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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 166





   METHYL BROMIDE






    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.

    First draft prepared by Dr. R.F. Hertel and Dr. T. Kielhorn.
    Fraunhofer Institute of Toxicology and Aerosol Research,
    Hanover, Germany

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

    World Health Orgnization
    Geneva, 1995


         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
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    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

    Methyl bromide.

        (Environmental health criteria ; 166)

        1.Hydrocarbons, Brominated - standards  2.Environmental exposure 
        I.Series

        ISBN 92 4 157166 7        (NLM Classification: WA 240)
        ISSN 0250-863X

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    CONTENTS

    1. SUMMARY

         1.1. Physical and chemical properties, and analytical
              methods
         1.2. Sources of human and environmental exposure
         1.3. Environmental transport, distribution, and
              transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on organisms in the environment
         1.7. Effects on experimental animals
         1.8. Effects on humans

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

         2.1. Identity
              2.1.1. Primary constituent
              2.1.2. Technical product
         2.2. Physical and chemical properties
              2.2.1. Physical properties
              2.2.2. Chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. Methyl bromide in air
              2.4.2. Methyl bromide in water
              2.4.3. Determination of methyl bromide in soil
              2.4.4. Methyl bromide in cereal grains and
                      other foods
              2.4.5. Methyl bromide in serum, plasma and blood
                      and post-mortem tissue
              2.4.6. Determination of inorganic bromide in air
              2.4.7. Determination of inorganic bromide in water
              2.4.8. Determination of inorganic bromide in soils
              2.4.9. Determination of inorganic bromide in plant
                      material/food
              2.4.10. Determination of inorganic bromide in
                      urine, blood/serum/plasma

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production levels and processes
                      3.2.1.1   Producers and world production
                                figures
                      3.2.1.2   Production processes

                      3.2.1.3   Losses to the environment during
                                normal production
                      3.2.1.4   Methods of transport
                      3.2.1.5   Accidental release or exposure
              3.2.2. Uses
                      3.2.2.1   Soil fumigation
                      3.2.2.2   Quarantine and non-quarantine
                                commodity treatments
                      3.2.2.3   Structural fumigation
                      3.2.2.4   Industrial uses
              3.2.3. Methyl bromide emission from motor
                      car exhausts

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Transport and distribution between media
              4.1.1. Transport in air
              4.1.2. Transport in water
              4.1.3. Transport in soil
              4.1.4. Vegetation and wildlife
              4.1.5. Entry into the food chain
         4.2. Biotransformation
              4.2.1. Biodegradation
                      4.2.1.1   Soil
                      4.2.1.2   Stored product fumigation
              4.2.2. Abiotic degradation
                      4.2.2.1   Hydrolysis
                      4.2.2.2   Light-assisted hydrolysis in water
                      4.2.2.3   Reaction with the hydroxyl radical
                      4.2.2.4   Photolysis in the atmosphere
              4.2.3. Bioaccumulation
         4.3. Interaction with other physical, chemical,
              or biological factors
         4.4. Ultimate fate following use
              4.4.1. Methyl bromide and the ozone layer
              4.4.2. Containment, recovery, recycling and disposal
                      options for methyl bromide

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
                      5.1.1.1   Global abundance
                      5.1.1.2   Measured oceanic and coastal air
                                levels of methyl bromide
                      5.1.1.3   Measured continental and urban
                                levels of methyl bromide
                      5.1.1.4   Vertical profiles of methyl bromide
                                in the atmosphere

                      5.1.1.5   Release of methyl bromide to
                                outside air from greenhouses
              5.1.2. Water
                      5.1.2.1   Seawater
                      5.1.2.2   Inland waters
                      5.1.2.3   Waters around greenhouses
              5.1.3. Soil
              5.1.4. Food
                      5.1.4.1   After soil fumigation
                      5.1.4.2   After post-harvest fumigation
              5.1.5. Animal feed
              5.1.6. Other products
              5.1.7. Terrestrial and aquatic organisms
         5.2. General population exposure
              5.2.1. Food
              5.2.2. Drinking-water
              5.2.3. Human breast milk
              5.2.4. Sub-populations at special risk
         5.3. Occupational exposure during manufacture,
              formulation, or use
              5.3.1. During manufacture
              5.3.2. During fumigation
                      5.3.2.1   Structural fumigation
                      5.3.2.2   Soil fumigation

    6. KINETICS AND METABOLISM

         6.1. Absorption
              6.1.1. Inhalation
                      6.1.1.1   Animal studies
                      6.1.1.2   Human studies
              6.1.2. Dermal
              6.1.3. Oral
              6.1.4. Intraperitoneal injection
         6.2. Distribution of methyl bromide and bromide
              in tissues
              6.2.1. Animal studies
              6.2.2. Human studies
         6.3. Metabolic transformation
              6.3.1. Binding to proteins and lipids
              6.3.2. Binding to DNA
              6.3.3. The role of glutathione in methyl
                      bromide metabolism
                      6.3.3.1   Mammals
                      6.3.3.2   Insects
         6.4. Elimination and excretion in expired air,
              faeces, urine
         6.5. Retention and turnover
         6.6. Reaction with body components

    7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1. Soil microorganisms
         7.2. Aquatic organisms
              7.2.1. Effect of methyl bromide
              7.2.2. Effect of bromide ion on aquatic organisms
         7.3. Terrestrial organisms
              7.3.1. Protozoa
              7.3.2. Plants
                      7.3.2.1   Seed fumigation
                      7.3.2.2   Fumigation of plants or plant
                                products
                      7.3.2.3   The effects on plants of soil
                                fumigation
              7.3.3. Soil invertebrates
              7.3.4. Insects and arachnids
              7.3.5. Gastropods
              7.3.6. Birds
              7.3.7. Other animals
         7.4. Population and ecosystem effects

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure
              8.1.1. Oral
              8.1.2. Inhalation
                      8.1.2.1   Guinea-pig and rabbit
                      8.1.2.2   Mouse
                      8.1.2.3   Rat
              8.1.3. Dermal
              8.1.4. Subcutaneous administration
         8.2. Short-term exposure
              8.2.1. Oral
              8.2.2. Inhalation studies
                      8.2.2.1   Guinea-pig, rabbit, monkey
                      8.2.2.2   Mouse
                      8.2.2.3   Rat
              8.2.3. Dermal
         8.3. Skin and eye irritation
         8.4. Long-term exposure
              8.4.1. Oral
                      8.4.1.1   Rat
              8.4.2. Inhalation studies
                      8.4.2.1   Mouse
                      8.4.2.2   Rat
         8.5. Reproduction, embryotoxicity, and teratogenicity
              8.5.1. Reproduction and embryotoxicity
              8.5.2. Teratogenicity

         8.6. Mutagenicity and related end-points
              8.6.1. DNA damage
              8.6.2. Mutation
              8.6.3. Chromosomal effects
                      8.6.3.1    In vitro studies
                      8.6.3.2    In vivo studies
              8.6.4. Cell transformation
         8.7. Carcinogenicity and related end-points
              8.7.1. Gavage studies
              8.7.2. Inhalation studies
         8.8. Special studies
              8.8.1. Target organ effects
                      8.8.1.1   Inhalation studies
              8.8.2. Neurotoxicity
              8.8.3. Immunotoxicity
         8.9. Factors modifying toxicity; toxicity of metabolites
         8.10. Mechanisms of toxicity - mode of action

    9. EFFECTS ON HUMANS

         9.1. Clinical findings
              9.1.1. Bromide levels in body tissues and fluids
              9.1.2. Dermal exposure
              9.1.3. Inhalation
         9.2. General population exposure
              9.2.1. Poisoning incidents
                      9.2.1.1   Poisoning associated with fire
                                extinguishers
                      9.2.1.2   Poisoning associated with bulk
                                or house fumigation
                      9.2.1.3   Poisoning associated with soil
                                fumigation
                      9.2.1.4   Miscellaneous incidents
         9.3. Controlled human studies
         9.4. Occupational exposure
              9.4.1. Occupational exposure during manufacture
              9.4.2. Occupational exposure due to methyl
                      bromide fumigation
                      9.4.2.1   Incidents involving bulk fumigation
                      9.4.2.2   Incidents involving soil fumigation
              9.4.3. Studies measuring the levels of bromide
                      ion in biological fluids and tissues
                      9.4.3.1   Manufacturing
                      9.4.3.2   Fumigation
              9.4.4. Haemoglobin adducts as a biological
                      index to methyl bromide exposure
              9.4.5. Neurobehavioural and other studies

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

         10.1. Human exposure
              10.1.1. Relevant animals studies
         10.2. Environment

    11. RECOMMENDATIONS FOR THE PROTECTION OF HUMAN HEALTH AND THE
         ENVIRONMENT

         11.1. Human health protection
         11.2. Environmental protection
         11.3. Recommendations for further research

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         12.1. FAO/WHO
         12.1. IARC
         12.3. UNEP

    REFERENCES

    RESUME

    RESUMEN
    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHYL BROMIDE

    Members

    Dr I. Chahoud, Institute for Toxicology and Embryo-pharmacology,
    Berlin, Germany

    Mr B. Chakrabarti, Ministry of Agriculture, Fisheries and
    Food, Slough, Berkshire, United Kingdom

    Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution,
    London, United Kingdom  (Chairman)

    Dr S. Eustis, National Institute of Environmental Health and Safety,
    Research Triangle Park, USA  (Joint Rapporteur)

    Dr K. Fujimori, National Institute of Health Sciences,
    Tokyo, Japan

    Dr L. Hansen, United States Environmental Protection
    Agency, Washington DC, USA

    Dr R.F. Hertel, Federal Health Office, Berlin, Germany

    Dr J. Kielhorn, Fraunhofer Institute of Toxicology and
    Aerosol Research, Hanover, Germany  (Joint Rapporteur)

    Dr G. Rosner, Fraunhofer Institute of Toxicology and
    Aerosol Research, Hanover, Germany

    Dr S.A. Soliman, College of Agriculture and Veterinary
    Medicine, King Saud University-Al-Qasseem, Bureidah,
    Saudi Arabia  (Vice-Chairman)

    Dr M. Tasheva, National Center of Hygiene, Ecology and
    Nutrition, Ministry of Health, Sofia, Bulgaria

    Dr P.W. Wester, National Institute of Public Health and
    Environmental Protection, Bilthoven, The Netherlands

    Prof. C. Zetzsch, Fraunhofer Institute of Toxicology and
    Aerosol Research, Hanover, Germany

     Observers

    Dr W.K. Hayes, Ethyl Corporation, Baton Rouge, LA, USA

    Dr M. Spiegelstein, Bromine Compounds Ltd., Beer Sheva,
    Israel

    Dr P. Montuschi, Catholic University of the Sacred Heart,
    Rome, Italy (Representing the International Union of
    Toxicology)

     Secretariat

    Dr D. McGregor, International Agency for Research on
    Cancer, Lyon, France

    Dr E. M. Smith, International Programme on Chemical
    Safety, World Health Organization, Geneva, Switzerland.

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication. In the interest of all users of the environmental health
    criteria monographs, readers are kindly requested to communicate any
    errors that may have occurred to the Director of the International
    Programme on Chemical Safety, World Health Organization, Geneva,
    Switzerland, in order that they may be included in corrigenda, 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, Case
    postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No.
    9799111).

                                    * * *

         This publication was made possible by grant number 5 U01
    ESO2617-15 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA, and by financial support
    from the European Commission.

    ENVIRONMENTAL HEALTH CRITERIA FOR METHYL BROMIDE

         A WHO Task Group on Environmental Health Criteria for Methyl
    Bromide met at the Fraunhofer Institute for Toxicology and Aerosol
    Research, Hanover, Germany, from 9 to 13 August 1993. Dr E.M. Smith,
    IPCS, welcomed the participants on behalf of Dr M. Mercier, Director
    of the IPCS, and the three IPCS cooperating organizations
    (UNEP/ILO/WHO). The Group reviewed and revised the draft and made an
    evaluation of the risks for human health and the environment from
    exposure to methyl bromide.

         The first draft of the EHC on methyl bromide was prepared by Dr
    R. F. Hertel and Dr J. Kielhorn at the Fraunhofer Institute of
    Toxicology and Aerosol Research in Hanover, Germany. Dr J. Kielhorn
    assisted the IPCS Central Unit in the preparation of the second draft,
    incorporating comments received following circulation of the first
    draft to the IPCS contact points for Environmental Health Criteria
    monographs.

         Dr E.M. Smith of the IPCS Central Unit was responsible for the
    scientific content of the monograph and Mrs M.O. Head, Oxford,
    England, for the editing.

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

    1. SUMMARY

    1.1  Physical and chemical properties, and analytical methods

         Methyl bromide is a colourless gas at room temperature and
    standard pressure with a boiling point of about 4 °C. It is heavier
    than air and easily liquefied below its critical points. It is
    odourless, except at high concentrations, when it has a
    chloroform-like smell. It is non-flammable in air, except in the
    concentration range of 10-16%, but burns in oxygen. Methyl bromide is
    slightly soluble in water but freely soluble in other common solvents.
    It can penetrate through many substances, such as concrete, leather,
    rubber, and certain plastics.

         Methyl bromide hydrolyses to methanol and hydrobromic acid in
    aqueous solution, the rate of hydrolysis depending on pH. It is an
    effective methylating agent that reacts with amines and
    sulfur-containing compounds. Most metals are inert to pure, dry methyl
    bromide, but surface reactions take place on zinc, tin, aluminium, and
    magnesium in the presence of impurities or moisture. Explosive
    reactions with aluminium and with dimethyl sulfoxide have been
    reported.

         Methyl bromide is commercially available as a liquefied gas.
    Formulations for soil fumigation contain chloropicrin (2%) or amyl
    acetate (0.3%) as warning agents. Other formulations include up to 70%
    chloropicrin or other fumigants or hydrocarbons as inert diluents. For
    commodity fumigation, 100% methyl bromide is used.

         Analytical methods are described for the determination of methyl
    bromide in air, water, soil, food, and animal feed. Direct methods for
    determining methyl bromide in air, under field conditions, include
    thermal conductivity gas analysers, colorimetric detector tubes,
    infra-red analysers, and photo-ionization detectors. Gas
    chromatography (GC) with electron capture detection (ECD) is
    recommended for routine measurements with occasional mass
    spectrometric (MS) confirmation in the laboratory.

         Purge and trap techniques as well as headspace sampling are used
    for the GC determination of methyl bromide in water. Extraction using
    acetone/water followed by headspace capillary gas chromatography with
    ECD is recommended for the routine determination of methyl bromide in
    foods. As some of the methyl bromide is converted to bromide in soil,
    foods, and biological materials, methods of bromide determination are
    also discussed. Colorimetric methods, X-ray spectroscopy,
    potentiometry, neutron activation analysis, gas chromatography, and
    high-performance liquid chromatography (HPLC) are some of the methods
    used for bromide determination in various matrices.

    1.2  Sources of human and environmental exposure

         Oceans are believed to be the major source of methyl bromide. The
    main anthropogenic source of methyl bromide is the fumigation of soils
    and indoor spaces. A small amount of methyl bromide is emitted from
    motor vehicles using leaded petrol.

         The world consumption of methyl bromide was over 67 million kg in
    1990, an increase of 46% over 1984. It is commonly produced by the
    interaction of methanol and hydrobromic acid, and, in some processes,
    it is a coproduct together with tetrabromobisphenol A. Methyl bromide
    is usually stored and transported as a liquefied gas, under pressure,
    in steel containers.

         About 77% of the methyl bromide produced is used for soil
    fumigation, 12% for quarantine and commodity fumigation, 5% for
    structural fumigation, and 6% for chemical intermediates.

         The gas is used as a soil fumigant in either fields or
    greenhouses for the control of pests. Methyl bromide is applied as a
    liquid prior to planting, either by injection into the soil, or by
    using evaporating jars under sheeting and allowing it to vaporize  in
     situ (cold method) or by heating (hot method). The methods permitted
    in various countries differ. The type of plastic sheeting is also
    important. 

         Doses of methyl bromide to be applied depend on the legal
    standards of different countries, the plant parasite to be controlled
    (type, extent of infestation), the following crop, type of soil, and
    the plastic cover used (covering time and plastic type). Methyl
    bromide is usually applied to soil at dosages of between 50 and 100
    g/m2.

         In space fumigation, methyl bromide is used for agricultural
    commodity fumigation (e.g., foods, grains, nuts, etc.), termite
    control, and rodent control. Dosages of 16-30 g methyl bromide/m3
    are used for most goods stored in sealed rooms and silos and under
    gas-proof sheets. A period of aeration must follow fumigation.
    Fumigation is also important for fresh vegetables and fruits where
    quarantine regulations have to be adhered to.

         The industrial uses of methyl bromide include organic synthesis,
    usually as a methylating agent, and as a low-boiling solvent, e.g.,
    for extracting oils from nuts, seeds, and flowers. The uses of methyl
    bromide as a refrigerant and as a general fire extinguishing agent are
    now only of historical importance.

    1.3  Environmental transport, distribution, and transformation

         Methyl bromide is present naturally in the atmosphere.
    Anthropogenic sources add to this. Although a small amount of methyl

    bromide reacts with the hydroxyl radical in the troposphere, some
    methyl bromide is transferred to the stratosphere by upward diffusion.
    Here photolysis of methyl bromide becomes of increasing importance, it
    being the most dominant loss mechanism in the lower stratosphere.
    Active bromine species react with ozone in the stratosphere and are
    thought to be partly responsible for the destruction of the ozone
    layer.

         In soil, methyl bromide is partially hydrolysed to bromide ion.
    After fumigation using methyl bromide, soil can be leached with water
    to prevent the bromide ions formed being taken up by plants
    subsequently planted on the sterilized soil. This increase in bromide
    levels may cause problems when surface water is used for leaching.
    Methyl bromide may diffuse through polyethylene drinking-water pipes,
    if the surrounding soil has been fumigated with methyl bromide.

         In the soil, methyl bromide can diffuse to a depth of 0.8 m,
    depending on the soil type, dosage, method of application, and length
    of fumigation, the highest content of methyl bromide remaining in the
    upper soil. The transport of the gas is caused by mass flow and
    molecular diffusion, but it is also influenced by simultaneously
    occurring sink processes, such as sorption and dissolution, and
    irreversible sink processes, such as hydrolysis. The amount of methyl
    bromide converted to bromide depends mainly on the organic matter
    content of the soil. The bromide produced is largely water soluble and
    can be taken up by plants or removed to lower soil levels by leaching
    with water.

         In plants, the amount of bromide accumulated depends on various
    factors, such as dosage, exposure time, aeration rate, the physical
    and chemical properties of the soil, the climatic trend (temperature
    and rainfall), the plant species, and the type of plant tissue.
    Especially leafy vegetables, such as lettuce and spinach, can take up
    relatively large amounts of bromide ion without phytotoxic symptoms.
    In contrast, other crops, such as carnations, citrus seedlings,
    cotton, celery, peppers, and onions, are particularly sensitive to
    methyl bromide fumigation.

         Methyl bromide and its reaction products, of which only bromide
    has been considered up to now, can enter the food chain in two ways;
    through consumption of food grown in greenhouses or fields fumigated
    before planting, or through eating food fumigated with methyl bromide
    during storage. At certain levels, bromide may be hazardous for health
    and tolerance levels are given for bromide in foodstuffs. Levels of
    other reaction products have not been investigated. 

         Methyl bromide is degraded in soil by hydrolysis and microbial
    degradation. The rate constant for hydrolysis varies with temperature
    and pH and is enhanced by light.

         The octanol/water partition coefficient (log Pow) of methyl
    bromide is 1.19, suggesting a low bioaccumulation.

         The methyl bromide that is not degraded during fumigation finds
    its way into the troposphere and by upward diffusion into the
    stratosphere. There does not seem to be a significant vertical
    gradient for methyl bromide in the troposphere, but levels decrease
    rapidly in the lower stratosphere where photolysis takes place.

    1.4  Environmental levels and human exposure

         Methyl bromide concentrations, measured in the air in unpopulated
    areas, range from 40 to 100 ng/m3 (10 to 26pptv), readings in the
    Northern hemisphere being higher than those in the Southern
    hemisphere. Most readings are in the range of 9-15 pptv. Seasonal
    differences have been found in some studies. In urban and industrial
    areas, the levels are much higher, with average values of up to 800
    ng/m3 and with some readings as high as 4 µg methyl bromide/m3. In
    the proximity of fields and greenhouses, during fumigation and
    aeration, the concentrations of methyl bromide are considerably
    higher, values of 1-4 mg/m3 being measured in one study at distances
    of up to 20 m from a greenhouse, a few hours after injection; a tenth
    of this value was found 4 days later.

         The methyl bromide concentration in a sample of surface seawater
    has been given as 140 ng/litre. The average value of bromide ion
    concentrations in samples of coastal water near the North Sea was 18.4
    mg/litre; the level of bromide ion in inland rivers was much lower,
    except in regions where fumigation with methyl bromide was practised,
    or, in areas of industrial pollution. In drainage water from a
    Netherlands greenhouse, levels of 9.3 mg methyl bromide/litre and 72
    mg bromide ion/litre were reported. In water discharged from a Belgian
    greenhouse, a value of 280 mg bromide/litre was recorded after
    fumigation.

         The natural bromide content of soil depends on the soil type, but
    is usually less than 10 mg/kg. The residue of bromide in fumigated
    soil depends on treatment, dosage, type of soil, amount of rain or
    leaching water, and temperature.

         Levels of methyl bromide or bromide may be elevated in foods that
    have either grown on soil previously treated with methyl bromide or
    have been fumigated post-harvest.

         On rare occasions, bromide levels in fresh vegetables, grown on
    soils previously fumigated with methyl bromide, have been observed to
    exceed the permitted residue level. In some countries, it is not
    permitted to grow vegetables on treated soils.

         Methyl bromide is widely used for fumigating post-harvest
    commodities, such as wheat and cereals, spices, nuts, dried and fresh
    fruits, and tobacco. Methyl bromide concentrations usually decrease
    rapidly after aeration and residues are not detectable after some
    weeks. Some foods, such as nuts, seeds, and fatty foods like cheese,
    tend to retain methyl bromide and inorganic bromide.

         Individuals may be exposed to the fumigant and residues of
    bromide ion. There could also be a risk of methyl bromide or increased
    bromide contents in water in shallow wells near methyl bromide
    fumigation operations.

         People living in close proximity to fields, greenhouses, or
    stores fumigated with methyl bromide, could be at risk of exposure to
    the gas. Individuals can also be endangered if they accidentally, or
    deliberately, enter private houses that have been fumigated to
    eradicate pests before it is declared safe to do so.

         Occupational exposure to methyl bromide is the most probable
    hazard for operators during production, filling processes, and
    fumigation operations. Because of strictly applied safety measures in
    production facilities, only fumigators are now considered a high-risk
    group. Fumigators engaged in structural fumigation may encounter
    exposure much higher than the TLV after 24 h aeration (80-2000
    mg/m3). However, properly trained operators will use appropriate
    protective equipment. Field workers during soil fumigation may be
    exposed for longer periods of time to transient doses of methyl
    bromide. Because of the nature of greenhouse fumigation, operators may
    also encounter higher concentrations (100-1200 mg/m3). However, risk
    management developed for various aspects of fumigation requires strict
    safety procedures and the use of protective equipment. Despite this,
    individual cases of accidental overexposure still occur.

    1.5  Kinetics and metabolism

         Inhalation studies on rats, beagles, and humans have shown that
    methyl bromide is rapidly absorbed through the lungs. It is also
    rapidly absorbed in rats following oral administration.

         After absorption, methyl bromide or metabolites are rapidly
    distributed to many tissues including the lung, adrenal gland, kidney,
    liver, nasal turbinates, brain, testis, and adipose tissue. In an
    inhalation study on rats, the methyl bromide concentration in tissues
    reached a maximum 1 h after exposure, but decreased rapidly, with no
    traces 48 h later. The metabolism of inhaled methyl bromide has not
    yet been elucidated, though glutathione may play a role.

         Methylation of proteins and lipids has been observed in the
    tissues of several species, including humans, exposed via inhalation.
    Methylated DNA adducts have also been detected following the  in vivo
    and  in vitro exposure of rodents or rodent cells.

         In inhalation studies using [14C] labelled methyl bromide, the
    exhalation of 14CO2 was the major route of elimination of 14C.
    A lesser amount of 14C was excreted in the urine. Following oral
    administration of methyl bromide, urinary excretion was the major
    route of elimination of 14C.

         The central nervous system is an important target for methyl
    bromide. Changes in monoamine, amino acid contents and, possibly,
    catecholamine contents may be factors involved in methyl
    bromide-induced neurotoxicity.

    1.6  Effects on organisms in the environment

         Methyl bromide is used commercially to control nematodes, weeds,
    and soil-borne fungi that cause diseases, such as damping off, crown
    rot, root rot, and wilt.

         There are few studies on the effects of methyl bromide on aquatic
    organisms, as methyl bromide itself is only slightly soluble in water.
    Values for LC50 range from a 4-h value of 17 mg/litre for  Cyprinus
     carpio L. to a 48-h value of 1.2 mg/litre for  Poecilia reticulata.
    At lethal concentrations, damage to the gills and oral epithelia was
    the probable cause of death.

         Bromide ion is formed from methyl bromide after fumigation and is
    found in water after leaching. Bromide ions showed acute toxicity in
    various freshwater organisms at concentrations ranging from 44 to 5800
    mg Br-/litre; the no-observed-effect concentration (NOEC) in
    long-term tests varied from 7.8 to 250 mg Br-/litre. Bromide ions
    markedly impaired reproduction in both crustaceans and fish.

         As a fumigant, methyl bromide can be applied directly to plant
    seeds, plant cuttings, or harvested plant products, for disinfestation
    during transportation and storage. Delay in germination or loss of
    germinative capacity can occur if the moisture level or temperature is
    too high.

         Some crops, particularly leafy vegetables, are sensitive to
    methyl bromide fumigation because of excess bromide in the soil, or,
    indirectly because of effects on soil microflora. Sometimes, methyl
    bromide has a positive effect on plants, increasing growth and crop
    yields.

         Methyl bromide fumigation eradicates not only target organisms
    but also part of the soil flora, gastropods, arachnids, and
    protozoans.

         Methyl bromide is often used in preference to other insecticides
    because of its ability to penetrate quickly and deeply into bulk
    materials and soils. Dosages for methyl bromide as a storage fumigant
    range mainly from 16 to 100 g/m3 for 2-3 days, the dosage depending

    on temperature. A higher dosage is required to kill eggs and pupae
    than adult insects. There is a variation in tolerance between
    different insect species and stages and between different strains of
    the same insect.

         There are no data on the direct effects of methyl bromide on
    birds and wild mammals.

    1.7  Effects on experimental animals

         Inhalation studies conducted on various mammalian species have
    shown that there are clear species-related and sex-related differences
    in susceptibility to methyl bromide. There was a steep dose-mortality
    response in all animal species tested.

         Neurological manifestations were the major clinical signs of
    toxicity in rats and mice and, at higher concentrations, irritation of
    the mucosal membranes was also observed.

         Neurological manifestations included twitching and paralysis. At
    lower dosages, changes in locomotor activity, dysfunction of the
    peripheral nerve changes in circadian rhythm, and conditioned taste
    aversion, have been reported by various authors.

         Histopathological changes have been described in the brain,
    kidney, nasal mucosa, heart, adrenal gland, liver, and testis of rats
    and mice exposed to various levels of methyl bromide.

         Olfactory sustentacular and mature sensory cells are damaged by
    short-term exposure to methyl bromide, but there is rapid repair and
    recovery.

         Long-term inhalation studies (up to 2 years) on rats showed
    lesions in the nasal mucosa and myocardium. In a similar long-term
    study on mice, the primary toxic effects were observed in the brain,
    heart, and nasal mucosa. Evidence of carcinogenicity was not observed
    in either species.

         Oral administration of 50 mg methyl bromide/kg body weight to
    rats for up to 25 weeks produced inflammation and severe hyperplasia
    of the forestomach epithelium. Following a post-exposure recovery
    period, fibrosis of the forestomach was the principle lesion observed.
    An early carcinoma of the forestomach was observed in the rat treated
    daily for 25 weeks.

         B6C3F mice and F344 rats exposed to up to 467 mg methyl
    bromide/m3 for 13 weeks showed slight changes in sperm morphology
    while the length of the estrous cycle was not affected.

         Inhalation exposure to up to 350 mg methyl bromide/m3 did not
    induce any noteworthy effects on the growth, reproductive processes,
    and offspring of two consecutive generations of CD Sprague-Dawley
    rats. The male and female fertility indices were reduced at the two
    highest dose levels in the F1 generation F2B litter.

         In studies on developmental toxicology with New Zealand White
    rabbits, exposure to 311 mg methyl bromide/m3 (6 h/day; days 7-19 of
    gestation) showed moderate to severe maternal toxicity. Developmental
    effects, observed at the maternal toxic dose, consisted of decreased
    fetal weights, an increase in the incidence of a minor skeletal
    variation, and malformations (mostly missing gallbladder or missing
    caudal lobe of the lung). However, at 272 mg/m3, maternal toxicity
    was less marked and there were no embryotoxic effects.

         No adverse maternal, embryonal, or fetal effects were observed in
    rabbits exposed to 78 or 156 mg methyl bromide/m3. A
    no-observed-effect level (NOEL) of 156 mg methyl bromide/m3 was
    given for maternal and development toxicity in New Zealand White
    rabbits.

         Methyl bromide has been found to be mutagenic in several  in
     vitro and   in vivo test systems. It induces sex-linked recessive
    lethal mutations in  Drosophila melanogaster and mutations in
    cultured mammalian cells. It does not induce unscheduled DNA synthesis
    or cell transformation in cultured mammalian cells. DNA methylation of
    the liver and spleen was observed in mice administered methyl bromide
    by various routes. Micronuclei were induced in bone-marrow and
    peripheral blood cells of rats and mice.

         The mechanism of methyl bromide toxicity is not known.

    1.8  Effects on humans

         Human exposure to methyl bromide may occur through inhalation of
    the gas or contact with the liquid. Exposure through ingestion of
    drinking-water contaminated with leaching water can also occur.

         A controlled human study showed that uptake following inhalation
    exposure was about 50% of the administered dose.

         Methyl bromide is damaging to the nervous system, lung, nasal
    mucosa, kidney, eye, and skin. Effects on the central nervous system
    include blurred vision, mental confusion, numbness, tremor, and speech
    defects. Topical exposure can cause skin irritation and burns, and eye
    injury.

         Exposure to high levels of methyl bromide causes pulmonary
    oedema. Central nervous system depression with respiratory paralysis
    and/or circulatory failure are often the immediate cause of death,
    which is preceded by convulsions and coma.

         Several different neuropsychiatric signs and symptoms have been
    observed during acute and long-term methyl bromide poisonings.
    Low-level short-term exposures to the vapour have produced a syndrome
    of polyneuropathy without overt central manifestations.

         Late sequelae include bronchopneumonia after severe pulmonary
    lesions, and renal failure with anuria and severe weakness with, or
    without, evidence of paralysis. Generally, these symptoms tend to
    subside over a period of a few weeks or months. However, deficits
    without recovery usually characterized by sensory disturbances,
    weakness, disturbances of gait and blurred vision, have been observed.

         Exposure to methyl bromide is accompanied by an increase in the
    bromide level in the blood. In fumigators, there is a relationship
    between the number of gas applications and the average plasma bromide
    level.

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

    2.1  Identity

    2.1.1  Primary constituent

    Chemical formula:                    CH3Br

    Chemical structure:

                                             H
                                             '
                                         H - C - Br
                                             '
                                             H

    Relative molecular mass:             94.94

    Common name:                         methyl bromide; bromomethane

    CAS name:                            bromomethane

    CAS registry number:                 74-83-9

    EEC No.                              602-002-00-2

    EINECS No.                           200-813-2

    Synonym:                             monobromomethane

    2.1.2  Technical product

         Methyl bromide is typically available as a liquefied gas
    (Matheson Gas Data Book, 1980).

    Purity:                              > 99.5%

    Max. water content:                  0.015%

    Max. acidity (as HBr):               0.0010%
                                         (Matheson Gas Data Book, 1980)

    Impurities:                          traces of chloromethane
                                         (Atochem, 1988)

         Formulations include mixtures with other fumigants, most
    frequently with chloropicrin or hydrocarbons, as inert diluents
    (Stenger, 1978). Chloropicrin (2%) or amyl acetate (0.3%) are added to
    methyl bromide to serve as a warning agent. Chloropicrin is a toxic
    chemical with lacrimatory and irritating effects. However, it is

    sensed at the 9 mg/m3 (1.3 ppm) level and a methyl bromide
    concentration could be well above regulatory exposure limits by the
    time the presence of chloropicrin is noticed.

         Chemical, environmental, and toxicological data concerning
    chloropicrin have been reviewed by Sassaman et al. (1986). For
    commodity fumigation, 100 % methyl bromide should be used (Ethyl
    Corporation, 1990).

         Methyl bromide is marketed under several different trade names,
    with formulations containing 30-100 % of the compound, e.g.,
    Brom-o-gas, Desbrom, Haltox, MBR-2, Metabrom, Methybrom, Methyl
    Bromide, Methyl-o-gas, Sobrom 9B, Terr-o-gas 100 (all 98-100% methyl
    bromide); Bromopic, Sobrom 67, Terr-o-gas (80-30%, with decreasing
    methyl bromide and increasing chloropicrin content).

    2.2  Physical and chemical properties

    2.2.1  Physical properties

         Methyl bromide is a colourless gas at normal temperature and
    pressure. Under increased pressure or below about 3 °C it is a clear,
    colourless to straw-coloured liquid. It is odourless except in
    relatively high concentrations, when it has a chloroform-like smell
    (Matheson Gas Data Book, 1980). Individual odour thresholds range
    between 80 mg/m3 and 4000 mg/m3 (Ruth, 1986).

         The gas can penetrate many substances, including concrete,
    leather, and rubber (Bond, 1984) as well as brick and wooden walls
    (BBA, 1989). Methyl bromide did not permeate through certain plastics
    (Herzel & Schmidt, 1984) or through metal or polyvinyl-chloride (PVC)
    pipes, but permeation through low-density polyethylene (LDPE)
    occurred. Permeation through LDPE pipes resulted in a concentration of
    6% in the contained water after one week. This was independent of the
    actual concentration outside the pipes. The methyl bromide seemed to
    concentrate within the polymer. Permeation through high density
    polyethylene (HDPE) was 5-8 times lower than through LDPE (Veenendahl
    & Dibbets, 1981).

         Liquid methyl bromide has a solvent action on many plastics and
    organic materials. Natural rubber is attacked and acquires a strong
    unpleasant smell (Thompson, 1966).

         The physical properties of methyl bromide are summarized in Table
    1.


        Table 1.  Physical properties of methyl bromide
                                                                                        
    Freezing point (1 atm):            -93 °Ca,b

    Boiling point (1 atm):             3.56 °Ca,b

    Flash point:                       194 °C, burns with difficultyc

    Flammability:                      13.5-14.5 % (by volume; flammable limits in air)a
                                       10-16%d

    Critical temperature               194 °Cc

    Autoignition temperature:          536.7 °Ca

    Vapour pressure (20 °C):           1893 kPa (1420 mmHg)b,e

    Density  (20 °C):                  3.974b
    (kg/m3)  (0 °C):                   1730a,b,c

    Vapour density:                    3.27c
    (rel.; air=1) (20 °C)

    Solubility in water:               18.5f (15.4 at 25 °C)f
    (g/litre; 20 °C)                   18.00g
                                       16h
                                       forms a voluminous crystalline hydrate
                                       (CH3Br.2OH2O) below 4 °Cb

    Solubility in other                freely soluble in alcohol, chloroform, ether,
    solvents:                          carbondisulfide, carbontetrachloride, and benzeneb

    log n-octanol/water partition      1.19i,j
    coefficient (log Pow):
                                                                                         

    Table 1. Con't
                                                                                         
    Henry's law constant:              0.533 (calculated using atmospheric
    (kPa m3/mol)                       pressure)b

    UV absorption:                     max. 202 nmk,l,m
                                                                                         

    a = Matheson Gas Data Book (1980); b = Windholz (1983);
    c = Hommel (1984); d = NFPA (1984); e = Stenger (1978);
    f = Wilhelm et al. (1977), g = Mackay & Shiu (1981); h = Atochem (1987);
    i = Hansch & Leo (1979); j = Sangster (1989); k = Robbins (1976b);
    l = Molina et al.(1982); m = Gillotay et al. (1989).
    

         There are discrepancies in values for the solubility of methyl
    bromide in water, some values in the literature being substantially
    lower than those given in Table 1.

         Methyl bromide is practically non-flammable in air, a narrow
    range of 13.5-14.5 % by volume being quoted in the Matheson Gas Data
    Book (1980), whereas a range of 16-20% is given in NFPA (1984). It
    burns in oxygen (Windholz, 1983).

    2.2.2  Chemical properties

         Methyl bromide hydrolyses to methanol and hydrobromic acid. It is
    a methylating agent reacting with amines, particularly the more basic
    ones, to form methylammonium bromide derivatives. Methyl bromide also
    reacts with sulfur compounds under alkaline conditions to give
    mercaptans, thioethers, and disulfides. Most metals, other than
    aluminium, are inert to pure, dry methyl bromide, but surface
    reactions take place on zinc, tin, and magnesium, in the presence of
    ethanol or moisture (Stenger, 1978). Explosions upon contact with
    aluminium, as well as with dimethyl sulfoxide, have been reported
    (NFPA, 1984). The liquid is corrosive to aluminium, magnesium and zinc
    metals and their alloys.

         Methyl bromide is not considered to be flammable. However, it
    will burn in air in the presence of a high-energy source of ignition
    and when within a narrow flammability range (see section 2.2.1).
    Methyl bromide has no flash point. Thermal decomposition in a glass
    vessel begins above 400 °C (Stenger, 1978). The products include HBr,
    bromine, carbon oxybromide, as well as carbon dioxide and carbon
    monoxide (von Oettingen, 1964).

    2.3  Conversion factors

    1 ppm = 3.89 mg/m3 at 25 °C, 1013 hPa
          or 3.95 mg/m3 at 20 °C, 1013 hPa

    1 mg/m3 = 0.257 ppm

    1% methyl bromide = 10 000 ppm = 39.52 g/m3 
    at 20 °C and 101.3 kPa

    2.4  Analytical methods

         Methyl bromide residues have been determined indirectly as total
    inorganic bromide. Methods are now available for the direct
    determination of methyl bromide.

    2.4.1  Methyl bromide in air

         A summary of methods for the detection of methyl bromide in air
    is given in Table 2.

         The detection of methyl bromide in air is important at three
    levels: control readings for warning fumigation workers; working place
    (e.g. production/packing and sealing/transport) measurements; and the
    measuring of levels of methyl bromide in the atmosphere.

         In the first case, exposed fumigation workers must be warned
    immediately of the presence of methyl bromide, as it is a toxic gas.
    Many formulations, particularly those for commodity fumigation, do not
    contain chloropicrin as a sensory warning.

         Halide lamps cannot detect methyl bromide around occupational
    exposure thresholds of 20 mg/m3 whereas electronic gas detectors,
    though not specific for methyl bromide, are extremely sensitive.
    Currently available gas detector tubes are also not specific for
    methyl bromide but can be used to provide a reasonably precise
    indication of methyl bromide level in a fumigation area before entry.

         Direct reading colorimetric indicators are available (Saltzman,
    1983; Leichnitz, 1985). However, Guillemin et al. (1990) noted that
    several batches of these tubes produced unreliable results.

         There is a direct-reading infrared analyser (MIRAN) that monitors
    from 10 mg/m3 (2.3 ppm) methyl bromide (Foxboro, 1989). As this
    instrument can measure methyl bromide below the threshold value, it
    has been used to determine whether buildings are safe for occupation
    after fumigation. However, Guillemin et al. (1990) reported that the
    portable systems were mechanically and electrically unstable under
    field conditions, and showed poor sensitivity and selectivity for
    methyl bromide.


        Table 2.  Methods for the analysis of methyl bromide in aira
                                                                                                                                    
    Sampling                  Analytical              Detector    Detection    Comment                      Reference
    method                    method                              limit
                                                                                                                                    
    Gas collected by pump     GC (30 m                ECD                      used for ambient             Harsch & Rasmussen
    and pressurized           capillary column)                                air                          (1977)
                               a ) isothermal runs                  40 ng/m3     determinations
                               b ) temperature                      2 ng/m3
                              programmed freeze-
                              out technique

    Injection of 5 ml sample  GC                      ECD         2 µg/m3      no common pollutants         Pellizzari et al.
                              (3 m steel              (scandium   (upper       interfere                    (1978)
                              column)                 tritide)    limit        with estimation
                                                                  1 mg/m3)

    Adsorb on charcoal;       100 m glass             MS          14 ng/m3                                  Pellizari et al.
    desorb (heat, purge with  capillary column                    (21°C)                                    (1978)
    helium); dry (calcium
    sulfate); readsorb
    (Tenax GC); desorb as
    before; trap liquid
    nitrogen cooled;
    vaporize onto GC

    Adsorb (polymeric                                 ECD         500 ng/m3                                 Krost et al. (1982)
    beads); desorb (heat,
    purge with helium); 
    trap directly on GC 
    column

    Gas collected by pump     GC                      ECD         40 µg/m3                                  Angerer (1982)
                              (2 m steel column)
                                                                                                                                    

    Table 2 (continued)
                                                                                                                                    
    Sampling                  Analytical              Detector    Detection    Comment                      Reference
    method                    method                              limit
                                                                                                                                    
    Adsorb on charcoal;       GC                      FID         1 mg/m3                                   Eller (1985),
    desorb (carbon disulfide                                                                                Peers (1985)
    inject aliquot

    Not given                 GC                      FID         2 ng         for fumigation               Dumas & Bond (1985)
                                                                               control

    Not given                 GC                      PID         10 pg        for ambient air              Dumas & Bond (1985)
                                                                               sampling

    Direct capillary          GC                      ECD         50 ng/m3     methyl bromide and           Kallio & Shibamoto
    trapping with pump                                                         chloropicrin                 (1988)
                                                                               detected

    Charcoal air sampling     GC                      ECD         50 ng        designed to handle           Woodrow et al. (1988)
    tube/headspace sampler                                                     large numbers of
                                                                               samples (45 samples
                                                                               in 24 h); not specific
                                                                               for methyl bromide

    HBr-treated activated     GC                      FID         1 mg/m3-     personal monitoring          Lefevre et al. (1989)
    charcoal tubes/solvent                            ECD         1 g/m3       method
    desorption
                                                                                                                            

    aAbbreviations:
    ECD = electron capture detector;                HECD = Hall electroconductivity detector;
    FID = flame ionization detector;                MS  = mass spectrometry;
    GC  = gas chromatography;                       PID = photoionization detector.
    

