blood dyscrasias (Milby & Samuels, 1971; Samuels &
    Milby, 1971; Morgan et al., 1980; Wang & Grufferman, 1981), and this
    was the final conclusion of the US Environmental Protection Agency
    (1984a).

    8.2  Occupational exposure

    8.2.1  Toxic effects

         Evaluation of the effects of gamma-HCH in occupationally
    exposed workers is seriously hampered by the fact that most of the
    studies are of workers who were exposed during manufacturing and
    handling of lindane, or in the handling or spraying of
    technical-grade HCH among other pesticides. All of these groups are
    also potentially exposed to other HCH isomers, to impurities and to
    other (process) chemicals. It is, therefore, difficult to relate the
    effects found in these studies to any individual substance. The only
    such studies mentioned here are those that were considered to be
    useful for the evaluation.

         Kolmodin-Hedman (1974) investigated blood levels of gamma-HCH
    in 54 spraymen exposed to 4% lindane and other insecticides in the
    form of aerosols and mists and who also occasionally diluted stock
    solutions. Their exposure varied from once daily to once weekly, and
    the length of exposure was 1-20 years; they did not always wear
    protective gloves and respirators. Spraymen exposed to lindane had
    mean plasma levels of gamma-HCH of 6.4, 7.5, and 9.9 µg/litre; a
    maximal concentration of 87.0 µg/litre was found. Antipyrine
    half-lives in exposed subjects and in controls were compared to
    investigate whether lindane induces drug metabolism in humans. In 26
    workers exposed mainly to lindane, the mean antipyrine plasma
    half-life was significantly shorter than that in 33 controls: 7.7 ±
    2.6 h compared with 13.1 ± 7.5 h, respectively. Induction occurred
    with plasma levels above 10 g/litre; workers who were exposed to
    lindane had shorter antipyrine and phenylbutazone half-lives when

    their serum levels were above this value. Hyperlipoproteinaemia
    (defined as a serum cholesterol level above 800 mg/litre and a
    phospholipid level above 1400 mg/litre in the HDL fraction of the
    serum lipoproteins) was found in 40% of the spraymen
    (Kolmodin-Hedman, 1974, 1984).

         Three workers mixed rapeseed manually with 75% lindane powder,
    which also contained 10% thiram, and usually closed the sacks by
    hand. This mixing procedure was repeated up to 80 times during a
    workshift. The working period comprised the spring months of each
    year, and the total exposure period varied between one and five
    years. Gloves and masks were not always used, so dermal and
    respiratory exposures were intensive. The plasma levels during
    exposure in the three people who prepared rapeseed were 102, 100,
    and 4.2 µg/litre; the last person had less frequent exposure than
    the other two. The plasma level in the person who had 100 µg/litre
    during exposure had decreased to the level before exposure within
    five months (Kolmodin-Hedman, 1974, 1984).

         Workers engaged in the production of lindane and exposed for at
    least six months (8 h/day; wearing face masks in an air-ventilated
    location) were tested for the presence of chromatid-type and labile
    chromosome-type aberrations in their lymphocytes. The frequency of
    stable chromosomal aberrations did not differ significantly from
    that in normal controls (Kiraly et al., 1979).

         Herbst (1976) examined workers engaged in the production of
    lindane in three factories. The people were exposed not only to the
    gamma isomer but also to the alpha, beta, delta, and epsilon
    isomers. The average length of service was slightly more than 10
    years. Of the 118 persons examined, 115 were men and three were
    women, and the average age was 39 years. No abnormality was detected
    in the haematopoietic system, the liver, the kidneys, or the nervous
    system.

         A series of reports were made on groups of 54-60 male workers
    (24-62 years of age) in a lindane-producing factory, with a
    geometric mean duration of exposure of 7.2 years (range, 1-30 years)
    (Baumann et al., 1981; Brassow et al., 1981; Tomczak et al., 1981).
    The lindane concentrations in serum were in the range 5-188
    µg/litre; that of alpha-HCH was 10-273 µg/litre, and that of
    beta-HCH, 17-760 µg/litre. None of the controls had a HCH
    concentration in serum above the limit of detection (O.7µg/litre).
    The time-weighted average threshold limit value of 0.5 mg/m3 was
    not exceeded at any of the workplaces (range, 0.004-0.15 mg/m3);
    the level of alpha-HCH was 0.002-1.99 mg/m3 and that of beta-HCH,
    0.001-0.38 mg/m3. Only small deviations were found in some
    laboratory tests: higher polymorphonuclear leukocyte count, lower
    lymphocyte count, higher reticulocyte count, lower prothrombin
    level, lower blood concentrations of creatinine and uric acid; these
    findings were regarded as of no pathological significance. No

    significant difference was observed in total red cell, white cell,
    and platelet counts, in haemoglobin content, or in levels of
    gamma-glutamine transferase, glutamic-oxaloacetic transaminase,
    glutamic-pyruvic transaminase, lactic dehydrogenase, cholinesterase,
    triglyceride, cholesterol or urea. No sign of health impairment was
    observed. Examination of reflexes, sensitivity, amplitude and
    frequency of fore-finger tremor and manual skills showed no
    significant difference between the HCH-exposed and the control
    groups. In addition, no pathological result was obtained in tests
    for electromyography, maximal motor nerve conduction velocity in
    ulnar nerves, or neuromuscular conduction. Furthermore,
    electroencephalographic recordings showed no specific pathological
    sign. The authors concluded that, even after decades of occupational
    exposure to HCH, no sign of neurological impairment or perturbation
    of neuromuscular function had occurred. Serum levels of luteinizing
    hormone were higher in HCH-exposed workers than in controls (8.8 vs
    5.7 mIU/ml). Levels of follicle stimulating hormone were
    insignificantly higher and testosterone levels were insignificantly
    lower in exposed men than in controls.

         In malaria-control workers, who sprayed technical-grade HCH for
    16 weeks, the serum level of gamma-HCH increased from a mean of
    0.009 to 0.037 mg/litre in previously unexposed workers, and from
    0.009 to 0.034 mg/litre in workers who had been exposed during three
    previous spraying seasons (Gupta et al., 1982). In comparison with
    the alpha and beta isomers, the gamma isomer was the least
    cumulative and the least persistent in serum. These findings, as
    well as those of Milby et al. (1968), suggest that gamma-HCH levels
    in blood are mainly a reflection of recent exposure to lindane.

         Nigam et al. (1986) studied 64 employees at a manufacturing
    plant who were directly or indirectly associated with the production
    of HCH. The exposed group comprised 19 workers who handled and
    packaged the insecticide, 26 plant operators and supervisors who
    were exposed indirectly to HCH, and 19 members of the maintenance
    staff who visited the plant frequently. The control group consisted
    of 14 workers who had no occupational contact with HCH. The length
    of exposure varied from 0 to 30 years. The mean serum concentrations
    of lindane in the four groups were: control, 0.0007, maintenance
    staff, 0.0227, indirect exposure, 0.016, and handlers, 0.0571
    mg/litre. Alpha-, beta-, and delta-HCH were also present; the total
    HCH concentrations in serum were 0.0514 mg/litre in the controls,
    0.1436 mg/litre in the maintenance staff, 0.2656 mg/litre in the
    indirectly exposed workers, and 0.604 mg/litre in the handlers. Most
    of the directly and indirectly exposed workers had paraesthesia of
    the face and extremities, headache, and giddiness, and some had
    symptoms of malaise, vomiting, tremors, apprehension, confusion,
    loss of sleep, impaired memory and loss of libido. The same symptoms
    were found in the group of maintenance workers but were less severe
    and occurred in fewer cases.

         Chattopadhyay et al. (1988) studied 45 male workers exposed to
    HCH during its manufacture and compared them with 22 matched
    controls. Paraesthesia of the face and extremities, headache,
    giddiness, vomiting, apprehension, and loss of sleep, as well as
    some changes in liver function were reported. These changes were
    found to be more closely related to intensity of exposure (as
    measured by HCH levels in blood serum) than to duration of exposure.
    The measured exposures to total HCH were 13 to 20 times higher than
    those in the control groups (details not given). Of the total HCH,
    60-80% was gamma-HCH.

         Plasma levels of gamma-HCH and urinary levels of three TCPs
    were measured in 45 forestry workers who were engaged in dipping
    conifer seedlings in a gamma-HCH solution, transporting the dipped
    seedlings to planting sites or planting the seedlings. Protective
    clothing was supplied. The work started in April, and until June the
    workers had plasma concentrations below the detection limit (5
    nmol/litre). From June onwards, there was an upward trend in the
    number of workers who had gamma-HCH levels in plasma of up to 40
    nmol/litre. In July, levels of 59, 75, and 123 nmol/litre were found
    in three workers, and the latter two had symptoms of poisoning that
    included feeling unwell with a flu-like illness, fatigue, sore
    throat, and nausea. No sign of hepatotoxicity was observed. People
    with levels greater than 70 nmol/litre were removed from further
    exposure. When exposure ceased at the end of July and the people who
    had had elevated levels were monitored in August, 80% of the workers
    had no detectable gamma-HCH in their plasma; the group mean
    concentration was 16 nmol/litre. By September, all plasma levels had
    returned to the pre-exposure level, below the detection limit. The
    mean half-life of gamma-HCH in plasma was calculated to be about
    eight days. 2,4,6-, 2,3,5-, and 2,4,5-TCP were the major metabolites
    of gamma-HCH (Drummond et al., 1988).

         Neurological studies on 37 workers exposed to lindane over a
    period of two years revealed three with serious
    electroencephalographic disturbances; minor symptoms and signs were
    seen in 14 of the workers. No change was observed in the
    electroencephalographic patterns of 21 of the exposed individuals.
    Blood levels of gamma-HCH were 0.002-0.34 mg/litre. The frequency of
    clinical symptoms and electroencephalographic changes was higher
    among individuals whose blood contained 0.02 mg/litre or more of
    gamma-HCH (Czeglédi-Janko & Avar, 1970; American Conference of
    Governmental Industrial Hygienists, Inc., 1986).

         Tolot et al. (1969) and Schüttmann (1972) reported peripheral
    neuropathies after contact with technical-grade HCH or lindane.

    8.2.2  Irritation and sensitization

         Behrbohm & Brandt (1959) described 26 cases of allergic and
    toxic dermatitis in workers exposed during the manufacture of
    technical-grade HCH. Patch testing with pure alpha-, beta-, gamma-,
    and delta-HCH gave negative results, but positive reactions were
    obtained with residual fractions. Baumgartner (1953) also described
    skin sensitization in four workers involved in lindane manufacture.
    Cases of allergic disease (rhinitis, conjunctivitis, and eczema)
    were also reported among workers in the USSR exposed to lindane
    (Krzhyzhanovskaya, 1973, and Bezuglikh et al., 1976; see Izmerov,
    1983).

         Patch tests were performed with 1% lindane dissolved in a
    petroleum solvent on the upper back of 200 subjects, 105 men and 95
    women, aged 18-76 years; 50 of them (34 men and 16 women) were
    agricultural workers, 24 (18 men and six women) had worked on the
    land in the past, and the other 53 men and 73 women had never used
    pesticides. Results were read after 48 and 72 h. A positive reaction
    was found in none of the 200 subjects tested (Lisi et al., 1986). 