         Portable gas chromatographs measuring down to 0.04 mg/m3 (0.01
    ppm) are also available for field work (Bond, 1984). Guillemin et al.
    (1990) recommended for field conditions a photo-ionization detector
    using a 10.2 eV source previously calibrated in the laboratory for
    methyl bromide. The limitations were that readings were not specific
    for methyl bromide and that sensitivity decreased with time.

         Linenberg et al. (1991) used a portable GC with an argon
    ionization detector (AID) to identify methyl bromide (0.12 mg/m3; 31
    ppb) in the presence of other halohydrocarbon compounds for on-site
    analysis.

          In situ measurement of methyl bromide in indoor air using long
    path Fourier transform infrared (FTIR) spectroscopy has been described
    (Green et al., 1991). Quantitative determinations were made by
    comparison with reference spectra of known concentration. Detection
    limits were given as 0.14 mg/m3 (35 ppb), but conditions could be
    optimized to obtain more sensitivity.

         Methyl bromide is present in the atmosphere and its degradation
    products may react with the ozone layer (see section 5.1.1).

         Air samples can be collected using the following methods:

               - cryogenesis using liquid nitrogen or helium,

               - adsorption on (activated) charcoal,

               - pumping into special containers,

               - entry into already evacuated containers (BUA, 1987).

         Plastic tubing or containers must not be used as they absorb
    methyl bromide (Herzel & Schmidt, 1984).

         Methods using electron capture detectors (ECD) are suitable for
    routine measurements. GC/MS may be used for confirmation purposes.

         In the monitoring of methyl bromide in air, stainless steel
    canisters are recommended for collection with analysis using automated
    cryogenic preconcentration followed by gas chromatography with a
    selective detector - flame ionization (FID) and electron capture
    detectors (ECD) connected in parallel (Jayanty, 1989).

    2.4.2  Methyl bromide in water

         Methods of determination of methyl bromide in water are
    summarized in Table 3.

         Purge and trap techniques, as well as headspace sampling, have
    been used for the GC determination of methyl bromide in water. Details
    of the collection, preservation, and handling of the water sample to
    be analysed for methyl bromide are given in most references mentioned
    in this section.

         The headspace sampling technique can be used for analysis of
    virtually any matrix.

         Wylie (1988) compared headspace with purge and trap techniques
    for the analysis of volatile priority pollutants. The headspace method
    is more easily automated running 24 samples against only up to 10 with
    a purge and trap unit with autosample. There is also less chance of
    contamination from foaming or from high concentrations of a previous
    analyte with headspace. Virtually any matrix can be used with
    headspace, and glassware is disposable, which minimizes contamination.
    Under some conditions, purge and trap is more sensitive than
    headspace. US EPA recommended the purge and trap method for the
    analysis of volatiles (EPA; 1984a).

         An evaluation of methods for testing groundwater recommended in
    US EPA Methods 8010 (GC/ECD) and 8240 (GC/MS) gave practical
    quantification limits of 20 and 10 µg/litre, respectively, for methyl
    bromide (Garman et al., 1987).

         US EPA Methods 601 (GC/ECD), 602 (GC/MS) (Driscoll et al., 1987;
    Duffy et al., 1988) and 624 (GC/MS) (Lopez-Avila et al., 1987) have
    been updated for use with capillary column GC, to provide greater
    sensitivity.

         A sensitive headspace method for the gas-chromatographic
    determination of methyl bromide in surface and drinking-waters was
    reported by Cirilli & Borgioli (1986). This method is based on the
    conversion of methyl bromide into methyl iodide by reaction with
    sodium iodide.


        Table 3.  Determination of methyl bromide in watera
                                                                                                                               
    Sampling method              Analytical       Detector     Detection      Comment                    Reference
                                 method                        limit
                                                                                                                               
    Headspace                    GC               ECD          1 µg/litre                                Wegman et al. (1981)

    Purge and trap               GC               ECD          (n.d.)a                                   US EPA (1982a)
                                                                                                         (Method 8010)

    Purge and trap               GC               MS           5 µg/litre                                US EPA (1982b)
                                                                                                         (Method 8240)

    Purge and trap               GC               MS           (n.d.)a                                   US EPA (1984a)
                                 (packed column)                                                         (Method 624)

    Purge and trap               GC               ECD          1.18 µg/                                  US EPA (1984b)
    desorb as vapour                                           litre                                     (Method 601)
    (heat to 180 °C, 
    backflush with inert
    gas) on to GC column

    Add internal standard        GC               MS           50 µg/litre                               US EPA (1984c)
    (isotope labelled                                                                                    (Method 1624)
    methyl bromide); purge,
    trap and desorb as above

    Purge (80 °C, nitrogen);     GC               ECD          0.05 µg/                                  Piet et al. (1985)
    trap (Ambersorb or                                         litre
    Porapak N); desorb                            MS           0.05 µg/
    (flash-heat) and trap                                      litre
    in "mini-trap" 
    (Ambersorb or Porapak N,
    - 30°C); desorb (flash-
    heat) on to GC column
                                                                                                                               

    Table 3  (continued)
                                                                                                                               
    Sampling method              Analytical       Detector     Detection      Comment                    Reference
                                 method                        limit
                                                                                                                               
    Headspace                    capillary GC     ECD          5 x 10-3       methyl bromide             Cirilli & Borgioli
                                                               µg/litre       converted quantitatively   (1986)
                                                                              to methyl iodide, which
                                                                              is then determined

    Purge and trap               capillary GC     ECD                         optimization of methods    Driscoll et al. (1987)
                                                               PID            601, 602 to capillary      Duffy et al. (1988)
                                                                              column

    Purge and trap               capillary GC     MS                          updating of methods;       Lopez-Avila et al.
                                                                              no separation of           (1987)
                                                                              bromomethane from
                                                                              chloromethane

    Headspace sampling           capillary GC     MS           20 µg/litre                               Gryder-Boutet &
                                                                                                         Kennish (1988)

    Samples purged for           capillary GC     FID          1 µg/litre                                Cochran (1988)
    45 seconds directly
    to a cryogenically
    cooled, capillary
    column

    Purge and trap               capillary GC     ECD          1.1 µg/litre                              Ho (1989)
                                                                                                                               

    a For other abbreviations see Table 2.
    n.d. = methyl bromide was not detected in the earlier determinations.
    

         Singh et al. (1983) described the analysis of methyl bromide in
    seawater samples. A 50-ml volume of seawater and an equal volume of
    ultra-pure air were enclosed in all-glass syringes of 100-ml volume.
    Once in the syringe, the equilibrium was allowed to reach completion
    (enhanced by repeated shaking) in 15-30 min. This also allowed the
    water to reach room temperature, which was carefully recorded. The air
    in equilibrium with the 50-ml seawater was analysed for methyl bromide
    using gas chromatography with ECD; the corresponding equilibrium
    concentration of methyl bromide in seawater was determined from
    solubility data at the measured room temperature, and the two were
    added to obtain the methyl bromide concentrations in seawater. The
    partition coefficient data and their temperature dependence for methyl
    bromide were taken from Wilhelm et al. (1977) for pure water. The
    salting-out coefficient of 1.2 was determined on the basis of
    available data on the measured solubility of moderately soluble gases
    in pure water and seawater.

    2.4.3  Determination of methyl bromide in soil

         Equipment and methods for sampling and analysing deep field soil
    atmospheres have been described (Kolbezen & Abu-El-Haj, 1972). Soil
    atmosphere samples were obtained from a vertical and horizontal grid
    of sampling points placed into the soil before it was treated with
    methyl bromide. The samples were withdrawn through fine stainless
    steel tubing into syringes that could be transported to the laboratory
    and directly applied to the gas chromatograph. A flame ionisation
    detector (FID) was used (detection limit 40 mg/m3).

         US EPA Methods 8010 and 8240 (Table 3) can also been used for the
    determination of methyl bromide in solid waste and soils (US EPA,
    1982a,b) with a detection limit of 1 µg/g. Extraction of non-aqueous
    samples is carried out using methanol or polyethylene glycol. 

    2.4.4  Methyl bromide in cereal grains and other foods

         Analytical methods are summarized in Table 4.


        Table 4.  Determination of methyl bromide in plant material and foodsa
                                                                                                                                     
    Medium           Sampling method           Analytical     Detector       Detection      Comment               Reference
                                               method                        limit
                                                                                                                                     
    Flour,           cold solvent extraction,  GC             FID            0.3 mg/kg      95% recovery          Heuser & Scudamore
    unground         extraction time                                                                              (1968; 1970),
    wheat,           increasing with food                                                                         Scudamore (1987)
    sultanas,        particle size
    peanuts,
    maize,
    ground-nuts

    Whole wheat,     extracted methyl          GC             ECD            0.01 mg/kg                           Fairall & Scudamore
    flour, ground-   bromide is reacted                                                                           (1980)
    nut, rapeseed,   to form methyl iodide
    dried milk
    powder, cocoa
    beans

    Grain            acetone/water             GC (Carbo-     ECD            0.05 mg/kg                           Greve & Hogendoorn
                     extraction; headspace     wax-20 M)                                                          (1979)
                     analysis

    Wheat            flasks containing         GC             FID            0.3 µg/kg      determination of      Dumas (1982)
                     wheat flushed with        (2 m Tenax)                                  methyl bromide in
                     nitrogen and trap at                                                   wheat after 
                     -78.5 °C                                                               fumigation

    Grapefruit       blended with water        GC             ECD            0.1 mg/kg                            King et al. (1981)
                     and vial sealed, 5 ml                                   2 µg/kg
                     headspace gas removed
                     with syringe and
                     injected
                                                                                                                                     

    Table 4 (continued)
                                                                                                                                     
    Medium           Sampling method           Analytical     Detector       Detection      Comment               Reference
                                               method                        limit
                                                                                                                                     
    Wheat,           water added,              GC             ECD            0.4 µg/kg                            De Vries et al. 
    flour,           equilibration at 30 °C                                                                           (1985)
    cocoa,           headspace
    peanuts

    Cereal           extract with acetone:     GC             ECD            150 µg/kg                            Scudamore (1985a)
    grains           water; add sodium
    and              chloride; separate
    other            layers; dry acetone
    foods            solution over 
                     anhydrous calcium
                     chloride; inject
                     aliquot

                     extract with acetone:     GC             ECD            10 µg/kg                             Scudamore (1985b)
                     water, inject aliquot
                     of headspace vapour

    Cherries         headspace; adapted        GC             ECD            0.5 mg/kg      determination of the  Sell et al. (1988)
                     from King et al.                                                       rate of desorption
                     (1981)                                                                 from fumigated 
                                                                                            cherries

    Apples           headspace; adapted        GC             ECD            0.01 mg/kg                           Sell & Moffitt (1990)
                     from King et al.
                     (1981)
                                                                                                                                     

    Table 4 (continued)
                                                                                                                                     
    Medium           Sampling method           Analytical     Detector       Detection      Comment               Reference
                                               method                        limit
                                                                                                                                     
    Food             extraction with 83%       GC             ECD,           55 µg/kg       poor recovery and     Daft (1987; 1988; 
                     acetone (grains), 20%     (packed        HECD           20 µg/kg       high coefficient      1989)
                     acetone (softer foods);   column)                                      of variation
                     residues partitioned
                     into isooctane by
                     shaking; fatty food
                     passed through micro-
                     Florisil columns

    Nuts,            comminuted food sample    GC             ECD            dependent                            Page & Avon (1989)
    food             with sodium sulfate;      (capillary)                   on lipid
                     aliquot to headspace;                                   content of
                     cryogenic focusing at                                   food 0.15-
                     -60°C and then elution by                               0.65 µg/kg
                     temperature programming

    Nuts             extraction with sodium    GC             ECD,                          suitable for          Daft (1992)
                     sulfate at 80 °C; purge   (capillary)    HECD                          screening nut 
                     overnight                                                              samples at ng/g 
                                                                                            levels; 40% 
                                                                                            recovery; 29% 
                                                                                            coefficient of 
                                                                                            variation

    Fish             homogenization            GC             MS             200 µg/kg                            Easley et al. (1981)
                     purge and trap
                                                                                                                                     

    a For abbreviations see Table 2.
    

         Although bromide levels in food have been measured and documented
    for several decades, the methods for the determination of methyl
    bromide in foods are still being refined. The cold extraction or
    soaking procedure was developed and optimum extraction times
    determined for several foods, the extraction time increasing with food
    particle size (Heuser & Scudamore, 1968, 1970). With several foods,
    there was evidence of methyl bromide loss through reaction with food
    components. The following extraction times for methyl bromide were
    reported: flour (1 h), unground wheat (8 h), sultanas (8 h), peanuts
    (8 h), maize (24 h), groundnuts (24 h), and cocoa beans (48 h). When
    the procedure was reevaluated, it was found that the longer extraction
    time required for unground grain, compared with flour, probably
    reflected the migration of methyl bromide into the interior of the
    grain (Scudamore, 1987).

         An acetone/water extraction of grain followed by headspace
    analysis was described by Greve & Hogendoorn (1979). The headspace
    method has also been developed for sampling other selected foods,
    e.g., grapefruit (King et al., 1981), flour, cocoa, unground wheat,
    and peanuts (DeVries et al., 1985), cherries and apples (Sell et al.,
    1988; Sell & Moffitt, 1990).

         Headspace capillary gas chromatography with electron capture
    detection was described by Page & Avon (1989). The difference between
    this and other headspace procedures is the particle size reduction by
    the blending or homogenization of the cold or frozen sample with ice
    and cold water with only minimal loss of methyl bromide, resulting in
    a rapid 1-h equilibrium in the headspace vial. An advantage of
    headspace is that nonvolatile material is not introduced into the
    chromatographic column or injector body, thus shortening the run. The
    method is sensitive with detection limits of 0.15-0.65 µg/kg. These
    different detection limits are due to an inverse relationship of
    methyl bromide headspace response and food lipid content. Duplicate
    samples from the same vial are not possible, and, for quantification,
    a separate calibration curve is necessary for each food item.

         Combining the methods of Page & Avon (1989) and Daft (1987, 1988,
    1989), an improved method for the detection of methyl bromide in nuts
    was developed using extraction with sodium sulfate solution at 80 °C
    and purging overnight (Daft, 1992). A Hall electrolytic conductivity
    detector, used in the determinative step, has been found to be about
    3 times more sensitive to methyl bromide than ECD. Additionally, the
    Hall detector is said to eliminate endogenous interference from the
    nut samples. The recovery was 40% (coefficient of variation, 29%) and
    the method can be used to screen assorted nut samples for ng/g levels
    of incurred residues.

         Siegwart (1987) suggested using the headspace method for
    screening, but that with positive findings, the methyl bromide
    concentration should be confirmed using mass spectography. In

    addition, methyl bromide should then be converted to methyl iodide and
    determined again. A detection limit of under 10 µg/kg, is given.

         US EPA Method 624 (GC/MS) has been adapted for the determination
    of methyl bromide in fish (Easley et al., 1981). 

    2.4.5  Methyl bromide in serum, plasma and blood, and post-mortem
           tissue

    Marraccini et al. (1983) used a purge and trap method followed by mass
    spectroscopy to determine methyl bromide levels in post-mortem
    tissues. Tissue levels lower than 1 mg/kg (1 ppm) were detectable.

         Honma et al. (1985) detected methyl bromide in rat tissues using
    GC/ECD. The tissues were extracted with toluene. The presence of
    methyl bromide was confirmed by GC/MS. No detection limit was given
    but the lowest values reported were 1 ng/g.

         Headspace gas chromatography with split flame-ionization,
    electron-capture detection has been used to detect volatile substances
    including methyl bromide in biological fluids. The method offered
    economy of time with a sensitivity equivalent to a packed column
    (Streete et al., 1992).

    2.4.6  Determination of inorganic bromide in air

    Analytical methods for the determination of inorganic bromide in air
    are not described here as the concentration of bromide is not
    specifically related to the amount of methyl bromide in the
    atmosphere.

    2.4.7  Determination of inorganic bromide in water

         Vanachter et al. (1981) carried out bromide determinations in
    leaching water using the colorimetric method described by Malkomes
    (1970), in which the sample is first heated to dryness, then phenol
    red and chloramine-T (sodium  p-toluenesulfochloramine) solution
    added. After 5 min, the reaction is stopped with sodium thiosulfate.
    The resulting blue colour is read on a spectrophotometer at 590 mµ.
    The detection limit is 0.1 mg/litre (0.1 ppm).

         In another method, water samples were evaporated to dryness at 90
    °C. Sulfuric acid, ethylene oxide in diisopropylether, and
    acetonitrile were added and the sample shaken. After 30 min, an
    aliquot was removed and solid ammonium sulfate added and shaken. After
    separation, the upper layer was removed and anhydrous sodium sulfate
    added. An aliquot of the dried sample was analysed using GC/ECD
    (detection limit 0.01 mg/litre) (Wegman et al., 1981, 1983).


        Table 5.  Inorganic bromide in plant material/fooda
                                                                                                                                       
    Medium       Sampling method                   Analytical     Detector       Detection      Comment               Reference
                                                   method                        limit
                                                                                                                                       
    Grain        grind samples, add acetonitrile,  GLC            ECD            0.07 mg/kg     not suitable for      Heuser & Scudamore
                 ethylene oxide, and sulfuric                                                   fresh vegetables      (1970)
                 acid (4 h, 20 °C); separate
                 supernatant with ammonium
                 sulfate; extract with anhydrous
                 sulfate; supernatant analysed

    Salad/       dry samples at 110 °C; grind;     GLC            ECD            0.1 mg/kg                            Roughan et al.
    vegetables   add NaOH, ethanol; evaporate                                    (fresh mass)                         (1983)
                 to dryness; add to ulfuric 
                 acid solution/slurry 
                 acetonitrile and ethylene oxide;
                 analyse 2-bromoethanol

    Vegetables   extract sample with aqueous       GC             ECD            0.5 mg/kg      interlaboratory       Greve & Grevenstuk
                 ethanol; ash aliquot of                                         (fresh mass)   study                 (1979)
                 extract in the presence of
                 NaOH; treat extract with 
                 ethylene oxide

    Cereals,     extraction of inorganic bromide   GC             ECD            1 mg/kg                              Thier & Zeumer 
    dried        and conversion to 2-bromoethanol                                (fresh mass)                         (1987)
    fruit,       by suspension in aqueous                                        5 mg/kg
    dried        ethylene oxide and acidification                                (dried mass)
    vegetablea   by sulfuric acid; 2-
                 bromoethanol partitioned into 
                 ethyl acetate and analysed
                                                                                                                                       

    Table 5 (continued)
                                                                                                                                       
    Medium       Sampling method                   Analytical     Detector       Detection      Comment               Reference
                                                   method                        limit
                                                                                                                                       
    Vegetables   dried for 3 days and comminuted   specific                      lowest value                         Basile &
                 aliquots soaked in alcoholic KOH  ion                           given                                Lamberti (1981)
                 and mineralized overnight at      electrode                     0.1 mg/kg
                 600 °C; ash homogenized with
                 diluted NaNO3; supernatant
                 analysed

                 grind sample, shake with water    potentiometric ECD            0.1 mg/kg                            Cova et al. (1986)
                 (6 h); centrifuge extract         measurement
                 (50 ml) + NaNO3; evaporate        with specific
                 residue, dissolve in water        electrode

    Peaches      peaches blended with              bromide-                      0.2 mg/litre                         Austin & Phillips
                 NaNO3 crystals and                selective                     (wet mass)                           (1985)
                 water; centrifugation             electrode
                 supernatant

    Cereals,     ground/minced; dried              X-ray                         5 mg/kg                              Love et al. (1979)
    nuts,        100 °C (18 h), ground             fluorescence
    spices,      powdered sample with boric        spectroscopy
    fruit        acid-sodium sulfate

    Grain        macerated grain refluxed          thiosulfate                   lowest value                         Urga (1983)
                 in ethanol-ethanolamine;          titration                     given 
                 alkali digested; ashed (600°C);                                 4.5 mg/kg
                 water extraction; oxidized
                 with sodium hypochlorite
                                                                                                                                       

    Table 5 (continued)
                                                                                                                                       
    Medium       Sampling method                   Analytical     Detector       Detection      Comment               Reference
                                                   method                        limit
                                                                                                                                       
    Vegetables   fresh sample homogenized and      HPLC           UV             4 mg/kg        pH of the mobile      Van Wees et al. 
                 macerated with water then                        (205 nm)                      phase must be (1984)
                 homogenate centrifuged;                                                        adjusted to 5.0 
                 supernatant filtered and the                                                   (at higher pH,
                 filtrate used for analysis                                                     e.g., 6.0-6.5, an
                                                                                                overlap between
                                                                                                Br- peak and
                                                                                                sample interferenaces
                                                                                                may occur)
                                                                                                                                       

    a For abbreviations see Table 2.
    


    2.4.8  Determination of inorganic bromide in soils

         The colorimetric method of Malkomes (1970) (section 2.4.7) can
    also be used for soil. The sample is first sieved, dry-ashed, boiled
    in distilled water, and filtered. The filtrate is then analysed. 

         Brown et al. (1979) determined bromide in soil by extracting with
    calcium nitrate solution (0.1 mol/litre) and using a bromide-specific
    electrode for detection in the extract. No detection limit was given.

    2.4.9  Determination of inorganic bromide in plant material/food

         Various methods, such as X-ray spectroscopy, potentiometry,
    thiosulfate titration, gas/liquid chromatography, and high-performance
    liquid chromatography, have been used to determine bromide content
    (section 5.1.4). A summary of methods is given in Table 5.

         In the method described by Heuser & Scudamore (1970), bromide ion
    is converted into 2-bromoethanol by reaction with ethylene oxide in
    acetonitrile-diisopropyl ether, under acidic conditions. The
    2-bromoethanol is then determined by gas-liquid chromatography with an
    electron-capture detector (ECD). This procedure is suitable for wheat
    and maize but is not ideal for salad crops (because of cleaning
    procedures) where problems arise, such as severe tailing, lack of
    resolution, and poor recovery (Roughan et al., 1983). These authors
    varied some conditions, such as preparing the ethylene oxide in
    acetonitrile and using Carbowax 20M TPA to prepare the GC column. The
    samples (e.g., lettuce) were hydrolysed with alcoholic sodium
    hydroxide overnight, ashed for 2 h at 500 °C (600 °C for oily
    substances), and ground, prior to digestion with 0.6 N sulfuric acid
    (Greve & Grevenstuk, 1976; 1979). Recoveries of 97 % were achieved and
    the method was used to determine bromide down to 0.1 mg/kg of
    substrate fresh mass (Roughan et al., 1983). A wide range of
    vegetables and other crops have been analysed using this method
    (section 5.1.4).

         A similar procedure for cereals, dried fruit, and vegetables has
    been described using GC/ECD (Thier & Zeumer, 1987). The finely ground
    sample is suspended in an aqueous solution of ethylene oxide acidified
    with sulfuric acid. The inorganic bromide is extracted simultaneously
    and converted to 2-bromoethanol. This derivative is partitioned into
    ethyl acetate and determined, without further clean up, by electron
    capture gas chromatography.

         Bromide concentration in plant material has also been determined
    by X-ray fluoroscopy with a detection limit of around 5 mg/kg (Brown
    et al., 1979; Love et al., 1979).

         A specific ion electrode can be used for inorganic bromide
    determination using a standard calibration curve with a detection
    limit of around 0.1 mg/kg (Basile & Lamberti, 1981; Cova et al.,
    1986). Austin & Phillips (1985) used a bromide-selective electrode to
    detect levels of bromide ion in peaches; the detection limit for peach
    extract was 0.2 mg/litre.

         Urga (1983) used a thiosulfate titration method: the macerated
    grain was refluxed in ethanol-ethanolamine mixture, and then ashed
    (600 °C). The bromide ion was extracted with water and determined by
    oxidizing with sodium hypochlorite solution. This was titrated with
    sodium thiosulfate, using starch solution as indicator. The lowest
    level measured was 4.5 mg/kg.

         A quick screening method for inorganic bromide in vegetables,
    using high-performance liquid chromatography (HPLC) with a detection
    limit of around 4 mg/kg, was described by Van Wees et al. (1984).

    2.4.10  Determination of inorganic bromide in urine, blood/
            serum/plasma

         Various methods for the determination of bromide in biological
    fluids have been described: colorimetry (Kisser, 1967), X-ray
    fluoroscopy (Rapaport et al., 1982; Shenberg et al., 1988), neutron
    activation analysis (Heurtebise & Ross, 1971; Ohmori & Hirata, 1982),
    ion-sensitive electrode (Angerer, 1977, 1980); and headspace GC with
    FID (Yamano et al., 1987). Koga et al. (1991) compared headspace GC
    and an ion chromatography coupled with a conductivity detector to
    evaluate levels of bromide ion in urine. GC was more sensitive with a
    detection limit of 0.04 mg/litre. Honma et al. (1985) used an GC/ECD
    method for their studies on rats (section 6.2). A summary of methods
    is given in Table 6.

         In forensic science studies (overdose of bromide-containing
    sleeping tablets as well as suspected methyl bromide poisoning),
    colorimetric methods, such as that of Kisser (1967), have been
    routinely used (Weller, 1982). For routine occupational studies, other
    methods are more suitable.


        Table 6.  Determination of bromide in biological fluids and tissuesa
                                                                                                                                     
    Medium  Sampling method                     Analytical            Detection           Comment             Reference
                                                method                limit
                                                                                                                                     
    Urine/  add soda solution; evaporate        + chloramine          -                   -                   Kisser (1967)
    blood   and ash (550°C); ash + water        T-solution, sodium
            ->filter filtrate->bromide            thiosulfate

    Urine   alkali ashing (Kisser, 1967);       ion-sensitive         1 mg/litre          suitable for        Angerer (1977, 
            with KMnO4, bromide->bromine;        electrode                                 occupational        1980)
            bromine + sulfide soln->bromide                                                exposure studies

    Urine   headspace; methylation              GC                    0.4 mg/litre        2.7% standard       Koga et al. (1991)
            with dimethylsulfate                                                          deviation

    Urine                                       ion chromatography    1.0 mg/litre        8.7% standard       Koga et al. (1991)
                                                                                          deviation

    Serum                                       X-ray fluorescence    0.05 µg                                 Rapaport et al., (1982);
                                                                                                              Shenberg et al. (1988)

    Urine,                                      neutron activation    not given                               Heurtebise & Ross 
    saliva,                                     analysis                                                      (1971)
    serum,
    plasma

    Serum/                                      neutron activation    120 µg/g; 4 µg/g    occupational        Ohmori & Hirata 
    hair                                        analysis              (estimated)         studies             (1982)

    Plasma  head space plasma + water +         GC/FID                0.5 mg/litre                            Yamano et al. (1987)
            dimethylsulfate (Br-->
            methyl bromide)
                                                                                                                                     

    a For abbreviations see Table 2.
    

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural sources

         The atmospheric levels of methyl bromide are controlled by the
    amounts from natural and anthropogenic (man-made) sources and by the
    atmospheric and surface removal processes. Observational data (UNEP,
    1992) indicate that the current best estimate for the globally
    averaged abundance of methyl bromide in the troposphere is between 9
    and 13 pptv, which is equivalent to a total atmospheric loading of
    150-220 million kg. If the atmospheric lifetime of methyl bromide is
    two years, i.e., only tropospheric removal by reaction with OH - is
    significant, then a total emission of about 75-110 million kg per year
    is required to maintain the observed atmospheric level. However, if
    the atmospheric lifetime is only one year (assuming surface removal
    comparable in magnitude to the atmospheric removal), a global emission
    of 150-220 million kg per year is required to maintain the atmospheric
    methyl bromide at the same level (UNEP, 1992).

         Khalil et al. (1993) have used similar input data (global
    abundance of 10 pptv, lifetime of two years) to calculate a global
    source of about 100 million kg/year. On the basis of their
    measurements of ocean abundance and supersaturation (which differ
    considerably from those of Singh et al. (1983)), they estimated an
    ocean source of 35±5 million kg/year. They proposed that the
    anthropogenic sources must be about 30 million kg/year, assuming that
    the differences in calculated emissions for the northern and southern
    hemispheres are solely due to man-made sources. This leaves about 35
    million kg/year of emissions that cannot be categorized but are
    believed to originate from the tropics.

         From the surface water and air observations of methyl bromide
    concentrations off the Pacific coasts of North and South America,
    Singh et al. (1983) estimated the total natural emissions of methyl
    bromide from the oceans to be 300 million kg/year. The total oceanic
    emission quantified from the extrapolation of the limited data may not
    be entirely justifiable. Using the currently accepted global
    atmospheric loading of 150-220 million kg, a tropospheric lifetime of
    6-9 months can be expected, meaning surface removal processes are even
    more important than reaction with OH. It would also mean that
    fumigation sources of methyl bromide are less than 10% of the total
    global emission.

         It is likely that the calibration standards of Singh et al.
    (1983) were in error, leading to overestimation of methyl bromide
    concentrations by a factor of about two. Corrections for this factor
    would resolve part of the discrepancy between the estimates of Khalil
    and Singh of the oceanic source. However, an unresolved difference in
    supersaturation measurements (140% and 180% from two Khalil voyages
    and 250% from Singh) leaves a conflict of about a factor of three that
    cannot be resolved without more measurements.

         In any event, the natural/anthropogenic balance of methyl bromide
    emissions is very uncertain.

         The major natural sources of methyl bromide are considered to be
    oceanic biological processes (mainly algal), but the mechanism for the
    production of methyl bromide in the marine environment, and its
    oceanic distribution, are not well understood (Rogozen et al., 1987;
    WMO, 1992).

         Methyl bromide occurs naturally in coastal waters together with
    methyl chloride and methyl iodide (Lovelock, 1975). This author
    suggested that methyl iodide produced by large kelp, such as
     Laminaria , reacts with the chloride and bromide ions in sea water
    to produce methyl chloride and methyl bromide, respectively.

         Harper (1985) reported the formation of methyl bromide from
    cultures of a common wood-rotting fungus  (Phellinus pomaceus) in the
    presence of sodium bromide solution, with cellulose as the substrate.

    3.2  Anthropogenic sources

         Anthropogenic sources, primarily soil fumigation, add to the
    amount of methyl bromide in the atmosphere. The amount released
    depends greatly on the regulations, methods used, dosage, type of
    plastic cover, length of covering, and precautions taken by the
    fumigators. The portion released is a question of dispute. Daelemans
    (1978) calculated that 70-90% of the applied amount of methyl bromide
    (50-100 g/m2) disappeared into the atmosphere. Using a common
    application method (15-25 cm injection with a 2-day cover), analysis
    predicted emissions ranging from 45 to 53% (UNEP; 1992). In contrast,
    Rolston & Glauz (1982) estimated that 70% of the applied methyl
    bromide escaped into the atmosphere after fumigation using injection
    chisels.

         During structural fumigation, up to 90% of the applied methyl
    bromide was estimated to escape into the environment (Reichmuth &
    Noack, 1983). During storage fumigation, an estimated 30% of the
    methyl bromide may escape from the fumigation chamber and enter the
    environment, while the rest decomposes to organic bromine and
    methylated derivatives of organic compounds (National Academy of
    Science, 1978). Other estimates give an 80% loss of methyl bromide
    used on perishable products (UNEP, 1992).

         On the basis of the inventory of use and emissions coupled with
    the analyses of Singh & Prather (UNEP, 1992), the current best
    estimate for total anthropogenic emissions of methyl bromide is about
    30 thousand tonnes per year, representing 25±10% of the total
    emissions.

         Methyl bromide is also emitted from motor vehicles using leaded
    petrol (section 3.2.3).

         Methyl bromide is listed as a controlled substance in the
    "Montreal Protocol on Substances that Deplete the Ozone Layer".

    3.2.1  Production levels and processes

    3.2.1.1  Producers and world production figures

         The total annual methyl bromide sales for the years 1984-90,
    tabulated according to region, are shown in Table 7; production
    figures for this period were almost identical. In Table 8, methyl
    bromide sales are tabulated according to use. These figures were
    provided by companies reporting to the Methyl Bromide Industry Panel,
    Chemical Manufacturers Association in February, 1992.


        Table 7.  Methyl bromide sales (tonnes) according to region for 1984-90a,b
                                                                                                
    Year     North      South    Europe     North    Afica     Asia      Australia    Total sales
             America    America             Africa
                                                                                                
    1984     19 659     1 389    11 364       183     1 595    10 678       704        45 572
    1985     20 062     1 503    14 414        45     1 975     9 743       531        48 273
    1986     20 410     1 775    13 870       380     2 205    11 278       538        50 445
    1987     23 004     1 820    15 359       385     1 751    12 816       555        55 690
    1988     24 848     2 058    17 478       277     1 582     3 555       812        60 610
    1989     26 083     1 701    16 952       618     2 075    14 386       755        62 570
    1990     28 101     1 621    19 119       432     1 838    14 605       928        66 641
                                                                                                
    Total   162 167    11 866   108 556     2 320    13 021    87 061     4,823       389 814
                                                                                                

    aCompiled by the Methyl Bromide Industry Panel, Chemical Manufacturers Association
     (unpublished report, February 1992).
    bThe 1990 production figures from other producing countries (e.g., India, China, former
     USSR) is estimated to be about 2500 metric tonnes.

    Table 8.   Methyl bromide sales (tonnes) according to use category for 1984-90a
                                                                                                 
    Year      Pre-plant  Post harvest    Structural    Residential/    Chemical        Total sales
                                                       commercial      intermediates
                                                                                                 
    1984      30 408        9 001          1 285           881            3 997          45 572
    1985      33 976        7 533          1 274           983            4 507          48 273
    1986      36 090        8 332          1 030           999            4 004          50 455
    1987      41 349        8 708          1 763         1 160            2 710          55 690
    1988      45 131        8 028          1 910         1 737            3 804          60 610
    1989      47 542        8 919          2 083         1 530            2 496          62 570
    1990      51 306        8 411          1 740         1 494            3 693          66 644
                                                                                                 
    Total    285 802       58 932         11 085         8 784           25 211         389 814
                                                                                                 

    aCompiled by the Methyl Bromide Industry Panel, Chemical Manufacturers Association (unpublished
     report, February 1992).
    

         The following is a list of the companies, including any related
    subsidiaries and/or joint ventures that reported production and
    release data:

    1.   Association of Methyl Bromide Industry Japan (Japan)

          (a) Sanko Kagaku Kogyo Co. Ltd

          (b) Teijin Chemicals Ltd

          (c) Nippon Chemicals Co. Ltd

          (d) Dohkal Chemicals Co. Ltd

          (e) Nippon Kayaku Co. Ltd

          (f) Ichikawa Gohsei Chemical Co. Ltd

    2.   Atochem S.A. (France)

          (a) Derivados Del Etilo, S.A. (Spain)

    3.   Dead Sea Bromine Group

          (a) Dead Sea Bromine (US)

          (b) Eurobrom B.V. (The Netherlands)

    4.   Ethyl Corporation (US)

          (a) Ethyl S.A. (Belgium)

    5.   Great Lakes Chemical Company (US)

          (a) Great Lakes Chemical (Europe) Ltd (UK)

    6.   Societa Azionaria Industria Bromo Italiano (Italy)

         According to Eurobrom B.V. (personal communication), Atochem is
    the sole producer of methyl bromide in Europe. Methyl bromide is also
    imported into Europe from the USA and Israel (Ethyl Corporation and
    Dead Sea Bromine Group).

         The average rate of increase in total world sales between 1984
    and 1990 was about 6% per year, more than 90% of these sales being in
    the Northern Hemisphere. Of the 51.3 thousand tonnes used as a
    pre-planting fumigant in 1990, about 80% was used in Europe and North
    America.

    3.2.1.2  Production processes

         Methyl bromide is commonly produced by the interaction of
    methanol (CH3OH) and hydrogen bromide (HBr). The hydrogen bromide
    can be generated  in situ from bromine and a reducing agent, such as
    sulfur or hydrogen sulfide (Dagani et al., 1985). Methyl bromide is
    distilled from the reactant mixture and the crude product purified by
    further low-temperature fractional distillation (National Academy of
    Science, 1978). Another method is to add sulfuric acid to a
    concentrated sodium bromide and methanol solution (National Academy of
    Sciences, 1978; Stenger, 1978).

         Ethyl Corporation and Great Lakes Chemical Co. both use a
    coproduction process that produces methyl bromide as a coproduct with
    the production of tetrabromobisphenol A (TBBPA). In this process,
    bisphenol A (BPA) is dissolved in methanol and then reacted with
    bromine to yield TBBPA and hydrobromic acid. The hydrobromic acid
    reacts with the methanol to yield methyl bromide (Ethyl Corporation,
    Personal communication to the IPCS, 1990).

         In the manufacturing process of a Japanese plant, bromine is
    first mixed with methyl alcohol and heated at 60-80 °C in a boiler.
    The methyl bromide produced is cooled, purified, and condensed. These
    processes are mainly conducted in a closed system (Kishi et al.,
    1991).

    3.2.1.3  Losses to the environment during normal production

         In 1973, the emission of methyl bromide from manufacturing
    processes in the USA was estimated to be 100 000 kg compared with 11.3
    million kg emitted when used as a fumigant (National Academy of
    Science, 1978).

         However, in 1990, in the USA, the total reported emission of
    methyl bromide from industry was 1000 kg (US EPA Toxic Release Index,
    1990). In general, because processes are enclosed, the amount of
    methyl bromide lost during manufacture is negligible compared with the
    amount released to the atmosphere when it is used as a fumigant.

    3.2.1.4  Methods of transport

         Methyl bromide is easily liquefied and is shipped in steel
    cylinders as a liquefied gas under its own vapour pressure (Matheson
    Gas Data Book, 1980). This may be augmented with nitrogen or carbon
    dioxide before shipment to permit rapid ejection at low temperatures
    (Stenger, 1978). Methyl bromide is also transported in cans and tanks.

         An industrial code of practice for the handling and
    transportation of methyl bromide in Europe has been recommended (EMBA,
    1988).

    3.2.1.5  Accidental release or exposure

         Incidents of methyl bromide poisoning occur through accidental
    exposure to the compound, particularly during soil or structural/space
    fumigation and also during manufacture (section 9).

    3.2.2  Uses

         Methyl bromide is used as follows: soil (pre-planting) fumigation
    (77%), quarantine and commodity fumigation (12%), structural
    fumigation (5%), and chemical intermediates (6%) (UNEP, 1992) (Table
    8).

         The general use of methyl bromide in fire extinguishers has been
    abandoned as it was the cause of a number of fatal accidents (see
    section 9). However, it is still used for special-purpose fire
    extinguishers (Matheson Gas Data Book, 1980).

         Since 1960, methyl bromide has been used as a fumigant for a wide
    range of stored, dry foodstuffs and other products, such as tobacco,
    fresh fruit, and vegetables, in particular to comply with quarantine
    regulations (Bond, 1984). It is used pre-harvest in glasshouses and in
    the open as well as post-harvest in mills and warehouses. It is also
    used to fumigate buildings, furniture, books, and archived material
    (Alexeeff & Kilgore, 1983).

         The techniques used for the different types of methyl bromide
    fumigation are given in Table 9.

    3.2.2.1  Soil fumigation

         The gas is a soil fumigant for the control of weeds, weed seeds,
    nematodes, insects, and soil-borne diseases (Meister, 1985). Methyl
    bromide can be applied to soil under sheeting in a vaporized form
    using either evaporating jars (cold method) or heating (hot method),
    or injected as a liquid and allowed to vaporize  in situ (Table 9).


        Table 9.  Outline of methyl bromide fumigation techniquesa
                                                                                                                                              
                   Examples of    Fumigation      Fumigation   Application technique                            Ventilation of
    Type           application    dosage          period                                                        methyl bromide residues
                                                                                                                                              
    1. Space       Buildings      0.5-1%          2-3 days     Sealing of all openings except one door with     Natural ventilation (opening
    fumigation     (mills,        in air                       plastic foil and adhesive tape; placement of     of doors, windows) assisted
                   factories,     (20-40 g/m3)                 methyl bromide cylinders at selected locations   by mechanical exhaust
                   museums)                                    inside building; opening of cylinders by team    ventilation if available
                                                               of operators working backwards towards escape
                                                               door; sealing of escape door

    2. Chamber     Dried food     0.8-1%          < 1 day      Permanently installed delivery systems,          Mechanical ventilation:
    fumigation     products,      chamber                      operated from outside of chamber                 continuous dilution with fresh
                   wood           volume                                                                        air in atm. pressure chambers,
                                  (32-40 g/m3)                                                                  batch dilution cycles in
                                                                                                                "vacuum" chambers

    3. Fumigation  Ducts, bins;   1-2%            1-3 days     Sealing of goods/machines under plastic foil     Removal of sheeting, natural
    with           stacked        in air                       or tarpaulins; methyl bromide injection through  ventilation
    movable        goods, pieces  (40-80 g/m3)                 ports via flexible tubing, using  (a) hot 
    delivery       of machinery                                vapour systems (methyl bromide passed through 
    system                                                     heat exchanger in a water boiler), or  (b) cold 
                                                               vapour systems (pressurized cylinders on 
                                                               trolleys)

    4. Surface     Soil, compost  50-100 g/m-2    2-5 days      (a) Hot vapour application using perforated       Removal of sheeting, latency
    fumigation                                                 tubing prepared under plastic sheeting;          period and/or watering before
                                                                (b) liquid methyl bromide injection, truck/       tillage
                                                               trailer with cylinders connected to injection
                                                               nozzles and reel unfolding plastic sheeting
                                                               behind truck;  (c) methyl bromide cans place in
                                                               puncturing cups underneath sheeting, punched
                                                               open by operator walking on the sheeting
                                                                                                                                              

    aFrom Guillemin et al. (1990).
    

         The methods practised in various countries differ. In the USA,
    methyl bromide is mainly applied by chisel application (injection).
    Methods of soil disinfestation used in Belgium, for example, are given
    in Table 10. In Israel, both soil fumigation in strips and blanket
    (large area) fumigation are widely used (Klein, 1989). The methods
    used are the hot gas method and injection method. Strip fumigation is
    not as effective as blanket fumigation but, in some circumstances, is
    more economical. 

        Table 10.  Soil disinfestation methods and products used in Belgium and their relative importancea
                                                                                  
    Physical methods:

    - steaming : - sheet steaming/steaming via drain pipes              7%
    - vacuum steaming of rockwool substrates                            2%
    - solarization                                                      0%
    - microwave radiation                                               0%
    - ozone                                                             0%

    Chemical methods:

    - methyl bromide (MB) : fumigation (greenhouse/outdoor)            50%
                     + injection (outdoor)
    - chloropicrin (CP) : injection (greenhouse/outdoor)               10%
    - MB + CP : injection (outdoor)                                    10%
    - metham-sodium : injection (greenhouse/outdoor)                    8%
    - dazomet : soil mixing (greenhouse/outdoor)                        3%
    - dichloropropene : injection (greenhouse/outdoor)                  8%
    - others                                                            2%
                                                                                  

    a From: Pauwels (1989).
    
         Not only the method of application but also the type of plastic
    sheeting used for covering is important for optimal fumigation
    conditions as well as for the safety of the fumigators and reduction
    of environmental pollution. Munnecke et al. (1978) showed that using
    gas-tight films very high concentrations of methyl bromide reached the
    soil, whereas, under low density polyethylene (LDPE) covers, these
    concentrations rapidly dissipated. In the Netherlands where extensive
    horticulture plays an important economic role, Wegman et al. (1981)
    reported that 2 million kg of methyl bromide were being used in
    glasshouses each year. De Heer et al. (1983) compared different
    plastic films in trials in the main glasshouse district of the
    Netherlands. They confirmed that the dose of methyl bromide could be
    substantially reduced, without affecting the concentration-time
    product in the soil, if gas-tight films were used instead of LDPE.
    They emphasized that the reduction of methyl bromide losses depends
    greatly on how the films are laid down and wetted and on how the

    methyl bromide is distributed under the films. The use of methyl
    bromide for soil fumigation was banned in the Netherlands in 1991.
    Prior to this date, the use of LDPE sheeting was prohibited, the
    mandatory cover time of the soil was extended to 10 days, and the dose
    reduced to 20 g/m2 (De Heer et al., 1983). In 1983, this dose was
    increased to 40 g/m2 but, in practice, doses of 60-80 g/m2 were
    used up to the phase-out in 1991, because applying the protective
    sheeting in a careful manner proved to be too time-consuming. In a
    comparison of methyl bromide diffusion through different plastic films
    40 µm thick, some showed excellent barrier properties to the gas
    whereas 75% of the methyl bromide applied was lost through LDPE and
    another type of plastic within 5 h (Van Wambeke et al., 1988).

         Doses of methyl bromide to be applied depend on:

         -    the legal standards (regulations differing for each   
              country) and methods used;

         -    the pest to be controlled (type/degree of infestation/   
              infection);

         -    temperature;

         -    soil type;

         -    the plastic soil cover (covering time and type of   
              plastic).

         Methyl bromide is particularly used in intensive horticulture,
    where, because of specialization, only a few selected crops are grown
    with a resulting increase in pests, microorganisms, and weeds that
    could decrease the quality and quantity of the crop.

         Table 11 gives examples of the use of methyl bromide as a soil
    fumigant and the recommended dosage. Common rates of application of
    methyl bromide to soil vary between 50 and 125 g/m2 (FAO, 1980).
    Industry recommends that the dosage should not exceed 100 g/m3.


        Table 11.  Pest controlling dose rates of a 98% methyl bromide formulation in g/m2 according to soil type (in United Kingdom)a,b
                                                                                                                                      
    Crops                                           Dosage in g/m2 b         Aeration            Remarks
                                                                                               
                           to control nematodes,    to control damping-      to control fungi    (days)e
                           annual and perennial     off fungi, e.g.          causing rotsd and
                           weedsc and broomrape      Rhizoctonia, Pythium      wilts, e.g., 
                                                     spp., Thielaviopsis      Scleroctiun
                                                     basicola, Phytophtora    rolfsii, Pythium
                                                     spp.                     spp., Verticillium 
                                                                              spp., Fusarium 
                                                                              spp., Pyrenochaeta 
                                                                              spp.
                                                                                                                                      
    Plant nurseries:       35-50                    50                                           7-14           do not fumigate heavy
    vegetables,                                                                                                 soils to be used for
    flowers                                                                                                     celery nurseries

    Vegetables:            35-50                    75                       75-100              7-14           for beta-alpha-type
    cucurbits, tomatoes,                                                                                        cucumbers, soil 
    eggplants, peppers,                                                                                         leaching is obligatory
    onions, radishes

    Leafy vegetables:      35-50                    75                       75                  7-21
    celery, chicory,
    cabbage, lettuce,
    spinach

    Strawberries           35-50                    75                       75                  7
    (nursery and field)

    flowers:               35-50                    75                       75-100              7-14           even light soils must
    annual,                                                                                                     be leached before
    perennial cut                                                                                               planting carnations
    flowers,
    ornamentals
                                                                                                                                      

    Table 11 (contd.)
                                                                                                                                      
    Crops                                           Dosage in g/m2 b         Aeration            Remarks
                                                                                               
                           to control nematodes,    to control damping-      to control fungi    (days)e
                           annual and perennial     off fungi, e.g.          causing rotsd and
                           weedsc and broomrape      Rhizoctonia, Pythium      wilts, e.g., 
                                                     spp., Thielaviopsis      Scleroctiun
                                                     basicola, Phytophtora    rolfsii, Pythium
                                                     spp.                     spp., Verticillium 
                                                                              spp., Fusarium 
                                                                              spp., Pyrenochaeta 
                                                                              spp.
                                                                                                                                      
    Bulbs and corms        35                       50                       75                  7
    (on light soils
    only)

    Citrus replanting                                                        50                  14

    Deciduous                                                                75-100              14
    replanting
                                                                                                                                      

    a From: Bromine & Chemicals Ltd. (1990).
    b When a dose range is given, the smaller dose relates to light soil, the larger to medium and heavy soils.
    c Purple nutsedge (nut grass) corms and seeds of horseweed, Erigeron  (Conyza) , mallow  (Malva) , and legumes are not
      efficiently controlled.
    d The dose rate to control  Fusarium on all soil types is 100 g/m2.
    e For light soils and/or high temperatures, the shorter aeration period is sufficient; for medium and heavy soils, and
      all soil types at low temperatures, the longer aeration period is required; the long aeration period is also desirable for
      direct seeded crops; if rain is expected during the aeration period, do not remove the plastic sheets entirely, but
      allow for aeration while protecting the soil from direct rain.
    

         In some cases, it is recommended that, after fumigation, the
    ground should be thoroughly leached to remove the bromide salts that
    are formed in the soil. Fumigation of peat soils before planting leafy
    vegetables is not recommended, because of the resulting high bromide
    residues. There are different national regulations concerning the
    crops permitted to be grown after soil fumigation. In some countries,
    the use of methyl bromide is severely restricted or prohibited.

    3.2.2.2  Quarantine and non-quarantine commodity treatments

         Methyl bromide is currently used for quarantine and
    non-quarantine commodity treatment, because it is rapidly effective
    (often less than 24 h) and can be used for pests on a wide range of
    commodities at fumigation temperatures exceeding 4 °C. Imports of
    products subject to infestation are often only permitted if the
    product is fumigated in the country of origin or at the ports of
    destination (UNEP, 1992).

         Commodities fumigated with methyl bromide include durable food
    commodities (such as cocoa and coffee beans, grains, dried fruit,
    nuts), perishable food commodities (mainly fruits and vegetables), and
    non-food commodities (forestry products, cut flowers, cotton, tobacco,
    packaging, animal feed stuffs, artifacts, and other commodities).
    Suggested dose rates for storage fumigation are given in Table 12 and
    Table 13.

          In special extermination problems, such as that of the
    khapra-beetle  (Trogoderma granarium Ev.) larvae in the transport of
    bulk-loaded expeller (pressed remains from oil and fat seeds that are
    used for making cattle feed), methyl bromide is used in combination
    with hydrogen phosphide (Wohlgemuth et al., 1976).

         Fumigation is followed by an aeration period when fresh air is
    passed through the fumigation chamber to remove methyl bromide from
    the air space. At least 2 h of aeration is required for fresh fruit
    fumigated with methyl bromide. In addition, the aeration must continue
    until the concentration of methyl bromide in the air vented from the
    chamber is below an exposure limit value of 20 mg/m3 (usually within
    4-12 h). This is to protect workers entering the fumigation chamber
    immediately after the aeration period (Sell et al., 1988).


        Table 12.  Dosage rates and exposure times for space fumigation with methyl bromide
                                                                                                                      
    Commodity       Vacuum chamber fumigation        Fumigation at atmospheric          Notes
                                                     pressurea
                                                                                 
                    Dosage          Exposure time    Dosage          Exposure time
                    rates (g/m3)b   (h)              rates (g/m3)b   (h)
                                                                                                                      
    Foods:

     coffee         32-55           3                16-40           16-24
     cocoa beans    32-55           3                16-40           16-24
     grains         -               -                20-38           24                 Maximum moisture content
                                                                                        of 12%; lower doses for
                                                                                        upright storage and higher
                                                                                        doses for flat storage;
                                                                                        do not fumigate seed grain;
                                                                                        values are for 21-25 °C;
                                                                                        between 10-15 °C multiply
                                                                                        dosage by 1.5; between
                                                                                        16-20 °C multiply by 1.25

     spices         40              3                16-24           16-24              At 20 °C and above only

     cigarette      54-80           4                20-32           45-72
     tobacco

    Packing         40-58           3-4              24-48           16-24              Compressed bales should
    materials:                                                                          be fumigated under vacuum
                                                                                        at 55 g/m3, for 48 h at
                                                                                        15 °C and above

    Factories       -               -                16-40           24                 Use lower doses of range
    and storage                                                                         for spaces over 14 000 m3
    premises
                                                                                                                      

    Table 12 (continued)
                                                                                                                      
    Commodity       Vacuum chamber fumigation        Fumigation at atmospheric          Notes
                                                     pressurea
                                                                                 
                    Dosage          Exposure time    Dosage          Exposure time
                    rates (g/m3)b   (h)              rates (g/m3)b   (h)
                                                                                                                      
    Transport       -               -                16-40           10-12              Multiply dose by 6 
    vessels,                                                                            against Khapra beetle
    freight
    containers
                                                                                                                      

    a Including stacks under gas-proof sheets.
    b Where a range is given, the fumigation dosage depends on temperature: the dosage rates are for a temperature
      range of 4-32 °C; at lower temperatures higher doses and longer times should be used.
    

        Table 13.  Use of methyl bromide as a storage fumigant in Germanya
                                                                        
    Area of use                                Dosage    Length of
                                               (g/m3)    fumigation
                                                         (h)
                                                                        
    Stored goods
    - mills                                    16-30     24-48
    - silos (elevators)                        16-30     24-48

    Expeller
    - in barges, inland and coastal
      motor boats
       a ) in sacks                              56-96     24
       b ) as bulk material b                     56-96     72
    - in railway carriages
      in sacks b                                 56-96     72

    Stored goods (apart from
    grain, expellers, tobacco)
    - in vacuum chambers with gas
      circulating apparatus                    50        2
    - in small silos with gas
      circulating apparatus                    70        16
    - packed in gastight 
      sheeting                                 16-30     24
    - in sufficiently gastight
      rooms                                    16-30     24
                                                                        

    a Adapted from: BUA (1987) and BBA (1989).
    b Together with hydrogen phosphide.
    
         The development of acceptable alternatives to methyl bromide for
    certain commodities is complex (UNEP, 1992).

    3.2.2.3 Structural fumigation

         Methyl bromide is used extensively as a structural fumigant, and
    this application currently accounts for about 5% of production. The
    current use of methyl bromide as a structural fumigant is widespread
    because of its efficacy, applicability for a wide variety of sites and
    pests, suitability for use on accessible and inaccessible pests, short
    fumigation period (about 1 day), lack of insect resistance, cost
    effectiveness, and because it does not damage food, structures, or
    equipment when used correctly. However, methyl bromide is toxic, must
    be applied by skilled operators, and, in some instances, requires
    multi-day aeration periods to reduce methyl bromide exposure to levels
    safe for humans (UNEP, 1992).

         In California and Florida, where homes are fumigated to eradicate
    insect pests, poisoning incidents have occurred through unauthorized
    access to buildings under fumigation (section 9.2.1.2). Fumigating
    food in houses is mentioned in section 5.2.1.

    3.2.2.4  Industrial uses

         Methyl bromide is used in organic synthesis, principally as a
    methylating agent (Torkelson & Rowe, 1981) and as a low-boiling
    solvent, for example, for extracting oils from nuts, seeds, and
    flowers (Windholz, 1983). Because of the toxicity of methyl bromide
    (section 9), its use as a refrigerant and as a general fire
    extinguishing agent is now of historical interest (likewise its use as
    an anaesthetic in the 19th century). Methyl bromide may still be used
    in fire extinguishers in special situations (Matheson Gas Data Book,
    1980).

    3.2.3  Methyl bromide emission from motor car exhausts

         Harsch & Rasmussen (1977) reported the presence of methyl bromide
    at sub-part per-billion concentration levels in urban areas (section
    5.1.1). The major source of methyl bromide in urban areas is believed
    to be automobile exhaust.

         Engines operating on "leaded" petrol, containing ethylene
    dibromide (EDB) as an additive, contribute a much larger amount of
    methyl bromide to urban atmospheres than engines with catalytic
    converters burning "unleaded" fuel. On the basis of an estimated
    consumption of 12 million tonnes of leaded petrol per year, Bell
    (1998) calculated that about 45 tonnes of methyl bromide is produced
    from car exhaust in the United Kingdom annually. Methyl bromide
    concentrations in the range of 90-190 µg/m3 have been measured in
    the exhaust emissions of motor vehicles using leaded petrol with EDB
    (Baumann & Heumann, 1987). According to these authors, the portion of
    organobromine compounds is 22-44% of the total bromine that is emitted
    in the exhaust gases, the concentration decreasing with increasing
    engine temperature. Furthermore, the methyl bromide content of these
    organic components varies between 64 and 82% (Baumann & Heumann,
    1987). On the basis of an estimated global consumption of 50 000
    tonnes of 1,2-dibromoethane as a petrol additive (Roskill, 1992), and,
    from the above figures, and assuming that the bromide from the EDB is
    emitted in full from the exhaust gases, it can be estimated that
    between 7000 and 18 000 tonnes of methyl bromide could be emitted
    annually from car exhaust. The increasing use of unleaded fuel should
    result in a decrease in these levels.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Transport in air

         In view of the destructive effects thatbromine compounds have on
    the ozone layer, the release of methyl bromide into the atmosphere may
    pose an environmental problem. Models indicate that inorganic bromine
    can significantly affect ozone levels in the stratosphere (Wofsy et
    al., 1975; Prather et al., 1984; Prather & Watson, 1990; UNEP, 1992).

         The atmospheric budget of methyl bromide is controlled by the
    magnitude of natural and anthropogenic sources (sections 3.1, 3.2, and
    5.1.1) and by the atmospheric and surface removal processes.

         The major natural source is oceanic and the major anthropogenic
    source is the release into the atmosphere of methyl bromide during its
    use as a fumigant and, to a lesser extent, from industrial and motor
    vehicle emissions. As far as is known, removal processes are mainly
    atmospheric. However, ocean and terrestrial surface removal could be
    significant, but this remains to be quantified (UNEP, 1992).

         There are three possible removal mechanisms for methyl bromide
    within the atmosphere:  (a) reaction with the hydroxyl radical and
    other chemical species in the troposphere;  (b) precipitation in the
    troposphere; and  (c) transport and subsequent photolytic and
    chemical removal in the stratosphere (section 4.2.2). Removal by
    precipitation is thought to be unimportant (UNEP, 1992). According to
    the report, the most significant removal process is that of the
    reaction of methyl bromide with the hydroxyl radical in the
    troposphere (estimated removal time of 2±0.5 years). A minor removal
    process is transport to the stratosphere followed by reaction with the
    hydroxyl radical and photodissociation with an estimated lifetime of
    about 30-40 years.

         Between 20 and 25 km above sea level, photodissociation is of
    equal importance to loss by diffusion and reaction with the hydroxyl
    radical. Above this, photolysis plays the most important role
    (Robbins, 1976a).

         From the sparse data available (section 5.1.1), it appears that
    methyl bromide has no significant vertical gradient in the
    troposphere, but decreases rapidly in the high-latitude lower
    stratosphere by at least a factor of 3-5 within 10 km of the
    tropopause (UNEP, 1992). Further details are discussed in sections
    4.2.2, 4.4, and 5.1.1.

    4.1.2  Transport in water

         The solubility of methyl bromide in water is between 16 and 18
    g/litre at 20 °C (Table 1). In soil, it is partially hydrolysed to
    bromide ion. After fumigation using methyl bromide, the soil may be
    leached with water to prevent the uptake by plants, subsequently
    planted on the sterilized soil, of the bromide ions formed. Between
    300 and 600 mm of irrigation water is necessary to remove the bromide
    ions effectively from the root zone of plants (Wegman et al., 1981).
    In the Netherlands, this leaching caused problems because the water
    was mostly withdrawn from surface waters and the drainage water after
    leaching was discharged again into the surface waters; thus the
    bromide ion concentration accumulated during leaching periods.

         Vanachter et al. (1981) found a linearity in the inorganic
    bromide amounts in the leaching water up to 200 mm. Between 200 and
    400 mm, a decreased concentration was seen in two types of soil
    tested, a sandy soil containing 2.15% organic matter and a loamy soil
    containing 7.22 % organic matter. There was a direct correlation
    between the initial bromide ion concentrations and the bromide ion
    concentrations in the first fractions of leaching water. The average
    half-life for methyl bromide in surface water, under field conditions,
    was calculated to be 6.6 h at a water temperature of about 11 °C, the
    decline being attributed to degradation and volatilization processes
    (Wegman et al., 1981).

         It has been found that methyl bromide is able to diffuse through,
    and is adsorbed by, certain plastics, e.g., polyethylene.
    Drinking-water pipes that are either free or in earth can thus be
    contaminated within a few days, if surrounded by methyl bromide that
    is being used for fumigation (Herzel & Schmidt, 1984).

    4.1.3  Transport in soil

         Methyl bromide is nearly four times heavier than air, and much of
    that used as a soil fumigant diffuses throughout the surface to depths
    of 60-240 cm, some of it being hydrolysed to bromide ion or decomposed
    by microorganisms, the remainder (45-90%) (section 4.1.1) eventually
    being dissipated into the atmosphere (Brown et al., 1979). Daelemans
    (1978) found the rate of degradation of methyl bromide in soil was
    about 6-14% per day at 20 °C.

         Lepschy et al. (1979) carried out short- and long-term studies on
    the effects of fumigation with methyl bromide on various soil types.
    They found that methyl bromide could be detected up to 3 weeks after
    fumigation in different soil types, the highest content being found in
    the upper soil layers (0-40 cm). Traces of methyl bromide could be
    measured down to a depth of 80 cm. The bromide derived from methyl
    bromide was largely water soluble, the water solubility and total
    bromide content reducing with time. Bromide levels were back to normal
    after 1 year of cultivation.

         During fumigation, the transport of methyl bromide gas through
    soil (pores) is caused by mass flow and molecular diffusion, but its
    transport is also influenced by simultaneously occurring sink
    processes, such as sorption and dissolution, and irreversible sink
    processes, such as hydrolysis (Brown & Rolston, 1980). Earlier
    experiments by Chisholm & Koblitsky (1943) showed that the reversible
    and irreversible methyl bromide sink capacities depended on soil
    moisture content and decreased in the sequence peat, clay, sand. A
    review of the mechanisms of breakdown of methyl bromide by Moje (1960)
    indicated that unimolecular nucleophilic substitution should be the
    major mechanism for the hydrolysis of methyl bromide in water. Maw &
    Kempton (1973) suggested that the reactions of dissolved methyl
    bromide with the soil organic matter involved the transference of the
    methyl group to the carboxy groups and N- and S-containing groups of
    the amino acids and proteins of soil organic matter. The reactions are
    expected to be first order because of the excess of organic matter and
    the production of bromide ion. Following fumigation by methyl bromide,
    methylation is expected to be highly dependent upon the amount of
    organic matter present.

         Laboratory experiments by Brown & Rolston (1980) confirmed this
    earlier work to a great extent, showing that rates of bromide
    production were significantly influenced by soil type, being greatest
    with muck, intermediate with loam, and least with sand. A first-order
    kinetic model for the reversible sink term described effluent curves
    more adequately than a linear, equilibrium model, though it appeared
    that both models were inadequate in completely describing the
    adsorption-desorption process. Irreversible sink processes had a
    negligible effect on bromide ion production.

         Methyl bromide is changed by the methylation of the organic
    matter and to a smaller extent by hydrolysis to form bromide ion. In
    contrast to naturally occurring bromide, the bromide formed from
    methyl bromide is at first only slightly bound to soil particles and
    is therefore free to move in the soil. Thus, it can be taken up by
    plants or can be washed out by leaching the soil. It can be completely
    leached out of sandy soils, but this is very difficult in clay soils
    (CEC, 1985). 

         Arvieu & Cuany (1985) also described the dependence of the
    adsorption and degradation of methyl bromide on the organic matter
    content of the soil. Adsorption on to organic matter reduces the
    available methyl bromide concentration in the aqueous and gaseous
    phases of the soil. Irreversibly adsorbed molecules no longer have
    biological activity and may persist as bound residues, if not
    hydrolysed. Organic matter is also a main factor involved in the
    degradation of methyl bromide in the soil. The reaction rate depends
    on its nature, composition, and stage of decomposition.

         Laboratory experiments carried out by Herzel & Schmidt (1984)
    confirmed that the degradation of methyl bromide in soil depends

    almost entirely, if not completely, on the organic composition of the
    soil. In soil with much humus, the "half-life" of methyl bromide was
    10 days, while, in a lighter soil, it was 30 days, and, in sand, about
    100 days. The authors concluded that although methyl bromide is
    degraded in shallow top soils, the fumigant is relatively persistent
    in the underlying strata, where its diffusion into the atmosphere is
    no longer possible. If there are unsuitable conditions, such as a high
    water table, low temperatures, and a low density of the underlying
    strata, then contamination of groundwater with methyl bromide after
    fumigation cannot be ruled out.

         Rolston & Glauz (1982) described a simulation model for the
    transport of methyl bromide gas from injection chisels within the
    field. The injected methyl bromide is assumed to form cylindrical,
    parallel sources at the depth of injection. Transport of methyl
    bromide is described by radial diffusion from the injection cylinders.

         A theoretical model has been developed giving profiles of the
    concentration of methyl bromide in the soil in both liquid and gas
    phases, making it possible to judge the extent of the soil zone
    treated and to forecast the behaviour of the substance (Mignard &
    Benet, 1989).

    4.1.4  Vegetation and wildlife

         Bromide accumulation in plants depends on various factors, such
    as the physical and chemical properties of the soil, the climatic
    conditions (temperature and rainfall), the plant species, and the type
    of plant tissue (Basile & Lamberti, 1981).

         Wheat and soil/bromide dynamics have been studied in methyl
    bromide-fumigated plots. The total crop bromine concentration was 0.5
    g/m2 (only aerial parts) (Fransi et al., 1987). The bromine
    concentration in the different parts of spring wheat decreased
    throughout its development, indicating that the largest rates of
    bromide uptake were in the first stages of growth. When the grain
    filling started, there was an increase in bromide concentration,
    except for the dried leaves fraction, coinciding with an increase in
    ambient temperature. This increase was more marked in the senescent
    leaves, which remained in the plant top and were subject to a higher
    transpiration rate. Afterwards, throughout the grain-filling period,
    the bromide concentration in all parts decreased sharply. The bromide
    concentration in the ears was low, especially in the grains. There was
    no scorching of plants. In another study, Brown & Jenkinson (1971)
    reported scorching of wheat grown on soil fumigated with methyl
    bromide by injection; the scorched plants contained up to 6.1%
    bromide.

         Leafy vegetables, such as lettuce and spinach, can take up
    relatively large amounts of bromide ion without phytotoxic symptoms
    (Wegman et al., 1981; see also section 5.1.4). In contrast, other

    crops, such as carnations, citrus seedlings, cotton, celery, pepper,
    and onions, are particularly sensitive to methyl bromide fumigation
    (Bromine & Chemicals Ltd., 1990).

         There are no data for accumulation in wildlife (see also section
    4.2.3).

    4.1.5  Entry into the food chain

         The two main uses of methyl bromide connected with soil and food
    fumigation, i.e., "sterilization" of soil prior to planting and
    fumigation of foods after harvesting, must be considered in relation
    to entry into the food chain. In the former case, the level of bromide
    ion must be considered. In post-harvest fumigation, it is possible
    that methyl bromide itself, as well as bromide and other possible
    reaction products, may be found in food.

         Most attention has been paid to bromide residues in foodstuffs,
    as methyl bromide seems to be only transient (sections 5.1.4 and 6.3).
    Possible methylation products are methionine sulfonium methyl bromide,
    1-methyl histidine,  S-methyl cysteine,  S-methyl-glutathione, and
    other minor methylated compounds. The composition and amount of each
    residue depends on the type of foodstuff fumigated (Starratt & Bond,
    1990a,b). These residues are also found in foodstuffs that have not
    been fumigated.

    4.2  Transformation

    4.2.1  Biodegradation

    4.2.1.1  Soil

         Methyl bromide is degraded by three species of nitrifying
    bacteria, the soil nitrifiers  Nitrosomonas europaea and
     Nitrosolobus multiformis , and the marine nitrifier  Nitrococcus
     oceanus (Rasche et al., 1990). Ammonia monooxygenase is thought to
    be the enzyme that catalyses the degradation. Oxidation results in
    dehalogenation with the release of bromide ions (Hyman & Wood, 1984).

    4.2.1.2  Stored product fumigation

         During stored product fumigation, most of the methyl bromide is
    converted to inorganic bromide and other residues (section 6.3),
    probably by reaction with amino or sulfhydryl groups in the products.

    4.2.2  Abiotic degradation

    4.2.2.1  Hydrolysis

         Methyl bromide hydrolyses at neutral pH in laboratory light to
    methanol, bromide, and hydrogen ion:

                       CH3Br + H2O -> CH3OH + H+ + Br-.

         The rate constant of 3.0 x 10-7 s-1, at 25 °C, reported by
    Moelwyn-Hughes (1938) has been confirmed by Castro & Belser (1981).

         The influence of temperature (18 °C and 30 °C) on the hydrolysis
    rate of methyl bromide was investigated using distilled water buffered
    at pH 3, 5, 7, and 8 (Gentile et al., 1989). The results are given in
    Table 14. The authors suggest two types of reaction. The dominant
    mechanism in pH region 3-8 (where the OH- concentration is low) is
    of the SN1 type. However, at higher pH values (>8), the faster SN2
    type reaction is dominant.

                                  H2O

             CH3Br -> CH3+ + Br- -> CH3OH + H+   (SN1)

    OH- + CH3Br -> [HO...CH3...Br]- -> CH3OH + Br-  (SN2)

        Table 14.  Hydrolysis constant (K) and half-life of methyl bromide in distilled 
                   water at different pH and at two different temperaturesa
                                                                             
    pH             18°C            Half-            30°C           Half-
                K(10-7s-1)     life             K(10-7s-1)    life
                   (±SD)          (days)            (±SD)         (days)
                                                                              
    3.0         2.70(±0.11)        29.0          2.84(±0.19)       28.00

    5.0         4.08(±0.10)        19.0          4.51(±0.22)       18.00

    7.0         6.63(±0.34)        12.0          7.80(±0.25)       10.00

    8.0         8.60(±0.44)         9.0         10.32(±0.15)        8.00
                                                                              

    a From: Gentile et al. (1989).  Distilled water was buffered at the given pH 3, 5,
      7 and 8 using 0.2 mol/litre phosphate-citrate buffer.  Methyl bromide was added
      to obtain a final concentration of 50.5 µmol/litre.
    
         The hydrolysis rate of methyl bromide in water taken from four
    different wells was also measured at 18 °C and 30 °C (Table 15). The
    authors could not explain the discrepancy between the results of the
    two sets of experiments. The results from well water are comparable
    with those given in Table 16 from other authors.

         No significant variation in pH occurred with time in well water
    after the addition, or during the hydrolysis, of methyl bromide
    (Gentile et al., 1989). The authors explained these results for
    natural waters by the low amounts of HBr produced by complete
    hydrolysis of the fumigant and by the presence of natural buffering
    systems, such as calcium bicarbonate.

         Experiments by Herzel & Schmidt (1984) on the persistence of
    methyl bromide in water confirmed the earlier work by Moelwyn-Hughes
    (1938), which showed that hydrolysis depends mainly on temperature.
    Whereas, at 40 °C, there was rapid degradation, at 22 °C, it took
    several days before there was a rapid decrease in methyl bromide
    concentrations. At 10 °C, there was an even slower rate of reaction.
    Fig. 1 shows graphically the rate of hydrolysis of methyl bromide in
    tap water at these three different temperatures.

         The rate constant for methyl bromide hydrolysis in tap water
    varies with temperature, not according to an equation of the Arrhenius
    type, but according to the following formula: 

               log10k = 112.656 - 10236/T - 34.259 log10T

    where T is the absolute temperature.

         This formula agrees with experimental observations by
    Moelwyn-Hughes (1938) carried out at temperatures of up to 100 °C.
    Table 16 shows the dependence of the rate constant and half-life on
    temperature.

         Addition of soil to water greatly enhanced the degradation of
    methyl bromide (Gentile et al., 1989).

         Degradation by hydrolysis is the primary route of degradation of
    methyl bromide in soils with a very low organic matter content. The
    adsorption isotherms in these soils were found to be linear but slopes
    were greatly reduced as moisture content increased (Arvieu, 1983). In
    soils containing organic matter, two different reactions occurred,
    adsorption and conversion through reaction with organic matter.


        Table 15.  Hydrolysis constant (K) and half-life of methyl bromide in well-water
    at 18 °C and 30 °Ca

                                                                                  
    Site or    pH          18 °C          Half-life   30°C           Half-life
    well no.               K(10-7s-1)     (days)      K(10-7s-1)     (days)
                           (± SD)                     (± SD)
                                                                                  
    1          7.4         2.20 (±0.33)   36.0        5.28 (±0.24)   15.0

    2          7.7         2.01 (±0.08)   40.0        4.62 (±0.34)   17.0

    3          7.7         1.81 (±0.28)   43.0        4.27 (±0.34)   18.0

    4          7.8         1.58 (±0.14)   50.0        3.95 (±0.53)   19.0
                                                                                  

    a From Gentile et al. (1989).  Methyl bromide was added to well water to obtain
      a concentration of 50.5 µmol/litre.
    

    Table 16.  Hydrolysis rate constant (k) and half-life of methyl
    bromide in water at different temperatures
                                                        
      Temperature   Observed           Half-life
      (°C)          rate constant
                    (sec-1)
                                                        
      17            a1.07 x 10-7       75 days

      25            b4.09 x 10-7       20 daysb

      25            a3.57 x 10-7       21.3 days

      35.7          a1.65 x 10-6       117 h

      46.3          a6.71 x 10-6       28.6 h

      100           a1.28 x 10-3       0.6 h
                                                        

    a Values from Moelwyn & Hughes (1938) using distilled water.
    b Values from Mabey & Mill (1978) using freshwater, pH 7.

    FIGURE 1

         Degradation occurred by the methylation of carboxylic groups on
    moist H-substituted peat. In soils containing other groups that can be
    methylated, the mechanism and factors of methyl bromide degradation
    are more complex.

         Adsorption on to organic matter reduced the available
    concentration of methyl bromide in the aqueous and gaseous phases of
    soil. Organic matter was also the main factor involved in the
    degradation of methyl bromide in the soil (Arvieu & Cuany, 1985).

    4.2.2.2  Light-assisted hydrolysis in water

         The UV-absorption cross sections for methyl bromide (174-262 nm)
    have been confirmed by several authors (Robbins 1976b; Uthman et al.,
    1978; Molina et al., 1982; Gillotay et al., 1989). The UV absorption
    spectrum has a maximum of 202 nm with a steep decrease at longer
    wavelengths reaching 0.2% of the maximum at 260 nm (Table 17). This is
    much shorter than 290 nm, which is the shortest wavelength radiation
    reaching the earth's surface from the sun.

         It should be noted that the photoactivation of methyl bromide, as
    well as its hydrolysis products in water or on soil surfaces, will
    differ from the gas phase activities of these processes. The
    hydrolysis products are in solution and differ energetically. Since
    the species energy levels are changed from those of the isolated
    molecule, critical absorption wavelengths would be shifted.

         The influence of sunlight versus dark using natural waters in a
    laboratory test showed little effect on the hydrolysis of methyl
    bromide (Gentile et al., 1989, 1992). 

         Irradiation with a "pen-ray" low-pressure mercury lamp at 254 nm
    gave a 6.6-fold increase in the rate constant. However, photolysis
    does not alter the stoichiometry of the hydrolysis (Castro & Belser,
    1981). The authors concluded that the almost exclusive path of decay
    (>99.6 %) was the direct hydrolysis of photoactivated methyl bromide
    with the formation of methanol, bromide ion, protons, and a trace of
    methane (<0.4%).

    4.2.2.3  Reaction with the hydroxyl radical

         Reaction of methyl bromide with the hydroxyl radical is believed
    to be the primary mechanism for the removal of methyl bromide from the
    lower troposphere (Singh et al., 1981).

         Methyl bromide reacts slowly with the hydroxyl radical:

                      CH3Br + OH- -> CH2Br- + H2O

    with a reaction rate constant of about 3 x 10-14 cm3/molecule per
    second at 298 °K (NASA, 1992). 

    Table 17.  Absorption cross sections of methyl bromidea
                                                      
        lambda   1020 sigma     lambda   1020 sigma
        (nm)     (cm2)          (nm)     (cm2)
                                                      
        190      44             230      15
        192      53             232      12
        194      62             234      9.9
        196      69             236      7.6
        198      76             238      5.9
        200      79             240      4.5
        202      80             242      3.3
        204      79             244      2.5
        206      77             246      1.8
        208      73             248      1.3
        210      67             250      0.96
        212      61             252      0.69
        214      56             254      0.49
        216      49             256      0.34
        218      44             258      0.23
        220      38             260      0.16
        222      32                      
        224      28                      
        226      23                      
        228      19                      
                                                      

    a Values recommended by NASA (1992) and taken from
      Gillotay et al. (1989). These authors measured the
      cross sections down to 210 K; for <210 nm, the
      temperature effect is negligible.

    Table 18 shows values for hydroxyl radical rate constants.

        Table 18.  Atmospheric reactions of methyl bromide
                                                                        
    Reaction     Rate constant     Height above   Reference
                                   sea level
                                   (km)
                                                                        
    CH3Br +  hv    1 x 10-11/s       16             Robbins (1976a)
                 1 x 10-9/s        20
                 1 x 10-6/s        30
                 5 x 10-5/sec      50

    CH3Br + OH-  3 x 10-14 cm3/s (298 °K)           NASA (1992)a

              k(T) = 3.6 x 10-12 exp [-(1430±150) K/T] cm3/s
                                                                        
    a Profiles of OH- and temperature of the stratosphere are given in NASA (1992).
    
         Recent laboratory data for the rate coefficient of the reaction
    of methyl bromide (Mellouki et al., 1992a,b) with the hydroxyl radical
    together with the estimated distribution of the hydroxyl radical (WMO,
    1992), gave an estimated OH--removal lifetime for methyl bromide of
    2±0.5 years (UNEP, 1992).

    4.2.2.4  Photolysis in the atmosphere

         In the upper stratosphere, above 25 km, the photodissociation of
    methyl bromide is the most dominant loss mechanism. Below this, as
    less UV radiation is able to penetrate through the atmosphere, the
    role of photolysis decreases. Between 20 and 25 km above sea level,
    photodissociation is equally as important as loss by diffusion and
    reaction with OH-. Below 20 km, down to the troposphere,
    photodissociation becomes negligible and losses by diffusion and
    reaction with OH- are of approximately equal importance (Robbins,
    1976a) (Table 18). 

         The end-products of photodissociation of methyl bromide and
    reactions with hydroxyl radicals in the atmosphere are probably carbon
    dioxide, carbon monoxide, and bromide species (BUA, 1987).

    4.2.3  Bioaccumulation

         There are no experimental data on bioaccumulation potential. The
    octanol/water partition coefficient (log Pow) of methyl bromide has
    been given as 1.19 (Hansch & Leo, 1979; Sangster, 1989), so it
    probably does not have any significant tendency to bioaccumulate (see
    also section 4.1.5). 

    4.3  Interaction with other physical, chemical, or biological factors

         It has been found that methyl bromide is able to diffuse through
    certain plastics (Herzel & Schmidt, 1984).

         A reaction is possible between methyl bromide and the following
    materials ( Bond, 1984):

         -    iodized salt, stabilized with sodium hyposulfite;

         -    certain baking sodas, salt blocks used for cattle licks, or
              foods containing reactive sulfur compounds;

         -    full fat soy flour;

         -    sponge rubber;

         -    foam rubber as used in rug padding, pillows, cushions, and
              mattresses;

         -    rubber stamps and similar forms of reclaimed rubber;

         -    furs, horsehair, and pillows (especially feather pillows);

         -    leather goods tanned using a sulfur process;

         -    woollens, especially angora; some adverse effects have been
              noted on woollen socks, sweaters, and yarn;

         -    viscose rayons, made by a process that uses carbon
              disulfide;

         -    cinder blocks or mixtures of mortar; mixed concrete
              occasionally picks up odours;

         -    charcoal, which not only becomes contaminated but absorbs
              great amounts of methyl bromide and, thus, reduces effective
              fumigant concentrations;

         -    paper that has been cured by a sulfide process and silver
              polishing papers;

         -    photographic chemicals, not including films;

         -    rug padding, vinyl, cellophane;

         -    any other materials that may contain reactive sulfur
              compounds.

    4.4  Ultimate fate following use

    4.4.1  Methyl bromide and the ozone layer

         Methyl bromide from natural and anthropogenic sources is released
    into the atmosphere. Once organic bromine compounds, such as methyl
    bromide and the halons (section 5.1.1), enter the stratosphere, they
    decompose to release bromine atoms. Fig. 2 depicts the key
    bromine-containing species in the stratosphere and shows the
    interconversion between reactive (Br- and BrO-) and reservoir
    (HBr, HOBr, BrCl, and BrONO2) species (UNEP, 1992).

         Yung et al. (1980) proposed the following reactions for ozone
    loss due to bromine:

         Br- + O3 -> BrO- + O2 

         Cl- + O3 -> ClO- + O2 

         BrO- + ClO- -> Br- + Cl- + O2

         Net 2O3 -> 3O2

         Ozone removal by bromine is far more efficient on a per molecule
    basis than that by chlorine. This bromine-catalysed ozone removal in
    the lower stratosphere is thought to occur via the reaction between
    BrO- and ClO- (WMO, 1992) whereby the efficiency of
    bromine-induced ozone loss increases with increasing abundance of
    stratospheric chlorine. Bromine catalysis is most efficient in the
    lower stratosphere where the ozone concentration is largest.

         Reactive bromine has been detected directly in the stratosphere
    in the polar regions, as well as OClO-, for which the only known
    source is the reaction of BrO- with ClO-. Analyses of these
    measurements indicate that the BrO- + ClO- catalytic cycle is
    responsible for roughly 25% of the observed total ozone loss in the
    appearance of the Antarctic ozone hole (an event mainly restricted to
    Antarctica and to the months of September-November, involving
    heterogenous reactions on polar stratospheric clouds) (WMO, 1992). 

    FIGURE 2

         Another possible catalytic cycle is that between BrO- and HO2
    (Poulet et al., 1992). 

         The Ozone Depletion Potential (ODP) represents the amount of
    ozone destroyed by the emission of one kg of a chosen gas over a
    particular time scale, compared with 1 kg of a reference molecule,
    usually CFC-11 (Table 19). The amount of ozone depletion from methyl
    bromide, and the ODP of the gas are dependent upon the atmospheric
    abundance of chlorine. On the basis of current understanding, the
    higher the abundance of chlorine, the higher the ODP of methyl bromide
    and the amount of ozone depletion it causes.