         In a study to establish the optimal test concentration of lindane 
    and the frequency of irritant and sensitization reactions, Lisi et al.
    (1987) tested 335 men and women, of whom 70 were employed in
    agriculture, 25 had been employed in agriculture in the past and 240
    had never been exposed to pesticides. The results of the patch test,
    using 1% lindane in a petroleum solvent, were all negative, and no
    sensitization reaction was observed.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Microorganisms

    9.1.1  Bacteria

         The effect of lindane at concentrations up to 100 times the
    recommended dose for field application (1 mg/kg of soil) was studied
    on organic mineralization and on nitrification rates in alluvial
    soil around Delhi, India. Lindane inhibited the evolution of CO2
    from soil at a concentration of 100 mg/kg but not or only slightly
    with 1 and 10 mg/kg over an incubation period of 120 days.
    Nitrification by the bacterial species  Nitrobacter and
     Nitrosomonas was decreased with the dose of 100 mg/kg, and 10
    mg/kg induced inhibition during the first three weeks after
    application. Nitrification was restored within 35 days (Gaur &
    Misra, 1977).

         The influence of technical-grade HCH on the nitrifying
    characteristics of  Nitrosomonas and  Nitrobacter species isolated
    from an alluvial soil was studied in artificial growth media and in
    a flooded, autoclaved soil. The concentrations tested were 0, 5, 20,
    and 50 mg/kg soil or culture medium; the observation period was
    10-40 days. The rate of nitrification was slower in autoclaved soil
    than in culture media. Technical-grade HCH inhibited nitrification
    at concentrations of 5 mg/kg and more (Ray, 1983).

         Oxidation of substrate nitrogen was evaluated on the basis of
    the appearance of nitrite in the medium in the presence of
     Nitrosomonas europaea and on the disappearance of nitrite in the
    presence of  Nitrobacter agilis. N. agilis was sensitive to lindane
    at concentrations as low as 1 µg/ml, and the highest concentration
    tested, 1000 µg/litre, delayed nitrate production. In  N. europaea,
    lindane induced complete inhibition at a concentration of 10 µg/ml
    within 6-7 days (Garretson & San Clemente, 1968).

    9.1.2  Algae

    9.1.2.1  Blue-green algae

         Bringmann & Kühn (1978) saw no inhibition of growth of
     Microcystis aeruginosa at concentrations of lindane up to 0.3
    mg/litre, and Palmer & Maloney (1955) found no inhibition of the
    growth of  Microcystis aeruginosa or  Cylindrospermum licheniforme
    at 2 mg/litre. Both concentrations are higher than those that would
    result in adverse effects in fish or crustaceans.

         Concentrations of 50, 60, and 80 µg/ml of lindane were lowered
    in the presence of 25 species of blue-green algae, thus reducing its
    toxicity (Das & Singh, 1977).

    9.1.2.2  Freshwater algae

         Lindane was lethal to  Scenedesmus acutus (age of culture 1,
    3, or 5 days) at a concentration of 5 mg/litre after 5 days'
    exposure. At concentrations of 1-5 mg/litre, 50% growth reduction
    occurred (Krishnakumari, 1977). Jeanne-Levain (1974) also observed
    about 50% inhibition of growth of  Dunaliella bioculata with
    lindane at 5 mg/litre; 10 mg/litre completely inhibited growth.
    Similar findings were described by Jeanne (1979). No observable
    inhibition of growth was found by Bringmann & Kühn (1978) in
     Scenedesmus quadricauda at concentrations up to 1.9 mg/litre; and
    Palmer & Maloney (1955) saw no inhibition in  Scenedesmus obliquus,
    Chlorella variegata, Gomphonema  parvulum, or  Nitzschia palea at
    the only dose tested, 2 mg/litre.

    9.1.2.3  Marine algae

         Growth inhibition was studied in three species of marine algae
    by Ukeles (1962), using concentrations of 1-9 mg/litre. No
    inhibitory effect was found in  Protococcus sp. at up to the
    highest concentration tested or in  Pheodactylum tricornutum at up
    to 1 mg/litre.  Chlorella sp. were slight inhibited at the lowest
    concentration tested, but the dose-response relationship indicated
    that the threshold was not far below this dose. In tests with green
    algae and diatoms, growth was not inhibited by lindane at
    concentrations below about 1 mg/litre.

    9.1.3  Dinoflagellates, flagellates, and ciliates

         Representative members of these three groups were exposed to
    lindane at concentrations of 0.5-60 mg/litre (Jeanne-Levain, 1974).
    Lethality was reached in  Amphidinium carteri (dinoflagellate) at 2
    mg/litre and in  Tetrahymena pyriformis (ciliate) at > 10
    mg/litre; no lethal effect was observed in  Euglena gracilis
    (flagellate) at up to the highest dose of 60 mg/litre. All doses had
    inhibitory effects.

         Ukeles (1962) observed inhibition of the growth of the
    flagellates  Monochrysis lutheri and  Dunaliella euchlora with
    concentrations of lindane > 5 mg/litre.

    9.2  Aquatic organisms

    9.2.1  Invertebrates

         Green et al. (1986) investigated a range of 10 common European
    freshwater macroinvertebrates in a continuous flow system to
    establish their response to lindane at concentrations ranging from
    25 ± 4.8 to 430 ± 32 µg/litre under similar test conditions: water
    temperature, 11 ± 1 °C; pH, 7.5-8.0; dissolved oxygen, > 96%; and
    hardness of water (as CaCO3), 92.9 ± 6.3 mg. The 96-h LC50 varied

    from 4.5 up to > 430 µg/litre (Table 14). The ephemeropteran
     Baetis rhodani and the plecopterans  Leuctra moselyi and
     Protonemura meyeri were the most sensitive species;  Physa
     fontinalis and  Polycelis tenuis were the most tolerant.

        Table 14.  LC50 values for invertebrates
                                                                        
    Taxon           Species                     96-h LC50 (µ/litre)
                                                                        
    Insecta
    Plecoptera      Pteronarcys california      4.5
                    Leuctra moselyi             < 130
                    Protonemura meyeri          < 130
    Ephemeroptera   Baetis rhodani              54
    Diptera         Chironomus riparius         235
    Trichoptera     Hudropsyche angustipennis   330

    Crustacea
    Amphipoda       Gammerus rhodani             48
                    Gammerus facia               10
                    Gammerus pulex              225
    Isopoda         Asellus aquaticus           375

    Mollusca
    Gastropoda      Physa fontinalis           > 430

    Platyhelminthes
    Tricladia       Polycelis tenui s          > 430

    Annelida
    Oligocheata     Limnodrilus hoffmeisteri   > 430

    9.2.1.1  Crustaceans

         The sensitivity of both freshwater and seawater crustaceans to
    the acute toxicity of lindane is summarized in Table 15. In general,
    freshwater crustaceans were much less sensitive to lindane than
    those living in seawater. The LC50 values for freshwater
    crustaceans are comparable to or about one order of magnitude higher
    than the median values for fish, whereas seawater crustaceans are
    generally an order of magnitude more sensitive than fish.

          Daphnia magna were exposed to lindane at 11-210 µg/litre
    continuously for 64 days, thus covering three succeeding generations
    (Macek et al., 1976). A clear dose-dependent depression of
    reproduction was found at higher concentrations. The authors

    assessed the NOEL to be between 11 and 19 µg/litre. In the same
    study,  Gammarus fasciatus was exposed to lindane at concentrations
    of 1.2-17.7 µg/litre. The NOEL for survival and reproductive success
    was 4.3 µg/litre.  Gammarus fasciatus is thus more sensitive to
    both the acute and chronic effects of lindane.

    9.2.1.2  Aquatic arthropods

         The results of studies on the acute toxicity of lindane in
    freshwater insects (mainly nymphs) are summarized in Table 15.
    Aquatic insects can be seen to be sensitive to lindane, with
    considerable differences between the tested species. The NOEL for
    continuous exposure of two successive generations of  Chironomus
     tentans was 2.2 µg/litre (Macek et al., 1976).

         The 48-h LC50 for the water mite  Hydrachna trilobata Viets,
    an aquatic arachnida, was 0.05 mg/litre (Nair, 1981).

    9.2.1.3  Molluscs

         The acute effects of lindane have been investigated in bivalves
    and gastropods; no data were available on cephalopods. The LC50
    values determined (Table 16) are all > 1 mg/litre, and therefore at
    least one order of magnitude higher than those reported for fish,
    indicating that molluscs are much less sensitive to the acute action
    of lindane.

         Butler (1963b) determined shell growth in oysters exposed to
    various concentrations of lindane. When sufficiently irritated,
    oysters close their shells, do not feed and therefore do not grow.
    Even at the lowest dose tested, 1 mg/litre, a decreased shell growth
    of 43% was observed.

         The freshwater snail  Lymnea stagnalis was exposed to lindane
    at concentrations of 1 or 2 mg/litre for periods up to seven weeks,
    and therefore at least two successive generations. No increase in
    mortality over that in controls was observed at either
    concentration. A slight decrease in shell growth was found at 2
    mg/litre, and egg production was reduced at 1 and 2 mg/litre.
    Embryonic development was also disturbed at both concentrations in a
    dose-dependent manner. A NOEL for reproduction was not obtained in
    this study, but the results suggest that it is close to 1 mg/litre
    (Bluzat & Seuge, 1979; Seuge & Bluzat, 1979a,b, 1982).

         In a study on the effects of lindane on egg production in the
    mud snail  Nassa obsoleta (Eisler, 1970a), the number of egg cases
    deposited by day 33 after treatment following initial exposure for
    96 h was measured. A clear NOEL was found at 1 mg/litre; the next
    dose tested (10 mg/litre) induced a clear decrease.

    
    Table 15.  Acute toxicity of gamma-HCH to freshwater and marine crustaceans
                                                                                                                        
    Species                               Size (g, mm,  Temperature  Test          96-h LC50   Reference
                                          cm, age)      (°C)         conditions    (µg/litre)

    Freshwater
    Daphnia magna                         24-h old      20           Static        516         Randall et al. (1979)
                                                                     Static        485         Juhnkje & Lüdemann (1978)
                                          18-h old      20           Static        1100        Sanders & Cope (1966)
    Daphnia pulex                         18-h old      21           Static        460         Sanders & Cope (1966)
    Gammarus fasciatus                                               Static        39          Juhnke & Lüdemann (1978)
    Gammarus pulex                        1.0-1.5 cm    15           Statica       34          Abel (1980)
    Gammarus lacustris                    2 months?     21           Static        48          Sanders (1969)
    Simocephalus serrulatus               18-h old      21           Static        880         Sanders & Cope (1966)

    Marine
    Pink shrimp (Penaeus duorarum)        30-52 mm      24-26        Flow-through  0.17        Schimmel et al. (1977)
    Brown shrimp (Penaeus aztecus)        Adult         30           Flow-through  0.4         Butler (1963b)
    Brown shrimp (Crangon crangon)        -             15           Static        1-3.3       Portmann (1970)
    Grass shrimp (Palaemonetes pugio)     -             23-27        Flow-through  4.4         Schimmel et al. (1977)
    Grass shrimp (Palaemonetes vulgaris)  0.47 g        20           Static        10          Eisler (1969)
    Sand shrimp (Crangon septemspinosa)   0.25 g        20           Static        5           Eisler (1969)
    Hermit crab (Pagurus longicarpus)     0.28 g        20           Static        5           Eisler (1969)
    Mysid shrimp (Mysidopsis bahia)       8-9.5 mm      23-25        Flow-through  6.3         Schimmel et al. (1977)

    a Water renewed regularly

    Table 16.  Acute toxicity of gamma-HCH to aquatic invertebrates
                                                                                                                                
    Species                    Freshwater/    Size (g, mm,   Temperature   Test         96-h LC50   Reference
                               Marine water   cm, age)       (°C)          conditions   (mg/litre)

    Bivalves
    Mytulis galtoprovincialis  Marine         50-70 mm       17            Static       5.5         Rao (1981)
    Mercenaria mercenaria      Marine         Eggs           20            Static       > 10        Eister (1970a)
                               Marine         Eggs           24            Static       > 10a       Davis & Hidu (1969)
    Crassostrea virginica      Marine         Eggs           24            Static       9.1a        Davis & Hidu (1969)
    Cardium edule              Marine         -              15            Static       10a         Portmann (1970)

    Gastropods
    Physa acuta                Freshwater     -              20-28         Static       8.1a        Hashimoto & Nishiuchi (1981)
    Semisulcospira libertina   Freshwater     -              20-28         Static       6.2a        Hashimoto & Nishiuchi (1981)
    Indoplanorbis exastus      Freshwater     -              20-28         Static       7.1a        Hashimoto & Nishiuchi (1981)
    Lymnea stagnalis           Freshwater                                  Staticb      7.3a        Bluzat & Seuge (1979)

    Insects
    Cloeon diprerum            Freshwater     -              20-28         Static       0.15a       Hashimoto & Nishiuchi (1981)
    Chironomus tentans         Freshwater                                  Static       0.207a      Juhnke & Lüdemann (1978)
    Pteronarcys californica    Freshwater     30-35 mm       15.5          Static       0.0045      Sanders & Cope (1968)

    a 48-h LC50
    b Water renewed regularly

    
         Davis & Hidu (1969) found 67% survival of the larvae of the
    hard clam  Mercenaria mercenaria over 12 days after exposure to
    lindane at a concentration of 10 mg/litre. For oysters  (Crassostrea
     virginica), 50% survival was seen after exposure at 9.1 mg/litre
    over 48 h.