        Table 19.  Lifetime and time-dependent depletion potential (ODP) for
    methyl bromide (CH3Br) in comparison with chlorofluorcarbonsa
                                                                         
    Speciesc        Total              Stratospheric       Steady-state
                    atmospheric        lifetime (year)     empirical polar
                    lifetime (year)                        ODPb
                                                                         
    CFC-11            55                55                 1,0
    (CFCl3)

    CFC-113          110               110                 1,10
    (CFC12CF2Cl

    CH3Br             2,0               35                 0,7
                                                                         

    a Values are relative to CFC-11 as the reference gas.
    b ODP = ozone depletion potential.
    c CFC = chlorofluorocarbon.
    
         The key factors influencing the ODP of methyl bromide include:
     (a) the atmospheric lifetime of the compound (relative to CFC-11);
     (b) the release of reactive bromine from methyl bromide (relative to
    CFC-11); and  (c) the relative efficiency of reactive bromine for
    ozone destruction compared with that of reactive chlorine (alpha
    factor).

     (a)     Atmospheric lifetimes for methyl bromide have been 
              estimated at 1.6 years (WMO, 1992) and 2.0 years  (UNEP,
              1992). However, oceanic and terrestrial surface removal
              processes have not been taken into account.

     (b)     As methyl bromide is a relatively short-lived molecule 
              within the stratosphere, it is expected that its release of 
              reactive bromine is faster than that of chlorine from
              CFC-11.

     (c)     The current best estimate of alpha in the lower polar 
              stratosphere is about 40 (UNEP, 1992).

         The current best estimate of the steady-state ODP for methyl
    bromide from the semi-empirical approach and models including both
    gas-phase and heterogeneous chemistry is 0.7 (UNEP, 1992). This
    assumes its lifetime is solely determined by reaction with OH- in
    the troposphere.

         The anthropogenic contribution to the current atmospheric
    abundance of methyl bromide is estimated to be about 3 pptv (UNEP,
    1992). If anthropogenic methyl bromide is about 13-14% of total
    atmospheric bromine (calculated by taking 25% of 11 pptv total methyl
    bromide (UNEP, 1992) = 2.75% of total atmospheric bromine from
    anthropogenic sources; and 55% of 20.8 pptv total organic bromine as
    methyl bromide (Schauffler et al., in press) = 11%), the global ozone
    loss due to anthropogenic methyl bromide is approximately 3%. 

    4.4.2  Containment, recovery, recycling, and disposal options for
           methyl bromide

         At present, after soil, commodity, and structural fumigation,
    there is no special effort at containment of methyl bromide (see
    section 3.2 for estimated emission rates from various fumigation
    processes). 

         The methyl bromide industry is currently investigating practical
    methods of recovering the gas by adsorption (using activated
    charcoal), condensation, and scrubbing techniques. Most of these
    methods are still in the research and development stage (UNEP, 1992).
    When methyl bromide cylinders are refilled, instead of the present
    practice of venting, it may be possible to recondense and recover the
    gas. In this way, 1-2% of the total methyl bromide used could be
    saved.

         Methyl bromide is a toxic gas and the recommended waste disposal
    method for large quantities is incineration by specialists. However,
    incineration may be difficult to arrange safely unless an efficient
    method of feeding the gas into the incinerator can be arranged.
    Incineration requires dilution with additional fuel. If a suitably
    designed combustion chamber is not available, return labelled
    containers to supplier. Any release into the atmosphere should take
    place in well-ventilated outdoor locations only.

         All national and local regulations should be observed when
    disposing of methyl bromide.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

    5.1.1.1  Global abundance

         The current best estimate for the global abundance of methyl
    bromide in the troposphere is between 9 and 13 pptv (section 3.1 and
    Tables 20 and 21) giving a total global burden of 150-220 million kg
    (UNEP, 1992). From observations taken from the surface waters of the
    Pacific, off North and South America, Singh et al. (1983) had
    previously estimated the total natural emission of methyl bromide from
    the oceans at 300 million kg/year with a residence time of 1.2 years.
    This estimate is probably too high because of the difficulties with
    absolute calibration.

         The most abundant bromine source gas is methyl bromide, which
    arises from both natural and anthropogenic sources (WMO, 1992; also
    sections 3.1 and 3.2). The main natural sources of methyl bromide are
    oceanic biological processes (mainly algal) where it is formed
    together with bromoform (CHBr3), methylene bromide (CH2Br2),
    CH2BrCl, and CHBrCl2 (WMO, 1992). Apart from methyl bromide, other
    anthropogenic sources are the halons, CBrF3 (CFC-13B1; Halon 1301),
    CBrClF2 (CFC-12B1; Halon 1211), and C2Br2F4 (Halon 2402),
    which are used as special purpose fire extinguishers (Singh et al.,
    1988; Schauffler et al., in press). 

         The atmospheric abundance of methyl bromide appears to be
    1.3±0.15 greater in the Northern than in the Southern hemisphere
    (Tables 20, 21) indicating an excess source in the Northern
    hemisphere. The major source of methyl chloride is also thought to be
    oceanic, but the atmospheric abundance of this gas appears to be
    comparable in both hemispheres (UNEP, 1992). Some atmospheric models
    compute the interhemispheric OH- concentration ratio
    (OHN-/OHS-) to be about 0.8 (Tie et al., 1992). Assuming
    reaction with OH- is the major tropospheric destructive process for
    methyl bromide, this southern excess of OH- could largely explain
    the lower southern atmospheric concentration of methyl bromide. In
    contrast, Spivakovsky et al. (1990), using a model based on different
    assumptions, calculated a higher OH- concentration in the northern
    than in the southern hemisphere.

         Ozone loss, catalysed by bromine, occurs mainly in the lower
    stratosphere.The primary cause of the Antarctic ozone hole is most
    certainly halogen chemistry (WMO, 1992). Bromine is now believed to
    have a greater potential per molecule to destroy stratospheric ozone
    than chlorine (section 4.4).

         The upward mass transfer of air from the troposphere to the
    stratosphere occurs mainly in the tropical latitudes between 30 °S and
    30 °N (WMO, 1992). Schauffler et al. (in press) give the mixing ratios
    of brominated compounds and total organic bromine from 12 samples
    collected at the tropical tropopause (altitude about 16 km) from
    January to March, 1992. The mean mixing ratio of total organic bromine
    was 20.8±0.8 pptv. Methyl bromide was found to contribute 55% of the
    total organic bromine, CH2Br2, about 7%, and the remaining 38% was
    nearly evenly distributed between Halon 1302, Halon 1211, and Halon
    2402. 

         It is against this background of the role of bromine in the ozone
    depletion in the stratosphere that there has been recent concern about
    levels of methyl bromide in the atmosphere and the potential effect of
    the continuing use of this fumigant (see also sections 3.1, 3.2, 4.4).

    5.1.1.2  Measured oceanic and coastal air levels of methyl bromide

         Table 20 shows levels of methyl bromide in oceanic areas,
    measured by ground-based, aircraft, and balloon techniques. The
    differences between the individual readings do not seem to be due to
    trends in abundance over the last decade or to seasonal variation, but
    more likely to variations in calibration (UNEP, 1992). An abundance of
    methyl bromide in the atmosphere of 9-13 pptv is equivalent to a total
    global burden of 150-220 million kg.

         Although there are differences in the values reported for the
    absolute magnitudes of the observed methyl bromide abundances, ranging
    from 10-26 pptv in the Northern hemisphere and 8-20 pptv in the
    Southern hemisphere, the N/S ratio is almost constant at 1.3 (Table
    20). The greater abundance of methyl bromide in the Northern than the
    Southern hemisphere has been confirmed by all studies published up to
    now. This is possible evidence for the anthropogenic addition of
    methyl bromide to the atmosphere from its use as a fumigant (see also
    sections 3.1, 3.2, and 4.4) as well as from motor vehicle exhaust.

         Methyl bromide concentrations in the atmosphere are summarized in
    Table 21, comparing oceanic and continental values with those in urban
    areas.


        Table 20.  Atmospheric abundance of methyl bromide at, or near, ground level (pptv)a
                                                                                                               
    Source       Time         Northern     Southern      N/S ratio   Observational       Reference
                 period       hemisphere   hemisphere                platform
                                                                                                               
    Singh        1981         26           20            1.3         Ship                Singh et al. (1983)

    Penkett      1982-83      15           11            1.4         Ship                Penkett et al. (1985)

    Rasmussen    1983-92      11            8            1.3         Coastal land        MBSW (1992)

    Cicerone     1985-87      12           10            1.2         Coastal land        Cicerone, et al. (1988)

    Rowland      1991         10            8            1.2         Coastal land        MBSW (1992)

    Heidt        1991         14            -            -           Aircraft            MBSW (1992)
                                                                                                               

    a From: UNEP (1992).
    b MBSW = Methyl Bromide Science Workshop (1992). 
    

         Measurements by Singh et al. (1983) of air and seawater
    concentrations of methyl halides in, and over, the Eastern Pacific
    (40° N-32° S) gave average concentrations of 90 ng/m3 (23 pptv) in
    air. However, there was a considerable difference between the readings
    in the northern (101 ng/m3 [26 pptv]) compared with the southern (74
    ng/m3 [19 pptv]) hemisphere. Because of the large scattering of
    values, a seasonal trend was not identifiable. As mentioned in section
    3.1, it is possible that calibration standards were in error, which
    would explain the higher values compared with those of other authors. 

         Rasmussen & Khalil (1984) found that the highest concentrations
    of methyl bromide in Arctic and Arctic haze were found in the summer
    (average - 48.2 ng/n3 (12.4 pptv)) compared with the autumn and
    winter (average - 39.7 ng/m3 (10.2 pptv)), and, that methyl bromide
    did not show the same seasonal patterns as other bromine-containing
    trace gases.

         Penkett et al. (1985) measured four different bromine compounds,
    including methyl bromide, over a large latitudinal range (40° N to 75°
    S). They found that there was a clear reduction in concentrations
    between the two hemispheres, the average concentration of methyl
    bromide in the Northern Hemisphere being 60±7 ng/m3 (15.4±1.9 pptv)
    compared with 41.2±3.5 ng/m3 (10.6±0.9 pptv) in the Southern
    Hemisphere. 

        Table 21.  Measured ambient concentrations of methyl bromide
                                                                                      
    Location                     Concentration pptv (ng/m3)a     Reference
                                                           
                                 mean             max
                                 or range
                                                                                      
    Oceanic and coastal air levels

    Eastern Pacific              40°N             26 (101)       Singh et al. (1983)
    Ocean                        32°S             19 (74)

    Arctic                       72°N             11.3 (44)      Rasmussen & Khalil
                                                                 (1984); 
                                                                 Berg et al. (1984) 
                                 90°S             7.5            Khalil & Rasmussen (1985)

    Atlantic Ocean               40°N             15.4 (60)      Penkett et al. (1985)
    Southern Ocean               75°S             10.6 (41)      

    Alaska                       71°N             11.16 (43)     Cicerone et al. (1988)
    Hawaii                       20°N             10.75 (42)
    Samoa                        14°S             10.23 (40)
    Tasmania                     44°S             9.58 (37)
                                                                                      

    Table 21 (continued)
                                                                                      
    Location                     Concentration pptv (ng/m3)a     Reference
                                                           
                                 mean             max
                                 or range
                                                                                      
    Alaska                       71°N             14.1           Khalil et al. (1993)c
    Oregon                       45°N             12.6
    Hawaii                       19°N             11.4
    Samoa                        14°S             8.5
    Tasmania                     42°S             7.5
    Antarctic                    64.5°S           9.0

    Continental air levels

    USA

    Pullman, Washington          < 10-220                        Harsch & Rasmussen
                                 (< 40-870)                      (1977)

    Los Angeles                  244 (950)        894 (3480)     Singh et al. (1981)
    Oakland                      55 (214)         108 (420)
    Phoenix                      67 (261)         190 (740)

    Badger Pass                  5 (19)           8 (31)         Brodzinsky & Singh
    Denver                       120 (467)        190 (740)      (1983)
    Houston                      100 (390)        170 (660)
    Jetmore                      5 (19)           5 (19)
    Los Angelesb                 150 (584)        580 (2256)
    Menlo Park                   16 (62)          16 (62)
    Mill Valley                  25 (97)          25 (97)
    Oaklandb                     55 (214)         78 (303)
    Palm Springs                 24 (93)          24 (93)

    Phoenixb                     67 (261)         120 (467)      Brodzinsky & Singh
    Point Arena                  17 (66)          20 (78)        (1983)
    Point Reyes                  93 (362)         93 (362)
    Reese River                  5 (19)           5 (19)
    Riverside                    250 (973)        560 (2180)
    San Jose                     31 (120)         31 (120)
    St. Louis                    81 (315)         100 (390)

    San Jose (California, USA)                                   Singh et al. (1992)
    [4-16 April 1985]            400
                                 (44-4661)
    [12-24 August 1985]          121
                                 (5-1067)
    [13-21 December 1985]        2869
                                 (239-15 424)
                                                                                      

    Table 21 (continued)
                                                                                      
    Location                     Concentration pptv (ng/m3)a     Reference
                                                           
                                 mean             max
                                 or range
                                                                                      
    Downey, California, USA
    [8-27 February 1984]         212
                                 (18-815)
    Houston, Texas, USA
    [9-17 March 1984]            23
                                 (11-48)
    Denver, CO, USA
    [24 March-1 April 1984]      22
                                 (13-64)

    The Netherlands

    Delft, Vlaardingen           50-200           100-900        Guicherit & Schulting
    and Terschellingd            (195-780)        (390-3500)     (1985)

    Japan

    urban and suburban           15-31                           JEA (1981)
                                 (59-122)
                                                                                      

    a The converted values in brackets ( ) are only approximate.
    b Includes substantial overlap with data reported in Singh et al. (1981).
    c Values given from spring 1991. Fig. 3 gives averages over the last decade. 
    d About 350 samples per site during 1989.
    
         Approximately 750 air samples from five surface sampling sites in
    Alaska, Hawaii (2), Samoa, and New Zealand were analysed by Cicerone
    et al. (1988) for methyl bromide between January 1985 and October 1987
    (using GC/MS). Methyl bromide concentrations were typically 40-44
    ng/m3 (10-11 pptv).

         Khalil et al. (1993) presented a series of 1700 measurements
    showing the latitudinal distribution of atmospheric methyl bromide
    from 1983 to 1992 (Table 21 and Fig. 3). The levels of atmospheric
    methyl bromide measured between 1988 and 1992 seemed to be higher than
    those measured between 1983 and 1988.

    FIGURE 3

    5.1.1.3  Measured continental and urban levels of methyl bromide

         Data from seven cities in the USA showed significant elevations
    of methyl bromide levels in urban areas with average concentrations of
    159-1004 ng/m3 (41-259 pptv) (Singh et al., 1982). Concentrations as
    high as 4000 ng/m3 were also reported. A further study of methyl
    bromide levels at 16 sites in the USA confirmed these findings,
    showing that the larger the city the higher the methyl bromide level
    (Brodzinsky & Singh, 1983). Methyl bromide is emitted from motor
    vehicles using leaded petrol. Since many of these urban studies were
    made, unleaded petrol has been introduced, which could mean that
    current urban levels of methyl bromide would be lower. Some background
    levels of 20 ng/m3 (5 pptv) appear to be lower than oceanic values
    (Singh et al., 1981). 

         The high values reported for 1984/85 by Singh (1992) in
    California (Table 21) may have been influenced by nearby soil
    fumigation. 

         In a 1980 environmental survey of methyl bromide levels in
    Japanese urban and suburban areas, the gas was detected in 5 out of 27
    samples with levels ranging from 59 to 122 ng/m3 (15 to 31 pptv)
    (JEA, 1981). In the Netherlands, a study of the concentrations of
    methyl bromide in ambient air was carried out by Guicherit & Schulting
    (1985). Between 1979 and 1981, air samples were measured in three
    locations: at the island of Terschelling in the north (little
    pollution); at Delft, a small city in the densely populated western
    part of The Netherlands, and in Vlaardingen, in a heavily
    industrialized area near Rotterdam. The study gave an average of
    195-778 ng/m3 (50-200 pptv) and a maximum 1-h concentration of
    390-3500 ng/m3 (100-900 pptv). The estimated daily (10.0 µg) and
    yearly (4.5 µg) average exposure values given were based on a total
    respiratory volume of 20 m3 per day.

    5.1.1.4  Vertical profiles of methyl bromide in the atmosphere

         Data on vertical levels of methyl bromide lead to a better
    understanding of the ultimate fate of methyl bromide in the atmosphere
    and its role in ozone reduction in the lower stratosphere (section
    4.4). Rasmussen & Khalil (1984) and Berg et al. (1984) showed no
    significant decrease in methyl bromide levels up to 7 km. Penkett et
    al. (1985) detected a methyl bromide level of 40 ng/m3 (10 pptv) in
    the upper troposphere. As shown in Fig. 4, Fabian et al. (1981)
    measured 1.2 pptv at 14.4 km, but could not detect any methyl bromide
    at an altitude of 20 km. It has been suggested (UNEP, 1992) that there
    is no significant vertical gradient in the troposphere, but that the
    level of methyl bromide decreases rapidly in the lower stratosphere
    (by at least a factor of 3-5 within 10 km above the tropopause). It is
    here that ozone loss occurs. Schauffler et al. (in press) gave methyl
    bromide levels in the mid to low troposphere of 13.6±1.4 pptv (37-45°
    N; 69° W) and 12.7±1.1 (22-26° N; 94-97° W). In the tropical
    tropopause (altitude 15.3-16.76 km; 24° N, 68-85° W), levels of
    11.4±0.5 pptv (mean of 12 samples) were measured.

    FIGURE 4

         Fig. 4 shows the vertical profile for methyl bromide (Schauffler
    et al., in press). Fig. 5 shows the vertical profile of methyl bromide
    together with other atmospheric source gases in the middle Northern
    hemisphere from air samples taken from the troposphere and
    stratosphere (Fabian, 1984).

    FIGURE 5

    5.1.1.5  Release of methyl bromide to the outside air from greenhouses

         During 1986, 400 000 kg methyl bromide were emitted into the air
    in the Westland area of the Netherlands (Van Doorn et al., 1989).
    Although soil disinfection is only allowed when the diluting capacity
    of the atmosphere (wind force) is sufficient, this is very difficult
    or impossible to control. Investigations by Netherlands Institutes
    (TNO and RIVM) showed that the hourly average concentrations within a
    20-m distance from the green-houses in 1981 (after the introduction of
    gas-tight film) during the first hours was 5.9 mg/m3 after
    fumigation with methyl bromide at a dose of 700 kg/ha. In 1982 and
    1983, a few hours after injection and at a probable dosage of 400
    kg/ha, concentrations measured ranged between 1 and 4 mg/m3 at
    distances of 20 m. After the first few hours, the concentration of
    methyl bromide decreased rapidly and, after 4 days, also at 20 m,
    hourly averages of 0.2 mg/m3 were measured. Ten days after
    fumigation, the covering foil was removed, after which the hourly
    average concentration increased to a maximum of 0.4 mg/m3 (Van Doorn
    et al., 1989).

    5.1.2  Water

    5.1.2.1  Seawater

         In 1975, samples of seawater from near the shore at Dorset,
    England were analysed for halomethanes and methyl bromide was detected
    at levels ranging from 2.0 to 3.9 x 10-9 ml gas/ml water [apprx. 10
    ng/litre] (Lovelock, 1975).

          Average concentrations of 1.2 ng methyl bromide/litre were
    measured in surface seawater in the Eastern Pacific Ocean (Singh et
    al., 1983). The authors estimated that the oceans are supersaturated
    with methyl bromide to 250%.

         Khalil et al. (1993) measured methyl bromide concentrations in
    ocean water in two open-ocean surveys, one covering latitudes from 45°
    N to about 30° S, the other from 67° N to 50° S. On the first survey,
    they found supersaturation of methyl bromide at 180% and, on the
    second, 140%.

    5.1.2.2  Inland waters

         In 1988, the California Department of Food and Agriculture (CDFA)
    reported the results of analyses of 43 056 well water samples taken
    from 2977 wells in various Californian counties. Residues of 10
    chemicals were detected. Methyl bromide detection was undertaken in 32
    counties, but in all the wells tested only one sample showed the
    presence of methyl bromide (CDFA, 1988).

    5.1.2.3  Waters around greenhouses

         In the Netherlands, where intensive horticulture in greenhouses
    is practised, the soil level is lower than sea level in some areas,
    with the result that water transport is very slow and the static water
    volume is very high. There is a high density of greenhouses and all
    holdings have to use the water from ditches as leaching water, thus,
    this water is successively loaded with bromide. However, it should be
    noted that, in 1992, methyl bromide was banned in the Netherlands for
    soil fumigation purposes.

         The concentrations of methyl bromide and bromide-ion were
    measured in irrigation water, drainage water, and surface water during
    the leaching periods in two Netherlands glasshouse soils after
    fumigation with methyl bromide (Wegman et al., 1981). Maximum
    concentrations in drainage water, determined within 24 h of the start
    of leaching, were 9.3 mg/litre (methyl bromide) and 72 mg/litre
    (Br-).

         Further studies of bromide ion concentrations in precipitation,
    surface water, and ground water in the polder district in the
    Netherlands (a main horticultural area) in 1979-80 gave maximum values

    of 0.98, 41, and 17 mg/litre respectively, the highest concentrations
    being found during the main fumigation/leaching time in
    September-October 1979 (Wegman et al., 1983). During these few weeks,
    an estimated 1.78 million kg methyl bromide (about 1.5 million kg
    bromide ion) were used for soil fumigation. From their measurements,
    Wegman et al. (1983) calculated that 14% of the applied methyl bromide
    was converted to bromide ion. This is in agreement with Daelemans
    (1978), whose studies showed that 10-30% of methyl bromide is
    converted to Br-. The fumigation method used was the "hot gas
    method", whereby the fumigant was discharged under thin low-density
    polyethylene (LDPE) sheeting. Subsequently, in June 1981, the use of
    LDPE for this purpose was forbidden.

         In 1985, bromide concentrations of 10-35 mg/litre were observed
    in Westland (the Netherlands) surface water with maximum
    concentrations in the Poel and Bosch polders of 38.7 and 31.7
    mg/litre, respectively (Van Doorn et al., 1989). Private water
    supplies from shallow pumps in the Netherlands near methyl bromide
    soil operations were expected to have increased bromide contents (Van
    Doorn et al., 1989). In 1986, in the Westland, 260 000 kg bromide
    ended up in surface water, at an average dosage of 700 kg/ha.

         Similar investigations were carried out by Vanachter et al.
    (1981) in the glasshouse crop growing region of Malines - Antwerp
    (Belgium) into bromide concentrations in surface water in periods of
    intense soil fumigation and leaching (August-September) compared with
    periods before and after this, when soil fumigation and leaching were
    less frequent. Sampling was also carried out during leaching, near the
    greenhouses, as well as in the ditches and draining water. For
    comparison, samples of natural Br- concentrations in surface water
    were taken from a region where methyl bromide fumigation was not
    carried out.

         The results showed that during the leaching period,
    concentrations of Br- in the surface water in the greenhouse crop
    growing area were significantly higher (maximum 9.6 mg/litre) but,
    five weeks later, were either not detectable (<0.1 mg/litre) or very
    low (1.59 mg/litre) in little brooks. The bromide concentration in
    rivers was less than 0.8 mg/litre, except for one site, where either
    sea water or the effluents from a local photographic plant resulted in
    concentrations of up to 4.5 mg/litre. In the direct drainage area of
    the glass houses, transient concentrations of up to 33 mg/litre were
    measured, decreasing rapidly within a few days.

         Guns (1989) measured groundwater levels in four greenhouses in
    Belgium from September 1986 to August 1988. The bromide content of
    groundwater depended, not only on the length of leaching, but also on
    the type of soil. When the deeper soil layers contained more clay, the
    concentration of the bromide ion in the groundwater, after fumigation
    and leaching, was still relatively high (48 mg/litre before and 280
    mg/litre after fumigation in one study). 

    5.1.3  Soil

         The natural bromide present in unfumigated soil depends on the
    soil type. Van Wambeke et al. (1974) gave values of 3.3 mg/litre for
    fresh sandy loam soil and 2.5 mg/litre for peat soil. Hoffman &
    Malkomes (1974) stated that the natural concentration of bromide in
    the soil was less than 10 mg/kg, depending on the type of soil and
    geographical situation.

         Fallico & Ferrante (1991) measured bromide concentrations in
    greenhouse soil before, and after, the application of methyl bromide
    (80 g/m2). Before fumigation, bromide levels were about 5 mg/kg. Two
    months after treatment, bromide levels of over 30 mg/kg were measured.
    After a further 3 months, levels had decreased to less than 10 mg/kg.

         Bromide ion concentrations following greenhouse and soil
    fumigation depend on the dosage, exposure time, aeration period,
    temperature, the type of soil, the amount of rain or leaching water,
    and the type of covering (sealing conditions). A year after fumigation
    with 70-80 g methyl bromide/m3, bromide values of 0.2-11.5 mg/kg
    were recorded in the upper 30 cm of soil (Basile et al., 1987).

         The bromide remaining in the soil after fumigation can affect
    soil fertility (Rovira & Ridge, 1979). As wheat particularly tends to
    concentrate bromine, soil and wheat dynamics were studied (1981-83) in
    methyl bromide-fumigated plots in a Mediterranean climate (Italy).
    Bromide residues ranged between 5 and 10 mg/kg in the fumigated soil
    to a depth of 50-60 cm. The total amount of bromide in the soil was
    5.8 g/m2 up to a depth of 1 m and remained almost constant during
    the wheat-growing period (Fransi et al., 1987). The amount of bromide
    residues was about 8 % of that applied (900 kg/ha) five months
    previously, compared with the 20 % found by Van Wambeke et al. (1974)
    in similar soils.

    5.1.4  Food

         When considering the published levels of methyl bromide and
    inorganic bromide in various foods, the method of analysis is
    important (section 2.4.9). Originally, bromide content only was
    measured and there is very little information on the methyl bromide
    content. Measurements of both entities are important as well as other
    residual products.

    5.1.4.1  After soil fumigation

         Bromide accumulation in plants depends on various factors, such
    as the physical and chemical properties of the soil, the climatic
    condition, the plant species and particular tissues, and the cultural
    practices (Basile & Lamberti, 1981). Moreover, it depends on dosage,
    exposure time, and aeration.

         A study was carried out in 1980 in Metaponto, in southern Italy,
    where methyl bromide was used to control nematodes and other plant
    pathogens in the soil (Basile & Lamberti, 1981). Bromide ion levels
    were 20-51 mg/kg (tomatoes), 8-44 mg/kg (string beans), 25-149 mg/kg
    (radishes), 18-60 mg/kg (aubergines), 6-165 mg/kg (cucumbers), 13-46
    mg/kg (courgettes), and 3-27 mg/kg (peppers) on a fresh weight basis.
    In experimental plot conditions, the methyl bromide concentration was
    60 g/m2 under a plastic cover with the soil temperature 14-17 °C at
    10 cm depth. The covering was removed after 2 days and the plot
    rotavated at a depth of 20 cm to eliminate residual gases.

         Roughan & Roughan (1984a,b) carried out surveys of bromide ion
    residues in lettuces, cucumbers, tomatoes, and self-blanching celery
    grown in soil fumigated with methyl bromide, and compared these values
    with those in a range of home-produced and imported fruit and
    vegetables. Lettuce grown on unfumigated soil contained less than 10
    mg bromide ion /kg, while most lettuces harvested from methyl bromide
    fumigated soil were found to contain considerably more, 30 %
    containing over 500 mg/kg and 2 % even in excess of 2000 mg/kg
    (Roughan & Roughan, 1984a).

         Studies on vegetables grown under protective covers on soil
    previously fumigated with methyl bromide showed levels ranging from 1
    to 109 mg/kg (fresh weight) in 29 late-season cucumbers, 5 to 326
    mg/kg in 242 tomato samples, and 2 to 521 mg/kg in 38 samples of
    celery (Roughan & Roughan, 1984b); 65 % of the late season cucumbers
    contained more than background of bromide levels up to 10 mg/kg. Crops
    of tomatoes (summer 1981) grown on sites where methyl bromide
    fumigation had taken place in 1980/1981, contained considerably higher
    levels than those grown on a site fumigated in 1979. In a survey from
    retail outlets (January-November 1979), tomatoes and cucumbers from
    the Canary Islands and Spain generally contained less than 10 mg/kg
    (fresh weight). Of those grown in the United Kingdom, levels exceeded
    10 mg/kg in 35 %, and 100 mg/kg in 5 %, ranging up to 177 mg/kg. These
    higher levels of bromide ion could be attributed to the plants having
    been grown on soil fumigated with methyl bromide prior to planting
    (Roughan & Roughan, 1984b). The total bromide ion contents of various
    crops obtained from retail outlets in the United Kingdom during the
    period June 1981 to July 1982 are summarized in Table 22. The survey
    indicated that vegetables, such as tomatoes, celery, cucumbers,
    lettuce, radishes, and aubergines, grown in United Kingdom and the
    Netherlands contained higher levels than elsewhere. Other crops had
    mean bromide levels of less than 10 mg/kg, similar to other figures
    published for background bromide ion content.

        Table 22.  Total bromide ion content of various crops obtained from retail
    outlets in United Kingdom during the period June 1981 to July 1982a
                                                                              
    Crop                Country of          Total No.      Bromide ion
                        origin              of samples     (mg/kg fresh weight)
                                                                               
                                                           Range    Mean
                                                                              
    apple               France              5              0.1-0.3   0.2
    aubergine           Netherlands         4              2-23     11
    avocado pear        not known           1              1
    banana              Windward Islands    2              2         2
    bean, broad         England             3              1-2       2
    bean, french        Guernsey            1              1
    bean, runner        England             2              1         1
    bean, sprouts       England             3              1         1
    cabbage             England             3              1-2       2
    calebrese           England             2              1         1
     (broccoli)
    carrot              England             1              2
    cauliflower         England             3              0.3-1     1
    Chinese             England             3              1-2       1
     leaves
    celery              England             12             1-178    28
                        Guernsey            1              9
                        Israel              4              7-14     10
                        Spain               16             2-8       4
                        USA                 1              4
    courgette           England             3              1-3       2
    cucumber            Canary Islands      15             0.3-10    3
                        England             36             0.2-87    9
                        Spain               3              0.2-10    4
                        Netherlands         7              0.1-14    7
    grapefruit
    segments            Cyprus/Israel,
                        S. Africa           4              0.1-0.4   0.3
    green pepper        Netherlands         7              0.4-5     2

    ettuce              Belgium             1              5
                        Cyprus              5              1         1
                        England             69             1-241    15
                        France              9              0.2-19    4
                        Israel              6              1-4       2
                        Spain               11             0.4-4     2
                        Netherlands         26             2-57     21
                        USA                 12             0.1-2     1
                                                                              

    Table 22 (continued)
                                                                              
    Crop                Country of          Total No.      Bromide ion
                        origin              of samples     (mg/kg fresh weight)
                                                                               
                                                           Range    Mean
                                                                              
    marrow              England             2              1-2       1
    mushroom            England             62             0.2-24    1
    onions              Israel,
                        Netherlands         3              0.4-1     1
    onion,              England             3              2-4       3
    spring
    orange              S. Africa, Spain    6              <0.1-0.4  0.2
    segments
    pea                 England             4              1-3       2
    potato              Cyprus, England     3              1-2       1
    radish              England             18             0.2-3     1
                        Israel              2              5         5
                        Netherlands         12             0.1-48   13
                        USA                 1              1
    strawberry          England             1              0.3
    tomato              Canary Islands      8              1-5       4
                        England             33             1-70     13
                        Spain               15             1-7       3
                        Netherlands         14             1-39     11
                                                                              

    a From: Roughan & Roughan (1984b).
    
         Brown et al. (1979) measured the bromide concentration in several
    plant species in unfumigated and methyl bromide-fumigated plots in
    California (Table 23). Many plants showed increased bromide
    concentrations. Strawberries and grapevines absorbed relatively
    little. As the interval increased between soil fumigation and
    planting, there was a general decline in bromide levels, though the
    interval could be as long as three years before the crops returned to
    a level of about 10 mg/kg (Brown et al., 1979; Roughan & Roughan,
    1984a). Table 24 shows bromide concentrations in plant material 1, 2,
    3, and 4 years after fumigation with methyl bromide.

         Fallico & Ferrante (1991) measured bromide levels in tomatoes in
    crops grown in soil that had been fumigated with methyl bromide ten
    days prior to planting. Bromide levels in tomatoes grown in the
    treated soil and harvested after 60 days were about double (55 mg/kg)
    those in tomatoes grown in untreated soil. The bromide levels
    decreased with each successive harvest, but were still higher than
    those in control plants after the fourth harvest. 



        Table 23.  Bromide concentrations in several plant species in unfumigated and methyl bromide-fumigated plotsa,b
                                                                                          
    Plant species      Treatment       Range of               Average bromide       S.E. of
    and part                           bromide                concentration         means
                                       concentrations         (mg/kg dry weight)
                                       (mg/kg dry weight)
                                                                                          
    barley             control         4 to 575               106 (19)c             38
    (whole top)        fumigated       120 to 5235            1788 (23)             373

    bur clover         control         1 to 407               96 (11)               40
    (whole top)        fumigated       196 to 2371            1334 (14)             155

    filaree            control         4 to 546               135 (14)              47
    (whole top)        fumigated       718 to 7380            2600 (10)             683

    wild oats          control         9 to 876               196 (14)              66
    (whole top)        fumigated       1233 to 5034           3364 (11)             441

    spinach (leaves)   fumigated       1772 to 3195           2521 (4)              387

    ryegrass           fumigated       1481 to 2790           2378 (4)              302

    sweet potato
      (leaves)
      1st sampling     fumigated       640 to 923             753 (4)               69
      4th sampling     fumigated       312 to 372             330 (4)               14

    sweet potato
    (root)             fumigated       204 to 237             220 (2)               17

    strawberry         control         14 to 129              63 (9)                16
    (leaves)d          fumigated       3 to 372               88 (36)               13

    grape (leaves)e    control         1 to 101               28 (90)               3
                       fumigated       1 to 402               48 (278)              4
                                                                                          

    Table 23 (continued)

    a From: Brown et al. (1979).
    b These data represent samples collected the first year after fumigation with MeBr at rates of 34-68 g/m2,
      except for grape leaves.
    c Numbers in parentheses refer to the number of samples in the average.
    d Strawberry leaves were collected after 1-6 annual fumigations with methyl bromide.
    e Grape leaves were collected 2-4 years after fumigation with methyl bromide.
    

    Table 24.  Bromide concentrations in plant material (mg/kg dry
    weight), 1, 2, 3, and 4 years after fumigation with methyl bromidea
                                                               
    County    Untreated           Years after fumigation
              controls                                         

                           1          2          3         4
                                                               
    Sonoma    94(19)b      3018(16)   360(15)    516(8)    12(3)

    Napa      163(21)      1476(15)   742(10)    430(2)
                                                               

    a From: Brown et al. (1979).
    b Numbers in parentheses = number of samples included in the
    average.

    Table 25.  Inorganic bromide residues detected in samples of fruit and
    vegetables in UK (1988 to 1989)a
                                                           
    Commodity            Concentration     Number of samples
                         range (mg/kg)c
                                                           
    Lettuces, produced   n.d.              0
     in United Kingdom
     (proposed CAC         1-20            48
     MRLb=100)            21-100           15
                         101-300           9
                         301-529           5

    Lettuces, imported   n.d.              0
                           1-20            21
                          21-45            3

    Rice, imported       n.d.              59
     [MRL=50               1-10            37
     (unprocessed         11-20            16
     rice)]               21-50            14
                          50-100           10
                         121 and 124       2

    Nuts (no MRL)

      almonds            n.d.              4
                         1-147             24

      brazil nuts        n.d.              0
                         3-140             22

                                                           

    Table 25 (continued)
                                                           
    Commodity            Concentration     Number of samples
                         range (mg/kg)c
                                                           
      cashew nuts        n.d.              16
                         3-53              5

      chestnuts          n.d.              5
                         3-23              3

      coconuts           n.d.              0
                         2-6               5

      hazel nuts         n.d.              7
                         1-194             10

      peanuts            n.d.              4
                         2-109             18

      pine nuts          n.d.              4
                         46                1
    Nuts (continued)

      pistachio nuts     n.d.              0
                           3-104           4

      tiger nuts         n.d.              0
                         17-20             4

      walnuts            n.d.              3
                          2-210            21

      sesame seed        n.d.              5
                          17-56            5

      sunflower seed     n.d.              3
                           2               6
                           3               1

    Dried fruits
     currants, imported
     (CAC MRL = 100)     n.d.              22
                                            1-3 9
                                            6-15 5

     sultanas            n.d.              20
     (CAC MRL = 100)      1-6              6
                                           6-12 7
                                                           

    Table 25 (continued)

    a From: MAFF (1990).
    b CAC = Codex Alimentarius Commission; MRL = maximum residue limit
    (mg/kg) legally permitted in, or on, food commodities or animal feed.
    c n.d. = not detected.

         The results of a further survey (1988-89) in the United Kingdom
    of inorganic bromide levels in fruit and vegetables are summarized in
    Table 25. Fourteen samples of lettuce produced in the United Kingdom
    exceeded the Codex Alimentarius Commission maximum residue limit (CAC
    MRL) for inorganic bromide of 100 mg/kg (MAFF, 1990).

         The effects of leaching following soil fumigation with methyl
    bromide up to 100 g/m2 are shown in Table 26. At sites with low soil
    bromide residues, the resulting bromide residues in lettuce were
    nearly unaffected by leaching. At other sites, there was a positive,
    but diminishing, response to increasing rates of leaching, very high
    residues probably being due to high levels of organic matter (Smart,
    1990). 

         Recent monitoring of samples of individual crops having a
    likelihood of being grown on soil fumigated with methyl bromide showed
    that only a small percentage contained residues above Codex
    Alimentarius Commission recommended limits. The high levels were
    mainly in lettuce. The report of Smart (1990) showed that the
    proportion of samples having high residues had declined since the late
    1970s, when, in some countries, residues in lettuce were as high as
    500-1000 mg/kg. Leaching of treated soils, attention to timing of
    application, and integrated pest control have all helped to reduce
    such residue levels.

         Bromide level tolerances for a variety of methyl bromide
    fumigated raw agricultural commodities in the USA are shown in Table
    27. However, according to the US EPA, because of its existing
    toxicological data base and its environmental ubiquity, inorganic
    bromide is not of toxicological concern. Requirements for residue data
    to support existing inorganic bromide tolerances were waived by the
    Agency (US EPA, 1989).


        Table 26.  Bromide residues in lettuce grown under protection of soil fumigated with bromomethane and leached with water
    before planting in the United Kingdoma
                                                                                                                           
    Site Soil texture      Soil organic   Number of     Interval between    Bromide residues in lettuce (mg/kg fresh weight)
                           matter (%)     applications  planting and        for the water application rates (mm)
                                          in previous   harvest                                                            
                                          years         (weeks)                0b    100     200    300     400
                                                                                                                           
    A    fine sandy loam    4             2             16                    81     102      92    150     142

    B    sandy loam        12             1             12                    62      70     232     93     114

    C    sandy loam        13             2             13                   307     215      98    157     117

    D    sandy loam                       1             24                   765     427     392    284     250

    E    sandy loam         8             4             21                   676     335     328    164     134

    Fc   loamy peat        51             4             14                  1958    1534    1001      -       -

    Mean sites A-E                                                           378     230     228    170     151
                                                                                                                           

    a Summarized from Food and Agriculture Organization (1985) by Smart (1990).
    b Residue figures for crops grown in soils not having any leaching.
    c At F, the leaching treatments were applied after planting the lettuce crop.
    

        Table 27.  USA tolerancesa
                                                                          
    Br in, or on, the following raw agricultural commodities,
    which have been fumigated with the antimicrobial agent
    and insecticide methyl bromide after harvest (with the
    exception of strawberries)                                      (mg/kg)
                                                                          
    corn (pop)                                                      240

    almonds, brazil nuts, bush nuts,                                200
    butternuts, cashews, chestnuts, 
    cottonseed, filberts, hickory nuts,
    peanuts, pecans, pistachio nuts, 
    soybeans, walnuts

    asparagus, copra, cumin (seed),                                 100
    ginger (roots), pomegranates

    avocados, coffee beans, potatoes,                                75
    sweet potatoes

    alfalfa (hay), barley, beans,                                    50
    beans (green), benas (lima), beans 
    (snap), cabbage, cippolini (bulbs),
    cocoa beans, corn, corn (sweet), 
    garlic, oats, peas, peas (blackeyed),
    rice, rye, sorghum (grain), timothy 
    (hay), wheat

    artichokes (Jerusalem), garden beets                             30
    (roots), sugar beets (roots), carrots,
    citrus citron, cucumbers, grapefruit,
    horseradish, kumquats, lemons, limes,
    okra, oranges, parsnips (roots), peppers,
    pimentos, radishes, rutabagas, salsify 
    (roots), squash (summer), tangerines,
    turnips (roots)

    apricots, blueberries, cantaloupes,                              20
    cherries, eggplant, grapes, honeydew
    melons, mangoes, muskmelons, nectarines,
    onions, papayas, peaches, pineapples,
    plums, pumpkins, squash (winter), squash
    (zucchini), tomatoes, watermelons

    apples, pears, quinces                                            5
                                                                          

    a From: US EPA (1988b; CFR 180.124).
    
    5.1.4.2  After post-harvest fumigation

         Methyl bromide is widely used as a post-harvest fumigant to kill,
    or prevent, pest infestation. In 1976, around 100 000 metric tonnes of
    food commodities were treated with methyl bromide in the United
    Kingdom (Fairall & Scudamore, 1980).

         Fairall & Scudamore (1980) measured methyl bromide residues in
    dried milk, wheat, flour, rapeseed, and groundnut samples after store
    fumigation (see Table 28). Products such as groundnuts and rapeseed
    retained higher amounts of methyl bromide. No methyl bromide was
    detected in any commodity after storage for 1 month (detection limit
    10 µg/kg).

         DeVries et al. (1985) measured the rate of decrease of methyl
    bromide in wheat, flour, cocoa, and peanuts after fumigation with the
    gas. Samples were analysed immediately and then after various time
    intervals of exposure of the sample to air. The methyl bromide
    concentration decreased very rapidly in all cases, no residual methyl
    bromide being found in any of the samples after 2 weeks (detection
    limit, 0.4 µg/kg).

     (a) Wheat and cereals

         Pesticide residues in home-grown and imported wheat were measured
    in the United Kingdom by Osborne et al. (1989); 45 samples were
    analysed for methyl bromide (method: Fairall & Scudamore, 1980) and
    inorganic bromide. No methyl bromide was found in excess of the
    detection limit (0.01 mg/kg); all samples contained inorganic bromide,
    but at levels of 4 mg/kg or less, which is given as the level
    naturally present in wheat as a result of uptake from the soil (Heuser
    & Scudamore, 1970; Osborne et al., 1989).

         Trials carried out on a commercial scale showed that CT
    (concentration x time) products for methyl bromide generally lay in
    the range of 50-2000 mg.h/litre (Scudamore, 1987). The higher values
    are usually found in pockets of grain at the bottom of silos or bins.
    Scudamore (1987) recommended careful monitoring, especially at
    increased temperature and moisture content, when treating more
    sorptive cereals, such as oats or maize, or those with which methyl
    bromide reacts more readily. In three samples of wheat from different
    parts of the United Kingdom, bromide levels increased between 2 and 3
    times over a range of 11-16 % moisture content.


        Table 28.  Methyl bromide residue levels (mg kg-1) during storagea
                                                                                            
                                                  Days
                                                                                            
    Commodity          0        0.04     0.25     1         2         4         7        11
                                                                                            
    dried milk         0.5      0.15     0.03     0.006     -         -         -        -

    wheat              0.8      0.42     0.33     0.08      0.04      n.d.b     -        -

    flour              0.28     0.09     0.04     0.02      n.d.      -         -        -

    rapeseed           4.2      3.0      1.5      -         0.95      0.5       0.10     0.08

    groundnuts         7.7      4.5      3.2      2.6       1.6       0.38      0.38     0.03
                                                                                            

    a From: Fairall & Scudamore (1980).
    b n.d. = none detected.
    

        Table 29.  Bromide ion and methyl bromide concentrations (mg/kg) in
    flours exposed to methyl bromide only in silos and in pastas obtained
    from these fumigated and unfumigated floursa
                                                                        
    Material     Treatment            Number of   Bromide ion    Methyl
                                      samples     (mean±S.D.)    bromideb
                                                                        
    flours       unfumigated          3           1.26±0.03      n.d.
                 fumigated            3           1.60±0.11      n.d.

    pasta        from unfumigated     6           1.24±0.13      n.d.
    (macaroni)   flours

                 from fumigated       6           1.91±0.22      n.d.
                 flours
                                                                        

    a From: Cova et al. (1986).
    b n.d. = not detected, i.e., lower than the detection limit of 0.01
      mg/kg.
    
         Stacks of bags containing stored grains and pulses (wheat,
    lentils, maize, barley, chick-peas, peas, and sorghum) were covered
    with PVC sheets and exposed to methyl bromide fumigation for 48 h
    (Urga, 1983). Following aeration, residues of less than 50 mg/kg
    bromide were measured, with the exception of 60 mg/kg after 24 h
    aeration and 59 mg/kg after 36 h aeration. Cova et al. (1986)
    investigated the effects of exposure to methyl bromide in flour, and
    pastas made from it. Flour was exposed to methyl bromide in silos
    (conditions: mean temperature - 18 °C, concentration - 24 g/m3,
    duration of treatment - 68 h, duration of ventilation - 3 days). Table
    29 shows levels of bromide ion before, and after, fumigation. Methyl
    bromide could not be detected. In a second experiment (summarized in
    Table 30) on pasta made from unfumigated flour, rice flour, and white
    flour, Cova et al. (1986) examined the influence of the type of
    packaging on the effects of fumigation. Every item was packed in two
    different ways, i.e., a cardboard box or a transparent envelope made
    of a double layer of polypropylene. The products were fumigated in a
    closed room under the conditions given above, and the mean bromide ion
    concentrations ranged between 2.03 mg/kg (pasta) and 46.23 mg/kg (egg
    pasta), while methyl bromide was not detected.

        Table 30.  Bromide ion and methyl bromide concentrations (mg/kg) in unfumigated
    and fumigated foodstuffs, treated in their retail packagingsa
                                                                            
    Material            Treatment      Number of     Bromide ion     Methyl 
                                       samples       (mean ± S.D.)   bromideb
                                                                            
    rice                unfumigated    3              0.72 ± 0.06    n.d.
                        funfumigated   3             10.63 ± 0.67    n.d.

    flour               unfumigated    3              3.17 ± 0.09    n.d.
                        funfumigated   3              6.66 ± 0.01    n.d.

    white flour         unfumigated    3              1.22 ± 0.15    n.d.
                        funfumigated   3              4.19 ± 0.82    n.d.

    pasta (macaroni)    unfumigated    6              2.40 ± 0.26    n.d.
                        funfumigated   6              2.60 ± 0.27    n.d.

    pasta (spaghetti)   unfumigated    6              1.92 ± 0.17    n.d.
                        funfumigated   6              2.03 ± 0.07    n.d.

    pasta with eggs     unfumigated    6              4.13 ± 0.12    n.d.
                        funfumigated   6             46.23 ± 1.57    n.d.

    pasta with eggs     unfumigated    6              4.62 ± 0.31    n.d.
    and spinach         funfumigated   6             39.00 ± 0.01    n.d.
                                                                            

    a From: Cova et al. (1986).
    b n.d. = not detected, i.e., lower than detection limit of 0.01 mg/kg.
    
     (b) Spices, nuts, and dried fruits

         In the USA in 1980, two warehouses containing imported spices
    were fumigated to eradicate a khapra beetle infestation. Methyl
    bromide and inorganic bromide residues were determined in the 52
    spices before, and after, fumigation (using GC-ECD). In addition, an
    ashing titration method for bromide ion residue was used, allowing a
    comparison of the two analytical methods (Reeves et al., 1985). Before
    fumigation, the highest methyl bromide residue was in parsley (14.9
    mg/kg). Seventy-two hours after fumigation with 100 g/m3 for 12 h,
    samples were collected and analysed. The highest methyl bromide
    residue was found in sage (65.8 mg/kg). Levels of inorganic bromide
    residues before fumigation (GC-ECD) were all lower than 200 mg/kg;
    after fumigation, only two samples contained higher levels.

         In a Canadian study, a number of spices, seeds, nuts, and dried
    fruits and vegetables, including samples of celery, mustard, sesame,
    coriander, pumpkin and sunflower seeds, cloves, peppercorns, dates,

    figs, prunes, raisins, beans, minced onion, a vegetable mix, walnuts,
    and peanuts were analysed for methyl bromide residues (Page & Avon,
    1989). Of the 30 samples, only a sample of pumpkin seeds was found to
    contain methyl bromide (3 µg/kg). Fifty-one chocolate and grain-based
    products were also analysed and found not to contain any methyl
    bromide.

         In contrast, when samples of food known to have been treated with
    methyl bromide were analysed, of the 60 samples, 16 contained residues
    >1 ng/kg and 5 contained >100 ng/kg methyl bromide. These samples
    included dried currants (2.9 mg methyl bromide/kg), chocolate-covered
    nuts (0.66 and 0.19 mg/kg), and rice (2.3 mg/kg) and maize (0.21
    mg/kg) flours. These findings were confirmed by mass spectrometry
    (Page & Avon, 1989).

         Bromide residues after methyl bromide fumigation were determined
    in samples of dried fruits, cereals, nuts, and spices imported into
    New Zealand in 1977 and early 1978 (Love et al., 1979). About one-half
    of the nut and spice samples contained total bromide levels exceeding
    50 mg/kg, and occasional high levels of bromide residues were found in
    cereals.

         Fairall & Scudamore (1980) showed that rapeseed and groundnut
    samples retained higher amounts of methyl bromide than other
    foodstuffs after store fumigation (Table 28). A survey of retail nuts,
    seeds, and nut products in October 1984 (Table 31) showed that levels
    of methyl bromide in some of these products were higher than the Codex
    Alimentarius Commission guideline (MAFF, 1989).

        Table 31.  Residues of methyl bromide in samples of nuts, seeds, and nut productsa,b
                                                                          
                       Number of samples        Residue concentrations
                                                (mg/kg)
                                                                          
                       tested     containing    rangec         mean
                                  residues
                                                                          
    almonds             5         2             n.d. to 0.06   < 0.02
    brazil nuts         4         0             n.d.           -
    dried chestnuts     1         1             0.2            -
    hazelnuts           4         0             n.d.           -
    mixed nuts          3         0             n.d.           -
    nuts and raisins    3         2             n.d. to 0.2    0.08
    peanuts            12         9             n.d. to 0.3    0.06
    walnuts             7         4             n.d. to 2.2    0.4
    othersd             6         0             n.d.           -
                                                                          
    a From: MAFF (1989).
    b 45 samples were obtained during October 1984. and analysed for
      residues of methyl bromide.  The CAC (1986) guideline level for
      methyl bromide in nuts is 0.01 mg/kg.

    Table 31  (continued)

    c n.d. = not detected (the limit of determination was 0.02 mg/kg).
    d One sample each of cashews, pecans, pine kernels, pistachios, sunflower seeds, and
      tiger nuts.
    
     (c) Fresh fruit

         Methyl bromide residues determined in laboratory studies on fresh
    fruits are summarized in Table 32. Studying the effects of fumigation
    dose and length of the following aeration periods, Sell & Moffitt
    (1990) and Sell et al. (1988) found that desorption of methyl bromide
    from apples and cherries, respectively, followed pseudo-first-order
    decay curves, the first component resulting from removal of the
    pesticide from free air space in the chamber, and the second, from the
    desorption from the fruits. Singh et al. (1982) found that methyl
    bromide absorption in avocados depended on oil content rather than
    skin thickness or protein content.

     (d) Milk and cheese

         Bromides may be present naturally in cows' milk in amounts up to
    8 mg/litre. When cows were fed on grain fumigated post-harvest with
    methyl bromide, higher levels of bromide were found in the milk, e.g.,
    cows fed grain containing bromide at 220 mg/kg had bromide levels in
    their milk of 10-20 mg/litre (Lynn et al., 1963).

         Cheese fumigated with methyl bromide showed high bromide residues
    (Laug, 1941).

    5.1.5  Animal feed

         Knight & Costner (1977) reported bromide residues of 6800-8400
    mg/kg in hay that was harvested in the spring after the field had been
    injected with methyl bromide. The resulting toxic effects on animals
    fed with this hay are reported in section 7.3.7.

    5.1.6  Other products

         The chlorine and bromine contents in tobacco and tobacco smoke
    were investigated by Häsänen et al. (1990). Smoke per cigarette
    contained 1 µg bromine in the particulate phase and 5 µg bromine in
    the gaseous phase. In the gaseous phase, methyl bromide accounted for
    80% of the total bromine. Methyl bromide is used widely as a fumigant
    in uncured tobacco storage and this can increase the bromine content
    in tobacco considerably.

         Methyl bromide has been used in growing tobacco seedlings (Ostrec
    & Korunic, 1989).

    5.1.7  Terrestrial and aquatic organisms

         No data are available.

    5.2  General population exposure

    5.2.1  Food

         The general population may be exposed to residues of methyl
    bromide and inorganic bromide, and other possible metabolic products,
    which may be present in food marketed for consumption. Levels of
    methyl bromide and inorganic bromide in food are described in section
    5.1.4.

         Food commodities containing higher levels of oil and fat, such as
    groundnut and rapeseed (Table 28), retain higher amounts of methyl
    bromide residues after fumigation, which disappear after a storage
    period of about one month (Fairall & Scudamore, 1980; DeVries et al.,
    1985). However, higher levels of inorganic bromide residues may remain
    in food commodities marketed after fumigation (section 5.1.4.2).

         Scheffrahn et al. (1992) investigated the effects of methyl
    bromide fumigation on foods in retail packages, in sealed and unsealed
    plastic containers, with a view to simulating conditions in which
    residues may be found in food products after fumigation of a
    residential house in the USA. Fatty commodities in unsealed packages
    contained higher residues (>1 mg/kg) than other foods. The fumigant
    may have entered the containers by two routes, diffusion through the
    air-spaces around the lids (opened peanut butter jar) or in porous
    packaging (parmesan cheese in cardboard box), and by permeation into
    polyurethane bagged foods. Factory sealed, polyethylene terephthalate
    (PETE) containers gave better protection. Vacuum-packed foods in metal
    (soup, coffee) or glass (sauce) containers yielded no residues.

         Bromide residues in foodstuffs were discussed by Van Leeuwen &
    Sangster (1987) in a review of the toxicity of the bromide ion. Total
    diet surveys in the United Kingdom in 1978 and 1979 gave a daily
    intake of 8.4 mg bromide per person. These values are consistent with
    those of two Dutch surveys where average daily intakes of 9.4 and 7.7
    mg bromide per person, respectively, were recorded, i.e.,
    approximately 3 mg/kg diet (Van Leeuwen & Sangster, 1987).


        Table 32.  Methyl bromide residues in fresh fruits after fumigation
                                                                                                          
    Fruit          Fumigation time     Storage      Timea     Residue           Reference
                   and dose            temperature  (mg/kg)
                                       (°C)
                                                                                                          
    grapefruit     2 h, 64 mg/litre    24           1 h       26.9b             King et al. (1981)
                                                    48 h      0.52              

    peaches        3.5 h, 32 g/m3      2.5          1 day     11.0              Austin & Phillips (1985)
                                                    7 days    4.0

    mango          N.D.c, 64 g/m3      N.D.         1 h       < 15.0            Stein & Wolfenbarger (1989)

    grapefruit     2h, 48 g/m3         15.6         5 days    < 5               King & Benschoter (1991)

    oranges,       2h, 48 g/m3         15.6         5 days    < 10
    mandarines,
    tongors

    avocado        2h, 32 g/m3         20           1 day     up to 0.5d        Singh et al. (1982)
                                                    2 days    up to 0.1
                                                                                                          

    a Time of analysis after end of fumigation period.
    b Aeration period: 15 min.
    c N.D. = no data given.
    d Aeration period: 30 min.
    
         The metabolites resulting from methyl bromide post-harvest
    fumigation of a number of crops have been analysed (Starratt & Bond,
    1990a,b). Both physically- and chemically-bound residues were
    measured. In 7 out of the 9 commodities, over half of the total
    residue was chemically bound 1 h after fumigation. These chemically
    bound residues were stable for at least 6 months. Most reaction
    products were O-, S-, and N-methylated proteins (section 6.3).
    Methylation of purines and pyrimidines in the nucleic acids accounted
    for 0.1-6 % of the chemically-bound residue, with N being the only
    site of methylation. The methylation products identified in this study
    are also known to occur naturally.

    5.2.2  Drinking-water

         In 1988, in California, only one sample out of 43 056 taken from
    2977 wells, showed any presence of methyl bromide (detection limit -
    1 µg/litre) (CDFA, 1988). 

         In areas, such as in the Netherlands, where private water
    supplies are from shallow wells near methyl bromide soil operations,
    there could be increased bromide contents in the water (Van Doorn et
    al., 1989).

    5.2.3  Human breast milk

         There are no data available.

    5.2.4  Sub-populations at special risk

         People who live in close proximity to greenhouses or to fields or
    storehouses that are being fumigated have a higher risk of exposure to
    methyl bromide gas than the general population. Similarly, persons
    inadvertently, or intentionally, entering buildings following, in
    particular, structural fumigation, are at risk.

    5.3  Occupational exposure during manufacture, formulation, or use

         The number of incidents and fatalities (section 9) show that
    occupational exposure, especially during fumigation, is potentially
    hazardous.

    5.3.1  During manufacture

         In a methyl bromide plant in the USA, workplace air
    concentrations of 78-116 mg/m3 (20-30 ppm) were recorded using
    direct measurement (Evans, 1979).

         In a methyl bromide-producing factory in Japan, methyl bromide
    concentrations in the worker's breathing zone were usually under 4
    mg/m3, but sometimes exceeded 20 mg/m3 (Kishi et al., 1988).

    5.3.2  During fumigation

         If safety procedures are not followed, workers may be exposed to
    methyl bromide accidentally during, or after, fumigation operations.

         Methyl bromide in low concentrations is odourless so that a toxic
    atmosphere may not be apparent to the worker. Only at higher
    concentrations (100 x the actual TLV(R) of 20 mg/m3 (5 ppm) does
    it have a sweet smell (Van Den Oever et al., 1982). An odour threshold
    of 65 mg/m3 has been reported for methyl bromide (Worthing & Walker,
    1983). Therefore, it is usually marketed in the form of 98% methyl
    bromide and 2% chloropicrin, as a lacrimatory agent. For post-harvest
    fumigation, 100% methyl bromide is used.

         The various fumigation techniques used together with methyl
    bromide exposure values and methods of application are outlined in
    Table 33 (Guillemin et al., 1990).

    5.3.2.1  Structural fumigation

         In carrying out the general fumigation of a building, sufficient
    gas must be liberated into the free space to kill the insects and then
    the toxic level maintained for a defined period of time.  After the
    treatment, the residual gas remaining in the building is dispersed to
    the outside atmosphere. However, there are basic differences in
    defining structures amongst various countries. In the USA, structural
    fumigations mainly involve residential houses whereas, in Europe, they
    generally refer to flour mills and food processing areas. The
    fumigation procedures and the safety aspects in these circumstances
    could be very different.

         Methyl bromide exposure levels for structural fumigation workers
    in California were measured by Anger et al. (1986). They described the
    work involved. "Structural fumigation is conducted by a work crew of
    2-4 men who cover the buildings to be fumigated with large vinyl
    tarpaulins and connect them by spring clamps. Cylindrical tubes filled
    with sand (sand snakes) are placed at the base of the structure to
    hold down the tarpaulins, thus sealing the building. After this one to
    two hour procedure, termed a closing, the fumigant is introduced into
    the unoccupied house via a tube or hose, and the fumigators leave the
    site. The fumigators wear self-contained breathing apparatus (SCBA).
    The next day the work crew removes the tarpaulins, opens the windows,
    and places fans in the house to clear the fumigant. It is in this 30-
    to 45-min process, termed the opening, that worker exposures may
    occur. Typically, each work crew, led by a State-licensed fumigator
    (the "licensee"), conducts three openings and/or closings each day".


        Table 33.  Integrated samples of methyl bromide in air taken in a survey of methyl bromide 
                   fumigation in Switzerlanda
                                                                                                
    Circumstances               Exposure                Sample           Range of values
    of sampling                 category                No.                                     

                                                                  Minimum            Maximum
                                                                  mg/m3(ppm)         mg/m3(ppm)
                                                                                                
    1. Space fumigation
       - during fumigationb     occupational             7        <0.8 (<0.2)       500 (128.4)
       - during aerationb       occupational             7         2.3  (0.6)       646 (166.0)
       - resuming operation     para-occupational       47        <0.8 (<0.2)         9   (2.3)
       - during fumigation      environmental           12        <0.8 (<0.2)        79  (20.4)
       - during aeration        environmental           12        <0.8 (<0.2)       105  (27.1)

    2. Soil fumigation
       - during fumigationb     occupational             5         2    (0.5)       151  (39.0)
       - removal of sheetingb   occupational             3        34    (8.8)       144  (36.9)
       - inside greenhousec     para-occupational        5        12    (0.3)         9   (2.2)

    3. Chamber fumigation
       - outside chamber        para-occupational        3        35    (8.9)       293  (75.3)
       - removing contents      para-occupational        4         5    (1.2)        17   (4.3)
                                                                                                

    a  From: Guillemin et al. (1990).
    b  Fumigators generally wore respiratory protection during these operations.
    c  Greenhouse only partially fumigated; includes post-fumigation soil tillage.   
    

         Personal samples from fumigators taken when they entered houses
    24 hours after fumigation with 23 000 to 31 000 mg methyl
    bromide/m3, indicated that a house might contain 80-2000 mg methyl
    bromide/m3 (Table 34). Personal samples taken on fumigators working
    outside the houses when they were opened again showed concentrations
    of between 0 and 8 mg/m3 in the half-hour periods during the cover
    removal (Anger et al., 1986). Area samples taken within 3 and 6 m from
    the buildings during the same period ranged from 0 to 31 and 0 to 10
    mg/m3, respectively (Anger et al., 1986).

         Concentrations of methyl bromide inside flour mills and in the
    atmosphere around the mills during, and after, fumigation were
    measured by Bond & Dumas (1987). Considerable variations in
    concentration were found in buildings of different structure and under
    varyious weather conditions. Concentrations ranging from trace amounts
    up to 90 mg/m3 (23 ppm) were found in the air around the mills
    during the aeration period.

        Table 34.  Methyl bromide exposure concentrations (mg/m3) 
                   in residential fumigationa
                                                                     
    State          Fumigators     Under     Within 3 m of   3-6 m from
    licensed       working        covers    house           house
    fumigator      outside house
    when inside
    house
                                                                     
    1875.0         5.1    2.0     46.7      32.3     0      0
      75.9         0      1.2               12.5     0      10.1
      90.3         0      7.0               0        17.5   10.1
    1042.1         3.9    3.1               0        0      0
     204.2         8.6    0                 0               0
                                                                     
    Mean
    657.4              3.1        46.7           7.0        3.9
                                                                     

    a Adapted from: Anger et al. (1986).
    
         Guillemin et al. (1990) conducted a survey in Switzerland on
    exposure during space fumigation. The maximum exposure levels for 7
    integrated samples was 646 mg/m3 (166 ppm) during aeration (see
    Table 33). Fumigators wore respiratory protection during these
    operations. Samples of transient air taken around the buildings not
    from any specific spot (distance not given), showed methyl bromide
    levels in the range of 0-105 mg/m3 (see Table 33).

    5.3.2.2  Soil fumigation

         The amount of methyl bromide released into the atmosphere during
    soil fumigation depends on the methods used (Table 9), the type and
    time of covering (section 3.2.2) and soil type.

     (a) Field fumigation

         A formulation of 75% methyl bromide was used to kill insects and
    nematodes in a strawberry crop, with 25% chloropicrin as a fungicide.
    The fumigant injected into the soil produced an equilibrium of 47
    000-58 000 mg/m3 which, under the covers, resulted in personal
    average exposures ranging from 0 to 24 mg/m3 for the fumigators
    (Anger et al., 1986). Personal sample measurements of methyl bromide
    in farm workers when removing the film ranged between 0 and 33
    mg/m3. Other data showed that the personal exposures of fumigators
    and farm workers, who covered the plastic film with earth were between
    0 and 29 mg/m3 and 0 and 17 mg/m3, respectively. Exposure of soil
    fumigators, about 8 h a day, was relatively constant during most of
    the year, whereas farm workers received only occasional exposures when
    fields were fumigated. Spot (area) samples, taken before and after
    film removal, showed that the airborne concentration under the intact
    film was 8950 mg/m3 before removal and 9.3 mg/m3 an hour after
    removal.

     (b) Greenhouse fumigation

         Roosels et al. (1981) compared two methods of methyl bromide
    fumigation in greenhouses, i.e., by injection into milled soil
    followed by covering with a plastic cover, or, by surface fumigation
    by means of plastic pipes under a plastic cover. Two different
    formulations (70 % methyl bromide/30 % chloropicrin and 98 % methyl
    bromide/1-2 % chloropicrin) were used and the concentrations of methyl
    bromide in the air were measured by GC-FID. During injection into
    soil, values of between 400 and 4000 mg/m3 (100 and 1000 ppm) were
    found with peaks up to 12 000 mg/m3 (3000 ppm) and, in one case, up
    to 40 000 mg/m3 (10 000 ppm). However, when preventive measures were
    taken, values of 800 mg/m3 (200 ppm) were obtained. During
    fumigation, concentrations ranged between 400 and 4000 mg/m3 (100
    and 1000 ppm). Using the piped surface fumigation method,
    concentrations around the treated area were between 320 and 3200
    mg/m3 (80 and 800 ppm) with short-term exposures of the operators to
    8000-12 000 mg/m3 (2000-3000 ppm) when the pipes were being
    connected.

         In another investigation, concentrations of 60-100 g methyl
    bromide/m2 were applied under a polyethylene cover (Van Den Oever et
    al., 1982). Depending on local ventilation, quite a lot of gas escaped
    into the surrounding atmosphere. The concentration during application
    varied from 117 to 11 700 mg/m3 (30 to 3000 ppm). Concentration in
    the air declined with time to 16 mg methyl bromide/m3 (4 ppm) five
    days after application. Removing the plastic sheet involved exposure
    to peak values as high as 800 mg/m3 (200 ppm), for a few seconds. On
    the ninth day after application, milling the soil exposed workers to
    up to 60 mg/m3 (15 ppm); on the eleventh day, no methyl bromide was
    detected in the air.

    6.  KINETICS AND METABOLISM

    6.1  Absorption

    6.1.1  Inhalation

    6.1.1.1  Animal studies

         Uptake of methyl bromide was investigated in male Fischer 344
    rats by Andersen et al. (1980). Following whole body exposures to
    recirculated atmospheres of 390-11 640 mg/m3 (100-3000 ppm), the
    uptake (i.e., disappearance from the atmosphere) was rapid and
    exhibited first-order kinetics without a saturable component, the rate
    constant being 0.44 kg-1 h-1. This rate constant was later
    recalculated as 0.55 kg-1 h-1 by Gargas & Andersen (1982).

         Medinsky et al. (1985) carried out a nose-only inhalation of 50,
    300, 5700, or 10 400 nmol (given as 6.2-1206 mg/m3) of [14C]
    methyl bromide/litre of air for 6 h in male F344 rat (5 animals/
    group). The results indicated that, at low concentrations (50-300
    nmol/litre), about 50% of the inhaled material was absorbed. At 5700
    nmol/litre, only 37% was absorbed and, at 10 400 nmol/litre, only 27%.
    The same amount of methyl bromide (650 µmol/kg body weight) was
    absorbed at the two higher exposure concentrations. At 10 400
    nmol/litre, the total volume inhaled by the rats was reduced (Medinsky
    et al., 1985).

         Raabe (1986) found about 40% uptake of inhaled methyl bromide in
    studies on beagle dogs. These results are compared in Fig. 6 with
    those from rats (Medinsky et al., 1985) and those from human
    volunteers (Raabe, 1988), described below.

    6.1.1.2  Human studies

         An inhalation study was carried out to determine systemic uptake
    of low concentrations of methyl bromide from air during nasal or oral
    breathing (Raabe, 1988). Two male and two female volunteers inhaled
    about 0.1 mg 14C-labelled methyl bromide/m3 (25 ppb), once through
    the nose and once through the mouth. The uptake (% of methyl bromide
    inhaled) was 55.4% nasally and 52.1% orally.

    6.1.2  Dermal

    Exclusively dermal exposure has only been observed in human incidents
    (section 9). There are no data dealing exclusively with dermal
    exposure in animals.

    6.1.3  Oral

    Methyl bromide (75 or 100 mg/kg) was administered to rats in olive oil
    by gavage (Miller & Haggard, 1943). The methyl bromide entered the
    blood stream with only a moderate degree of hydrolysis in the
    intestine.

    FIGURE 6


    6.1.4  Intraperitoneal injection

         Methyl bromide (120-180 mg/kg body weight) was administered i.p.
    in hourly doses to rats (Miller & Haggard, 1943). The percentage of
    methyl bromide eliminated was between 24 and 45%. Medinsky et al.
    (1984) administered [14C] methyl bromide i.p., and reported that the
    major route of elimination was exhalation of 14CO2 (46%) (section
    6.4).

    6.2  Distribution of methyl bromide and bromide in tissues

    6.2.1  Animal studies

         Methyl bromide is rapidly distributed to all tissues after
    inhalation and rapidly metabolized. A small percentage is cleared
    slowly and incorporated into metabolic pools (Jaskot et al., 1988).

         At 72 h after oral or i.p. administration of 250 µmol of [14C]
    methyl bromide/kg body weight, 14-17% of the 14C remained in the
    rats, the liver and kidney being the major organs of retention
    (Medinsky et al., 1984).

         In rats exposed, nose only, to 337 nmol [14C] methyl
    bromide/litre air, radioactivity was found widely distributed in
    tissues immediately following exposures. The lung, adrenal gland,
    kidney, liver, and nasal turbinates contained the highest
    concentrations (250, 240, 180, 130, 110 nmol equivalents/g,
    respectively) (see Table 35). Immediately after exposure,
    radioactivity in the liver accounted for about 17% and all other
    tissues about 10% of the absorbed methyl bromide (Bond et al., 1985).
    Similarly, Jaskot et al. (1988) found that the liver, lung, and kidney
    were the major organs of [14C] distribution in rats immediately
    after exposure to [14C] methyl bromide at 214 mg/m3 (55 ppm) for
    3 min.

         Honma et al. (1985) measured methyl bromide levels in male
    Sprague-Dawley rats exposed to 973 mg methyl bromide/m3 (250 ppm)
    for 8 h and then sacrificed at successive time intervals. The
    concentrations found in adipose tissue (maximum 1 µg methyl bromide/g
    tissue) were much greater than those in blood (max. 0.1 µg/g) and
    other tissues - brain, liver, muscle, and kidney (maximum about 0.01
    µg/g; see Fig. 7). The methyl bromide in all tissues described reached
    a maximum in 1 h after exposure commenced and maintained almost the
    same concentrations during exposure. Honma et al. (1985) found peak
    concentrations of bromine in blood at 4 h after cessation of methyl
    bromide exposure, and in kidney and liver, 8 h after (Fig. 8).


        Table 35.  Concentration (nmol/g) of 14C in tissues from rats exposed for 6 h to 337 nmol 
                   14C-methyl bromide/litre aira,b
                                                                                                             
                             0 hc                 8 h                   24 h                60 h
                                                                                                             
    lung              250.4 ± 27.7 (3.6)     40.3 ±  5.5 (0.5)     19.5 ±  2.3 (0.2)     19.7 ± 2.3 (0.3)
    adrenal           242.0 ± 16.8 (0.9)     25.8 ± 10.2 (0.1)     23.0 ±  1.4 (0.0)     19.5 ± 3.4 (0.0)
    kidney            180.4 ±  4.6 (4.3)     76.1 ± 11.4 (1.5)     36.9 ±  2.6 (0.8)     35.1 ± 3.4 (0.7)
    liver             129.9 ±  7.0(16.7)    119.6 ± 13.1(11.6)     82.4 ± 10.3 (9.0)     37.8 ± 7.5 (3.9)
    turbinates        110.2 ±  6.5 (0.2)     35.2 ±  5.1 (0.1)     13.3 ±  1.4 (0.0)     18.9 ± 3.2 (0.0)
    spleen             98.6 ±  3.4 (0.7)     28.8 ±  5.8 (0.2)     15.9 ±  2.1 (0.1)     15.8 ± 1.7 (0.1)
    small intestine    96.5 ± 14.6 (2.0)     36.3 ±  0.8 (0.4)     19.9 ±  1.8 (0.2)     15.5 ± 3.2 (0.2)
    trachea            84.3 ±  1.4 (0.1)     36.4 ±  6.3 (0.0)     15.5 ±  3.9 (0.0)     18.8 ± 4.3 (0.0)
    stomach            80.0 ±  1.8 (1.3)     37.8 ±  5.3 (0.6)     31.9 ±  1.0 (0.5)     27.0 ± 8.3 (0.4)
    large intestine    66.3 ±  9.2 (0.9)     43.6 ±  8.6 (0.6)     19.0 ±  2.3 (0.1)     17.8 ± 2.3 (0.2)
    testes             65.4 ±  3.6 (2.5)     34.5 ±  3.9 (1.4)     17.1 ±  2.6 (0.6)     12.9 ± 2.3 (0.5)
    larynx             61.1 ±  4.9 (0.0)     27.1 ±  5.9 (0.0)     10.5 ±  1.2 (0.0)     11.6 ± 2.0 (0.0)
    brain              53.6 ±  9.5 (0.8)     35.8 ±  4.2 (0.6)      8.8 ±  1.1 (0.2)      7.4 ± 0.7 (0.1)
    heart              51.7 ±  1.9 (0.6)     35.1 ±  5.3 (0.4)     16.8 ±  1.5 (0.2)     17.6 ± 2.9 (0.2)
    thymus             48.4 ±  0.5 (0.2)     33.3 ±  6.7 (0.1)     19.9 ±  2.3 (0.1)     23.4 ± 3.1 (0.1)
    urinary bladder    45.6 ±  6.9 (0.1)     27.7 ±  5.5 (0.0)     12.6 ±  1.9 (0.0)     11.8 ± 1.4 (0.0)
    thyroid            28.7 ± 24.4 (0.0)     34.8 ±  6.1 (0.0)     16.1 ±  2.6 (0.0)     16.4 ± 1.4 (0.0)
                                                                                                             

    a From: Bond et al. (1985).
    b Values represent the x ± SE of 2-3 rats. Values in parentheses are percentages of the absorbed 14C-methyl bromide.
    c Time after end of exposure.
    

    FIGURE 7

         Calves fed for 49 days on a diet containing about 4650 mg
    bromide/kg showed bromide concentrations in kidney, liver, and muscle
    of 1808, 1015, and 465 mg/kg, respectively, on day 49. Serum and organ
    bromide concentrations decreased markedly 14 days after the feeding of
    this diet was discontinued (Knight & Reina-Guerra, 1977).

    FIGURE 8

    6.2.2  Human studies

    Data on the concentrations of bromide in various human tissues after
    methyl bromide poisoning are scarce. In an autopsy study of a methyl
    bromide-exposed patient, Heimann (1944) reported the following bromide
    values: lung (127 mg/kg), liver (187 mg/kg), brain (207 mg/kg), and,
    in a composite sample of heart, kidney, and pancreas (107 mg/kg).
    Traces of methyl alcohol and formaldehyde were also found in all the
    tissues examined.

         In four lethal cases of people exposed to methyl bromide,
    Marraccini et al. (1983) found bromide ion concentrations in serum or
    plasma ranging from 40 to 583 mg/litre. Methyl bromide was detected in
    the brain of one patient (detection limit <1 mg/kg).

         Values of 0.9 mg/kg in lymph nodes, 3.3 and 5.1 in ovaries and
    testes, 7.5 in lung, and 8.2 mg/kg wet weight in kidney cortex have
    been reported in autopsy samples (from accident victims) (Hamilton et
    al., 1972/73). A study of the levels of bromide in adipose tissue from
    human subjects in three countries showed the highest levels in the
    United Kingdom, where 5.6% of the specimens contained levels ranging
    from 4.0 to 4.5 mg/kg fat; the lowest levels were found in Germany
    (0-0.9 mg/kg fat) whereas levels of 1-3.7 mg/kg were found in the
    Netherlands samples (Crampton et al., 1971). Van Leeuwen & Sangster
    (1987) stated that there was no evidence in humans of bromide
    concentration in any particular organ that might indicate a specific
    physiological function of this ion.

    6.3  Metabolic transformation

         The metabolism of methyl bromide has not been elucidated.

         Bromide concentrations in blood (and target organs) were reported
    to be increased in humans (Clarke et al., 1945; Rathus & Landy, 1961;
    Hine, 1969) and in laboratory animals (Irish et al., 1940, 1941) after
    exposure to methyl bromide. Miller & Haggard (1943) postulated that
    methyl bromide is hydrolysed in the body with the formation of
    inorganic bromide and methyl alcohol. In part, this hydrolysis may
    occur intracellularly, resulting in a distribution of bromide that
    differs from that for bromide given orally as sodium bromide. Sodium
    bromide and methyl alcohol, given at the levels produced after methyl
    bromide exposure, did not produce the same toxic and functional
    response (Irish et al., 1940, 1941). This suggested that the toxicity
    of methyl bromide was due to the reaction of the halide molecule with
    the tissue and was not attributable to the hydrolytic products.

         Hallier et al. (1990a) measured the cytosolic turnover rate of
    methyl bromide in both liver and kidney from five different strains of
    mice and rats, with  in vitro incubation. The turnover rate in both
    organs was consistently higher in tissues isolated from females. On
    the basis of a similar effect with methyl chloride, this effect could
    be attributed to a higher rate of glutathione conjugation in females. 

         The reaction products of methyl bromide in wheat were
    characterized by Winteringham et al. (1955) using 14C- or
    82Br-labelled methyl bromide. It was pointed out that, although most
    attention is given to the bromide ion because it is the only part of
    the residue that is easily determined, methyl methionine sulfonium
    bromide, the methylated histidines, and possibly other residues of
    methylation were also produced.

    6.3.1  Binding to proteins and lipids

         Methylation of cysteine- S and histidine- N residues of haemo-
    globin in suspended mouse erythrocytes was found after  in vitro
    treatment with radiolabelled methyl bromide (Djalali-Behzad et al.,

    1981). After inhalation of methyl bromide, alkylation of cysteine- S
    residues was seen in mouse haemoglobin and liver proteins
    (Djalali-Behzad et al., 1981).

         Adducts result from reactions between toxic chemicals and amino
    acids in haemoglobin or other proteins (or nucleosides in DNA - see
    below).  S-methyl-cysteine has been studied as a haemoglobin adduct
    in mice (Iwasaki, 1988a,b) and rats (Xu et al., 1990) and as a serum
    albumin adduct in human blood samples (Müller et al., 1991, 1992).
    Both haemoglobin and serum albumin adducts have been studied in blood
    samples of workers occupationally exposed to methyl bromide and these
    have been proposed as suitable parameters for the biomonitoring of
    exposure to the fumigant (Iwasaki et al., 1989; Müller et al., 1991,
    1992) (see also section 9.4.4).

         In the insect  Triatoma infestans , Castro et al. (1976)
    demonstrated that methyl bromide is irreversibly bound to lipids and
    to proteins in both the nymph adult and eggs and that exposure to
    methyl bromide significantly decreased the content of sulfhydryl
    groups in nymph adult and egg proteins.

         Studies on methylation by methyl bromide of wool, silk, collagen,
    and gelatin (Blackburn & Phillips, 1944), wheat flour (Bridges, 1955;
    Winteringham et al., 1955), and cocoa beans (Asante-Poku et al., 1974)
    indicated that  N-,  O-, and  S- methylation of proteins occurs
    (Cova et al., 1986; Starratt & Bond, 1990b). The main site of
    decomposition of methyl bromide in cocoa beans was shown to be in the
    alcohol- insoluble proteins of the shell (Asante-Poku et al., 1974).
    The methyl group of the fumigant became covalently bound to the
    alpha-amino group of the various amino acids, the imidazole ring of
    histidine, and the epsilon-amino group of lysine.

         Winteringham et al. (1955) found that the gluten fraction of
    whole-wheat flour exposed to [14C]methyl bromide was responsible for
    80% of the decomposition of the absorbed fumigant with  N-methyl,
    dimethylsulfonium, and methoxyl and thiomethoxyl derivatives
    accounting for 50, 30, and 20%, respectively, in this fraction.
    Bridges (1955) reported that 1- N-methylhistidine,
    3- N-methylhistidine and 1,3- N,N-dimethylhistidine accounted for
    75% of the  N-methyl derivatives, and that 10% was due to probably
    epsilon- N-methyllysine.

         Starratt & Bond (1990a,b) used [14C]methyl bromide to
    distinguish naturally occurring residues from those formed during the
    fumigation of a variety of commodities: maize, wheat, oatmeal,
    peanuts, almonds, alfalfa, potatoes, oranges, and apples. In order to
    get higher incorporation of the tracer, fumigation was carried out at
    a level of 48 mg/litre, for 3 days. Methyl bromide was bound both
    physically and chemically to the commodities. To measure the
    physically-bound residue, a parallel test was run using unlabelled
    fumigant. Methyl bromide levels were determined 1 h following

    fumigation and then at 1, 2, 4, and 10 days. The levels in all the
    commodities declined rapidly.

         Extraction of the [14C]methyl bromide-fumigated commodities
    with diethyl ether removed very little radioactivity, showing that
    fats and other non-polar lipids were not methylated during treatment.
    In maize, fractions corresponding to albumins, glutamines, zein, and
    glutelin were all methylated. 

         Methylation of methionine is one of the main reactions forming
    the relatively unstable methylmethionylsulfonium derivative.
    Spontaneous decomposition yields dimethyl sulfide. Analysis of the
    sites of methylation was uncertain as both acidic and basic hydrolysis
    caused partial decomposition (Starratt & Bond, 1990a,b). The volatile
    products included methanol, methyl mercaptan, and dimethyl sulfide.
    Different commodities produced different residues (Starratt & Bond,
    1990a,b). In potato and orange extracts, the main methylated
    components were identified as  S-methyl-glutathione,
    gamma-glutamyl- S-methylcysteine and  S-methyl cysteine. These
    compounds were not found in maize. 1- N-methylhistidine and
    3- N-methylhistidine were the major components from the fumigated
    maize, almonds and other commodities. The highest level of histidine
    methylation occurred in almonds, accounting for about 54% of the
    chemically-bound residue.

    6.3.2  Binding to DNA

         Labelled 7-methylguanine was identified in DNA from liver and
    spleen cells of mice exposed to [14C] methyl bromide (Djalali-Behzad
    et al., 1981). In  in vitro experiments with DNA solutions treated
    with [14C] methyl bromide, predominantly [14C] 7-methylguanine was
    identified (Starratt & Bond, 1988b).

         Calf thymus DNA treated in the solid state with [14C] methyl
    bromide, showed, on analysis, four major radiolabelled peaks with
    retention times corresponding to 1-methyladenine, 7-methylguanine,
    3-methyladenine, and 3- methylcytosine (Starratt & Bond, 1988b).