         Overall, these studies show that reproduction of molluscs is
    not adversely affected at concentrations just below 1 mg/litre, a
    level much higher than the NOELs for fish and crustaceans.

    9.2.2  Fish

    9.2.2.1  Acute toxicity

         The results of studies on the acute toxicity of lindane in fish
    have been reported in the literature since 1959, although in most of
    these no data were given on the purity of the lindane used. Since
    there is no significant difference in the values reported around
    1960 and those reported in 1975-80, however, data on the acute
    toxicity of lindane are summarized here regardless of whether the
    purity of the compound tested was reported.

         LC50 values for lindane in several fish species are
    summarized in Table 17. Most values fall within a range of 0.02-0.09
    mg/litre, the majority being around 0.05 mg/litre. Only Macek &
    McAllister (1970) found an extraordinarily low LC50 value for
    brown trout of 0.002 mg/litre.

         The symptoms of acute poisoning are mainly gross irritability,
    loss of equilibrium, changes in pigmentation and localized
    peripheral haemorrhage. Irritability appears within the first
    minutes of exposure and is accompanied by loss of equilibrium and
    disturbed swimming motion. Poisoned fish show signs of respiratory
    distress. Haemorrhages appear at sub-lethal doses 2-4 days after the
    beginning of exposure.

         A clear temperature dependence of the LC50 was found in
    bluegills (Cope, 1965; Macek et al., 1969), lindane being more toxic
    at higher temperatures, although the range of LC50 values was the
    same. Macek et al. (1969) found LC50 values of 0.054 mg/litre at
    12.7 °C and 0.037 mg/litre at 23.8 °C.

         In two studies, wild populations of mosquito fish were compared
    to laboratory strains and to each other with respect to the toxic
    action of lindane (Culley & Ferguson, 1969). Wild populations from
    areas that had previously been treated with lindane tolerated higher
    concentrations of the substance: one wild population had a LC50
    value of 3.104 mg/litre, whereas a susceptible population from a
    different region had a value of 0.074 mg/litre. These results
    suggest that wild populations can adapt to lindane when exposed
    repeatedly. Boyd & Ferguson (1964) found a similar effect.

    9.2.2.2  Long-term toxicity

         Macek et al. (1969) exposed bluegills to lindane at 0.6-9.1
    µg/litre for 18 months. No adverse effect was observed at any of the
    tested concentrations; the NOEL was therefore considered to be
    > 9.1 µg/litre. In the same study, fathead minnows  (Pimephales
     promelas) were exposed to lindane at 1.4-23.5 µg/litre for 43
    weeks. A statistically significant increase in mortality was
    observed at the highest dose. Growth of the surviving fish was not
    adversely affected, and spawning appeared to be normal in all test
    groups. The NOEL in this experiment was considered to be 9.1
    µg/litre.

         Macek et al. (1969) exposed brook trout  (Salvelinus
     fontinalis) to lindane at concentrations of 1.0-16.6 µg/litre for
    261 days. Only slight effects on growth were observed at the end of
    the exposure period. Although no statistical assessment of spawning
    was performed, fish exposed to the highest test level were adversely
    affected in this respect, and the NOEL was set at 8.8 µg/litre.

         The results of these studies indicate that concentrations not
    far below those inducing 50% mortality are well tolerated for long
    periods (up to 18 months). A 5-10-fold difference can be seen
    between the maximum dose tolerated in long-term tests and the LC50
    in the three species tested (Macek et al., 1976).

    9.2.2.3  Reproduction

         The reproductive effects of lindane were tested in bluegills,
    fathead minnows, and brook trout (Macek et al., 1969). Spawning,
    hatchability of eggs, and survival of the fry appeared not to be
    adversely affected by concentrations of up to 9.1 µg/litre in
    guppies, up to 23.4 µg/litre in fathead minnows, and up to 2.1
    µg/litre in brook trout.

    9.2.3  Amphibia

    9.2.3.1  Acute toxicity

         All of the published studies on the acute toxicity of lindane
    in amphibia (Table 18) were undertaken with tadpoles. Tests on
    tadpoles are considered to be the most reliable for assessing
    possible adverse effects to aquatic organisms since these larvae
    live exclusively in an aquatic environment, whereas adults spend a
    major part of their lifetime outside the water. The results show
    that larvae of amphibia are less sensitive to lindane than fish.

    
    Table 17.  Acute toxicity of gamma-HCH to fish
                                                                                                                                             
    Species                               Freshwater/   Size (g,      Temperature  Test conditions   96-h LC50   Reference
                                          Marine water  mm, cm)       (°C)                           (µg/litre)

    Rainbow trout (Salmo gairdneri)       Freshwater    0.69 g        12           Statica           32          McLeay (1976)
                                          Freshwater    3.2 g         20           Static            38          Katz (1961)
                                                        0.6-1.7 g     13           Static            27          Macek & McAllister (1970)
                                                        0.7 g         13           Static            22          Cope (1965)
                                                        3-cm fry      12           Flow-through      22          Tooby & Durbin (1975)
                                                        Yearling      12           Flow-through      30          Tooby & Durbin (1975)
                                                        2.6 g         15           No detail         34b         Dion (1984)

    Brown trout (Salmo trutta)            Freshwater    0.6-1.7 g     13           Static            2           Macek & McAllister (1970)
                                                        1.1 g         15           No detail         38b         Dion (1984)

    Coho salmon (Oncorhynchus kisutch)    Freshwater    2.7-4.1 g     20           Static            50          Katz (1961)
                                                        0.6-1.7 g     13           Static            41          Macek & McAllister (1970)

    Chinook salmon (Oncorhynchus          Freshwater    1.5-5 g       20           Static            40          Katz (1961)
    tschawytscha)

    Bluegill (Lepomis macrochirus)        Freshwater    0.6-1.7 g     18           Static            68          Macek & McAllister (1970)
                                                        1.0 g         18           Static            53          Cope (1965)
                                                        0.26 g        19           Static            57          Randall et al. (1979)
                                                        -             25           Static            77          Henderson et al. (1959)
                                                        0.6-1.5 g     18           Static            51          Macek et al. (1969)

    Redear sunfish (Lepomis microlophus)  Freshwater    0.6-1.7 g     18           Static            83          Macek & McAllister (1970)

    Threespine stickleback (Gasterosteus  Freshwater    0.38-0.77 g   Room         Static            44 and      Katz (1961)
    aculeatus)                                                        temperature                    50c

    Carp (Cyprimus carpio)                Freshwater    0.6-1.7 g     18           Static            90          Macek & McAllister (1970)
                                                        6.8 cm        17-19        Static            280b        Lüdemann & Neumann (1960a)
                                                        -             -            Static            310b        Hashimoto & Nishiuchi (1981)

    Table 18.  Acute toxicity (48-h LC50) of lindane in tadpodes of freshwater amphibia under static conditions

    Species                Size (g, mm, cm, age)  Temperature (°C)  LC50 (mg/litre)   Reference

    Pseudacris triserata   7-days old             15.5              3.8               Sanders (1970)

    Bufo woodhousii        4-5-weeks old          15.5              5.4               Sanders (1970)

    Bufo bufo japonicus    -                      -                 24                Hashimoto & Nishiuchi (1981)

    Bufo bufo L.           25-30 mm               18-21             0.3               Lüdemann & Neumann (1960b)

    
    9.2.3.2  Effects on hatching and larval development

         Marchal-Segault & Ramade (1981) exposed eggs and larvae of
     Xenopus laevis to lindane at concentrations of 0.5-2 mg/litre in
    tap water. Hatchability was reduced by the highest dose only;
    however, development of the larvae was disturbed at all
    concentrations testing, as seen by lowered body weights, longer
    periods (four weeks) from hatching to metamorphosis, and
    morphological abnormalities. Altered function of the
    hypothalamo-hypophyseal axis, which regulates growth and
    metamorphosis, and dysfunction of the intermediate lobe of the
    hypophysis, which controls pigmentation, were suggested. A NOEL
    could not be established.

    9.3  Terrestrial organisms

    9.3.1  Honey-bees

         Atkins et al. (1973) estimated the LD50 in the honey-bee to
    be 0.56 µg.

    9.3.2  Birds

    9.3.2.1  Acute toxicity

         Some of the studies of the acute toxicity of lindane in birds
    were undertaken soon after its introduction as an insecticide, and,
    in these, the quality of lindane used is not specified.
    Nevertheless, these studies are included in this review, as well as
    studies in which no precise LD50 could be obtained.

         The results are summarized in Table 19. The values obtained
    cover a wide range, but most are in the order of 100 mg/kg body
    weight. Common symptoms of poisoning are vomiting and loss of
    appetite, loss of weight, and hyperexcitability; central nervous
    system symptoms occur as incoordination, convulsions, and tremors
    (Rosenberg et al.,1953; Dahlen & Haugen, 1954; Adamic, 1958; Turtle
    et al., 1963; Dittrich, 1966).

         In hens, lethal oral doses of 330-1440 mg/kg body weight caused
    inflammation of the gastrointestinal tract, degeneration of the
    liver and kidneys, and changes in ganglionic cells (Adamic, 1958).
    Similar findings were obtained in bobwhite quails and mourning doves
    (Rosenberg et al., 1953; Dahlen & Haugen, 1954) at 120-210 mg/kg
    body weight. In doves, doses of > 300 mg/kg body weight caused
    mainly liver atrophy, congested lungs and kidneys, and haemorrhage.