         The DNA adducts, [14C]3-methyladenine, [14C]7-methylguanine,
    and [14C]O6-methylguanine, have been found in the stomach and
    forestomach of rats after both oral and inhalation exposure of
    [14C]methyl bromide (Gansewendt et al., 1991).

         In maize and wheat, 7-methylguanine and 1-methyladenine were
    identified as major products after hydrolysis together with lesser
    amounts of 3-methylcytosine and 3-methyladenine (Starratt & Bond,
    1988a). Although the yields of DNA were low, Starratt & Bond (1990a)
    also found evidence of radioactively-labelled 7-methylguanine and
    1-methyladenine in [14C]methyl bromide-fumigated almonds and
    potatoes.

    6.3.3  The role of glutathione in methyl bromide metabolism

    6.3.3.1  Mammals

         Liver, kidney, lung, and brain from mice, exposed via inhalation
    for 1 h to methyl bromide concentrations of from 870 to 5930 mg/m3,
    were analysed for glutathione and bromide ion (Alexeeff et al., 1985).
    The liver glutathione levels of the 4700 and 5930 mg/m3 exposure
    groups were significantly lower than that of the controls. Bromide ion
    levels were highest in the liver and kidney and lowest in the whole
    blood. The lung and brain bromide levels were intermediate.

         Methyl bromide has been shown in rats to increase the activity of
    glutathione  S-alkyl transferase and decrease the nonprotein
    sulfhydryl content (Roycroft et al., 1981). A group of male
    Sprague-Dawley rats were exposed to methyl bromide (117 mg/m3; 6
    h/day; 10 days) and killed immediately after the last dose.
    Biochemical analyses showed that glutathione  S-alkyl transferase was
    significantly increased in the lung (12%), liver (11.9%), and kidney
    (6.9%). Non-protein sulfhydryl was significantly reduced by 11.4% in
    the liver and 13.9% in the kidney. Glucose-6-phosphate dehydrogenase
    was significantly increased in the kidney (8.5%), but not in the lung
    or liver.

         Studies on rats by Davenport et al. (1992) showed that
    glutathione was depleted and regional brain
    glutathione- S-transferase inhibited by methyl bromide inhalation
    (584 mg methyl bromide/m3; 6 h/day; 5 days) [see sections 8.8.2 and
    8.10].

         In a preliminary report, Thomas & Morgan (1988) reported that
    treatment of rats with buthionine sulfoximine (BSO) depleted
    glutathione levels, prior to methyl bromide exposure, and increased
    the toxicity of methyl bromide. This is in contrast to the findings of
    Chellman et al. (1986) for methyl chloride in mice, who found that
    glutathione depletion by BSO decreased methyl chloride toxicity in the
    brain and kidney. However, the observation is consistent with those of
    Tanaka et al. (1988), who showed that treatment of rats with
    glutathione reduced the detrimental effects of methyl bromide on
    sleep-wakefulness and its circadian rhythm and increased the LD50
    value (section 8.8.2).

         In whole body inhalation studies on rats exposed for 6 h/day, for
    5 or 10 days, to 117 mg methyl bromide/m3 (30 ppm), glutathione
    (GSH)  S-transferase and glucose-6-phosphate dehydrogenase (G-6-PDH)
    activities were increased in the lung. Decreases in GSH-reductase and
    GSH- S-transferase activities were found in the liver (Jaskot et al.,
    1988).

         When human erythrocyte cytoplasm was incubated with methyl
    bromide or methyl iodide in the presence of excess glutathione (GSH),
    a spontaneous non-enzymatic conjugation was observed (Deutschmann et

    al., 1989). This was verified in parallel experiments with boiled
    cytoplasm and GSH added after boiling.

         Enzymatic conjugation of methyl bromide with reduced glutathione
    to produce  S-methyl cysteine (the analysis) appears to be
    isoenzyme-specific, since conjugation was observed in the erythrocyte
    cytoplasm of a majority (13/20) of the population. The same
    individuals also conjugated methyl chloride, a reaction that is
    dependent on glutathione- S-transferase rho (GSTrho), a minor form of
    the enzyme (Hallier et al., 1990b). 

         Later studies on the properties of the glutathione-
     S-transferase (GST) responsible for methyl bromide conjugation with
    GSH (measured by methyl bromide depletion) have separated the enzyme
    GSTsigma from human erythrocytes; this new enzyme has not been found
    in various non-human species (Schröder et al., 1992).

         Measurement of methyl bromide disappearance in head-space vials
    containing whole human blood cultures in an atmosphere of 19 460
    mg/m3 (5000 ppm) at 37 °C indicated that the methyl bromide
    concentration had fallen to zero within 1 h, in the presence of blood
    from glutathione conjugators, whereas it had fallen to approximately
    5836 mg/m3 (1500 ppm) at 1 h, in the presence of blood from
    non-conjugators. Further reduction was slow, the methyl bromide
    concentration being about 3890 mg/m3 (1000 ppm) after 6 h (Hallier
    et al., 1993).

    6.3.3.2  Insects

         Glutathione is depleted and glutathione  S-transferase can be
    induced in the larvae of the khapra beetle  (Trogoderma granarium) by
    fumigation with methyl bromide at a lethal dose (Shivanandappa &
    Rajendran, 1987).

         Starratt & Bond (1981) demonstrated that, in the granary weevil
    ( Sitophilus granarius L.), the major pathway for the detoxication of
    methyl bromide residues was by conjugation, primarily with
    glutathione, and that increasing amounts of glutathione in the insects
    resulted in increasing tolerance to methyl bromide exposure. Both
    strains of the insect (methyl bromide sensitive and methyl bromide
    resistant) metabolized methyl bromide primarily to substances that, on
    thin layer chromatography, behaved consistently with their
    identification as  S-methyl glutathione.

    6.4  Elimination and excretion in expired air, faeces, urine

         The route of administration of methyl bromide affects the
    pathways of excretion.

         Miller & Haggard (1943) investigated the amount of methyl bromide
    eliminated and the amount of bromide retained in the body after i.p.

    administration of methyl bromide. Following a single i.p. injection of
    60 mg methyl bromide/kg body weight, elimination continued for about
    45 min and more than 90% was eliminated in the first 30 min. With
    lethal i.p. doses of 120-180 mg methyl bromide/kg, 24- 45% of the
    methyl bromide was eliminated; the amounts of fixed and nonvolatile
    bromide being 94.9-126.6 mg/kg. In rats dosed orally (75-100 mg methyl
    bromide/kg), similar bromide levels were found, but the methyl bromide
    eliminated was given as only 2.4-4.6%.

         These results have been confirmed by studies using radioactively
    labelled methyl bromide (Medinsky et al., 1984). In rats dosed
    intraperitoneally with [14C] methyl bromide, the major route of
    elimination was the exhalation of 14CO2 (46%). In contrast,
    urinary excretion of [14C] was the major route of elimination (43%
    of the dose), when methyl bromide was given orally. Very little
    appeared in the faeces (<3% of the dose), regardless of the route of
    administration. In rats with bile duct cannulations, 46% of an oral
    dose appeared in the bile over a 24-h period (Medinsky et al., 1984).
    The authors suggested that reabsorption of biliary metabolites from
    the gut played a significant role in the disposition of [14C] methyl
    bromide.

         In inhalation studies on rats exposed for 6 h to 337 nmol [14C]
    methyl bromide/litre air, Bond et al. (1985) showed that excretion of
    [14C] as 14CO2 was the major route of elimination, about 47%
    (3900 nmol/rat) of the total [14C] methyl bromide absorbed being
    excreted by this route. CO2 excretion exhibited a biphasic
    elimination pattern with 85% of the 14CO2 being excreted with a
    half-time of 3.9 h and 15% excreted with a half-time of 11.2 h.
    Half-times for the elimination of 14C in urine and faeces were 9.6
    and 16.1 h, respectively; 65 h after exposure, about 75% of the
    initial radioactivity had been excreted with 25% remaining in the body
    (Bond et al., 1985). Elimination half-times of [14C] from tissues
    were 1.5-8 h. In all tissues examined, over 90% of the 14C in the
    tissues were methyl bromide metabolites (Bond et al., 1985). The data
    from this study indicate that, after inhalation, methyl bromide is
    rapidly metabolized in tissues and readily eliminated.

         Male CD rats were exposed (nose only) to [14C]-methyl bromide
    at 214 mg/m3 (55 ppm) for 3 min. The liver, lung, and kidney were
    the major organs of [14C] distribution, immediately after exposure.
    Up to 32 h after exposure, the major routes of excretion were
    pulmonary and renal with elimination of 43% and 21% of the total
    inhaled label, respectively (Jaskot et al., 1988).

         Studies into the time course of methyl bromide and bromide
    elimination in rat tissue have been described by Honma et al. (1985).
    Male Sprague-Dawley rats were exposed to 973 mg methyl bromide/m3
    (250 ppm) for 8 h and methyl bromide and bromine concentrations
    measured at successive time intervals (see also section 6.2). The
    results are shown in Fig. 7 (bromine) and Fig. 8 (methyl bromide). The

    methyl bromide levels in all tissues described reached a maximum in 1
    h following exposure and remained at almost the same levels during
    exposure. Methyl bromide levels decreased rapidly after exposure;
    after 30 min only half of the methyl bromide concentrations in adipose
    tissue and blood were still present (Fig. 7). The methyl bromide
    levels in the brain and liver were very low, but the elimination of
    methyl bromide from these organs was slower. Forty-eight hours after
    exposure, methyl bromide could not be detected in any tissue examined
    (Honma et al., 1985). In contrast to the methyl bromide study, peak
    concentrations of bromine in blood, kidneys, and liver occurred 4-8 h
    after bromide exposure, and the half-life in these tissues was about
    5 days.

         Honma et al. (1985) carried out a regression analysis of methyl
    bromide and bromine concentrations in blood, kidney, liver, brain and
    adipose in male rats after a 2-h exposure to 0, 973, 1946, 2918, or
    3890 mg methyl bromide/m3 (0, 250, 500, 750, or 1000 ppm). Linear
    relationships were obtained between exposure concentrations and the
    tissue methyl bromide or bromine values.

         Over 95% of the bromide ion in mice exposed to methyl bromide was
    eliminated within 2.5 days, bringing the concentration close to the
    control levels and the limit of detection (Alexeeff et al., 1985).

         Lactating cows fed a methyl bromide fumigated grain ration (220
    mg bromide/kg food) compared with unfumigated diets secreted increased
    levels of bromide in the milk, i.e., 10-20 mg/litre instead of about
    5 mg/litre (Lynn et al., 1963).

    6.5  Retention and turnover

         The biological half-life of bromide ions in human blood was found
    to be about 12 days (Söremark, 1960).

         The half-lives of bromide in the blood and brain of rats after
    i.p. injection of methyl bromide were approximately 8.7 and 4.3 days,
    respectively (Tanaka et al., 1988). In inhalation studies, a half-life
    of bromide of about 5 days was reported in the blood, kidneys, and
    liver (Honma et al., 1985). In contrast, methyl bromide concentrations
    in the blood and adipose tissue were reduced by half after 30 min,
    though elimination from the brain and liver was much slower (Honma et
    al., 1985).

    6.6  Reaction with body components

         Honma et al. (1987) suggested that the main target of methyl
    bromide in the body was the central nervous system. The nor-
    epinephrine content of the hypothalamus and cortex with hippo-campus
    was reduced on exposure to methyl bromide (Honma et al., 1982) and
    changes in the amino acid content and metabolism in the brain were
    noted (Honma et al., 1983). The results of further studies suggested

    that alterations in catecholamine metabolism might be a factor in
    methyl bromide-induced neurotoxicity (Honma et al., 1987) (see section
    8.8). Kato et al. (1986) described histopathological changes in the
    brain. 

         Eustis et al, (1986, 1988) found clear species- and sex- related
    differences in the susceptibility of specific organs and tissues to
    methyl bromide effects (section 8.8.1). In rats, neuronal necrosis
    occurred primarily in the cerebral cortex, hippocampus, and thalamus
    of the brain, whereas in mice, necrosis of the internal granular layer
    of the cerebellar folia was more frequently observed. Nephrosis
    occurred in all treated mice. Myocardial degeneration was observed in
    male and female rats more frequently than male mice. Atrophy of the
    adrenal cortex and testis and necrosis of the olfactory epithelium
    were described. Similar findings were described by Hurtt et al.
    (1987). Degeneration and regeneration of the olfactory epithelium were
    also described by Hurtt et al. (1988) and Hastings et al. (1989);
    Hastings (1990).

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Soil microorganisms

         Methyl bromide is used commercially to control soil- borne fungi
    that cause:

         -    damping off:  Rhizoctonia solani, Pythium spp.,  Sclerotium
               bataticola (Macrophomina phaseolina), Phytophtora spp.,
              and  Thielaviopsis basicola.

         -    crown rot:  Sclerotium rolfsii and  Sclerotinia spp.

         -    root rot:  Pythium spp.,  Stromatinia, Fusarium spp.,
               Sclerotium bataticola, (Macrophomina phaseolina),
              Rhizoctonia solani, Pyrenochaeta spp. (corky root, pink
              root),  Armillaria and Phytophthora spp.

         -    wilt:  Fusarium spp., and  Verticillium spp.

         Generally, concentration-time products of methyl bromide required
    to kill fungi are much higher than those needed to control insect and
    nematode pests, susceptibility increasing with temperature. To control
    fungi, methyl bromide is generally used at rates of 40-100 g/m2
    (Davis et al., 1977).

         Filip & Roth (1977) demonstrated the efficacy of methyl bromide
    against  Armillaria root rot in the stumps of ponderosa pine ( Pinus
     ponderosa Laws). The survival of young pine trees in areas infected
    with such fungi was increased after the elimination of the fungus,
    using the fumigant.

         Heungens & Roos (1982) recovered non-pathogenic fungi
     (Penicillium and  Mucor) following the application of methyl
    bromide (300 g/m2) to pine litter, but no pathogenic fungi were
    recovered.

         After an initial reduction, the numbers of bacteria and fungi in
    fumigated soil remained high and low, respectively, in comparison with
    those in untreated soil (Sivasithamparam et al., 1987). In the
    fumigated soil,  Trichoderma species rapidly recolonized the soil,
    becoming the dominant fungus within 15 days. In a study on the
    microflora in the rhizosphere of wheat, the same authors found that,
    though there was no difference in the total number of bacteria,
    actinomycetes, and fungi, before and after fumigation with methyl
    bromide, there were some fungal species differences with  Fusarium
     merismoides, T. koningii , and  T. viride present in significantly
    higher numbers, other fungi being less abundant.

         Kelley & Rodriguez-Kabana (1979) reported that methyl bromide did
    not cause any permanent changes in soil enzyme activities or adversely
    affect the mycorrhizal root development of pine seedlings.

         Methyl bromide is used for controlling fungal infections in the
    poultry industry (Harry et al., 1972; Davis et al., 1977).

         Methyl bromide is much less frequently used as a bactericide than
    as an insecticide (Davis et al., 1977). It is used to control certain
    soil-borne bacteria, e.g., bacterial canker  (Corynebacterium
     michiganese) , and bacterial wilt  (Pseudomonas solanacerum)
    (Bromine & Chemicals Ltd.,1990). A summary of the acute toxic effects
    of methyl bromide on bacteria and viruses is given in Table 36.

         Methyl bromide, used at a concentration-time product of 800
    mg.h/litre at 25 °C, with a relative humidity of 70%, eliminated
    salmonellae from artificially contaminated poultry foodstuffs (Tucker
    et al., 1974).

         Although there have been many studies on the effectiveness of
    methyl bromide in reducing diseases produced by pathogenic
    micro-organisms, there are fewer data on its effects on soil microbes.

         Matta & Porta-Puglia (1968) tested methyl bromide on several
    morphologically and functionally different groups of soil microbes. In
    isolated soil samples, treated and maintained under constant
    temperature (22-23 °C) and humidity (16-18%), microorganisms were
    counted at 2, 21, 54, and 87 days following fumigation with 300 g
    methyl bromide/m3. After 2 days, most bacteria were dead; after 87
    days, there were very low counts of fungi, aerobic nitrogen-fixing,
    nitrifying, and cellulolytic bacteria, whereas denitrifying,
    proteolytic, amylolytic, and ammonifying bacteria showed a marked
    resurgence in recolonization (Matta & Porta-Puglia, 1968). The
    selective-action effects of methyl bromide fumigation on a given
    microbe population in soil appear to be more significant than the
    effects on microbe number.


        Table 36.  Effects of methyl bromide fumigation on bacteria and virusesa
                                                                                                                      
    Organism                        Dosage                 Conditions                         Reference
                                                                                                                      
     Vibrio cholera, Shigella         33 g/m3                10-h exposure LD100                Saiki (1952)
     dysenteriae, Salmonella
     typhi, Salmonella paratyphi A,
     Salmonella paratyphi B

     Corynebacterium                  10 % bromomethane,     18-h exposure LD100                Richardson & Monro (1962)
     sepedonicum                      5 % ethylene oxide     85 % CO2

    Arabis mosaic virus               0.32 kg/m3             controlled virus on strawberry     Harrison et al. (1963)
                                                             plants

    Tobacco mosaic virus,             640 g/m3               inactivated virus                  Inouye et al. (1967)
    Cucumber green mottle virus       110 g/m3               inactivated at 27°C
                                      320 g/m3               inactivated at 14-16°C

     Escherichia coli 1257            1000 g/m3              40°C and 90 % relative humidity    Prishchep &Nikiforova
                                                             provided control                   (1969)

     Bacillus larvae, Bacillus        5000 g/m3              5-day exposure controlled          Smirnov (1970)
     paraalvei, Streptococcus                                bacteria in bee honeycombs
     apis, Streptococcus pluton,
     Pseudomonas apisepticus

    Tobacco mosaic virus              200 g/m3               inactivated virus in 3 kg soil     Doraiswamy et al. (1972)
                                                             in which tomatoes were grown

     Salmonella typhimurium           800 mg-h/litre         25 °C and 70% relative humidity    Tucker et al. (1974)
                                                             provided control

     Xanthomonas begoniae             0.32 kg/m3             24-h exposure eliminated           Strider (1975)
                                                             bacterial blight from  Rieger
                                                              begonia
                                                                                                                      

    a Adapted from: Davis et al. (1977).
    

         In a study on bacterial flora involved in the nitrogen cycle, hot
    fumigation with methyl bromide at concentrations of 80 g/m3 was
    carried out in greenhouses at 6 different sites (Turtura et al.,
    1988). Seven months after treatment, the total aerobic mesophile
    bacteria count, aerobic nitrogen-fixing, ammonifying,
    ammonia-oxidizing, and nitrite-oxidizing bacteria, always showed
    higher values in fumigated than in unfumigated control soils.
    Recolonization was more marked in the upper 0-30 cm soil samples in
    which the development of ammonifying and nitrifying bacteria was
    highly significant.

         Rovira & Ridge (1979) found no long-term effects on aerobic soil
    bacteria or actinomycetes with application of 22 g methyl bromide/m2.

         Yeates et al. (1991) described the recolonization of soils
    sterilized in the laboratory and returned to their original pasture
    and forest sites, under four different types of field conditions.
    Sampling took place over 166 days (midsummer to midwinter) with two of
    the sites having a moderate, and two a high, rainfall. Both microbial
    biomass and dehydrogenase activity recovered rapidly but remained
    consistently lower in the fumigated than in the untreated samples in
    all four sites. Bacterial numbers also recovered rapidly. Fungal
    hyphal lengths were 25% lower in the fumigated soil. Fumigation showed
    no detectable effects on the subsequent rates of nitrogen
    mineralization and little effect on nitrification rates. Protozoa were
    almost completely eliminated by fumigation, numbers recovering most
    rapidly in moist forest soil and slowly in dry pasture soil. Nematodes
    were eliminated by fumigation; recolonization was first detected on
    day 26. Numbers (10 and 62/g, respectively) and species (10 and 31,
    respectively) remained much lower in fumigated, compared with
    untreated, soil.

         After sterilization of greenhouse soil with methyl bromide (75
    g/m2), there were profound qualitative and quantitative disturbances
    up to a soil depth of 30 cm (Bourbos & Skoudridakis, 1991); 7-9
    species of soil mycoflora were isolated from the fumigated soil
    compared with 107 from control soils. The 31-40 cm soil layer was not
    affected by disinfestation. After two months, recolonization had taken
    place of only 35-40% in species and 60-63% in density of the primary
    microflora.

         The use of methyl bromide as an effective fumigant for
    greenhouses has been questioned (Bourbos & Skoudridakis, 1991).
    Certain saprophytic fungi have developed a degree of tolerance.
    Disinfested soil was quickly contaminated by certain pathogens
    ( Fusarium and  Pythium spp.) and there was also a possibility of
    reinfection from the lower layer of soil not reached by the fumigant.
    Some fungi controlled by methyl bromide are listed in Table 37.

    7.2  Aquatic organisms

    7.2.1  Effect of methyl bromide

         LC50 (96-h) values of 11 mg methyl bromide/litre and 12 mg
    methyl bromide/litre for bluegill sunfish,  Lepomis macrochirus 
    (freshwater) and tidewater silversides,  Menidia beryllina 
    (saltwater), respectively, have been determined following exposure to
    methyl bromide (Dawson et al., 1975/77).

         The acute toxicity of methyl bromide for carp ( Cyprinus carpio
    L.) was determined in studies with a 4-h exposure period (Segers et
    al., 1984). The 4-h LC50 was calculated to be approximately 17
    mg/litre. Damage to the gill epithelium was the most pronounced
    morphological damage, which probably caused the death of the fish by
    suffocation.

         In a short-term study, triplicate groups of 10 fish ( P.
     reticulata (guppy) and  Oryzias latipes (medaka)) were exposed to
    0.56, 1.0, or 1.8 mg methyl bromide/litre for 4 days. All methyl
    bromide-exposed fish displayed abnormal behaviour (reduced activity).
    Limited mortality was noted in  P. reticulata exposed to 1.0 and 1.8
    mg/litre and  O. latipes exposed to 1.8 mg/litre, but there was no
    increase in mortality in the next lower concentration groups (Wester
    et al., 1988).

         In a long-term study,  P. reticulata and  O. latipes were
    exposed for 1 and 3 months to 0.032-3.2 mg methyl bromide/litre
    (Wester et al., 1988). All guppies died in the 3.2 mg/litre group
    within 3 days, and, in the 1.0 mg/litre group, within 3 weeks. The
    NOLC (no observed lethal concentration) and NOEC (no observed effect
    concentration: behaviour, appearance) values were 0.32 and 0.1
    mg/litre, respectively. A significant decrease in weight was noted in
    both sexes in the 0.32 mg/litre group.

         All medaka embryos exposed to 1.8 or 3.2 mg/litre and most of the
    1.0 mg/litre group died before hatching. The NOLC after 3 months was
    0.32 mg/litre. The NOEC values, on the basis of behaviour and
    appearance, were 0.56 mg/litre and 0.32 mg/litre after 1 and 3 months,
    respectively (Wester et al., 1988).

         A short-term study with (lethal) concentrations of 0.56, 1.0, or
    1.8 mg methyl bromide/litre showed (using scanning electron
    microscopy) major degenerative and regenerative changes in the
    superficial epithelia, especially of the gills and oral mucosa,
    caused, apparently, by the local irritating action of this compound.
    Necrotic changes were also seen in the thymic cortex and the testis
    (Wester et al., 1988). In a long-term study on guppies and medakas
    exposed to the highest concentrations for 1 month and 3 months,
    respectively, no significant organ or tissue changes could be detected
    in routine histopathology. 


        Table 37.  Some fungi controlled by methyl bromide
                                                                                                       
    Fungus                     Dose,                      Crop/             Reference
                               Surface application/m2,    commodity
                               commodity fumigation/m3
                                                                                                       
     Alternaria sp.              1.6-3.3 g/m3               pecan             Wells & Payne (1975)

     Armillaria melea            4-98 g/m2                  citrus/           Munnecke et al. (1969)
                                                            grape             Kissler et al. (1973)

     Aspergillus sp.             1.6-5 g/m2                 pecan/            Wells & Payne (1975)
                                                            honeycomb         Smirnov (1970)

     Byssochalamy fuloa          60-120 mg/kg               starch            Ito et al. (1972)

     Cladosporium sp.            1.6-3.3 g/m2               pecan             Wells & Payne (1975)

     Eumargodes laivgi           24 g/m2                    not stated        Hitchcock (1968)

     Fusarium sp.                45-100 g/m3                tomato            Westeijn (1973)
                                                                             Weihing et al. (1971)
                                                                             Wells & Payne (1975)
                                                                             Perrotta (1968)
                                                                             Vanachter (1974)

     Monochaeta sp.              1.6-3.3 g/m3               pecan             Wells & Payne (1975)

     Penicillium sp.             1.6-3.3 g/m3               pecan             

     Pestalotia sp.              1.6-3.3 g/m3               pecan             

     Phoma sp.                   1.6-3.3 g/m3               pecan             Wells & Payne (1975)

     Phytophora parasitica        49 g/m2                   citrus            Grimm & Alexander (1971)

     Phytophora capsici           40 g/m2                   green peppers     Alfaro Moreno & Vehg (1971)
                                                                                                       

    Table 37 (continued)
                                                                                                       
    Fungus                     Dose,                      Crop/             Reference
                               Surface application/m2,    commodity
                               commodity fumigation/m3
                                                                                                       
     Plasmodiophora brassicae    50-150 g/m2                cabbage           Winstead & Garriss (1960)

     Plasmosisphora brassicae    48 g/m2                    cabbage           Wimalajewa (1975)

     Pyrenochaeta lycopersici    125 g/m3                   soil              Vanachter (1974)

     Rhizoctania solani          50-150 g/m2                soil              Winstead & Garriss (1960)

     Sclerotium rolfsii          50 g/m2                    iris              Kiewnick (1968)

     Sclerotina sclerotiorum     50 g/m2                    tobacco           Hartill & Campbell (1973)

     Thielaviopsis basicola      50 g/m3                    tobacco           Mounat & Hitier (1959)

     Verticillium sp.           45-70 g/m2                  tomato            Perrotta (1968)
                                                                                                       

    Table 38.  Effects on aquatic organisms of short-term exposure to sodium bromidea
                                                                                               
                                                             Results (g Br-/litre) at:
                                                                                               
    Test species        Parameter                       24 h        48 h        72 h        96 h
                                                                                               
     Scenedesmus          EC50 (growth)                   5.8         7.8         8.5         10
     pannonicus           NOEC (growth)                   2.5         2.5         2.5         2.5
    (alga)

     Daphnia magna        LC50 (mortality)               11          11           -           -
    (crustacea)           EC50 (mort./abn. behaviour)     5.8         5.8         -           -
                          NOLC (mortality)                7.8         7.8         -           -
                          NOEC (mort./abn. behaviour)     4.3         4.3         -           -
                       
     Poecilia             LC50 (mortality)               16          16          16          16
     reticulata           EC50 (mort./abn. behaviour)     0.44        0.14        0.044       0.044
    (fish)                NOLC (mortality)                7.8         7.8         7.8         7.8
                          NOEC (mort./abn. behaviour)     0.25        0.078       0.025       0.025

     Oryzias latipes      LC50 (mortality)               26          25          24          24
    (fish)                EC50 (mort./abn. behaviour)     0.44        0.44        0.44        0.44
                          NOLC (mortality)                7.8         7.8         7.8         7.8
                          NOEC (mort./abn. behaviour)     0.25        0.25        0.25        0.25
                                                                                               

    a From: Canton et al. (1983).
    b NOE(L)C = no observed (specified) effect concentration.
    

    7.2.2  Effect of bromide ion on aquatic organisms

         The main degradation product of methyl bromide is inorganic
    bromide.

         To evaluate the potential impact of pollution with the bromide
    ion, Canton et al.(1983) investigated the short-term effects of sodium
    bromide on various freshwater organisms, using algae  (Scenedesmus
     pannonicus) , crustaceans (Daphnia magna), and fish  (P. reticulata
    and  O. latipes) (Table 38). Depending on the species tested, acute
    toxic effects were seen at concentrations ranging from 44 to 5800 mg
    Br-/litre and, in long-term tests, the NOEC varied from 7.8 to 250
    mg Br-/litre. Bromide ion markedly impaired reproduction in both
    crustaceans and fish.

         Further tests were performed on  P. reticulata (guppy) and  O.
     latipes (medaka) following sodium bromide exposure for 1 and 3
    months at concentration ranges of 10-32 000 mg/litre (guppy) and
    180-56 000 mg/litre (medaka). NOLC values for guppies were 10 000
    mg/litre and 1000 mg/litre after 1 and 3 months, respectively. The
    NOEC value was 32 mg/litre in both studies. Histopathological changes
    were observed at concentrations of 100 mg/litre or more (Wester et
    al., 1988). For medakas, the NOLC values were 5600 and 3200 mg/litre
    after 3 weeks and 3 months, respectively, whereas the NOEC value
    (behaviour) for both periods was 320 mg/litre (Wester et al., 1988).

         The relative susceptibility to sodium bromide of 11 taxonomically
    different freshwater species was determined in medium-term toxicity
    tests by Slooff & Canton (1983). The data are summarized in Table 39.

         In semi-static, long-term toxicity tests on Daphnia magna, EC50
    and EC10 values of 27 and 18 mg/litre, respectively, were determined
    (Van Leeuwen et al., 1986).

    7.3  Terrestrial organisms

    7.3.1  Protozoa

         Long et al. (1972) studied the effect of methyl bromide on
    protozoa  (Eimeria tenella and  E. acervulina) at a dosage of 5
    g/m3 for 20 h at 25 °C; 100 % control (destruction of oocysts) was
    achieved.

    7.3.2  Plants

         Methyl bromide is often applied, as a fumigant, directly to plant
    seeds, plant cuttings, or harvested plant products to disinfect
    before, and during, transportation or storage (Davis et al., 1977).
    Additionally, methyl bromide is used as a soil fumigant to control
    certain plant pathogens and weed seeds in areas to be planted.

        Table 39.  Summary of the results of medium-term toxicity tests using
    sodium bromide on 11 different freshwater test speciesa
                                                                            
    Test species             Exposure  Criteria                  NOL(E)C
                             time                                valuesb
                             (days)                              (mg/litre)
                                                                            
    Pseudomonas               0.3     specific growth rate        3200
    fluorescens
    (bacterium)

    Microcytis aeruginosa     4       specific growth rate        3200
    (cyanobacterium)

    Scenedesmus               4       growth (biomass)            3200
    pannonicus
    (alga)

    Lemna minor (plant)        7       specific growth rate        3200

    Daphnia magna             21       mortality                   3200
    (crustacea)                        reproduction                  10

    Culex pipiens             25       mortality                    100
    (insect)                           development                  100

    Hydra oligactis           21       specific growth rate        1000
    (hydrozoan)

    Lymnaea stagnalis         40       mortality                   3200
    (mollusc)                          reproduction                  10
                                       hatching                    3200

    Poecilia recticulata      28       mortality                    100
    (viviparous fish)                  mortality and behaviour       32
                                       growth                       320

    Oryzias latipes          40        mortality                   3200
    (viviparous fish)                  mortality and behaviour      320
                                       hatching growth           10 000

    Xenopus laevis           100       mortality                     32
    (amphibian)                        development                  320
                                       development                  320
                                                                            

    a Adapted from: Slooff & Canton (1983).
    b NOL(E)C = no observed (specified) effect concentration.
    
         As chloropicrin is phytotoxic, methyl bromide formulations that
    contain it as a warning agent are not used on nursery stock or other
    living plants (Bond, 1984).

    7.3.2.1  Seed fumigation

         As shown in Table 40, fumigation with methyl bromide can result
    in delay in the germination of seeds and some loss of total
    germinative capacity, depending on the variety, moisture content, and
    the extent of exposure to the gas (Davis et al., 1977). This was
    confirmed by Sittisuang & Nakakita (1985) who compared the effects of
    methyl bromide on the germination of rice seeds ( Oryza sativa L.,
    Japicona type) and corn (maize) seeds ( Zea mays L.). No detrimental
    effect of methyl bromide up to 4 mg/litre was observed in rice seeds
    at a moisture content of 11%, but as the moisture content and
    temperature increased, methyl bromide had an increasing effect on
    germination. Maize seeds were much more tolerant to methyl bromide.
    Exposure to 5 mg methyl bromide/litre, which caused heavy damage to
    rice seeds in most cases, did not generally produce any harmful effect
    on the germination of maize seeds, regardless of the moisture content
    and temperature. At concentrations higher than 10 mg/litre, the
    viability of maize seeds declined in a similar way to that of rice
    seeds. Rice seeds were found to absorb more methyl bromide than corn
    seeds. Seeds with a higher moisture content absorbed more methyl
    bromide and seeds with the same moisture content absorbed more methyl
    bromide at higher temperatures than at lower temperatures. The authors
    suggested that changes in certain proteins and enzymes were major
    factors in seed viability.

         The effects of methyl bromide fumigation on the germination of
    different cultivars of wheat seed have been investigated. The
    germination of all cultivars was reduced following fumigation at a
    dose of 16 mg/litre for 24 h (11% moisture, temperature not given).
    The optimal conditions were a moisture content of 9% and a temperature
    of 18 °C. With increasing moisture or temperature, the percentage
    germination decreased. At higher levels of moisture, the concentration
    of methyl bromide appeared to be a more important factor than exposure
    time at a constant concentration x time product (CTP) of 768
    mg.h/litre (Khanna & Yadav, 1987).

         Hanson et al. (1987) found that fumigation with methyl bromide
    not only caused a delay in germination and loss of germinative
    capacity but also that certain varieties of seed barley were damaged,
    exhibiting symptoms of albinism and stunted growth. The authors
    suggested that great care should be taken in the selection of stored
    barley intended for seed and, in particular, in the fumigation of
    samples in standard reference collections. A CTP of 200 mg.h/litre is
    used commercially, but higher concentrations may be attained if the
    distribution during fumigation is poor.


        Table 40.  Effects on germination of seeds fumigated with methyl bromidea
                                                                                                                                     
    Seed                  Fumigation conditions             Germination results                            Reference
                                                                                                                                     
    hemp                  70-140 g/m3                       5-23 % reduction                               Tkalich (1974)

    onion                 42 g/m3 for 24 h                  95 % reduction in laboratory                   Powell (1975)
                                                            11.5% reduction in cool soil

    peanuts               32 mg/litre (24 h, 27°C, 80%      reduction of:                                  Leesch et al. (1974)
     paper container      relative humidity), applied       21.7%
     burlap bags          under cover, aerated 72 h         11.4%

    oat, wheat, rye,      0, 600, or 1200 g.h/m3            at 8, 11at 18% moisture content:               Blackith & Lubatti (1965)
    barley                14, or 18% moisture content       - no germination after 6 years storage

                                                            at 8% moisture content:
                                                            - 90% germination after 6 years storageb

     Picea abies, Picea   seeds at various moisture         germination normal after storage               Jones (1968)
     glauca, Pinus mugo   content; 48 g/m3, 24°C, 2-5 h,    only if seeds aerated 24 h before
     mughus, Pinus        then aerated 1-25 h and stored    storage; all but  P. sylvestris 
     sylvestris (seeds)   in sealed containers at 7°C for   required drying to 5% moisture content
                          1 year                            before storage

    tobacco seed          16-32 g/m3 or                     germination satisfactory at <10 % seed         Guthrie & Kincaid (1957)
                          32-48 g/m3                        moisture content: germination dcreased at
                                                            seed moisture contents above 10%

    barley, corn, grain   32 g/m3 (< 24 h, 26°C);           unimpaired germination seed                    Whitney et al. (1958)
    sorghum, oats, wheat                                    moisture content less than 12%
                                                                                                                                     

    a From: Davis et al. (1977).
    b Except rye, germinated well only up to 3 years storage.
    

    7.3.2.2  Fumigation of plants or plant products

         Direct fumigation of plants or plant products is used to retard,
    or prevent, pest infestations and to overcome quarantine barriers.
    Post-harvest fumigation is discussed in section 5.1.4.2.

    7.3.2.3  The effects on plants of soil fumigation

         Methyl bromide can have adverse as well as positive effects on
    plants.

         The phytotoxic effects of methyl bromide as a soil sterilant can
    be caused by:

         (1)  the action on plants of methyl bromide itself;

         (2)  the action of inorganic bromide formed by the breakdown of
              methyl bromide in the soil;

         (3)  indirect action through effects of either methyl bromide or
              inorganic bromide on soil microflora, soil structure, or
              composition (Maw & Kempton,  1973).

         Where the crops are affected by lack of mycorrhizae, the plants
    are stunted. Experiments have proved that this problem can be
    rectified by fertilizing with phosphoric acid in the irrigation water,
    using a trickle system (Bromine & Chemicals Ltd., 1990).

         The phytotoxicity of methyl bromide is thought to be due mainly
    to the high level of bromide ion. Drosihn et al. (1968) showed that
    the degree of susceptibility of carnations to methyl bromide
    fumigation of the soil depends on the intensity of subsequent leaching
    of the soil. Similar findings were described by Kempton & Maw (1974).
    In contrast to this, tomato plants were relatively insensitive to
    bromide; growing tomatoes tolerated up to 0.1 mg bromide/g soil
    without signs of injury or growth retardation (Maw & Kempton, 1973).
    These authors found lettuce to be particularly resistant to inorganic
    bromide, with some varieties growing in the presence of as much as 5
    mg Br-/g soil.

         Reichmuth & Noack (1983) determined the threshold concentration
    of methyl bromide in air that should not be exceeded in the vicinity
    of fumigated buildings, in order to protect plants. The test plants
    ( Lactuca sativa capitata (lettuce) and  Nasturtium officinale
    (water cress)) were exposed to concentrations of between 4 and 1400
    mg methyl bromide/m3 for 72 h. At 400 mg/m3, yellowing of lettuce
    leaves became apparent, while no visible effects were observed on
    water cress up to the highest concentration.

     (a) Cultivated plants

         Only a limited number of genera, species, or varieties of plants
    are susceptible to methyl bromide. Of the 441 species of glasshouse
    plants tested by Latta & Cowgill (1941), 414 (93.9%) were not affected
    and only 27 sustained various levels of damage; of these, five species
    were severely burned. For example, roses showed no pronounced toxic
    effects, when planted in soils aerated for four days after methyl
    bromide fumigation, however, carnations were extremely sensitive to
    both residual methyl bromide gas and inorganic bromide in the soil
    (Kempton & Maw, 1974). Other crops, such as cotton, celery, pepper,
    and onion, do not reach adequate growth, when grown in fumigated soil
    (Bromine & Chemicals Ltd., 1990). Plants, actively growing, are more
    likely to sustain injury than dormant plants (Bond, 1984).

     (b) Weeds

         The phytotoxic effects of methyl bromide on weeds are important
    in soil fumigation. 

         Table 11 shows that the recommended dose rates to eradicate weeds
    is 35-50 g/m2, though purple nutsedge (nut grass), corms and seeds
    of horseweed  Erigeron (Conyza) , mallow  (Malva) , and legumes are
    not efficiently controlled at this dose (Bromine & Chemicals Ltd.,
    1990).

         Methyl bromide (40-80 g/m2) is mentioned as being the best soil
    fumigant against yellow nutsedge ( Cyperus esculentus L.), but the
    weed was not completely eradicated because dormant tubers below the
    tillage depth survived (Rotteveel & Naber, 1987).

    7.3.3  Soil invertebrates

         Soil fumigation with methyl bromide (and chloropicrin) results
    generally in toxic effects in both target and non-target organisms.
    The concentrations used are sufficiently high to eradicate populations
    of a wide variety of organisms. Fumigants, including methyl bromide
    and chloropicrin, were all strongly nematocidal. Methyl bromide killed
    virtually all soil arthropods, including mites; Collembola were almost
    completely eradicated. Methyl bromide was very toxic for symphylids
    and millipedes (details of dose not given) (Edwards & Thompson, 1973).
    Methyl bromide (concentration not given) and chloropicrin were very
    toxic for earthworms, even those that lived in deep burrows (Van Rhee,
    1977). Chloropicrin was repellent to most arthropods in soil (Edwards
    & Thompson, 1973). To control nematodes, methyl bromide is generally
    used at rates of up to 80 g/m2 (Table 41).

    7.3.4  Insects and arachnids

         Methyl bromide is used as a fumigant to control insect pests.
    Although it is not as toxic for insect species as some other
    fumigants, such as HCN, acrylonitrile, and ethylene dibromide, its
    ability to penetrate quickly and deeply into sorptive materials makes
    it an effective and versatile fumigant (Davis et al., 1977; Sassaman
    et al., 1986). The commercial dosage for methyl bromide as a storage
    fumigant ranges from 16 to 100 g/m3 for up to 3 days (Tables 12 and
    13).

         The dosage required depends also on the temperature. The
    threshold concentration levels identified at 15 and 25 °C differed by
    a factor of two or three. These investigations by Bell (1988) were
    carried out on the adult beetle. The dosage of methyl bromide required
    to kill eggs and pupae is greater than that required to kill all
    adults. Pupae and older larvae of  Tribolium spp., for example,
    required CTPs of up to 180 mg.h/litre for control (Hole, 1981). For
    other species and exposure conditions see Table 42.

         In an FAO study, it was found that there was a variation in
    tolerance to methyl bromide in different strains of eight species of
    stored product beetles collected from different parts of the world
    (Hole, 1981). Although resistant strains have been identified in the
    laboratory, there have been no reports of resistance to methyl bromide
    in practice (Bell, 1988).

         The effects of lethal concentrations of methyl bromide (48 g/m3
    for 2 h) on embryos of the codling moth ( Cydia pomonella L.) were
    assessed using light microscopy and transmission electron microscopy
    (Cheetham, 1990). Cell division stopped within one hour in nearly all
    embryos, a small number of terata being produced.

         Methyl bromide is used to eradicate various wood and household
    pests, particularly in the warmer climates of southern and western
    USA. The primary targets are drywood termites (Kalotermitidiae).
    Scheffrahn & Su (1992) have assessed the toxicity of methyl bromide at
    27 °C against pseudergates, nymphs, or alates of several species.
    Estimates of lethal accumulated doses for 50 and 99% mortality ranged,
    respectively, from 11.4 and 16.5 for  R. hesperus pseudergates to
    45.9 and 75.0 mg h/litre for  C. cavifrons pseudergates and nymphs.
    Alates were more susceptible to methyl bromide than pseudergates or
    nymphs. Boczek et al. (1975) reported three periods in the development
    of  Acarus siro that have increased sensitivity to methyl bromide:
     (a) before the beginning of gastrulation movements in the germ band;
     (b) during the formation of the nervous system; and  (c) the period
    preceding dorsal closure. For this species, Burkholder (1966) found
    LD100 values ranging from 3.4 to 16.8 g/m3 at various exposure
    times at 16 °C and 85% relative humidity whilst achieving the same CTP
    (65-83 g.h/m3).



        Table 41.  Effects of methyl bromide on nematodes
                                                                                                                              
    Nematode                       Effective               Exposure                                     Reference
                                   control                 Conditions
                                   concentration
                                                                                                                              
     Anguina agrostis                CTP 600-800             12% moisture                                 Hague (1963)
                                     mg.h/litre

     Belonolaimus                    98 g/m2                 98% methyl bromide                           Darby et al. (1962)
      longicaudans                                           2% chloropicrin: covered 48 h

     Ditylenchus dipsaci             CTP 850                 10-14% moisture                              Hague & Clark (1959)
                                     mg.h/litre

     Dorylaimus sp.                  2.3 g/m3                40 h                                         Van Gundy et al. (1972)

     Hemicyclophora parvana          98 g/m2                 98% methyl bromide                           Darby et al. (1962)
                                                             2% chloropicrin: covered 48 h

     Heterodera rostochiensis        Ct 500-1000             treatment with water before fumigation       Hague (1959)
                                     mg.h/litre              enhanced penetration of methyl bromide

     Heterodera rostochiensis        111 g/m2                covered 16 days: 98 % methyl bromide         Whitehead et al. 
                                                             and 2% chloropicrin                          (1972)

     Heterodera schachtii            0.5-30 g/m3             1-21 days                                    Abdalla & Lear (1975)

     Hoplolaimus columbus            23 g/m2                 potted seedlings, covered,                   Bird et al. (1974)
                                                             aerated for 1 h after 24 h

     Hoplolaimus tylenchiformis      98 g/m2                 98% methyl bromide                           Darby et al. (1962)
                                                             2% chloropicrin: covered 48 h

     Meloidogyne sp.                 50 g/m2                 manure applied prior to fumigation           Scotto La Massese 
                                                             decreased nematocidal effect                 & Mars (1975)
                                                                                                                              

    Table 41 (continued)
                                                                                                                              
    Nematode                       Effective               Exposure                                     Reference
                                   control                 Conditions
                                   concentration
                                                                                                                              
     Meloidogyne incognita           2.3 g/m3                38 h                                         Van Gundy et al. (1972)

     Meloidogyne incognita           23 g/m2                 potted seedlings, covered,                   Bird et al. (1974)
                                                             aerated for 1 h after 24 h

     Meloidogyne incognita           45-67 g/m2              covered                                      Raski et al. (1975)

     Meloidogyne incognita           0.6-2.5 g/m3            1-21 days                                    Abdalla & Lear (1975)

     Meloidogyne incognita           17-22 g/m2              chisel applicator, covered or rolled         Sher et al. (1958)
     acrita

     Meloidogyne javanica            45-67 g/m2              covered                                      Raski et al. (1975)

     Meloidogyne javanica            22-34 g/m2              chisel application, covered                  Thomason (1959)

     Meloidogyne javanica            56-112 g/m2             98% methyl bromide                           Milne (1962)
                                                             and 2% chloropicrin

     Pratylenchus sp.                45-67 g/m2              covered                                      Raski et al. (1975)

     Pratylenchus sp.                4.9-9.7 g/m3            1-3 days                                     Abdalla & Lear (1975)

     Pratylenchus brachynrus         23 g/m2                 potted seedlings, covered,                   Bird et al. (1974)
                                                             aerated for 1 h after 24 h

     Pratylenchus brachyurus         25-51 g/m3              24 hours; 25°C                               Minton & Gillenwater
                                                                                                        (1973)

     Pratylenchus penetrans          50 g/m2                 not stated                                   Chen et al. (1962)
                                                                                                                              

    Table 41 (continued)
                                                                                                                              
    Nematode                       Effective               Exposure                                     Reference
                                   control                 Conditions
                                   concentration
                                                                                                                              
     Pratylenchus thornei            49 g/m2                 covered after application                    Van Gundy et al. (1974)
                                                             for unspecified time

     Pratylenchus zeae               100 g/m2                covered for 48 h                             Oakes et al. (1956)
                                                             following fumigation

     Trichoderus christiei           98 g/m2                 98% methyl bromide                           Darby et al. (1962)
                                                             2% chloropicrin:
                                                             covered 48 h

     Xiphinema americanum            45-67 g/m2              covered                                      Raski et al. (1975)

     Xiphinema index                 2.3 g/m3                28 h                                         Van Gundy et al. (1972)

     Xiphinema index                 45-67 g/m2              covered                                      Raski et al. (1975)

     Xiphinema index                 0.2-2.0 g/m3            1-21 days                                    Abdalla & Lear (1975) 
                                                                                                                              

    Table 42.  Some insects controlled by methyl bromidea
                                                                                                                       
    Insect                         LD50 (g/m3)        LD95 (g/m3)         LD100 (g/m3)            Reference
                                                                                                                       
     Antagenus picus                  32                                                             Pence & Morganroth
    (black carpet beetle)                                                                            (1962)

     Anthonomus grandis                                  16-80                                       Roth & Kennedy (1972)
    (cotton boll weevil)

     Anthrenus flavipes                                                      32                      Pence & Morgenroth
    (furniture carpet beetle)                                                                        (1962)

     Anthrenus verbasci                                                      32
    (varied carpet beetle)

     Araecerus fasciculatus        6.2 (eggs)                                                        Majumder et al. (1961)
                                   3.4 (larvae)
                                   7.4 (pupae)
                                   4.5 (adults)

     Blatta orientalis                                                       64                      Hickin (1961)
    (cockroach)

     Blatella germanica                                                      64
    (cockroach)

     Bruchus rufimanus                                                       28                      Roth & Richardson
    (broad bean weevil)                                                                              (1974)

     Cadra cautella                                                          32                      Leesch et al. (1974)
    (almond moth)
                                                                                                                       

    Table 42 (continued)
                                                                                                                       
    Insect                         LD50 (g/m3)         LD95 (g/m3)         LD100 (g/m3)            Reference
                                                                                                                       
     Callosobruchus                  0.85 (eggs)         1.25 (eggs)                                 Adu & Muthu (1985)
     chinensis (L)                   2.2 (instar         2.72 (instar
    (cowpea weevil)                  larvae)             larvae)
                                     0.89 (pupae)        3.98 (pupae)
                                     1.17 (adult)        1.4 (adult)

     Chilo agamemnon                                                         20 (larvae)             Isa et al. (1970)
    (corn borer)

     Corcyra cephalonica             1.66-1.78 (eggs)                                                El-Buzz et al. (1974)
    (rice moth)                      1.10-1.68 (instar 
                                     larvae)
                                     2.79 (pupae)

     Curcilio caryae                                                         32-112                  Leesch & Gillenwater
    (pecan weevil)                                                                                   (1976)

     Ephestia kuehniella             2.02-2.46                                                       Mostafa et al. (1972)
    (mediterranean flour moth)

     Gnorimoschema operculella       11.74 (larvae)                                                  Pradhan et al. (1960)
    (potato tuber moth)

     Gryllotalpa                                         70-100 g/m2                                 Dzidzariya (1972)
    (mole cricket)

    Hemp leaf roller                                                       40-45                     Tkalich (1972)

     Laspeyresia pomonella                                                   32                      Morgan et al. (1974)
    (codling moth)                                                           32                      Anthon et al. (1975)

     Megastigmus acuelatus                                                   50                      Vodolagin (1971)
    (dog rose weevil)
                                                                                                                       

    Table 42 (continued)
                                                                                                                       
    Insect                         LD50 (g/m3)         LD95 (g/m3)         LD100 (g/m3)            Reference
                                                                                                                       
     Musca domestica                                                         64                      Hickin (1961)
    (housefly)

     Onychuirus hortensis                                                    89 g/m2                 Edwards (1962)
    (springtail)

     Oryzaephilus mercator                                                   200                     Joshi (1974)
    (merchant grain beetle)                                                  32                      Leesch et al. (1974)

     Ostrinia nubilalis                                                      20 (larvae)             Isa et al. (1970)
    (corn borer)

     Periplaneta americana                                                   64                      Hickin (1961)
    (cockroach)

     Plodia interpunctella           5.5  (normal larvae)                                            Sardesai (1972)
    (indian meal moth)              10.2 (diapausing larvae)
                                                                             32                      Leesch et al. (1974)

     Sitophilus oryzae               5.45-6.19
    (rice weevil)

     Sitotroga cerealella            1.85-2.21
    (angoumois grain moth)

     Tenebroides mauritanicus        16                                      23                      Bond (1956)
    (cadelle)                        25.5-43.3                                                       Monro et al. (1966)

     Isoptera
    (termites; 5 species)                                                    64                      Hickin (1961)

     Tribolium castaneum             0.009 (adults)
    (red flour beetle)               3.06-6.19                                                       Mostafa et al. (1972)
                                                                                                                       

    Table 42 (continued)
                                                                                                                       
    Insect                         LD50 (g/m3)         LD95 (g/m3)         LD100 (g/m3)            Reference
                                                                                                                       
     Trilobium confusum              3.6 - 91            4.64-145.14                                 Kenaga (1961)
    (confused flour beetle)                              15b
                                    21.5-23.7                                                       Monro et al. (1966)

     Trogoderma granaria             0.038 (larvae)                                                  Pradhan & Govindan
    (grain beetle)                                                                                   (1954)

     Trogoderma variable                                                     32-40 (eggs)            Vincent & Lindgren
    (warehouse beetle)                                                                               (1975)
                                                                             16-56 (instar larvae)
                                                                             32-72 (pupae)
                                                                             24-36 (adults)
                                                                                                                       

    a A range of LD values reflects effects of time, temperature, or pressure.
    b Preceded by gamma radiation (50 krad).
    

         LD100 values have been determined for  Rhipicephalus sanguineus
    (brown dog tick) ranging from 6 to 96 g/m3 (3.5 h, 22 °C and 6 h, 11
    °C, respectively) (Roth, 1973).

    7.3.5  Gastropods

         The effects of methyl bromide on various gastropods (slugs,
    snails, limpets) have been studied. Roth & Kennedy (1973) found an
    LD100 for  Helidella candidula and  H. conspurcata, exposed for 24
    h at a dosage of 240 g/m3 . Similarly, for  Cochicella barbara (72
    h, 13 °C) and  Theba pisana (10 h, 13 °C) a dosage of 128 g/m3 was
    lethal (Richardson & Roth, 1965).

    7.3.6  Birds

         Rhode Island Red female hens were fed, from hatching, on diets
    that had been fumigated with methyl bromide at the concentration
    recommended for the elimination of salmonellae (800 mg.h/litre) or at
    1´ times this value (Cooper et al., 1978). Body weight, egg weight,
    and egg number were not significantly affected by treatments, but
    sexual maturity may have been slightly delayed. The egg flavour was
    adversely affected. The same group had previously shown that the taste
    of meat from broiler chickens was similarly tainted (Griffiths et al.,
    1978).

         No adverse effects on either the fertility or hatchability of
    hens' eggs, previously fumigated with methyl bromide at 32 g/m3 for
    24 h, were observed (Devaney & Beerwinkle, 1982).

    7.3.7  Other animals

         Data are not available on the direct environmental exposure to
    methyl bromide of other animals. Effects on test animals are given in
    section 8.

         Bromide intoxication was reported by Knight & Costner (1977)
    after horses, goats, and cattle were accidentally fed oat hay that had
    been cut from a field treated with methyl bromide the previous autumn.
    The bromide content of the hay ranged from 6800 to 8400 mg/kg so that
    the estimated mean daily intake was 9, 49, and 70 g of bromide ion in
    goats, horses, and cattle, respectively. Signs of intoxication
    reported included lethargy, weakness, and ataxia. Similar symptoms
    were noticed between the 7th and 9th days in animals fed this hay on
    an experimental basis. Signs of in-coordination (between 10th and 12th
    days) were correlated with serum bromide concentrations of 30
    mEq/litre (2.4 g/litre) or more (Knight & Reina-Guerra, 1977). Serum
    bromide concentrations and the associated neurological signs subsided
    markedly 14 days after feeding discontinued (Knight & Reina-Guerra,
    1977). Methyl bromide is not approved for use prior to the planting of
    forage crops.

    7.4  Population and ecosystem effects

         Application of methyl bromide as a soil fumigant resulted in the
    almost complete eradication of populations of a wide variety of
    microflora and fauna, as well as other soil organisms, thus altering,
    at least temporarily, the trophic structure of the soil environment
    (Sassaman et al., 1986).

         Treatment with 100% methyl bromide and other methyl
    bromide/chloropicrin formulations reduced populations of  Fusarium,
     Pythium, and  Rhizooctonia species in soil. Nine weeks after
    application, populations were still significantly lower. Seedlings
    grown in treated plots had the least amount of damping off and root
    rot (Enebak et al., 1988).

         Methyl bromide dosed under plastic sheeting at a rate of 300
    g/m3 (for 30 cm depth 100 g/m2) killed all insects, though small
    numbers of soil nematodes and mites were collected during subsequent
    sampling (Heungens & Roos, 1982).

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    8.1  Single exposure

    8.1.1  Oral

         A summary of acute oral toxicity data is given in Table 43. Very
    few studies have been carried out, mainly because methyl bromide is a
    gas at temperatures above 4 °C. The minimum lethal oral dose of methyl
    bromide for rabbits was found to be 60-65 mg/kg body weight (Dudley et
    al., 1940; Dudley & Neal, 1942).  Miller & Haggard (1943) found that
    all rats given a single oral dose of 100 mg/kg body weight in olive
    oil died in 5-7 h.

    8.1.2  Inhalation

    8.1.2.1  Guinea-pig and rabbit

         Single exposure toxicity tests conducted on various mammalian
    species have shown that methyl bromide is highly toxic. A summary of
    the acute toxicity data is presented in Table 44.

         Studies on guinea-pigs (Sayers et al., 1929) and rabbits (Irish
    et al., 1940) were carried out. Rabbits were exposed to concentrations
    of 420, 852, 1000, 2000, 10 000, 20 000, and 50 000 mg methyl
    bromide/m3. Table 45 shows the exposure times giving 100% survival
    and 100% mortality. Concentrations of methyl bromide above 10 000
    mg/m3 sometimes caused the rabbits to close their eyes; otherwise
    they appeared normal until they became too weak to hold up their heads
    (Irish et al., 1940). Rabbits that survived 1000 mg methyl
    bromide/m3 for 2 days after exposure usually became paralysed (Irish
    et al., 1940).

         Toxicity is a function of the concentration levels and the
    exposure times (see also Table 45). The steep dose-mortality response
    to methyl bromide found by many authors can be seen in Fig. 9.

    8.1.2.2  Mouse

         The results of single exposure inhalation studies on mice,
    carried out by Alexeeff et al. (1985), Yamano (1991), and the Japanese
    Ministry of Labour (1992), are given in Tables 46 and 47. The sharp
    onset of lethal toxicity was shown in all cases. Alexeeff et al.
    (1985) exposed male mice to methyl bromide (870-5930 mg/m3) for 1 h
    and observed that clinical signs and mortality were dose related, with
    the possibility of delayed effects in target organs, such as the
    kidney.


        Table 43.  Acute and short-term oral (gavage) toxicity
                                                                                                                                   
    Species/  Number of    Exposure        Dose            Effect                                            Reference
    strain    animals/     time            (mg/kg
              groupa                       body weight)
                                                                                                                                   
    rabbit    n.d.         single          56-71           all rabbits given an oral dose of                 Dudley et al. (1940)
                                                           63.9 mg/kg died; one rabbit receiving             Dudley & Neal (1942)
                                                           56.3 mg/kg died; all rabbits given
                                                           56.1 mg/kg or less survived;
                                                           destruction of superficial layers of 
                                                           stomach and duodenum with accompanying 
                                                           haemorrhage and hyperaemia; minimal lethal
                                                           dose: 60-65 mg/kg body weight

    rat       n.d.         single          100             all died in 5-7 h                                 Miller & Haggard (1943)

    rat       n.d;         single          190-239         LD50, 214 mg/kg                                   Danse et al. (1984)

    rat       n.d.         4 weeks;        50              epithelial hyperplasia, hyperkeratosis
                           7 days/week                     and ulceration of the forestomach

    rat       10 (male)    13 weeks;       0               10 and 50 mg/kg: proliferative 
    (Wistar)  10 (female)  5 days/week     0.4             alterations of forestomach mucosa;
                                           2               50 mg/kg: haematological changes
                                           10              13/20 squamous cell carcinomas of
                                           50              forestomach

    rat       15           13-25 weeks;    0               treated group: week 13: forestomach               Boorman et al.(1986)
                           12 weeks        50              acanthosis, fibrosis, pseudoepitheliomatous 
                           recovery for                    hyperplasia; week 25: hyperplastic lesions 
                           some groups                     of forestomach

                                                           recovery group: regression of stomach lesions,
                                                           but adhesions, fibrosis, and mild acanthosis
                                                           remained; evidence of malignancy in one rat
                                                                                                                                   

    Table 43 (continued)
                                                                                                                                   
    Species/  Number of    Exposure        Dose            Effect                                            Reference
    strain    animals/     time            (mg/kg
              groupa                       body weight)
                                                                                                                                   
    rat       n.d.         4,8,13, and     0               treated groups: forestomach ulceration            Hubbs & Hartington (1986)
    (n.d.)                 17 weeks;       25              pseudoepitheliomatous hyperplasia
                           5 days/week     50

              n.d.         13 weeks;       0               recovery period: marked but incomplete 
                           5 days/week     25              regression of lesions;
                           recovery for    50              no evidence of malignancy
                           4-8 weeks
                                                                                                                                   

    a n.d.= no details given.
    

        Table 44.  Single exposure inhalation studies of methyl bromide on mammalsa
                                                                                     
    Species Concentration   Length of     Effect                   References
            (mg/m3)         exposure
                            (min)b
                                                                                     
    mouse    94 950         25            100 % died within 6 h    Bachem (1927)

    mouse       700         n.d.          100 % survived           Bachem (1927)

    rat      20 000         6             100 % survived           Irish et al. (1940)
                            24            100 % died

    rat      43 000         3             survived                 Clarke et al. (1945)

    rat      50 000         3             100 % survived           Irish et al. (1940)
                            6             100 % died

    rabbit       70         40            change in motor          Balander & Polyak 
                                          reflex behaviour         (1962)

    rabbit   19 000         25            deep (fatigued)          Beyne & Goett
                                          breathing                (1934)

    rabbit   20 000         36            100 % survived           Irish et al. (1940)

    rabbit   20 000         84            100 % died

    rabbit   25 000         30            died                     Beyne & Goett
                                                                   (1934)

    rabbit   31 600         5             died after 8-10 h        Duvoir et al. (1937)

    rabbit   36 000         25            died                     Beyne & Goett
                                                                   (1934)

    rabbit   50 000         12            100 % survived           Irish et al. (1940)
                            30            100 % died

    dog      10 000         5-6 h         died                     Beyne & Goett
                                                                   (1934)

    dog      17 000         n.d.          died                     Merzbach (1928)

    dog      19 000         n.d.          died                     Beyne & Goett
                                                                   (1934)

    dog      34 000         60            died                     Merzbach (1928)
                                                                                     

    Table 44 (continued)
                                                                                     
    Species Concentration   Length of     Effect                   References
            (mg/m3)         exposure
                            (min)b
                                                                                     
    dog      48 000         40            died                     Duvoir et al. (1937)

    dog      50 000         45            died                     Merzbach (1928)
                                                                                     

    a Adapted from Henschler (1990).
    b n.d. = no details given.
    

    FIGURE 9

        Table 45.  Acute inhalation toxicity of methyl bromide for rats and rabbitsa
                                                                                         
    Concentration                               Exposure time in hours
    (mg/m3)                           Rats                             Rabbits
                                                                                         

                       100 % fatality    100 % survival    100 % fatality    100 % survival
                                                                                         
    50 000              0.1                0.03              0.5               0.2
    20 000              0.4                0.1               1.4               0.6
    10 000              0.7                0.4               2.2               1.0
     2 000              6                  2                11                 6
     1 000             22                  8                24                15
       852             26                 12                32                20
       420             -b                 22                -b                -b
                                                                                         

    a From: Irish et al. (1940).
    b No data.
    

    Table 46.  LC50 values for methyl bromide
                                                                        
    Species    Concentration     Exposure    Reference
               (mg/m3)           time

                                                                        
    mouse       6 600            30 min      Bakhishev (1973)
    mouse       4 680             1 h        Alexeeff et al.  (1985)
    mouse       1 540             2 h        Balander & Polyak (1962)
    mouse       1 575             4 h        Yamano (1991)
    rat        11 000            30 min      Bakhishev (1973)
    rat         7 300             1 h        Zwart (1988); Zwart et al.
                                              (1992)
    rat         3 034             4 h        Kato et al.(1986)
    rat         1 175             8 h        Honma et al. (1985)
                                                                        


         Further details of target organ studies and biochemical findings
    from the series of mouse studies (Alexeeff et al., 1985) are given in
    sections 8.8 and 6.3, respectively.

         An LC50 of 1575 mg methyl bromide/m3 (405 ppm ± 20) was
    determined after a 4 h exposure (Yamano, 1991). In a further study,
    the author exposed mice to 1945 mg methyl bromide/m3 (500 ppm).
    After 2 h of exposure, there were no deaths, but, after a further 30
    min, there was 85% mortality. Mice treated prior to exposure with
    glutathione (500 mg/kg i.p.) showed only 5.3% mortality after this
    time.


        Table 47.  Some single exposure inhalation studies
                                                                                                                                     
    Species/           No. of           Exposure time    Concentration         Observed effectsa                       Reference
    strain             animals/                          (mg/m3)
                       exposure group
                                                                                                                                     
    mouse               6 (male)        (nose only)      0                                                             Alexeeff et al.
    (Swiss-Webster)                     1 h, surviving   870          (+); no toxic response                           (1985)
                                        mice sacrificed  1720         (+); no toxic response
                                        one week         2200         (+); significantly decreased lung and
                                        later            2720           liver weights
                                                         3500         (+); additionally enlarged, pale kidneys
                                                                        and kidney lesions
                                                         3820         (-); additionally abnormal clinical 
                                                                        signs, weight loss and mortality;
                                                                        cerebral haemorrhage
                                                         4700         (-); additionally liver lesion, liver
                                                                        congestion and haemorrhage
                                                         5770         (-); additionally decreased motor 
                                                                        coordination; cerebral congestion;
                                                                        colonic haemorrhage;  congested
                                                                        kidneys
                                                         5930         (-); all effects mentioned above

                                                                      (1 h-LC50 of 4680 mg/m3 determined)
                                                                                                                                     

    a (+) = Able to recall a single task passive avoidance test. 
    b (-) = Not able to recall a single task passive avoidance test.

    Table 47  (continued)
                                                                                                                                     
    Species/           No. of           Exposure time    Concentration         Observed effectsa                       Reference
    strain             animals/                          (mg/m3)
                       exposure group
                                                                                                                                     
    mouse              10 (male)        4 h              389          0% mortality                                     Japanese
    (Crj: BDF1)        10 (female)                       584          0% mortality                                     Ministry of
                                                         873          0% mortality                                     Labour (1992)
                                                         1315         0% mortality
                                                                      Pathology: respiratory metaplasia of the
                                                                      olfactory epithelium of the nasal cavity
                                                                      (female)
                                                         1970         80% mortality (male) and 100% mortality
                                                                      (female)
                                                                      Clinical signs: decrease in locomotor
                                                                      movement, tremor, convulsion, diarrhoea,
                                                                      bradypnoea, dyspnoea (dead)
                                                                      Pathology: 
                                                                      Dead: congestion of the lung, necrosis
                                                                      and degeneration of the liver, tubular 
                                                                      necrosis of the kidney, karyorrhexis of the
                                                                      thymus and lymph node, necrosis of the 
                                                                      olfactory epithelium of the nasal cavity
                                                                      Survived: tubular necrosis and regeneration
                                                                      of the kidney, necrosis and respiratory 
                                                                      metaplasia of the olfactory epithelium of the
                                                                      nasal cavity
                                                         2950         100% mortality
                                                                      clinical sign and pathology:  same as
                                                                      1970 mg/m3 dead animals

    mouse                               1 h 45 min       1945         0% mortality                                     Yamano (1991)
                                        2 h                           0% mortality
                                        2 h 10 min                    11% mortality
                                        2 h 20 min                    15% mortality
                                        2 h 30 min                    85% mortality
                                        3 h                           90% mortality
                                                                                                                                     

    Table 47  (continued)
                                                                                                                                     
    Species/           No. of           Exposure time    Concentration         Observed effectsa                       Reference
    strain             animals/                          (mg/m3)
                       exposure group
                                                                                                                                     
    rat                10(male)         4 h              584          0% mortality                                     Japanese
    (F344/DuCrj)       10(female)                        875          0% mortality                                     Ministry of
                                                                      Pathology: disarrangement and                    Labour (1992)
                                                                      respiratory metaplasia of the olfactory
                                                                      epithelium of the nasal cavity
                                                         1315         0% mortality; Pathology: same as 875 mg/m3
                                                         1970         0% mortality; Pathology: same as 875 mg/m3
                                                         2956         100% mortality
                                                                      Clinical signs: closed eyelid, decrease in
                                                                      locomotor movement, ataxic gait, serous
                                                                      discharge of nose, lacrimation, diarrhoea,
                                                                      irregular breathing and bradypnoea
                                                                      Pathology: congestion of the lung, 
                                                                      degeneration of the liver, tubular necrosis 
                                                                      of the kidney, haemorrhage of heart, 
                                                                      haemorrhage or necrosis of the adrenal glands,
                                                                      necrosis of the olfactory epithelium of the
                                                                      nasal cavity, congestion of the thymus

                                                         4435         100% mortality
                                                                      Clinical signs and pathology: same as 2956 mg/m3

    rat                2 (male)         5.2-86 min       7500-        1-h LC50 was 7300 mg/m3.                         Zwart (1988)
    (SPF-Wistar)                                         57 000       Rangec: 3.5-min LC50 = 75 700 mg/m3              Zwart et al.
                                                                           480-min LC50 = 1300 mg/m3                   (1992)

    rat                5 (male)         8 h              1042-        LC50 = 1175 mg/m3                                Honma et al.
    (Sprague-Dawley)                                     2085                                                          (1985)
                                                                                                                                     

    Table 47  (continued)
                                                                                                                                     
    Species/           No. of           Exposure time    Concentration         Observed effectsa                       Reference
    strain             animals/                          (mg/m3)
                       exposure group
                                                                                                                                     
    rat                8 (male)         8 h              245-         locomotor activity decreased at
    (Sprague-Dawley)                                      972         731 mg/m3; rectal temperature fell
                                                                      2°C at 486 mg/m3; decrease in feed
                                                                      consumption and body weight gain at
                                                                      486 mg/m3; all animals lost righting
                                                                      reflex at 245 mg/m3

    rat                8 (male)         6 h              778          extensive destruction of the                     Hurtt et 
    (F-344)                                                           olfactory epithelium                             al. (1988)
                                                                                                                                     

    c Total of 23 combinations of time and dosage; the animals were observed for up to 2 weeks.
    

         Groups (10 male+10 female) of BDF1 mice were exposed to methyl
    bromide (99.9% pure) concentrations of 389, 584, 873, 1315, 1970, or
    2950 mg/m3 (100, 150, 225, 338, 506, or 760 ppm) for 4 h (Japanese
    Ministry of Labour, 1992). Mice exposed to concentrations of 1970 and
    2950 mg/m3 showed decreased locomotor activity, tremor, convulsions,
    diarrhoea, dyspnoea, and bradypnoea. In the 2950 mg/m3 group, all
    the mice died; at 1970 mg/m3, 2 males survived. Mice exposed to
    concentrations of between 389 and 1315 mg/m3 did not exhibit any
    abnormal clinical signs.

         Pathology in a female mouse exposed to 1315 mg/m3 showed
    metaplasia of the olfactory epithelium. In the 2 male mice surviving
    exposure to 1970 mg/m3, there was renal tubular necrosis and
    regeneration, and necrosis and metaplasia of the olfactory epithelium.
    In the other mice exposed to 1970 and 2950 mg/m3, there was
    pulmonary congestion, hepatic degeneration and necrosis, renal tubular
    necrosis, karyorrhexis of the thymus and lymph nodes, and necrosis of
    the olfactory epithelium.

    8.1.2.3  Rat

         Irish et al. (1940) exposed rats to concentrations of 420, 852,
    1000, 2000, 10 000, 20 000, or 50 000 mg methyl bromide/m3. Table 45
    shows the exposure time in hours resulting in 100 % survival and 100
    % fatality. Rats exposed to concentrations below 10 000 mg/m3 showed
    roughening of the fur, hunching of the back, drowsiness, heavy
    breathing, and sometimes lacrimation. At higher concentrations, the
    first signs were nose irritation and lacrimation followed by the
    reactions already mentioned. Those exposed for 20 h to 1000 mg methyl
    bromide/m3 often became hyperactive until exhausted.

         As well as neurological manifestations of toxicity in rats,
    methyl bromide at concentrations of 1000-20 000 mg/m3 caused
    irritation of the lungs, producing acute congestion and oedema (Irish
    et al., 1940).

         Groups (10 male + 10 female) of F344 rats were exposed to methyl
    bromide (99.9% pure) concentrations of 584, 875, 1315, 1970, 2956, or
    4435 mg/m3 (150, 225, 338, 506, 760, or 1140 ppm) for 4 h in a
    chamber (Japanese Ministry of Labour, 1992). At concentrations of 1315
    mg/m3 and above, there was decreased locomotor activity, ataxia,
    nasal discharge, lacrimation, diarrhoea, and irregular breathing and
    bradypnoea. In the 2956 and 4435 mg/m3 exposure groups, all the rats
    died. Pathology of these groups showed pulmonary congestion, hepatic
    degeneration, renal necrosis, myocardial haemorrhages, haemorrhage and
    necrosis of the adrenal glands, and congestion of the thymus. In rats
    exposed to 875, 1315, or 1970 mg/m3, there was metaplasia of the
    olfactory epithelium and, in those exposed to the two highest doses,
    also necrosis of the olfactory epithelium.

         A single 6-h exposure of rats to 780 mg methyl bromide/m3
    caused extensive destruction of the olfactory mucosal epithelium
    (Hurtt et al., 1988).

         Kato et al. (1986) determined a 4-h LC50 for methyl bromide in
    male Sprague-Dawley rats (Fig. 9). Groups of 5 rats were exposed for
    4 h to methyl bromide at concentrations of 1952, 2420, 3108, or 3485
    mg/m3 (502, 622, 799, or 896 ppm), and approximate values of 100%
    survival and 100% lethal concentration were determined (2529 and 3501
    mg/m3, respectively). In a further test, 10 rats each were exposed
    to 2727, 2984, 3143, 3178, or 3236 mg/m3 (701, 767, 808, 817, or 832
    ppm). An LC50 value of 3034 mg/m3 (780 ppm) was calculated from
    mortality at one week after exposure (Kato et al., 1986).

         The dependence of methyl bromide toxicity on time and
    concentration was demonstrated in studies performed by Zwart (1988)
    and Zwart et al. (1992). Male SPF-Wistar rats were exposed to a total
    of 23 combinations (2 rats each) of time and concentration and LC50
    values were determined at seven time points ranging from 3.5 to 480
    min. LC50s ranged from 75 700 mg/m3 at 3.5 min to 1300 mg/m3 at
    480 min. The 1-h LC50 was 7300 mg/m3. Most animals showed some
    incoordination, decreased response to stimuli, and had lame limbs,
    directly after exposure. All mortalities occurred during the first
    week and, on examination, red discoloured lungs and red/black spots in
    the thymus were found in most dead rats. After two weeks, the
    surviving animals were sacrificed. Some of these rats showed clear or
    light red stained fluid in the lungs (Zwart, 1988).

         Honma et al. (1985) carried out various investigations into the
    effects of a single, 8-h exposure to methyl bromide on male
    Sprague-Dawley rats. An acute toxicity study was carried out with five
    groups of five animals exposed to 1042, 1303, 1564, 1824, or 2085
    mg/m3 (268, 335, 402, 469, or 536 ppm), respectively. An 8-h LC50
    of 1175 mg/m3 (302 ppm) with 95% confidence limits of 1040-1323
    mg/m3 (267-340 ppm) was determined.

          Body temperature was measured in four groups of five rats each
    exposed to 245, 486, or 972 mg methyl bromide/m3 (63, 125, or 250
    ppm). Exposure to 245 mg/m3 did not effect rectal temperature, while
    8-h exposure at 486 or 972 mg/m3 decreased body temperature by about
    2°C; however, this normalized within one day (Honma et al., 1985).

         The effects of methyl bromide on body weight gain were
    investigated. Food deprivation (feeding only twice a day) was started
    at least 2 weeks before exposure. Rats were exposed to 245, 486, or
    972 mg methyl bromide/m3 (63, 125, or 250 ppm) for 8 h and feed was
    provided immediately afterwards. Decrease in food consumption and
    depression in body weight gain were observed in groups exposed to 486
    and 972 mg methyl bromide/m3, but not in groups exposed to 245 mg
    methyl bromide/m3. The control group gained 15 g/day whereas with
    exposure to 972 mg methyl bromide/m3, weight gain was almost fully
    suppressed and was still partially depressed (+10 g) the following day
    (Honma et al., 1985).

    8.1.3  Dermal

         Toxicity studies concerning the dermal route of exposure in
    animals have not been reported.

    8.1.4  Subcutaneous administration

         For a single subcutaneous administration in Sprague-Dawley male
    rats (9 rats/group) an LD50 for methyl bromide was found to be 135
    mg/kg body weight (range 75- 250 mg/kg body weight) (Tanaka et al.,
    1988).

    8.2  Short-term exposure

    8.2.1  Oral

         A summary of studies concerned with oral exposure to methyl
    bromide by gavage is given in Table 43.

         A group of 12 rabbits was fed a mixed diet that had been
    fumigated with methyl bromide for 24 h. The rabbits were fed
    immediately after the fumigation was completed and the content of
    methyl bromide in the feed was 3865 mg/kg. The first animal died 3
    days after feeding was begun and the last in 13 days. All were
    paralysed prior to death and all showed pulmonary damage. No changes
    in the gastrointestinal tract were found (Dudley et al., 1940).

         Studies on rats (8-week preliminary test, 16-week, and 20-week
    test) and rabbits (52 weeks) were carried out by Dudley & Neal (1942).
    Results from the rat study showed that, when high (5290-6200 mg Br/kg
    food) amounts of organic and inorganic bromides were present in food
    after fumigation with methyl bromide, mortality increased, body weight
    gain and activity were reduced, and general health and reproductivity
    were adversely affected. When feed containing 240-300 mg Br/kg,
    following fumigation with 58 g methyl bromide/m3 for 24 h, was fed,
    or when fumigated fruits and vegetables were fed, few or no
    deleterious effects were noted (Dudley & Neal, 1942). Activity,
    general condition, body weight gain, and reproductivity were normal.
    Dudley & Neal (1942) carried out similar studies on rabbits. All 12
    rabbits died within 2 weeks of being fed a diet containing about 3000
    mg Br/kg. However, the 12 rabbits fed a diet of 60-100 mg Br/kg for 52
    weeks showed few or no deleterious effects.

         No apparent effects on appearance and general behaviour were
    observed in Wistar rats (male and female) given doses, by gavage, of
    up to 50 mg methyl bromide/kg body weight in a 90-day study (Danse et
    al., 1984). Body weight gain in the male rats was significantly less
    than that of controls, though this was not the case for females. There
    were slight haematological changes and, in the two higher dosage
    groups, several animals showed proliferative alterations of the
    forestomach mucosa, characterized by hyperkeratosis and papilloma
    (section 8.7).

         A study by Boorman et al. (1986), based on a study design by
    Danse et al. (1984), included dose groups with a recovery period, in
    order to study the progression or regression of lesions. Details are
    given in section 8.7 and Table 43. Boorman et al. (1986) found
    forestomach lesions similar to those described by Danse et al. (1984),
    but these lesions regressed in the 60-day recovery period.

         Similar findings were reported by Hubbs & Harrington (1986). They
    administered methyl bromide in peanut oil to rats at doses of 0, 25,
    or 50 mg/kg body weight per day for up to 120 days. In a regression
    study, some of the rats were treated for 90 days and then allowed to
    recover for 30-60 days (Table 43 and section 8.7).

         Three groups of four beagle dogs (3 male, 1 female) were fed
    methyl bromide-fumigated food for 6-8 weeks in doses equivalent to an
    average daily ingestion of 35, 75, or 150 mg/kg body weight of bromide
    ion, respectively (Rosenblum et al., 1960). A further group of 4 dogs
    received 128 mg sodium bromide/kg per day (equivalent to 100 mg
    bromide ion/kg per day). A control group of 6 dogs (3 male and 3
    female) received only dog chow. After one year of observation and
    monthly blood and urine tests, the remaining dogs were killed, the
    organs weighed, and histological studies carried out. No evidence of
    toxicity that could be attributed to bromide was observed in animals
    that received 35 or 75 mg bromide/kg per day. Dogs in the group
    receiving 150 mg/kg per day became lethargic and had occasional
    episodes of salivation and diarrhoea. No significant effects on blood
    chemistry, haematology, or urinary values were reported, nor were
    treatment-related deaths or histological lesions noted.

    8.2.2  Inhalation studies

    8.2.2.1  Guinea-pig, rabbit, monkey

         A summary of short-term exposure studies is given in Table 48.

         Irish et al. (1940) carried out extensive studies into the
    long-term exposure of animals to methyl bromide. A total number of 135
    rats, 98 guinea-pigs, 104 rabbits, and 13 monkeys were exposed to 65,
    130, 250, 420, or 850 mg methyl bromide/m3, 7-8 h/day, 5 days/week
    for 6 months, or, until the majority had either died or shown a severe
    reaction (Table 49).

    8.2.2.2  Mouse

         In the short-term studies on male and female B6C3F1 mice, exposed
    6 h/day for 10 days over 14 days (778 mg methyl bromide/m3),
    described by NTP (1992), five mice/dose group per sex were evaluated
    for haematology, serum pseudocholinesterase activity, and pathology.
    Necropsied animals from the two highest dosage groups were examined
    histopathologically. The results are summarized in Table 48.

         Eustis et al. (1988) carried out a special target organ study on
    B6C3F1 mice (and F344/N rats). Male and female B6C3F1 mice were
    exposed to either 622 mg methyl bromide/m3 (160 ppm) or air for 6
    h/day, 5 days/week. The animals were scheduled for sacrifice after 3,
    10, or 30 exposures. When 50% mortality was observed in any group, the
    surviving animals in that group were sacrificed. Mice were evaluated
    for body weight, mortality, organ weights, haematology, and
    histopathology. In addition to these end-points, urine chemistry and
    plasma enzymes were assessed in the rats. Significantly different
    mortality rates were observed between the two species, with the mice
    demonstrating a higher sensitivity to 622 mg methyl bromide/m3 than
    rats. Body weight differences were exposure-related (Eustis et al.,
    1988). The results are summarized in Table 48. Mortality exceeded 50%
    after 8 and 6 exposures in male and female mice, respectively. The
    remaining male mice were killed after 10 exposures and the females
    after 8 exposures. There were significant reductions in body weight
    and corresponding reductions in organ weights in both sexes, whereas
    there were sex differences in the haematological parameters. The
    responses to exposure were minimal in males, but marked in females, in
    which there were large and significant reductions in RBC, haemoglobin,
    haematocrit values, and mean corpuscular haemoglobin concentrations,
    and increases in WBC and mean corpuscular volume (Eustis et al.,
    1988). Histopathological changes in target organs are described in
    section 8.8.

         BDF1 mice (groups 10 males/10 females) were exposed to methyl
    bromide at concentrations of 599, 778, 1011, 1315, or 1712 mg/m3
    (154, 200, 260, 338, or 440 ppm) 6 h/day, 5 days/week, for 2 weeks
    (Japanese Ministry of Labour, 1992). Survival was reduced at all
    exposure concentrations and none of the mice exposed to 1315 or 1712
    mg methyl bromide/m3 survived. At all exposure concentrations, mice
    exhibited decreased locomotor activity, piloerection, lacrimation,
    ataxia, and tremor.