    
    Table 19.  Toxicity of lindane to birds

    Species                                     Parameter   Concentration (mg/kg)a  Reference

    Bobwhite quail (Colinus virginianus)        5-d LC50    882 (755-1041)          Hill et al. (1975)
                                                acute LD50  120-130 (male)          Dahlen & Haugen (1954)
                                                acute LD50  190-210 (female)        Dahlen & Haugen (1954)

    Japanese quail (Cotumix coturnix japonica)  5-d LC50    490 (408-589)           Hill & Camardese (1986)
                                                            205 and 425 (347-520)   Clausing et al. (1980)

    Ring-necked pheasant (Phasianus colchicus)  5-d LC50    561 (445-590)           Hill et al. (1975)

    Mallard (Anas platyrhynchos)                acute LD50  > 2000 (male)           Hudson et al. (1984)
                                                5-d LC50    > 5000                  Hill et al. (1975)

    Starling (Stumus vulgaris)                  acute LD50  100                     Schafer (1972)

    Red-winged blackbird (Agelaius phoeniceus)  acute LD50  75                      Schafer (1972)

    Common grackle (Quiscalus quiscula)         acute LD50  > 100                   Schafer (1972)

    House sparrow (Passer domesticus)           acute LD50  56 (320-100)            Schafer (1972)

    Common crow (Corvus brachyrhynchos)         acute LD50  > 100                   Schafer (1972)

    Mourning dove (Streptopelia risoria)        acute LD50  350-400                 Dahlen & Haugen (1954)

    Feral pigeon (Columba livia)                acute LD50  > 600                   Turtle et al. (1963)

    a Acute LD50 expressed as milligrams per kilogram body weight in a single oral dose; otherwise,
      concentration expressed as milligrams per kilogram food (i.e., birds were fed with a dosed diet
      for 5 days followed by a "clean" diet for 3 days)

    
         The concentrations of lindane in the diet that caused 50%
    mortality in young and adult bobwhite quail, ring-necked pheasants
    and mallard ducks within < 10 days and < 100 days (Dewitt et al.,
    1963) are summarized in Table 20.

    Table 20.  Oral LD50 of lindane in birdsa

    Species                       Lindane intake (mg/kg body weight)
                                  < 10 days           < 100 days
                                                                    
    Young bobwhite                1070                930
    Adult bobwhite                -                   1050
    Young ring-necked pheasant    175                 > 1800
    Adult ring-necked pheasant    -                   > 630
    Young mallard                 415                 -
    Adult mallard                 1000                -

    a From Dewitt et al. (1963)

    9.3.2.2  Short-term toxicity

         Chen & Liang (1956) fed white leghorn chickens and hybrid
    native ducks diets containing lindane at 2, 4, or 10 mg/kg of diet
    for three months. No adverse effect was observed in either species
    at any dose.

         When laying hens were fed diets containing lindane at 0.01,
    0.1, 1, or 10 mg/kg of diet for 60 days, no effect was observed on
    body weight gain, mortality, clinical symptoms, or egg production.
    The authors concluded that lindane does not adversely affect
    reproduction in hens at doses up to 10 mg/kg of diet (Ware & Naber,
    1961).

         Harrison et al. (1963) fed diets containing lindane at 4, 16,
    or 64 mg/kg to white Leghorn x Australorp chickens for 27 days.
    Increased mortality was seen in the highest dose group, and the two
    higher doses resulted in enlarged livers. No pathological change was
    found in the animals given the lowest dose, but in the two higher
    dose groups dose-dependent liver hypertrophy was observed. Tissues
    were not examined microscopically. The NOEL in this experiment was
    concluded to be 4 mg/kg of diet.

         The 30-day oral LD50 for male mallard ducks (12 animals) was
    30 mg/kg body weight; as the acute LD50 was > 2000 mg/kg body
    weight, the toxic action of lindane appears to be cumulative (Hudson
    et al., 1984).

         The LC50 values for lindane given in the diet for five days
    were 882 mg/kg of diet in bobwhite quail (aged 9 days), 425 mg/kg of
    diet in Japanese quail (aged 7 days), 561 mg/kg of diet in
    ring-necked pheasant (aged 10 days), and > 5000 mg/kg of diet in
    mallard ducks (aged 15 days) (Hill et al., 1975).

          (a) Effect on egg-shell quality: Whitehead et al. (1972a,b,
    1974) found that the shells of hens' eggs were not adversely
    affected by administration of lindane in amounts up to 200 mg/kg of
    diet; however, egg production was reduced at 100 and 200 mg/kg of
    diet. Doses of up to 100 mg/kg of diet had no effect on
    hatchability, egg weight, yolk weight, shell thickness, calcium
    content, shearing strength or structure. The NOEL was 10 mg/kg of
    diet. Similar findings were obtained in Japanese quail.

          (b) Field experience: A population of Canada geese  (Branta
     canadensis) living in the Pacific Northwest of the USA was
    observed from 1978 through 1981. Lowered reproductive success,
    increased mortality among adults and a population decline in this
    region were associated with the use of heptachlor for treating wheat
    seed. This hypothesis was supported by the results of analyses of
    eggs and tissues. In 1979, heptachlor was replaced by lindane for
    use in this area; the reproductive success of the geese increased,
    mortality decreased, and the population increased. There was no
    evidence of either biomagnification of lindane from treated seed to
    goose tissues or eggs or of induction of adverse effects by lindane
    (Blus et al., 1984).

    9.3.2.3  Reproduction

         Lindane (99.8% in olive oil) was administered by stomach tube
    to four groups of laying ducks  (Anas platyrhynchus domesticus),
    comprising one drake and four ducks, at doses of 0 or 20 mg/kg body
    weight daily, three times per week, or twice a week for eight weeks.
    Egg laying stopped immediately in the groups treated daily and three
    times weekly and was irregular when it resumed, with drastically
    reduced clutch sizes. The effect in the group treated twice weekly
    was marginal. At the end of treatment, the laying frequencies for
    the four groups were 50%, 8.3%, 11.7%, and 40%, respectively.
    Hepatic, plasma, and ovarian vitellogenin levels were reduced in the
    groups treated daily and three times per week; the ovaries of the
    birds in these groups lacked mature vitellogenic follicles, and the
    thecal layer of moderately differentiated oocytes became highly
    atrophic. Levels of liver RNA were markedly reduced. A single
    injection of stilboestrol at 50 mg/kg body weight restored egg
    laying and the other parameters to normal within 24 h, suggesting
    that lindane imposed its effects by inducing oestradiol
    insufficiency (Chakravarty et al., 1986).

    9.3.3  Mammals

         The toxicity of lindane to bats has been studied because of its
    use in timber treatment. Racey & Swift (1986) exposed pipistrelle
    bats  (Pipistrellus pipistrellus) to 1% lindane, both in
    combination with 5% pentachlorophenol in an organic solvent and
    alone. When it was applied in combination with pentachlorophenol, at
    the rates recommended by the manufacturer, to wooden roosting boxes
    six weeks before bats used them, the animals were killed within
    seven days; when the combination was applied 14 months before use,
    the animals died within 23 days. When lindane was applied alone two
    weeks before exposure of bats in the boxes, all animals died within
    four days. These results were significant at the 0.1% level.

         Boyd et al. (1988) exposed pipistrelle bats to wood blocks
    coated with lindane at 9.9 mg/m2 for 44 days and then for a further
    44 days to blocks coated with lindane at 866 mg/m2, 24 h after
    coating the blocks. Significant mortality ( p < 0.007) was
    recorded. In a second experiment, all bats exposed to lindane at
    either 147 or 211 mg/m2 died within 17 days, whereas no death
    occurred among controls exposed to the solvent only.

         Turner (1979) studied the distribution and concentration of
    gamma-HCH in maternal and fetal tissues of a 6.5-year-old desert
    bighorn  (Ovis canadensis cremnobates). The maternal organs and
    tissues and the tissues of the term ram fetus contained residue
    levels ranging from none detected to 0.01 mg/kg on a fat basis.
    Residues of 0.01 mg/kg were present in adipose tissues, muscle,
    liver, gonads, and placenta. Placental transfer of gamma-HCH thus
    appears to be very low.

    9.4  Appraisal

         The toxicity of lindane to organisms in the environment must be
    assessed on the basis of the results of laboratory toxicity tests
    and of the probable bioavailability of lindane to similar organisms
    exposed in the wild. The strong adsorption of lindane to particles
    might be expected to reduce its toxic effects below that seen in
    laboratory studies of microorganisms in culture and of aquatic
    organisms in water without sediment; however, there is insufficient
    information to substantiate this hypothesis. No information was
    available on the toxicity of lindane to organisms that feed on or
    live in sediment.

         Low levels of residues in birds in the wild, coupled with the
    reported low toxicity of lindane in laboratory tests, make it
    unlikely that it affects birds in the wild.

         Bats are killed by applications of lindane to wood at normal
    rates and are affected by residues of past wood treatment. Since
    many bat species are declining in numbers or are extremely rare,
    lindane must be regarded as a major hazard and its use avoided in
    areas where bats might be found. Other mammals are unlikely to be
    adversely affected by this compound.

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer (1987)
    evaluated the hexachlorocyclohexanes and concluded that there is
    sufficient evidence for the carcinogenicity to experimental animals
    of the technical grade and the alpha isomer; such evidence was
    considered to be limited for the beta and gamma isomers. There is
    considered to be inadequate evidence for their carcinogenicity in
    humans. Hexachlorocyclohexanes were thus classified into group 2B,
    possibly carcinogenic to humans.

         WHO (1990) classified technical-grade lindane as 'moderately 
    hazardous' in normal use, on the basis of an LD50 of 88 mg/kg. 
    The WHO/FAO (1975) issued a data sheet on lindane (No. 12), dealing 
    with labelling, safe handling, transport, storage, disposal, 
    decontamination, training, and medical supervision of workers, 
    first-aid and medical treatment.

         Lindane was evaluated by the FAO/WHO Joint Meeting on Pesticide
    Residues in 1966, 1967, 1968, 1969, 1973, 1974, 1975, 1977, 1979,
    and 1989 (FAO/WHO, 1967, 1968, 1969, 1970, 1974, 1975, 1976, 1978,
    1980, 1990). A maximal acceptable daily intake of lindane in humans
    was established at 0-0.008 mg/kg body weight by the 1989 Joint
    Meeting (WHO, 1990). This value is based on a NOAEL of 10 mg/kg in
    the diet, equivalent to 0.75 mg/kg body weight per day in rats and
    1.6 mg/kg body weight per day in dogs. Maximum residue limits have
    been recommended for more than 35 commodities, ranging from 0.01
    mg/kg in milk to 3 mg/kg on strawberries; a limit of 0.5 mg/kg was
    recommended for most fruit and vegetables (Codex Alimentarius
    Commission, 1986; Table 21).

    Table 21.  Maximum residue limits (MRL) for gamma-HCH of the
               Codex Alimentarius Commission (1986)
                                                                 
    Crop/Commodity                                    MRL (mg/kg)

    Apples                                            0.5
    Beans (dried)                                     1
    Brussels sprouts                                  0.5
    Cabbage                                           0.5
    Cabbage, Savoy                                    0.5
    Carrots                                           0.2 Eb
    Cattle, carcase meat (in the carcase fat)         2
    Cauliflower                                       0.5
    Cereal grains (including rice)                    0.5
    Cherries                                          0.5
    Cocoa beans                                       1
    Cocoa butter                                      1
    Cocoa mass                                        1
    Cranberries                                       3
    Currants (red)                                    0.5
    Eggs (on a shell-free basis)                      0.1 E
    Endive                                            2
    Grapes                                            0.5
    Kohlrabi                                          1
    Lettuce                                           2
    Milk                                              0.01
    Pears                                             0.5
    Peas                                              0.1
    Pigs, carcase meat (in the carcase fat)           2
    Plums                                             0.5
    Potatoes                                          0.05a
    Poultry (in the carcase fat)                      0.7 E
    Radishes                                          1
    Rapeseed                                          0.05a
    Sheep, carcase meat (in the carcase fat)          2
    Strawberries                                      3
    Sugar beets (roots)                               0.1
    Sugar beets (tops)                                0.1
    Spinach                                           2
    Tomatoes                                          2

    a Level at or about the limit of determination
    b E, Extraneous residue limit

    APPENDIX I.  CHEMICAL STRUCTURE

         The basic structure of HCH is a closed chain of six carbon
    atoms. The structure can have two spatial forms, a  cis and a
     trans configuration. Each carbon atom is bound to a hydrogen and a
    chlorine atom, and one of these substituents forms a plane with the
    two connecting carbon atoms. Since this plane is parallel to the
    'equator' of the molecule, this atom is said to be in the equatorial
    position. The bond with the other atom is parallel to the 'axis' of
    the molecule and is thus in the axial position. Owing to the size of
    the chlorine atom, the carbon atoms are not free to rotate, so the
    positions of the chlorine and hydrogen atoms are fixed: one is
    always in the equatorial position and the other in the axial
    position.

         The various combinations of the spatial orientations of the
    hydrogen and chlorine atoms on each of the carbon atoms of
    cyclohexane result in different isomeric compounds. Theoretically,
    17 isomers of HCH are possible; but, owing to spatial
    incompatibilities and thermodynamic instability, only nine isomers
    have been detected. They all have the trans configuration. In the
    beta isomer, all of the chlorine atoms are in the equatorial
    position. The positions in the major isomers of HCH are shown in
    Table 22 (Demozay & Marechal, 1972; Van Velsen, 1986).

        Table 22.  Positions of chlorine atoms in the major isomers of
               HCHa

    Isomer           Chlorine positionb       Physical structure

    alphac           AAEEEE                   Monoclinic prisms
    ß                EEEEEE                   Octahedral cubic
    lamda            AAAEEE                   Monoclinic crystals
    delta            AEEEEE                   Crystals/fine patelets
    epsilon          AEEAEE                   Monoclinic needles
                                              or hexagonal
                                              monoclinic crystals

    a From van Velsen (1986)
    b A, axial position; E, equatorial position
    c Racemate of two optical isomers
    
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    RESUME ET EVALUATION; CONCLUSIONS; RECOMMANDATIONS

    1.  Résumé et évaluation

    1.1  Propriétés générales

         L'hexachlorocyclohexane technique (HCH) est composé de 65-70%
    d'alpha-HCH, de 7-10% de beta-HCH, de 14-15% de gamma-HCH, et
    d'environ 10% d'autres isomères et composés. Le lindane contient
    > 99% de gamma-HCH. C'est un solide, avec une tension de vapeur
    faible, peu soluble dans l'eau mais très soluble dans les solvants
    organiques comme l'acétone, et dans les solvants aromatiques et
    chlorés. Le coefficient de partage  n-octanol/eau (Log Poe) est
    de 3,2-3,7.

         Le lindane peut être dosé à part des autres isomères du HCH
    après extraction par partage liquide/liquide, chromatographie sur
    colonne et chromatographie en phase gazeuse avec détection par
    capture d'électrons. Extrêmement sensibles, ces méthodes analytiques
    permettent d'identifier des résidus de lindane de l'ordre du
    nanogramme par kilogramme ou par litre.

         Depuis le début des années 50, le lindane est utilisé comme
    insecticide à large spectre; le secteur agricole y a recours
    notamment pour traiter les semences et les sols; on l'utilise pour
    traiter les arbres, le bois de construction et les matériaux
    entreposés; on l'applique sur le pelage des animaux pour éliminer
    les ectoparasites; on en fait également usage dans le domaine de la
    santé publique.

    1.2  Transport, réparation et transformation dans l'environnement

         Le lindane est fortement adsorbé aux sols contenant une grande
    quantité de matière organique; en outre, il peut s'imprégner dans le
    sol à la faveur d'une chute de pluie ou d'une irrigation
    artificielle. Sous l'effet des températures élevées des régions
    tropicales, il se dissipe en grande partie par volatilisation.

         Le lindane subit une dégradation rapide (déchloration) sous
    l'action des rayons ultra-violets, pour former des
    pentachlorocyclohexènes (PCCHS) et des tetrachlorocyclohexènes
    (TCCHs). Lorsque le lindane se dégrade en sol humide ou inondé ou en
    plein champ, sa demi-vie peut aller de quelques jours à trois ans,
    selon le type de sol, le climat, la profondeur à laquelle il se
    trouve, etc. Dans les sols consacrés aux cultures que l'on trouve
    habituellement en Europe, sa demi-vie est de 40 à 70 jours. Les sols
    non-stériles permettent une biodégradation plus rapide du lindane
    que les sols stériles. Les conditions anaérobies sont les plus
    propices à sa métabolisation microbienne. Le lindane présent dans
    l'eau se dégrade sous l'action des microorganismes contenus dans les
    sédiments, pour former les mêmes produits.

         Le lindane et les gamma-PCCHs sont fixés en quantité limitée
    par les plantes où ils subissent une translocation, surtout lorsque
    les sols contiennent une forte proportion de matières organiques. On
    trouve les résidus essentiellement dans les racines des plantes; la
    translocation ne s'effectue que peu - ou pas du tout - dans les
    tiges, les feuilles ou les fruits. La bioconcentration est rapide
    chez les microorganismes, les invertébrés, les poissons, les oiseaux
    et l'homme, mais la biotransformation et l'élimination le sont
    également lorsque l'exposition est interrompue. Les organismes
    aquatiques le fixent en plus grande quantité à partir de l'eau qu'à
    partir de la nourriture. Les facteurs de bioconcentration dans les
    organismes aquatiques vont de 10 à 6000 en laboratoire, et de 10 à
    2600 sur le terrain.

    1.3  Concentration dans l'environnement et exposition humaine

         On a trouvé du lindane en suspension dans l'air au-dessus des
    océans à des niveaux de concentration de 0,039-0,68 ng/m3; son
    niveau de concentration a atteint 1 ng/m3 dans l'air de certains
    pays. Les concentrations dans les eaux de surface de nombreux pays
    européens étaient la plupart du temps inférieures à 0,1 µg/litre.
    Dans le cas du Rhin et de ses affluents, le niveau de concentration
    variait entre 0,01 et 0,4 µg/litre de 1969 à 1974; après 1974, il
    était inférieur à 0,1 µg/litre. Dans l'eau de mer, des
    concentrations de 0,001-0,002 µg/litre ont été enregistrées. Les
    concentrations de lindane dans le sol sont généralement faibles -
    l'ordre de 0,001-0,01 mg/kg, sauf dans les zones de décharge.

         On a découvert du gamma-HCH chez les poissons et les crustacés,
    à des niveaux de concentration allant de 'indécelable' à 2,5 mg/kg
    (calculés par rapport aux matières grasses) selon qu'ils vivent en
    eau douce ou dans l'eau de mer et en fonction de leur teneur - faible
    ou élevée - en matières grasses. Des valeurs d'environ 330 et 440
    µg/kg (poids humide) ont été trouvées dans le tissu adipeux des ours
    polaires respectivement en 1982 et 1984. La concentration de lindane
    dans le foie des oiseaux prédateurs variait entre 0,01 et 0,1 mg/kg.
    En 1972-73, on a mesuré dans des oeufs d'épervier, en République
    fédérale d'Allemagne, des valeurs allant de 0,6 mg/kg à 11,1 mg/kg
    (calculées par rapport aux matières grasses).

         Les niveaux de concentration de lindane dans l'eau potable sont
    généralement inférieurs à 0,001 µg/litre, et dans les pays
    industrialisés, c'est dans la nourriture que se trouve 90% du
    lindane absorbé par l'homme. Au cours des 25 dernières années, on a
    analysé dans bon nombre de pays certains produits alimentaires à la
    recherche de leur teneur en lindane: dans les céréales, les fruits,
    les légumes, les légumes à gousse, les huiles végétales, les
    concentrations allaient de 'indécelable' à 5 mg/kg de produit. En ce
    qui concerne le lait, les matières grasses animales, la viande et
    les oeufs, les concentrations allaient de 'indécelable' à 5,1 mg/kg
    de produit (calculés par rapport aux matières grasses). On a

    rarement trouvé des concentrations plus élevées. Les niveaux de
    concentration dans le poisson étaient généralement très inférieurs à
    0,05 mg/kg de produit (calculés par rapport aux matières grasses).
    Des études de ration totale et de panier de la ménagère pour estimer
    l'apport quotidien de lindane chez l'homme, ont révélé d'importantes
    variations en fonction des époques: vers 1970, l'apport quotidien
    était égal ou inférieur à 0,05 µg/kg de poids corporel; en 1980, par
    contre, cet apport a diminué pour n'être plus qu'égal ou inférieur à
    0,003 µg/kg. Aux USA, l'apport journalier de gamma-HCH entre 1976 et
    1979 a diminué, passant de 0,005 à 0,001 µg/kg pour les tout-petits
    et de 0,01 à 0,006 µg/kg pour les enfants.

         Dans un certain nombre de pays, on a déterminé la concentration
    en lindane dans des tissus d'individus appartenant à la population
    générale. Aux Pays-Bas, la teneur du sang était de l'ordre de
    < 0,1-0,2 µg/litre, mais des concentrations bien supérieures ont été
    trouvées dans le sang d'individus vivant dans des pays utilisant du
    HCH technique. Dans différents pays, on a mesuré des niveaux moyens
    de concentrations dans le tissu adipeux de l'homme allant de < 0,0
    1 à 0,2 mg/kg (calculés par rapport aux matières grasses). Dans le
    lait humain, les concentrations de lindane sont généralement plutôt
    faibles, avec des moyennes allant de moins de 0,001 à 0,1 mg/kg,
    rapportées aux matières grasses; toutefois, on a constaté que ces
    valeurs s'abaissaient à la longue.

         Ainsi, le lindane est présent partout dans le monde; on le
    retrouve dans l'air, l'eau, le sol, les sédiments, les organismes
    aquatiques et terrestres, ainsi que dans la nourriture, encore que
    les concentrations dans ces compartiments du milieu soient
    généralement faibles et diminuent peu à peu. L'homme est exposé
    quotidiennement, par les aliments qu'il consomme; c'est ainsi que
    l'on peut trouver du lindane dans le sang, les tissus adipeux, et
    dans le lait de femme; toutefois, les doses ingérées sont également
    en diminution.

    1.4  Cinétique et métabolisme

         Chez les rats, le lindane est absorbé rapidement au niveau des
    voies digestives et se répartit dans l'ensemble des organes et
    tissus en quelques heures. C'est dans les tissus adipeux et la peau
    que l'on trouve les niveaux de concentration les plus élevés;
    diverses études ont fait état d'un rapport teneur des
    graisses/teneur du sang égal à 150-200, d'un rapport foie/sang de
    5,3-9,6, et d'un rapport cerveau/sang de 4-6,5. Un rapport
    graisses/sang identique a été trouvé chez des rats ayant inhalé du
    lindane. Ces rapports, qui varient en fonction du sexe, sont
    supérieurs chez les femelles. Au niveau de la peau, la résorption
    s'effectue très lentement et dans une faible proportion, ce qui
    explique la faible toxicité du lindane après exposition cutanée.

         Le lindane est métabolisé essentiellement dans le foie selon
    quatre réactions enzymatiques: la déshydrogénation en gamma-HCH, la
    déshydrochloration en gamma-PCCH, la déchloration en gamma-TCCH et
    l'hydroxylation en hexachlorocyclohexanol. Les produits finals après
    biotransformation sont des dérivés di-, tri-, tetra-, penta-, et
    hexachlorés. Ces métabolites sont excrétés essentiellement dans les
    urines sous forme libre ou conjugués à l'acide glucuronique, à
    l'acide sulfurique ou à la  N-acétylcystéine. Le processus
    d'élimination est relativement rapide, avec des demi-vies de 3-4
    jours chez le rat. Les bactéries et les champignons métabolisent le
    lindane en TCCH et en PCCH. La vitesse de la transformation
    métabolique dans les plantes est faible, la voie de dégradation
    principale passant par le PCCH pour aboutir au tetrachlorophenol, à
    des conjugués avec le bêta-glucose et à d'autres composés inconnus.
    Rien ne prouve que le lindane s'isomérise en alpha-HCH.

    1.5  Effets sur les êtres vivants dans leur milieu naturel

         Le lindane n'est pas très toxique pour les bactéries, les
    algues, les protozoaires: la dose sans effet est généralement de
    1 mg/litre. Son action sur les champignons est variable, avec des
    doses sans effet variant entre 1 et 30 mg/litre, selon l'espèce. Il
    est modérément toxique pour les invertébrés et les poissons, les
    valeurs CL(E)50 pour ces organismes étant de 20-90 µg/litre. Les
    études à court et à long terme portant sur trois espèces de poisson
    ont révélé que la dose sans effet est de 9 µg/litre; des
    concentrations de 2,1-23,4 µg/litre n'ont aucune conséquence sur la
    reproduction. Les valeurs de la CL50 pour les crustacés d'eau
    douce et marins varient entre 1 et 1100 µg/litre. Chez  Daphnia
     magna, il y a réduction, fonction de la dose, du taux de
    reproduction; la dose sans effet se situe entre 11 et 19 µg/litre.
    Une dose de 1 mg/litre n'a eu aucun effet néfaste sur la
    reproduction des mollusques.

         La DL50 pour les abeilles domestiques est de 0,56 µg/abeille.

         Les DL50 orales aiguës pour un certain nombre d'espère
    d'oiseaux se situent entre 100 et 1000 mg/kg de poids corporel. Des
    études à courte terme sur les oiseaux ont permis d'établir que des
    doses de 4-10 mg/kg de nourriture n'ont aucun effet, pas même sur la
    qualité de la coquille des oeufs. On a néanmoins constaté une
    moindre ponte chez les canes exposées à des doses de lindane allant
    jusqu'à 20 mg/kg de poids corporel.

         Des chauves-souris sont mortes dans les 17 jours qui ont suivi
    leur exposition à des copeaux sur lesquels on avait appliqué du
    lindane à la dose indiquée; les copeaux en contenaient initialement
    10-866 mg/m2. On ne possède aucune donnée concernant les effets
    sur les individus et les écosystèmes.

    1.6  Effets sur les animaux de laboratoire et effets in vitro

         La toxicité orale aiguë du lindane est modérée: la DL50 pour
    les souris et les rats est de l'ordre de 60-250 mg/kg de poids
    corporel, selon le véhicule utilisé. La LD50 dermique pour les
    rats est d'environ 900 mg/kg de poids corporel. La toxicité est
    révélée par des signes d'excitation au niveau du système nerveux
    central.

         Le lindane ne provoque aucune irritation ou sensibilisation de
    la peau; il est légèrement irritant pour les yeux.

         Une étude de 90 jours sur des rats a permis d'établir à 10
    mg/kg de nourriture (soit 0,5 mg/kg de poids corporel) la dose sans
    effet. A 50 et 250 mg/kg de nourriture, il y avait augmentation du
    poids du foie, des reins et de la thyroïde; à 250 mg/kg de
    nourriture, on constatait une augmentation de l'activité enzymatique
    du foie. Cette augmentation de l'activité enzymatique accélère la
    dégradation du lindane et autres dérivés. Une autre étude de 90
    jours sur des rats a montré qu'une dose de 4 mg/kg de nourriture
    (soit 0,2 mg/kg de poids corporel) pouvait être définie comme dose
    sans effet nocif; on a observé que des concentrations égales ou
    supérieures à 20 mg/kg de nourriture pouvaient avoir un effet
    toxique au niveau des reins et du foie. Une étude toxicologique à
    court-terme sur les souris n'a pas permis de définir la dose sans
    effet.

         On a constaté aucun effet toxique après administration de
    lindane à des chiens, pendant 63 semaines, 15 mg/kg de nourriture
    (soit 0,6 mg/kg de poids corporel). Une étude toxicologique menée
    pendant 2 ans sur des chiens et au cours de laquelle un grand nombre
    de paramètres ont été mesurés, a permis d'établir que
    l'administration de doses égales ou supérieures à 50 mg/kg de
    nourriture (soit 2 mg/kg de poids corporel) ne provoquait aucune
    anomalie apparente liée au traitement. Chez les animaux auxquels on
    avait administré des doses de 100 mg/kg de nourriture, on constatait
    toutefois une hausse des niveaux de phosphatage alcaline; avec des
    doses de 200 mg/kg, on observait des anomalies du tracé électro-
    encéphalographique, indiquant une excitation neuronale aspécifique.

         Chez des rats ayant inhalé du lindane à raison de 0,02-4,54
    mg/m3, 6 heures par jour pendant 3 mois, la dose la plus forte a
    entraîné une élévation des valeurs du cytochrome P450 hépatique; la
    dose sans effet nocif a été fixée à 0,6 mg/m3. Lors de deux études
    au long cours menées sur des rats de nombreuses années auparavant,
    on a expérimenté des doses de 10-1600 mg/kg de nourriture. L'une de
    ces études fixe à 50 mg/kg de nourriture la dose sans effet nocif. A
    100 mg/kg de nourriture, le foie augmente, une hypertrophie
    hépatocellulaire apparaît, ainsi qu'une dégénérescence graisseuse et
    une nécrose. L'autre étude établit à 25 mg/kg de nourriture (soit
    1,25 mg/kg de poids corporel) la dose sans effet; en doublant cette

    dose, on note une hypertrophie hépatocellulaire et une
    dégénérescence graisseuse.

         Des recherches ont été entreprises pour vérifier les effets que
    le lindane, après avoir été administré à des souris, des rats, des
    chiens et des porcs par voie orale, sous-cutanée et
    intrapéritonéale, pouvait avoir sur tous les aspects de la
    reproduction (chez les rats, sur trois générations), et évaluer sa
    toxicité pour l'embryon et sa tératogénicité. Le lindane administré
    par voie orale et parentérale n'a eu aucun effet tératogène (les
    côtes surnuméraires étant considérées comme des variations). Des
    doses de 10 mg/kg de poids corporel et plus administrées oralement-
    par gavage-se sont avérées toxiques pour le foetus et/ou la mère; on
    considère qu'une dose de 5 mg/kg de poids corporel est sans effet
    nocif. L'étude effectuée sur trois générations de rats, a montré que
    des doses de lindane allant jusqu'à 100 mg/kg de nourriture
    n'avaient d'influence ni sur la reproduction, ni sur la maturation;
    avec 50 mg/kg de nourriture, des modifications morphologiques inter-
    venaient au niveau du foie parmi la progéniture de la troisième
    génération, preuve d'une induction enzymatique. La dose sans effet
    était dans ce cas de 25 mg/kg (soit 1,25 mg/kg de poids corporel).

         Dans une étude de 22 jours effectuée sur des rats, on a
    déterminé que la dose sans effet neurotoxique était de 2,5 mg/kg de
    poids corporel.

         Des études bien conçues ont été effectuées pour déterminer la
    mutagénicité du lindane. Selon les résultats des recherches très
    larges entreprises, le lindane ne peut en aucun cas provoquer des
    mutations génétiques chez les bactéries ni dans des cellules
    mammaliennes; il n'entraîne pas non plus, chez  Drosophila
     melanogaster, des mutations récessives liées au sexe. D'autres
    expériences -  in vitro et  in vivo - ont montré qu'en outre le
    lindane ne provoque ni anomalies chromosomiques, ni échange de
    chromatides soeurs dans des cellules mammaliennes. La recherche de
    lésions de l'ADN bactérien et de liaisons covalentes avec l'ADN dans
    le foie de rats et de souris  in vivo, après administration par
    voie orale, a également donné des résultats négatifs. Les rares
    études où des résultats positifs ont été obtenus péchaient soit par
    une mauvaise conception d'ensemble, soit par le fait que la pureté
    du composé étudié n'avait pas été précisée. Quoi qu'il en soit, on
    peut dire que le lindane n'a globalement aucun pouvoir mutagène.

         Des études de cancérogénécité ont été effectuées chez la souris
    et le rat, avec des doses allant respectivement jusqu'à 600 mg/kg de
    nourriture et 1600 mg/kg de nourriture. Aux doses égales ou
    supérieures à 160 mg/kg de nourriture, on a observé des nodules
    hyperplasiques et/ou des adénomes hépatocellulaires chez les souris;
    lors de certaines études, les doses administrées ont dépassé le
    maximum toléré. Deux expériences ont montré qu'aucune élévation de
    l'incidence des tumeurs n'intervient lorsque l'on donne à des souris

    et à des rats des doses allant respectivement jusqu'à 160 et 640
    mg/kg de nourriture.

         Les résultats d'études sur l'initiation-promotion de la
    cancérogénicité, sur le mode d'action du lindane et sur sa
    mutagénicité indiquent que la réponse tumorigène observée avec le
    gamma-HCH chez la souris est sous la dépendance d'un mécanisme non
    génétique.

    1.7  Effets sur l'homme

         Le lindane a été à l'origine de plusieurs cas d'intoxications
    mortelles et non mortelles; il s'agissait soit d'accidents, soit
    d'absorption délibérée (suicide), soit d'une simple négligence
    (absence de précautions) ou d'utilisation impropre de produits
    médicaux contenant du lindane. Les symptômes consistaient en
    nausées, agitation, maux de tête, vomissements, tremblements,
    ataxie, convulsions toniques-cloniques et/ou modifications du tracé
    électroencéphalographique. Ces effets sont réversibles après
    interruption de l'exposition ou traitement symptomatique.

         Depuis 40 ans, l'utilisation du lindane est très répandue;
    pourtant on cite peu de cas d'intoxications survenant dans le
    contexte professionnel. Chez les individus qui travaillent à la
    fabrication du lindane ou à son épandage, donc soumis à une
    exposition prolongée, on a seulement constaté une augmentation de
    l'activité des enzymes métabolisantes au niveau du foie. Rien ne
    prouve l'existence d'une quelconque relation - évoquée dans
    certaines publications - entre exposition au lindane et apparition
    d'anomalies hématologiques. Quelques études de toxicologie aiguë ou
    à courte terme chez l'homme indiquent qu'une dose d'environ 1,0
    mg/kg de poids corporel ne provoque pas d'intoxication; en revanche,
    à la dose de 15-17 mg/kg de poids corporel, apparaissent de graves
    symptômes d'intoxication.

         Appliqué sur la peau, le lindane est absorbé à hauteur
    d'environ 10%; la proportion est plus élevée s'il y a lésions.

    2.  Conclusions

    2.1  Population générale

         Le lindane circule dans l'environnement et il est présent dans
    les chaînes alimentaires; de ce fait, l'homme ne peut échapper à
    l'exposition. Toutefois, l'apport alimentaire quotidien et
    l'exposition totale de la population dans son ensemble diminuent peu
    à peu, et, nettement inférieurs à la dose journalière admissible
    (DJA) conseillés, ne constituent pas une menace sérieuse pour la
    santé publique.

    2.2  Groupes de population particulièrement exposés

         La présence de lindane dans le lait maternel expose les enfants
    nourris au sein, à des doses généralement inférieures à la DJA, donc
    non toxiques. Les niveaux d'exposition existants - que l'on les
    souhaiterait tout de même inférieur - n'interdisent pas
    l'allaitement au sein.

         En ce qui concerne l'utilisation thérapeutique du lindane pour
    traiter la gale et les poux de corps, il convient de se conformer
    strictement aux doses prescrites.

    2.3  Exposition professionnelle

         Manipuler du lindane ne présente aucun danger, à condition de
    prendre toutes les précautions indiquées pour éviter le plus
    possible l'exposition.

    2.4  Effets sur l'environnement

         Les chauves-souris, qui s'accrochent au bois traité avec du
    lindane aux doses indiquées, en subissent les effets toxiques.
    Exception faite des résultats d'étude concernant les déversements
    accidentels dans le milieu aquatique, rien ne permet d'affirmer que
    la présence de lindane dans l'environnement constitue un danger
    sérieux pour d'autres êtres vivants.

    3.  Recommandations

    1.   Afin de réduire au minimum la pollution de l'environnement par
         d'autres isomères de HCH, il convient d'utiliser le lindane
         (> 99% de gamma-HCH) au lieu du HCH technique.

    2.   Afin d'éviter la pollution de l'environnement, il faut adopter
         des solutions adéquates pour se débarrasser des sous-produits
         et des effluents provenant des usines de fabrication de
         lindane.

    3.   Il faut prendre garde à ce que les déchets de lindane ne
         polluent ni les sols, ni les eaux.

    4.   Il faut donner à ceux qui manipulent du lindane les indications
         nécessaires sur les méthodes d'application et les précautions
         d'utilisation.

    5.   Il faut effectuer des études de cancérogénécité au long cours,
         qui soient conformes aux nonnes actuelles.

    6.   Il faut poursuivre la surveillance de la dose de lindane
         quotidiennement absorbée par la population générale.

    RESUMEN Y EVALUACIONES; CONCLUSIONES; RECOMENDACIONES

    Resumen y evaluación

    1.1  Propiedades generales

         El hexaclorociclohexano (HCH) de calidad técnica está formado
    por un 65-70% de alfa-HCH, un 7-10% de beta-HCH, un 14-15% de gamma-
    HCH y aproximadamente un 10% de otros isómeros y compuestos. El
    lindano contiene más del 99% de gamma-HCH. Es un compuesto sólido,
    con baja presión de vapor y poco soluble en agua, pero muy soluble
    en disolventes orgánicos, como la acetona, y en disolventes
    aromáticos y clorados. El coeficiente de reparto n-octanol/agua
    (log Poa) es de 3,2-3,7.

         El lindano puede determinarse por separado de los demás
    isómeros del HCH tras su extracción por reparto líquido/líquido,
    cromatografía en columna y detección por cromatografía de gases con
    captura de electrones. Como estos métodos analíticos son sumamente
    sensibles, es posible identificar residuos de lindano del orden de
    nanogramos por kilogramo o por litro.

         El lindano lleva utilizándose desde el comienzo los años 50
    como insecticida de amplio espectro con fines agrícolas y de otro
    tipo, de los que cabe mencionar el tratamiento de semillas y de
    suelos, las aplicaciones en árboles, madera y materiales
    almacenados, el tratamiento de animales contra los ectoparásitos y
    en la salud pública.

    1.2  Transporte, distribución y transformación en el medio ambiente

         En los suelos con un alto contenido de materia orgánica se
    observa una intensa adsorción del lindano; además, puede penetrar en
    el suelo con el agua de la lluvia o del riego artificial. La
    volatilización parece ser una importante vía de dispersión en las
    elevadas temperaturas de las regiones tropicales.

         El lindano experimenta una rápida degradación (descloración)
    por acción de los rayos ultravioleta, formando
    pentaclorociclohexenos (PCCH) y tetraclorociclohexenos (TCCH).
    Cuando el lindano se descompone en el medio ambiente en condiciones
    de humedad o inmersión y en condiciones de campo, su semivida varía
    de unos días a tres años, en función del tipo de suelo, del clima,
    de la profundidad a la que se haya aplicado y de otros factores. En
    los suelos agrícolas normales en Europa su semivida es de 40 a 70
    días. La biodegradación del lindano es mucho más rápida en suelos no
    esterilizados que en los esterilizados. Las condiciones anaerobias
    son las más favorables para su metabolización microbiana. El lindano
    presente en el agua es degradado principalmente por microorganismos
    de los sedimentos para formar los mismos productos de degradación.

         Las plantas absorben y translocan en su interior cantidades
    limitadas de lindano y de gamma-PCCH, especialmente en suelos con un
    elevado contenido de materia orgánica. Los residuos se depositan
    sobre todo en las raíces de las plantas, y son pocos o ninguno los
    que se desplazan a las ramas, las hojas o los frutos. En los
    microorganismos, los invertebrados, los peces, las aves y el hombre
    tiene lugar una bioconcentración rápida, pero cuando se interrumpe
    la exposición se biotransforman y eliminan en un tiempo
    relativamente breve. En los organismos acuáticos es más importante
    su absorción a partir del agua que de los alimentos. Los factores de
    bioconcentración de estos organismos en condiciones de laboratorio
    variaron desde un valor aproximado de 10 hasta 6000; en condiciones
    de campo oscilaron entre 10 y 2600.

    1.3  Niveles medioambientales y exposición humana

         En el aire oceánico se han encontrado concentraciones de
    lindano de 0,039-0,68 ng/m3, y en el aire de algunos países se han
    medido cantidades de hasta 11 ng/m3. Las concentraciones estimadas
    en aguas de superficie de varios países europeos fueron en general
    inferiores a 0,1 µ/litro. Su concentración en el río Rin y sus
    afluentes en el período 1969-74 osciló entre 0,01 y 0,4 µg/litro;
    después de 1974 se mantuvo por debajo de 0,1 µg/litro. En el agua
    marina se han detectado niveles de 0,001-0,02 µg/litro. Las
    concentraciones de lindano en el suelo son por lo general bajas, del
    orden de 0,001-0,01 mg/kg, excepto en zonas de vertido de basuras.

         En pescados y mariscos se han detectado concentraciones de
    gamma-HCH que oscilan entre valores no detectables y 2,5 mg/kg
    (valores referidos a las grasas), dependiendo de que vivan en agua
    dulce o agua marina y de que su contenido en grasa sea alto o bajo.
    En el tejido adiposo de los osos polares se encontraron en 1982 y
    1984 niveles aproximados de 330 y 440 µg/kg (peso húmedo)
    respectivamente. La concentración de lindano en el hígado de aves
    predadoras oscilaba entre 0,01 y 0,1 mg/kg. Los huevos de gavilán
    recogidos en 1972-73 en la República Federal de Alemania contenían
    entre 0,6 y 11,1 mg/kg (cálculo referido a las grasas).

         Las concentraciones de lindano en el agua potable generalmente
    son inferiores a 0,001 µg/litro; en los países industrializados más
    del 90% de la ingestión humana de lindano procede de los alimentos.
    En los últimos 25 años se ha analizado el contenido de lindano de
    determinados productos alimenticios de un gran número de países. Las
    concentraciones halladas en cereales, frutas, hortalizas, legumbres
    y aceites vegetales variaron entre valores no detectables y 5 mg/kg
    de producto, y en la leche, las grasas, la carne y los huevos, entre
    valores no detectables y 5,1 mg/kg (referido a las grasas). Sólo en
    unos pocos casos se detectaron concentraciones más altas. Sus
    niveles en el pescado eran, en general, muy inferiores a 0,05 mg/kg
    de producto (referido a las grasas).

         En estudios sobre dieta total y cesta de la compra para estimar
    la ingestión humana diaria de lindano, se observó una clara
    diferencia con el paso del tiempo: la ingestión en el período de
    alrededor de 1970 llegaba a 0,05 µg/kg de peso corporal al día,
    mientras que en 1980 esta cifra había descendido a 0,003 µg/kg de
    peso corporal al día o menos. En los Estados Unidos, la ingestión de
    gamma-HCH entre 1976 y 1979 disminuyó de 0,005 a 0,001 µg/kg de peso
    corporal al día en los lactantes y de 0,01 a 0,006 µg/kg de peso
    corporal al día en los niños de corta edad.

         En algunos países se ha determinado el contenido de lindano en
    los tejidos corporales de la población general. En los Países Bajos,
    el contenido en la sangre era del orden de < 0,1-0, µg/litro, pero
    se hallaron concentraciones mucho más altas en varios países en los
    que se utilizaba HCH de calidad técnica. Las concentraciones medias
    en el tejido adiposo humano en distintos países varió entre < 0,01
    y 0,2 mg/kg (referido a las grasas). La concentración de lindano en
    la leche humana suele ser bastante baja, con unos niveles medios que
    van desde < 0,001 hasta 0,1 mg/kilo (referido a las grasas); sin
    embargo, se ha producido una disminución manifiesta con el tiempo.

         Así pues, el lindano se halla distribuido por todo el mundo y
    se puede detectar en el aire, el agua, el suelo, los sedimentos, los
    organismos acuáticos y terrestres y los alimentos, aunque las
    concentraciones en estos distintos compartimentos ambientales son en
    general bajas y están decreciendo progresivamente. El hombre está
    expuesto a diario por conducto de los alimentos, habiéndose
    detectado lindano en los tejidos sanguíneo y adiposo y en la leche
    materna; sin embargo, los niveles de ingestión también están
    disminuyendo.

    1.4  Cinética y metabolismo

         En las ratas, el lindano se absorbe rápidamente de¡ tracto
    gastrointestinal y en unas horas se distribuye por todos los órganos
    y tejidos. Las concentraciones más elevadas se dan en el tejido
    adiposo y en la piel; en varios estudios, el cociente grasa:sangre
    era de alrededor de 150-200, el cociente hígado:sangre, 5,3-9,6 y el
    cociente cerebro:sangre, 4-6,5. El mismo cociente grasa:sangre se
    encontró en ratas expuestas por inhalación. Estos cocientes varían
    en función del sexo, siendo más elevados en las hembras. La
    absorción por la piel tras la aplicación cutánea de lindano es lenta
    y muy limitada; esto puede explicar la baja toxicidad del lindano
    después de la exposición cutánea.

         El lindano se metaboliza sobre todo en el hígado mediante
    cuatro reacciones enzimáticas: deshidrogenación a gamma-HCH,
    deshidrocloración a gamma-PCCH, descloración a gamma-TCCH e
    hidroxilación a hexaclorociclohexanol. Los productos finales de la
    biotransformación son compuestos di-, tri-, tetra-, penta- y
    hexaclorados. Estos metabolitos se excretan fundamentalmente por la

    orina, en forma libre o conjugada con ácido glucurónico, ácido
    sulfúrico o  N-acetilcisteína. La eliminación es relativamente
    rápida, con una semivida en ratas de 3 a 4 días. Las bacterias y los
    hongos metabolizan el lindano a TCCH y PCCH. La velocidad de
    transformación metabólica en las plantas es baja, y la vía de
    degradación más importante es a través del PCCH a tri- y
    tetraclorofenol y productos conjugados con beta-glucosa y otros
    compuestos desconocidos. No existen pruebas de la isomerización del
    lindano a alfa HCH.

    1.5  Efectos en los seres vivos del medio ambiente

         El lindano no es muy tóxico para las bacterias, las algas ni
    los protozoos: el nivel carente de efecto fue en general de 1
    mg/litro. Su acción sobre los hongos es variable; los niveles sin
    observación de efectos fueron de 1 a 30 mg/litro, según las
    especies. Es moderadamente tóxico para los invertebrados y los
    peces, siendo los valores de la C(E)L50 para esos organismos de
    20-9 µg/litro. En estudios de corta y larga duración con tres
    especies de peces, el nivel sin observación de efectos fue de 9
    µg/litro; no se observaron efectos en la reproducción con niveles de
    2,1-23,4 µg/litro. Los valores de la CL50 para crustáceos
    dulceacuícolas y marinos variaron entre 1 y 1100 µg/litro. La
    inhibición de la reproducción de  Daphnia magna dependía de la
    dosis; el nivel sin observación de efectos fue del orden de 11-19
    µg/litro. No se observaron efectos adversos en la reproducción de
    moluscos con dosis de 1 mg/litro.

         La DL50 para la abeja de la miel fue de 0,56 µg/abeja.

         Los valores de la DL50 aguda por vía oral para varias
    especies de aves fueron de 100 a 1000 mg/kg de peso corporal. En
    estudios de corta duración con aves, las dosis de 4-10 mg/kg en la
    dieta no tuvieron efecto, ni siquiera sobre la calidad de la cáscara
    de los huevos. Sin embargo, en patas ponedoras tratadas con dosis de
    lindano de hasta 20 mg/kg de peso corporal disminuyó la producción
    de huevos.

         Todos los murciélagos expuestos a virutas de madera con un
    contenido inicial de lindano de 10-866 mg/M2, resultado de la
    aplicación de la dosis recomendada, murieron en un plazo de 17 días.
    No se obtuvieron datos acerca de los efectos en poblaciones y
    ecosistemas.

    1.6  Efectos en los animales de experimentación e in vitro

         La toxicidad aguda por via oral del lindano es moderada: la
    DL50 para ratones y ratas oscila entre 60 y 250 mg/kg de peso
    corporal, en función del vehículo utilizado. La DL50 por vía
    cutánea en ratas es de aproximadamente 900 mg/kg de peso corporal.

    La toxicidad se manifestó en forma de estimulación del sistema
    nervioso central.

         El lindano no irrita ni sensibiliza la piel; es ligeramente
    irritante para los ojos.

         En un estudio de 90 días en ratas, la concentración máxima sin
    efecto fue de 10 mg/kg alimento (equivalente a 0,5 mg/kg de peso
    corporal). Con niveles de 50 y 250 mg/kg de alimento aumentaron los
    pesos del hígado, los riñones y el tiroides; con 250 mg/kg de
    alimento, se observó un aumento en la actividad enzimática del
    hígado. Este aumento acelera la degradación del lindano y de otros
    compuestos. En otro estudio de 90 días en ratas, se consideró que el
    nivel máximo sin efectos adversos era de 4 mg/kg de alimento
    (equivalente a 0,2 mg/kg de peso corporal); se observó toxicidad
    renal y hepática a concentraciones de 20 mg/kg y superiores. Un
    estudio de toxicidad de corta duración en ratones se consideró
    insuficiente para establecer la concentración sin efectos.

         La administración de lindano a perros en dosis de 15 mg/kg de
    alimento (equivalentes a 0,6 mg/kg de peso corporal) durante 63
    semanas no tuvo efectos tóxicos. En un estudio de dos años de
    duración sobre la toxicidad de este compuesto en perros, en el que
    se midió un gran número de parámetros, no se observaron anomalías
    relacionadas con el tratamiento con dosis de 50 mg/kg de alimento
    (equivalentes a 2 mg/kg de peso corporal) e inferiores. Sin embargo,
    en el grupo que recibió 100 mg/kg de alimento aumentó el nivel de
    fosfatasa alcalina; y con 200 mg/kg de alimento aparecieron
    anomalías electroencefalográficas indicativas de irritación neurona]
    inespecífico.

         En ratas expuestas por vía respiratoria a concentraciones de
    lindano de 0,02-4,54 mg/m3, 6 horas al día durante 3 meses, la
    dosis más alta indujo un incremento de los valores del citocromo
    P450 hepático; el nivel sin observación de efectos adversos fue de
    0,6 mg/m33. En dos estudios de larga duración en ratas, realizados
    hace muchos años, se ensayaron dosis de 10-1600 mg/kg de alimentos.
    En uno de estos estudios se determinó un nivel sin observación de
    efectos adversos de 50 mg/kg de alimento (equivalente a 2,5 mg/kg de
    peso corporal). Con 100 mg/kg de alimento se producía un aumento del
    peso del hígado, hipertrofia hepatocelular, degeneración grasas y
    necrosis. En el otro estudio, la dosis de 25 mg/kg de alimento
    (equivalente a 1,25 mg/kg de peso corporal) no tenía efectos, pero
    con 50 mg/kg de alimento se observaron signos de hipertrofia
    hepatocelular y degeneración grasas.

         Se han investigado los efectos del lindano en todos los
    aspectos de la reproducción (en tres generaciones de ratas), y su
    embriotoxicidad y teratogenia tras la administración oral,
    subcutánea e intraperitoneal en ratones, ratas, perros y cerdos. No
    se observaron efectos teratogénicos tras la administración oral o

    parenteral (las costillas supernumerarias se consideraron
    variaciones). Se pusieron de manifiesto fetoxicidad y/o efectos
    tóxicos matemos con dosis de 10 mg/kg de peso corporal y superiores
    administradas mediante sonda oral; se considera que el nivel sin
    efectos adversos es de 5 mg/kg de peso corporal. En el estudio de
    tres generaciones de ratas con dosis de hasta 100 mg/kg de alimentos
    el lindano no ejerció efecto alguno en la reproducción ni la
    maduración, pero con 50 mg/kg de alimento se produjeron cambios
    morfológicos en el hígado, que demostraban la inducción enzimática
    registrada en la descendencia de la tercera generación. El nivel sin
    observación de efectos en este ensayo fue de 25 mg/kg de alimento
    (equivalente a 1,25 mg/kg peso corporal).

         En un estudio de 22 días en ratas se observó que la dosis sin
    efecto neurotóxico era de 2,5 mg/kg de peso corporal.

         Se han hecho estudios suficientes sobre la mutagenicidad del
    lindano. En las amplias investigaciones realizadas sobre su
    capacidad para inducir mutaciones génicas en bacterias y células de
    mamiferos y para provocar mutaciones letales recesivas ligadas al
    sexo en  Drosophila melanogaster, se obtuvieron siempre resultados
    negativos. El lindano también dio resultados negativos en los
    ensayos  in vitro e  in vivo realizados con células de mamíferos
    sobre lesiones cromosómicas e intercambio de cromátidas hermanas.
    Tambien fueron negativos los resultados de los ensayos para
    determinar las lesiones en el ADN de bacterias y los de las pruebas
     in vivo para observar la formación de enlaces covalentes con el
    ADN de hepatocitos de ratones y ratas tras su administración oral.
    En los escasos ensayos en los que se obtuvieron resultados
    positivos, el sistema de estudio no era adecuado o no se informó
    sobre la pureza del compuesto ensayado. Sin embargo, en conjunto, el
    lindano no parece tener potencial mutagénico.

         Se han llevado a cabo estudios en ratones y ratas para
    determinar el potencial carcinogénico del lindano con dosis de hasta
    600 mg/kg de alimento en ratones y de hasta 1600 mg/kg de alimento
    en ratas. En ratones que recibieron dosis de 160 mg/kg de alimento o
    superiores se observaron nódulos hiperplásicos y/o adenomas
    hepatocelulares; en algunos estudios, las dosis utilizadas superaban
    la máxima tolerada. En dos estudios en ratones con dosis de hasta
    160 mg/kg de alimentos como máximo y uno en ratas con 640 mg/kg de
    alimentos no se vio ningún aumento en la incidencia de tumores.

         Los resultados de los estudios sobre la iniciación y el
    estímulo de la carcinogenicidad, sobre el mecanismo de acción y
    sobre la mutagenicidad ponen de manifiesto que en la respuesta
    tumorigénica observada con el gamma-HCH en ratones interviene un
    mecanismo no genético.

    1.7  Efectos en el ser humano

         Se ha informado de varios casos de envenenamiento mortal y de
    enfermedad no mortal por lindano, producidos de manera accidental,
    intencionada (suicidio) o por una grave negligencia en las
    precauciones de seguridad o la utilización inadecuada de productos
    médicos con lindano. Los síntomas son náuseas, agitación, dolor de
    cabeza, vómitos, temblor, ataxia, convulsiones tónico-clónicas y/o
    cambios en el trazado electroencefalográfico. Estos efectos eran
    reversibles tras la interrupción de la exposición o el tratamiento
    sintomático.

         A pesar de su uso generalizado durante 40 años, se ha informado
    de muy pocos casos de envenenamiento en el trabajo. En los
    trabajadores expuestos durante largos períodos, en la fabricación o
    la aplicación del lindano, el único síntoma observado fue una mayor
    actividad de las enzimas hepáticas metabolizadoras de fármacos. No
    hay pruebas de la relación, sugerida en algunas publicaciones, entre
    la exposición al lindano y la aparición de anomalías hematológicas.
    Algunos estudios de toxicidad aguda y de corta duración en la
    especie humana indican que una dosis aproximada de 1,0 mg/kg de peso
    corporal no produce envenenamiento; sin embargo, con una dosis de
    15-17 mg/kg de peso corporal se observaron síntomas de intoxicación
    grave.

         Se absorbe alrededor del 10% de la dosis de aplicación cutánea,
    aunque a través de la piel lesionada pasa mayor cantidad.

    2.  Conclusiones

    2.1  Población general

         El lindano circula en el medio ambiente y está presente en las
    cadenas troficas, de manera que la especie humana seguirá estando
    expuesta. Sin embargo, la ingestión diaria y la exposición total de
    la población general están disminuyendo gradualmente; se encuentran
    claramente por debajo de la ingestión diaria admisible y no
    constituyen un problema para la salud pública.

    2.2  Subpoblaciones especialmente expuestas

         La presencia de lindano en la leche materna determina la
    exposición de los lactantes a niveles que generalmente son
    inferiores a la ingesta diaria admisible y que, por consiguiente, no
    son un problema para la salud. Aunque sería preferible que los
    niveles de exposición fueran inferiores, los actuales no representan
    un factor limitante de la práctica de la lactancia natural.

         Se deben seguir rigurosamente las prescripciones en relación
    con el uso terapéutico de¡ lindano contra la sarna y los piojos.

    2.3  Exposición profesional

         El lindano se puede manejar sin riesgo siempre que se observen
    las precauciones recomendadas para reducir al mínimo la exposición.

    2.4  Efectos en el medio ambiente

         El lindano es tóxico para los murciélagos que reposan en
    estrecho contacto con madera tratada de acuerdo con las
    recomendaciones para la aplicación. Si se exceptúan los resultados
    obtenidos en los estudios sobre derrames en el medio acuático, no
    hay pruebas que indiquen que la presencia de lindano en el medio
    ambiente plantee un riesgo importante para las poblaciones de otros
    organismos.

    3.  Recomendaciones

    1.   A fin de reducir al mínimo la contaminación del medio ambiente
         por otros isómeros del HCH, se debe utilizar lindano (> 99% de
         gamma-HCH) en lugar de HCH de calidad técnica.

    2.   Con objeto de evitar la contaminación del medio ambiente, los
         subproductos y efluentes de la fabricación del lindano se deben
         eliminar de manera adecuada.

    3.   En la eliminación de lindano, hay que tomar precauciones para
         evitar la contaminación de las aguas naturales y del suelo.

    4.   Como en el caso de otros plaguicidas, las personas encargadas
         del manejo del lindano deben recibir instrucciones adecuadas
         acerca de la manera de aplicarlo.

    5.   Se deben realizar ensayos de carcinogenicidad de larga duración
         diseñados con arreglo a las normas actuales.

    6.   Se debe seguir vigilando la ingestión diaria de lindano por
         parte de la población general.

    See Also:
       Toxicological Abbreviations
       Lindane (HSG 54, 1991)
       Lindane (ICSC)
       Lindane (PDS)
       Lindane (PIM 859)
       Lindane (FAO Meeting Report PL/1965/10/1)
       Lindane (FAO/PL:1967/M/11/1)
       Lindane (JMPR Evaluations 2002 Part II Toxicological)
       Lindane (FAO/PL:1968/M/9/1)
       Lindane (FAO/PL:1969/M/17/1)
       Lindane (WHO Pesticide Residues Series 3)
       Lindane (WHO Pesticide Residues Series 4)
       Lindane (WHO Pesticide Residues Series 5)
       Lindane (Pesticide residues in food: 1977 evaluations)
       Lindane (Pesticide residues in food: 1978 evaluations)
       Lindane (Pesticide residues in food: 1979 evaluations)
       Lindane (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Lindane (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)