        Table 48.  Short-term exposure inhalation studies
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
    Mouse              10 (male)        6 h/day; 5 days/week;    477         78 mg/m3 group: 9 male, 6 female died;         NTP (1992)
     (B6C3F1)          10 (female)      2 weeks                   97         All groups: no body weight changes; bloody
                                                                 195         urine; trembling, jumpiness, paralysis in 
                                                                 389         all groups, but most pronounced in highest 
                                                                 778         dosage groups; haematology parameters/
                                                                             pseudo cholinesterase activity - no 
                                                                             consistent dose-related effects
                                                                             1 female mouse showed minimal
                                                                             hyperaemia of lungs, liver, kidneys

    Mouse              20 (male)        6 h/day; 5 days/week;    622         50% mortality (male) after 8 exp. days,        Eustis et 
     (B6C3F1)          20 (female)      10 exp. days                         50% mortality (female) after 6 exp. days;      al. (1988)
                                        for males and                        exposure-related lesions were seen in
                                        8 exp. days                          the brain, heart, kidneys, thymus, and 
                                        for females                          spleen of both sexes; in the testes,
                                                                             nose, and lungs of males, and in the 
                                                                             adrenal glands of females      

    Mouse              15 (male)        6 h/day; 5 days/week;      0                                                        Eustis et al. (1988)
     (B6C3F1)          15 (female)      6 weeks                  622         lethargy; curling and crossing                 
     (continued)                                                             of hind-limbs, forelimb twitching
                                                                             and tremors; decrease in body weight
                                                                             gain after 5 days; decrease in organ
                                                                             weight (lung, heart, thymus, brain, 
                                                                             liver) neuronal necrosis; nephrosis; 
                                                                             atrophy of inner zone of adrenal
                                                                             cortex; testicular degeneration;
                                                                             decrease in RBC, increase in WBC 
                                                                             (females only)
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
    Mouse              18-30 (males)    5 days/week; 6 h/day;      0         All dose groups: no significant organ          NTP (1992)
     (B6C3F1)          18-30 (female)   13 weeks                  39         weight effects;                                 
                                                                  78                                                    
                                                                 156         decrease in Hb and MCV, increase in RBC (males);
                                                                 311         decrease in Hb and MCV, increase in RBC (males);
                                                                 467         17 % mortality in males; decrease in body weight,
                                                                             additionally severe curling and crossing
                                                                             of hindlimbs and twitching of forelimbs 
                                                                             (male > female)

    Mouse              10 (male)        6 h/day; 5 days/week       0                                                        Japanese
     (Crj:BDF1)        10 (female)      13 weeks                  29         no toxic effects;                              Ministry of
                                                                  58         no toxic effects;                              Labour
                                                                 117         no toxic effects;                              (1992)
                                                                 234         depression of body weight gain;
                                                                             Haematology: increase in MCV in females;
                                                                             Urinalysis: increased protein in females

    Mouse              10 (male)        6 h/day; 5 days/week     599         10% mortality (male) and 0% (female)           Japanese
     (Crj:BDF1)        10 (female)      2 weeks                              depression of body weight gain;                Ministry of
     (continued)                                                             Clinical signs:                                Labour (1992)
                                                                             Dead mice: decrease in locomotor activity,
                                                                             piloerection, lacrimation, bradypnoea,
                                                                             opacity of eye, diarrhoea
                                                                             Surviving mice: decrease in locomotor activity,
                                                                             bradypnoea, ataxic gait, sub-normal
                                                                             temperature, tremor, lacrimation, soiled,
                                                                             pallor, hunched posture, piloerection 
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             Pathology:
                                                                             Dead mice: tubular necrosis of the kidney,
                                                                             ulcer of the stomach, testicular 
                                                                             atrophy, atrophy of the spleen, atrophy
                                                                             and karyorrhexis of the lymph node,
                                                                             myocardial necrosis
                                                                             Surviving mice: degeneration of the granular
                                                                             layer of the cerebellum, tubular necrosis and
                                                                             regeneration of the kidney, necrosis and 
                                                                             respiratory metaplasia of the olfactory 
                                                                             epithelium

    Mouse                                                        778         50% mortality of males and 80% mortality of    Japanese Ministry
     (Crj:BDF1)                                                              females, depression of body weight gain;       of Labour (1992)
     (continued)                                                             Clinical signs: same as 599 mg/m3 group
                                                                             Pathology: Dead mice: degeneration of the
                                                                             granular layer of the cerebellum, tubular 
                                                                             necrosis and regeneration of the kidney, 
                                                                             extramedullary haematopoiesis and atrophy 
                                                                             of the spleen, karyorrhexis of the thymus, 
                                                                             myocardial necrosis, necrosis of the 
                                                                             olfactory epithelium

                                                                1011         90% mortality (male and female)
                                                                             depression of body weight gain;
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             Clinical signs: piloerection, soiled,
                                                                             bloody nose discharge;
                                                                             Pathology: disarrangement, necrosis and
                                                                             respiratory metaplasia of the olfactory 
                                                                             epithelium of the nasal cavity, vacuolic 
                                                                             change of the adrenal glands, myocardial 
                                                                             damage

                                                                1315         100% mortality (male and female);
                                                                             Clinical signs: same as mice dying 
                                                                             in 599 mg/m3 group
                                                                             Pathology: congestion of the lung,
                                                                             degeneration of the liver, hyaline droplet 
                                                                             and tubular necrosis of the kidney, 
                                                                             karyorrhexis of the thymus and spleen, 
                                                                             myocardial necrosis, necrosis of the olfactory
                                                                             epithelium.

    Mouse                                                       1712         100% mortality (male and female);              Japanese Ministry
     (Crj:BDF1)                                                              Clinical signs: same as mice dying             of Labour
     (continued)                                                             in the 599 mg/m3 group                         (1992)
                                                                             Pathology: congestion of the lung,
                                                                             degeneration of the liver, tubular 
                                                                             necrosis of the kidney, karyorrhexis 
                                                                             of the thymus and spleen.

                                                                 467         mortality, 10% in males and 90% in females;
                                                                             depression of body weight gain;
                                                                             Clinical signs:  ataxic gait;
                                                                             Haematology: increased MCV in males;
                                                                             Urinalysis: same as 234 mg/m3 group;
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             Pathology: degeneration of the granular
                                                                             layer of the cerebellum, necrosis of the
                                                                             brain, congestion of the lung, karyorrhexis
                                                                             and atrophy of the thymus, tubular necrosis
                                                                             of the kidney, necrosis of the heart, 
                                                                             vacuolic change of the adrenal glands 

    Rat                6 (male)         6 h/day; 5 days            0                                                        NTP (1992)
     (SPF Wistar)                       (week 1)                 150         brain weight depression 4-5%          
                       6 h/day;         3 days                   375         (dose related) at 750 mg/m3;
                                        (week 2)                 750         additionally, marked growth retardation;
                                                                             tremors, motor incoordination; liver
                                                                             weights decreased by 26%; no distinct
                                                                             microscopic changes in eight organs (but
                                                                             lungs of three high-dose rats were
                                                                             hyperaemic)

    Rat                6 (male)         6 h/day; 5 days/week       0         no toxic effects;                              NTP (1992)
    (SPF Wistar)       6 (female)       (week 1,2,3)              70         no toxic effects (marginal no-effect level);   (Dutch 
                                        6 h/day; 7 days/week     200         decrease in feed consumption, decrease         Study)
                                        (week 4)                             in body weight gain; 
                                                                             disturbed gait and tremors;
                                                                 600         histopathological changes in heart
                                                                             and lungs, 8 rats died before end
                                                                             of study

    Rat                10 (male)        6 h/day; 5 day/week;       0         no deaths; no clinical findings; no            Wilmer et 
    (Wistar)           10 (female)      13 weeks                   4         change in body weight                          al. (1983)
                                                                  25
                                                                 166         minimal changes in liver
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
    Rat                10 (male)        6 h/day; 5 days/week;    599         depression of body weight gain                 Japanese Ministry
    (F344/DuCrj)       10 (female)      2 weeks                              in females;                                    of Labour (1992)
                                                                             Pathology: disarrangement and
                                                                             respiratory metaplasia of the
                                                                             olfactory epithelium

                                                                 778         depression of body weight gain;
                                                                             Pathology: disarrangement and respiratory
                                                                             metaplasia of the olfactory epithelium
                                                                             of the nasal cavity, cellular
                                                                             vacuolization in the adrenal glands

                                                                1011         depression of body weight gain;
                                                                             Clinical signs: piloerection, soiled,
                                                                             bloody nose discharge;
                                                                             Pathology: disarrangement, necrosis and
                                                                             respiratory metaplasia of the olfactory 
                                                                             epithelium of the nasal cavity, vacuolic 
                                                                             change of the adrenal glands, myocardial 
                                                                             damage

    Rat                10 (male)        6 h/day; 5 days/week;   1315         70% mortality in males and 10% mortality       Japanese Ministry
    (F344/DuCrj)       10 (female)      2 weeks                              in females;                                    of Labour (1992)
    (continued)                                                              Dead mice: depression of body weight gain;       (continued)
                                                                             Clinical signs: decrease in locomotor
                                                                             movement, soiled, piloerection, lacrimation,
                                                                             serous or bloody nose discharge, diarrhoea, 
                                                                             pallor, irregular breathing;
                                                                             Dead and surviving mice: decrease in 
                                                                             locomotor movement, hunched posture, soiled, 
                                                                             piloerection, haemorrhagic discharge of nose, 
                                                                             lacrimation
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             Pathology: interstitial pneumonia, 
                                                                             karryorrhexis of of the thymus, 
                                                                             myocardial damage, cellular vacuolization
                                                                             of the adrenal glands, disarrangement and
                                                                             respiratory metaplasia of the olfactory 
                                                                             epithelium

                                                                1712         100% mortality;
                                                                             Clinical signs: same as 338 ppm group dead 
                                                                             rats;
                                                                             Pathology: congestion and haemorrhage of
                                                                             the lung, congestion, necrosis, and fatty
                                                                             changes in the liver, tubular necrosis of
                                                                             the kidney, myocardial necrosis, haemorrhage,
                                                                             necrosis and cellular vacuolization of the 
                                                                             adrenal glands, necrosis and
                                                                             respiratory metaplasia of the olfactory
                                                                             epithelium, congestion of the thymus,
                                                                             inflammation of the bone marrow

    Rat                10-12 (male)     4 h/day; 6 weeks         584         decrease in body weight,                       Kato et 
    (Sprague-                                                                no clinical changes;                           al. (1986)
    Dawley)                                                      778         decrease in body weight,
                                                                             no clinical changes;
                                                                1167         3/12: paralysis of hindlimbs;
                                                                1556         5/10: ataxia after 2 weeks, paralysis 
                                                                             after 3 weeks, 1/10: died after 4 weeks,
                                                                             3/10: died after 5 weeks;
                                                                             Haematology: no change in RBC, Hb, Hct, WBC
                                                                             1167 mg/m3 group: increase in serum enzyme 
                                                                             activities;
                                                                                                                                             


    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             Organ weights: decrease in all groups, but 
                                                                             no clear dose dependency;
                                                                             Residual bromide: increase in all groups
                                                                             584 mg/m3: spleen>kidney>liver;
                                                                             higher dosage groups: kidney>spleen>liver;
                                                                             Histopathological changes: in brain, heart
                                                                             and testes

    Rat                5 (male)         3 weeks                    4         biochemical changes                            Sato et 
    (Sprague-                                                     20                                                        al. (1985)
    Dawley)                                                       39

    Rat                10 (male)        6 h/day; 5 days          350         no observable effects;                         Hurtt et  
    (F-344)                                                      680         dose-dependent vacuolar degeneration           al. (1987)
                                                                             of zona fasciculata (adrenal gland),
                                                                             cerebellar granular cell degeneration 
                                                                             and olfactory sensory cell degeneration;
                                                                 973         as above, plus: diarrhoea, haemoglobinuria, 
                                                                1264         some gait disturbances and convulsions;
                                                                             hepatocellular degeneration (at 1264
                                                                             mg/m3 only) - cerebral cortical degeneation
                                                                             ation and minor alterations in testicular
                                                                             histology

    Rat                total 84         6 h/day; 5 days          778         increase in mean body weight;                  Hurtt et al. (1988)
    (F-344)            (male)                                                degeneration and regeneration
                                                                             of olfactory epithelium

                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
    Rat                40 (male);       6 h/day; 5 days          778         decrease in plasma testosterone                Hurtt & Working
    (F-344)            10 (male)                                             concentration and nonprotein sulfhydryl        (1988)
                       killed on                                             contents of liver and testis
                       each of day                        
                       1,3,5 and 8                        

                       35 (male);       6 h/day; 5 days        
                       5 killed on                         
                       each of day 6,
                       10, 17, 24, 38,
                       52, 73

    Rat                5 (male)         6 h/day (3 days)         622         50 % mortality in males after 14 exp.          Eustis et 
    (F-344)            5 (female)                                            days; remaining males sacrificed;              al. (1988)
                                                                             females killed after 6 weeks;clear
                       5 + 10 (male)    6 h/day, 5 days/week                 sex-related differences in susceptibility
                       5 (female)       (2 weeks)                            of specific organs to CH3Br:brain, kidney,
                                                                             nasal cavity, heart, adrenal, liver, and 
                       10 (female)      6 h/day, 5 days/week                 testis; neuronal necrosis in cerebral cortex, 
                                        (6 weeks)                            hippocampus and thalamus of brain; necrosis of 
                                                                             olfactory epithelium; myocardial degeneration;
                                                                             testicular degeneration

    Rat                18               6 h/day; 5 day/week;       0         All dose groups: no deaths or clinical         Haber et al. 
    (F-344/N)          18 (female)      13 weeks                  117        signs; no consistent organ weight effects;     (1985) [abstract]
                                                                  234        * body weight (females)                        NTP (1990)
                                                                  467        * body weight (both sexes);
                                                                             minor neurobehavioural changes; (females)
                                                                             * Hct, * Hb, * RBC;
                                                                             olfactory epithelial dysplasia and cysts

                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
    Rat                36 (male)        6 h/day; 5 and           117         GSH and G-6-PDH activities: increase in        Jaskot et 
    (CD)                                10 days                              lung and decrease in liver;                    al. (1988)
                                                                             serum: decrease in cholinesterase, BUN,
                                                                             uric acid, cholesterol,
                                                                             increase in leucine amino-peptidase

    Rat                total 30         4 h/day; 4 days/week,    778         damage of olfactory epithelium;                Hastings 
    (Long-Evans)       (15 control)     2 weeks                              repair by day 4; impaired nasal                (1990)
                                                                             function recovered after 4 days

    Rat                10 (male)        6 h/day; 5 day/week;       0                                                        Japanese Ministry 
                       10 (female)      13 weeks                  29         no toxic effects                               of Labour
                                                                  73         Blood biochemistry: * K (male), ** total        (1992)
                                                                             cholesterol (female)
                                                                 183         Blood biochemistry: * in potassium (male)
                                                                             ** in total cholesterol, GOT, GPT (female)
                                                                 455         * of body weight gain
                                                                             Haematology: ** Hct, ** MCV, ** platelet 
                                                                             (male) ** MCV (female)
                                                                             Blood biochemistry: * K (male), ** total
                                                                             ** total cholesterol, GOT, GPT * glucose,
                                                                             creatinine (female)

    Rat                                                         1140         100% mortality;                                Japanese
    (continued)                                                              Clinical signs: * locomotor activity,          Ministry of Labour
                                                                             hunchback position, piloerection,              (1992) (continued)
                                                                             soiled, ataxic gait, tremor, convulsion,
                                                                             diarrhoea, loose stool or cyanosis,
                                                                             haematuria, serous or haemorrhagic
                                                                             discharge of nose, haemorrhagic discharge of
                                                                             eye, lacrimation, irregular breathing
                                                                                                                                             

    Table 48 (continued)
                                                                                                                                             
    Species/           No. of           Exposure time           Concentration        Observed effects                       Reference
    strain             animals/                                 (mg/m3)
                       exposure group
                                                                                                                                             
                                                                             pathology:  degeneration of the granular 
                                                                             layer of the cerebellum, necrosis of the 
                                                                             brain, karyorrhexis, haemorrhage and atrophy
                                                                             of the thymus, tubular necrosis of the kidney, 
                                                                             atrophy of the testis, foamy cell accumulation
                                                                             and interstitial pneumonia, myocardial damage,
                                                                             cellular vacuolization of the adrenal glands,
                                                                             pigmentation of the Harderian glands,
                                                                             necrosis, disarrangement and respiratory 
                                                                             metaplasia of the olfactory epithelium
                                                                                                                                             


    GSH = glutathione S-transferase; G-6-PDH = glucose-6-phosphate dehydrogenase; BUN = blood urea nitrogen;
    RBC = red blood cell count; exp. = exposure; p.c. = post copulation.
    * = decrease; ** = increase
    

         Histopathology showed degenerative cerebellar changes, renal
    tubular necrosis and regeneration, and metaplasia and necrosis of
    olfactory epithelium in all exposed groups. In male mice exposed to
    599 mg/m3, there were also stomach ulceration, testicular atrophy,
    atrophy of the spleen, and atrophy and karyorrhexis in the lymph
    nodes. At concentrations above 778 mg/m3, there were, also karyor-
    rhexis of the thymus, and myocardial necrosis. Hepatic degeneration
    and pulmonary congestion were found at 1315 and 1712 mg methyl
    bromide/m3. For further details see Table 48.

         B6C3F1 mice were exposed to methyl bromide concentrations of 0,
    39, 78, 156, 312, or 468 mg/m3 for 6 h per day on five days a week
    for 13 weeks (NTP, 1992). There were reductions in survival and body
    weight gain among male mice exposed to 468 mg/m3. No reduction was
    observed among males in the other groups or in female mice in any
    group. Clinical findings in the high-dose group were severe curling
    and crossing of the hindlimbs and twitching of the forelimbs. These
    signs were more severe among male than among female mice. Mild
    behavioural test response deviations reached a maximum after about 6
    weeks with no further increase in severity in the later 7 weeks of the
    study. Plasma cholinesterase activity was unaffected by treatment.  No
    exposure-related histopathological changes were described.

         BDF1 mice (groups 10 males/10 females) were exposed to methyl
    bromide at concentrations of 0, 29, 58, 117, 234, or 467 mg/m3 (0,
    7.5, 15, 30, 60, or 120 ppm) for 13 weeks, 6 h/day, and 5 days/week
    (Japanese Ministry of Labour, 1992). At 467 mg/m3, there was a
    mortality rate of 10% (males) and 90% (females). Ataxia was noted in
    mice exposed to 467 mg/m3. There were no abnormal clinical signs at
    concentrations of between 29 and 234 mg/m3. Slight increases in mean
    corpuscular volume (MCV) in female mice exposed to 234 mg/m3 and in
    male mice exposed to 467 mg/m3 were not accompanied by other
    haematological effects. Blood biochemistry showed no abnormalities. No
    treatment-related, histopathological effects were observed in the 29
    and 234 mg/m3 groups. In the mice that did not survive exposure to
    467 mg/m3, there were cerebellar degeneration and brain necrosis,
    pulmonary congestion, thymic atrophy, myocardial damage, renal tubular
    necrosis, and vacuolization of the adrenal glands (Table 49).


        Table 49.  Long-term exposure inhalation studies
                                                                                                                                     
    Species/  No. of            Exposure time    Concentration         Observed effects                           Reference
    strain    animals per                        (mg/m3)
              exposure group
                                                                                                                                     
    mouse     86 (male)         5 days/week;        0        All dose groups: no biologically significant         NTP (1992)
    (B6C3F1)  86 (female)       6 h/day;2 year     39        haematology values; no carcinogenic
              [planned;         (interim          128        effects; increased incidence of
              because of high   sacrifice at 6    389        nonneoplastic lesions in brain, bone, 
              mortality,        and 15 months)               heart, and nose
              regime altered]                                389 mg/m3 dosage group: high mortality
                                                             (40/86 males and 9/86 females) after 20
                                                             weeks; decrease in body weight and
                                                             in thymus weight;
                                                             tremors, abnormal posture and limb paralysis;
                                                             significant behavioural differences at 3
                                                             months (males), less so in females

    mouse     50 (male)         6 h/day; 5 days/    0                                                             Japanese
    (Crj:     50 (female)       week;              16        no toxic effects;                                    Ministry of
    BDF1)                       2 years            62        no toxic effects;                                    Labour (1992)
                                                  250        no mortality change;
                                                             depression of body weight gain
                                                             Blood biochemistry: increase in CPK, inorganic
                                                             phosphorus (male), chloride; decrease
                                                             in albumin (female);
                                                             Pathology: atrophy of the granular layer of
                                                             the cerebellum no increase in neoplastic change
                                                             was considered
                                                                                                                                     

    Table 49 (continued)
                                                                                                                                     
    Species/  No. of            Exposure time    Concentration         Observed effects                           Reference
    strain    animals per                        (mg/m3)
              exposure group
                                                                                                                                     
    rat       90 (male)         6 h/day; 5 days/    0        All dose groups: degenerative and                    Dreef-van der 
    (Wistar)  80 (female)       week; 29 months    12        hyperplastic lesions in nasal mucosa; no             Meulen et al. 
                                                  117        tumours induced by methyl bromide;                   (1989)
                                                  350        350 mg/m3 group: * body weight gain;                 Reuzel et al.
                                                             * absolute brain weight; hyperkeratosis in           (1991)
                                                             oesophagus and forestomach; ** incidence
                                                             of haemothorax, myocardial degeneration;
                                                             thrombi in the heart; and increased 
                                                             mortality

    rat       50 (male)         6 h/day; 5 days/   16        Pathology: ** incidence and severity of              Japanese
    (F344/    50 (female)       week; 2 years                inflammation of the nasal cavity (male);             Ministry of
    DuCrj)                                         78        Urinalysis: * in protein (male);                     Labour (1992)
                                                             Pathology: same as 16 mg/m3
                                                  389        no mortality change, * body weight gain;
                                                             Haematology: ** RBC, Hb, Hct (male)
                                                             ** Hb, Hct (female);
                                                             Blood biochemistry: * LDH, CPK, Na+, K+,
                                                             Cl- (male), * Glu, CPK, Ca2+, ** LAP (female);

    rat                                                      Urinalysis: * protein
    (F344/DuCrj)                                             Pathology: ** incidence of necrosis and
    (continued)                                              respiratory metaplasia of the olfactory
                                                             epithelium; ** incidence and severity of
                                                             inflammation of the nasal cavity (male);
                                                             marginal ** necrosis of the olfactory
                                                             epithelium and inflammation of the nasal
                                                             cavity (female);
                                                             no increase in neoplasms observed
                                                                                                                                     

    Table 49 (continued)
                                                                                                                                     
    Species/  No. of            Exposure time    Concentration         Observed effects                           Reference
    strain    animals per                        (mg/m3)
              exposure group
                                                                                                                                     
    rat       8                 6 h/day; 5 days/    0        no effect on nerve conduction velocity,              Anger et al. 
    (Sprague- 32 (n.g.)b        week; 36 weeks    214        open field activity, or coordination                 (1981)
    Dawley)                     over 12 months

                                                                                                                                     

    a RBC = red blood count; Hb = haemoglobin; Hct = haematocrit; WBC = white blood count; MCV = mean cell volume.
    b n.g.= sex not given;  * = decrease; ** = increase.
    

    8.2.2.3  Rat

         F344-rats (groups 10 males/10 females) were exposed to methyl
    bromide at concentrations of 599, 778, 1011, 1315, or 1712 mg/m3
    (154, 200, 260, 338, or 440 ppm) 6 h/day, 5 days/week, for 2 weeks
    (Japanese Ministry of Labour, 1992). All rats in the 1712 mg/m3
    group and 7 males and one female in the 1315 mg/m3 group died before
    the end of the study. Piloerection and haemorrhagic nasal discharge
    were reported at exposure concentrations of 1011, 1315, and 1712
    mg/m3. In addition, decreased locomotor activity, a hunched position
    and lacrimation were observed in rats that survived exposure to 1315
    mg/m3. Diarrhoea and irregular breathing were noted in the rats that
    died following exposure to 1315 and 1712 mg/m3.

         Pathology showed metaplasia of the olfactory epithelium at methyl
    bromide concentrations of 599 and 778 mg/m3, plus necrosis at
    concentrations between 1011 and 1712 mg/m3. Vacuolization of the
    adrenal glands was found at concentrations of 778, 1011, and 1315
    mg/m3 with necrosis at 1712 mg/m3. Myocardial damage was reported
    at concentrations between 1011 and 1712 mg/m3. In the rats exposed
    to 1315 and 1712 mg/m3, there was also pulmonary congestion and
    haemorrhage, renal tubular necrosis and congestion of the thymus; bone
    marrow inflammation was reported at 1712 mg/m3 (Table 48).

         Two short-term range finding studies were conducted in SPF Wistar
    rats (NTP, 1992). In the first study, groups of six male rats were
    exposed to up to 750 mg methyl bromide/m3 for 6 h/day for 2 weeks
    (see Table 48). In the second range-finding study, groups of six male
    and six female rats were exposed to up to 600 mg methyl bromide/m3
    for 4 weeks. Five male and three female rats in the high-dose group
    died before the end of the study. The most important histopathological
    changes occurred in the heart and lungs of animals in the high-dose
    group. Diffuse fatty vacuolization and diffuse myocardial fibre
    degeneration appeared. The lungs showed hyperaemic and dilated
    alveoli; in some animals, interstitial pneumonia was noted (NTP,
    1992).

         Male Sprague-Dawley rats were exposed to up to 1556 mg methyl
    bromide/m3 for 4 h/day for 6 weeks (Kato et al., 1986). Changes in
    body weight, general condition, haematology parameters, organ weight,
    tissue bromide ion concentration, and the histopathology of several
    organs were determined. Suppression of body weight gain, abnormal
    clinical signs, and severe weakness were observed at 1556 mg methyl
    bromide/m3. Bromide ion accumulation was seen, especially in the
    kidney and spleen, without significant dose-related change. Pronounced
    histopathological changes were noted in the brain (section 8.8) and
    multiple small necrotic foci in the heart.

         Other short-term, inhalation exposure studies concentrated on one
    aspect/target organ of methyl bromide exposure.

         Sato et al. (1985) described biochemical findings in rats exposed
    to 4, 20, or 39 mg methyl bromide/m3, continuously, for 3 weeks.
    After sacrifice, the organs were weighed and biochemical examinations
    were performed on the blood and a homogenate of heart, liver, and
    lungs. The results showed no differences between the 4 mg/m3 and the
    control group. In the 20 mg/m3 group, several changes were observed;
    serum creatine phosphokinase (CPK), phospholipids (PL), and blood
    glucose levels, and thymus weight decreased, while blood haemoglobin
    (Hb), reduced glutathione (GSH), serum total protein, and lung
    gamma-glutamate-pyruvate transaminase (GTP) levels increased after
    exposure. In the 39 mg/m3 group, increases were observed in serum
    glutamate oxaloacetate transaminase (GOT), lactate dehydrogenase
    (LDH), alpha-hydroxy-butyrate dehydrogenase (alpha-HBDH), total
    protein, blood Hb, GSH, lung acid phosphatase (AcP), gamma-GTP, LDH
    total, liver PL, and triglycerides (TriG), while decreases were noted
    in serum cholinesterase (ChE), CPK, PL, TriG, lung alkaline
    phosphatase (AlP), free-cholesterol (f-Chol), lactate, blood glucose,
    heart lactate, glucose, lung AlP, liver free fatty acids (FFA), and
    glycogen. Pulmonary haemorrhage was observed in almost all animals in
    this group. 

         The effects of short-term inhalation exposure to 1264 mg methyl
    bromide/m3 (6 h/day for 5 days) including those on the target organ
    histopathology of male F-344 rats were studied by Hurtt et al. (1987).
    Clinical changes (noted only in the 973 and 1264 mg/m3 groups) were
    diarrhoea, haemoglobinuria, and, in a few cases, gait disturbances and
    convulsions. A dose-dependent vacuolar degeneration of the zona
    fasciculata of the adrenal glands, cerebellar granule cell
    degeneration, and olfactory sensory cell degeneration were seen in the
    680, 973, and 1264 mg/m3 groups. Cerebral cortical degeneration and
    minor alterations in testicular histology were seen only in the 1264
    mg/m3 group whereas hepatocellular degeneration was also found in
    the 973 mg/m3 group. No changes were found in the kidneys or
    epididymides.

         In a further study, the degeneration and regeneration of the
    olfactory epithelium were examined following exposure of a total of 84
    rats to 778 mg methyl bromide/m3 for 6 h/day for 5 days (Hurtt et
    al., 1988). Groups of five rats were sacrificed after days 1, 3, and
    5 and after exposure weeks 1, 2, 3, 5, and 10. Cell replication rate
    and histopathology were used to assess the kinetics of repair. In
    addition, olfactory function was assessed using a buried food test.
    Extensive damage to the olfactory epithelium was evident in animals
    killed directly after 6 h of exposure. The specific site of damage
    appeared to be in the olfactory sustentacular cells and mature sensory
    cells, the basal cells generally being unaffected. By day 3, despite
    continuous exposure, there was replacement of the olfactory epithelium
    by a squamous cell layer that increased in thickness and basophilic
    staining over the next 2 days. One week after exposure, the epithelial
    region was covered by a layer of polyhedral, basophilic cells and from
    2 to 10 weeks exposure, the epithelium exhibited progressive

    reorganization to restore the original olfactory epithelium pattern;
    75-80% of the olfactory epithelium appeared morphologically normal by
    week 10.

         In the same study, the ability of the rats to locate feed was not
    affected by exposure to 350 mg methyl bromide/m3, but treatment with
    778 mg methyl bromide/m3 rendered all animals temporarily incapable
    of locating buried pellets, though they demonstrated searching
    activity. Four to six days after treatment the animals recovered
    sufficient olfactory function to find food pellets.

         Similar results were reported by Hastings et al. (1989) and
    Hastings (1990). Studies on Long-Evans rats showed that, after 4 h
    exposure to methyl bromide (778 mg/m3), recovery of buried food was
    greatly impaired but, even with continuous exposure, recovery occurred
    until, by day 4 of exposure, olfactory function was essentially
    normal. Extensive damage to the olfactory epithelium was evident after
    day 1 of exposure; repair of the epithelium was in progress by day 4.
    The specific site of damage appeared to be in the olfactory
    sustentacular cell population while the respiratory epithelium was
    largely spared (Hastings et al.,1989; Hastings, 1990). Bolon et al.
    (1990) suggested that prior exposure to methyl bromide as well as
    caging conditions (e.g., inhalation of ammonia from soiled bedding)
    could influence the olfactory epithelial response.

         Evans & Hastings (1992) reported that methyl bromide induced an
    olfactory function deficit in rats. The olfactory threshold to ethyl
    acetate was measured in six rats using a conditioned suppression
    behavioural protocol. Three out of the six rats showed an increase in
    absolute threshold or threshold response variability after a single,
    6-h exposure to 778 mg methyl bromide/m3.

         F-344 rats (20 male + 20 female) were exposed (6 h/day; 5
    days/week) to 0 or 622 mg methyl bromide/m3 (0 or 160 ppm) for 3,
    10, or 30 days (Eustis et al., 1988). Toxicological end-points
    assessed included clinical observations, mortality, body and organ
    weights, haematology, clinical chemistry, urinalysis, gross pathology,
    and histopathology. There were no apparent treatment- related changes
    in any of the clinical chemistry and urinalysis analytes measured.
    Treatment-related effects in rats included neuronal necrosis in the
    brain, myocardial degeneration, olfactory epithelial degeneration and
    atrophy, and testicular degeneration and atrophy.

         A study by Eustis et al. (1988) confirmed the very steep
    concentration-response curve for methyl bromide in rats (and mice).
    The authors also found clear species and sex differences in
    sensitivity to methyl bromide toxicity. When rats were compared with
    mice, the order of susceptibility was female mice>male mice>male
    rats> female rats. Species and sex-related differences in the
    histopathology of certain organs were also observed.

         Kato et al. (1986) exposed Sprague-Dawley rats for 11 weeks, 4
    h/day, to 584 mg methyl bromide/m3. No abnormal clinical signs were
    reported. Small necrotic foci and fibrosis were observed in the heart
    muscle.

         F-344 rats (groups 10 males/10 females) were exposed to methyl
    bromide at concentrations of 0, 29, 73, 183, 455, or 1140 mg/m3 (0,
    7.5, 18.8, 46.9, 117, or 293 ppm) for 13 weeks for 6 h/day, 5
    days/week (Japanese Ministry of Labour, 1992). At 1140 mg/m3, there
    was 100% mortality. At this concentration of methyl bromide, rats
    exhibited decreased locomotor activity, piloerection, ataxia, tremor,
    cyanosis, haematuria, and nasal and ocular discharge. No clinical
    signs were reported at lower doses.

         Haematological studies showed increased MCV in male and female
    rats exposed to 455 mg/m3; there was also an increased number of
    platelets in the male rats. Serum potassium was decreased in male rats
    exposed to concentrations of 73 mg/m3 or more. Glutamic oxalacetic
    transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels were
    significantly increased in female rats exposed to concentrations of
    183, 455, and 1140 mg/m3. Serum glucose and creatinine levels were
    significantly decreased in female rats at 455 mg/m3.

         There were no abnormal histopathological findings in rats exposed
    to methyl bromide concentrations of between 29 and 455 mg/m3. Rats
    exposed to 1140 mg/m3 exhibited cerebellar degeneration and brain
    necrosis, thymic haemorrhages and atrophy, renal tubular necrosis,
    pneumonitis, myocardial damage, adrenal vacuolization, Harderian gland
    pigmentation and metaplasia, and necrosis of the olfactory epithelium
    (Table 49).

         Thirteen-week inhalation toxicity studies were conducted in which
    groups of ten male and ten female Wistar rats were exposed to methyl
    bromide at target concentrations of up to 166 mg/m3 for 6 h/day, 5
    days/week (Wilmer et al., 1983). No deaths occurred, and no abnormal
    clinical findings were observed. Body weight gain was not affected in
    any of the exposed groups. Leukocyte counts were 22% higher in high-
    dose males than in male control animals. Plasma alkaline phosphatase
    activity was lower in both high-dose males (32%) and females (53%)
    than in controls, and the plasma albumin concentration was 10% higher
    in high-dose females than in controls. The absolute and relative liver
    weights were up to 16% lower for high-dose males and females compared
    with controls. The only exposure-related histopathological change,
    which occurred in the liver of high-dose male and female rats, was
    characterized by small hepatocytes with homogeneous eosinophilic
    cytoplasm. This alteration varied in extent from slight to severe and
    was seen in 6/10 males and 7/10 females. The no-adverse-effect level
    for these 13-week inhalation toxicity studies was considered to be 25
    mg/m3.

         Groups of 18 rats of each sex were exposed to up to 467 mg/m3
    for 6 h/day and 5 days/week over 13 weeks (NTP, 1992). All rats
    survived to the end of the studies, few or no clinical effects of
    exposure to methyl bromide could be seen. Significant decreases in
    body weight gain were noted in both sexes at 467 mg/m3 and in
    females at 234 mg/m3. No consistent organ weight effects were
    observed. Minor neurobehavioural changes were noted in both sexes in
    the highest dosage group. Females, but not males, of this group had
    significantly lower haematocrit, haemoglobin levels, and erythrocyte
    counts compared with those of controls. Olfactory epithelial dysplasia
    and cysts, characterized by irregularity in mucosal thickness and
    focal cavitated spaces, respectively, were seen in both sexes at 467
    mg/m3.

    8.2.3  Dermal

         There are no reports of studies on short-term dermal exposure.

    8.3  Skin and eye irritation

         Irish et al. (1940) noticed lacrimation in rats after inhalation
    of methyl bromide levels above 10 000 mg/m3. Irritation of the eye
    membranes in mice at concentrations of 3200 mg methyl bromide/m3 was
    described by Balander & Polyak (1962). There are no reports on skin
    effects in animals.

    8.4  Long-term exposure

    8.4.1  Oral

    8.4.1.1  Rat

         Rats were fed for 7-8 months on wheat grain or peanuts fumigated
    with methyl bromide having residual bromide levels of 20 and 22-46
    mg/kg, respectively. There were no effects on weight gain of the
    animals, haemoglobin content, or red or white blood cell numbers.
    However, a decrease in iodine and calcium levels in the blood and
    abnormal changes in the thyroid and parathyroid glands were reported
    (Vitte et al., 1970).

         A two-year, oral, long-term toxicity and carcinogenicity study
    was carried out on 60 male and 60 female F-344 rats per group fed
    diets fumigated with methyl bromide (Mitsumori et al., 1990). Diets
    containing 80, 200, or 500 mg total bromide/kg food (methyl bromide
    concentration <20 mg/kg food) were fed, the controls receiving
    commercial basal diet (containing 30 mg bromide/kg) and a diet
    containing 500 mg potassium bromide/kg. No effects were observed on
    the behaviour of the rats in any of the groups fed the fumigated or
    KBr- containing diets. In rats fed the diets fumigated with methyl
    bromide, there were no marked toxic changes, except for a slight
    depression in body weight from week 60 onwards in males in the 500

    mg/kg group. Tumour incidence was unaffected. Rats given a diet
    containing KBr did not show any treatment-related changes. The
    no-effect level was 200 mg/kg (equivalent to 6.77 mg total bromine/kg
    body weight per day) in males. No effects were observed in females at
    the doses studied.

    8.4.2  Inhalation studies

         Long-term exposure inhalation studies are summarized in Table 49.

    8.4.2.1  Mouse

         In a carcinogenicity study, 86 B6C3F1 mice/sex were exposed to
    39, 128, or 389 mg methyl bromide/m3 for 6 h/day, 5 days/week, for
    2 years with scheduled interim sacrifices at 6 months and 15 months
    (NTP, 1992). Because of the high mortality early in this study in the
    389 mg/m3 group (27/86 males, 7/86 females), the exposure to methyl
    bromide at this level was stopped at 20 weeks and the surviving mice
    were exposed to air for the rest of the study.

         Terminal survival rates (Kaplan-Meier determinations) in the
    control, 39 mg/m3, 128 mg/m3, and 389 mg/m3 groups were: males
    82%, 74%, 80%, and 23%; and females, 71%, 82%, 90%, and 65%,
    respectively. Significantly lower mean body weights of the highest
    dosage group compared with controls appeared by week 11 and persisted
    after termination of dosing at week 20 until the end of the studies.
    The only biologically significant change appeared to be reduced
    absolute and relative thymus weights in both sexes. Neurological signs
    were also observed, mostly in the highest dosage group, including
    tremors, abnormal posture (lateral curvature of the spine), and limb
    paralysis. These symptoms generally persisted (NTP, 1992).
    Exposure-related histological lesions occurred primarily in the 389
    mg/m3 exposure group and included degeneration in the cerebellum,
    cerebrum and heart, chronic cardiomyopathy, sternal dysplasia, and
    either necrosis or metaplasia of the olfactory epithelium. There were
    no neoplasms attributed to exposure to methyl bromide.

         Quantitative neurobehavioural testing showed significant
    differences in the behaviour of the high-dose males at 3 months. The
    animals were less active and demonstrated a reduction in startle
    response latency. Because of the high early mortality in high-dose
    males, only males in the controls and two lower dosage groups were
    tested after 3 months. After 6 months of exposure, the 389 mg/m3
    females had significantly lower activity scores than females in other
    groups, but their higher startle responses had disappeared. Although
    at 9 months of exposure no behavioural differences were apparent,
    lower activity and heightened startle response were again noted at the
    2-year testing time (NTP, 1992).

         Toxicity and carcinogenicity studies were conducted by inhalation
    exposure of groups of 50 male and 50 female Crj:BDF1 mice (6 h/day, 5

    days/week) to methyl bromide (99.9% pure) for 104 weeks (Japanese
    Ministry of Labour, 1992). Methyl bromide concentrations of 0, 16, 62,
    and 250 mg/m3 were used.

         Body weight gains in male and female mice exposed to 250 mg/m3
    were lower than those in chamber controls. No significant differences
    in survival were observed between exposed and control groups of either
    sex. Increased incidences of atrophy (slight) of the granular layer of
    the cerebellum were observed in male and female mice exposed to 250
    mg/m3. There were no treatment-related neoplasms in male or female
    mice.

    8.4.2.2  Rat

         Toxicity and carcinogenicity studies were also conducted by
    inhalation exposure to methyl bromide (99.9% pure) of groups of 50
    male and 50 female F344/DuCrj rats (6 h/day, 5 days/week) for 104
    weeks (Japanese Ministry of Labour, 1992). Methyl bromide
    concentrations of 0, 16, 78, and 389 mg/m3 were used. Body weight
    gains in males and female rats exposed to 389 mg methyl bromide/m3
    were lower than those in chamber controls. No significant differences
    in survival were observed between exposed and control groups of either
    sex. Increased incidences of necrosis and respiratory metaplasia of
    the olfactory epithelium of the nasal cavity were observed in male
    rats exposed to 389 mg methyl bromide/m3, and increased incidence
    and severity of inflammation of the nasal cavity were observed in male
    rats exposed at all concentrations used. Necrosis of the olfactory
    epithelium and inflammation of the nasal cavity were marginally
    increased in female rats exposed to 389 mg methyl bromide/m3. There
    were no exposure-related increased incidences of neoplasms in male and
    female rats.

         In a long-term inhalation study, a total of 360 male and 360
    female rats (Wistar) were exposed to concentrations of up to 350 mg
    methyl bromide/m3 for 6 h/day, 5 days/week for 29 months (Dreef-van
    der Meulen et al., 1989; Reuzel et al., 1991). Non-neoplastic and
    neoplastic lesions were scored in all control and high-level animals
    of the main group, and the nose examined histopathologically at all
    exposure levels. Mortality was higher in males and females at the 350
    mg/m3 level than in controls from the end of the second year
    onwards. Body weights in the 350 mg/m3 group (both sexes) were
    slightly lower than controls from week 4 onwards. No essential
    differences between groups were observed in haematology, clinical and
    blood chemistry, and urine analysis at three months and one year. The
    absolute brain weight was decreased in females at 350 mg/m3. A
    higher incidence of haemothorax was seen in males and females at 350
    mg/m3 than in controls. In the heart there was an increased
    incidence of thrombi and myocardial degeneration in rats exposed to
    350 mg/m3. There was hyperkeratosis of the oesophagus and
    forestomach. The incidences of neoplastic lesions did not differ
    significantly among the groups.

    8.5  Reproduction, embryotoxicity, and teratogenicity

    8.5.1  Reproduction and embryotoxicity

         McGregor (1981) conducted a sperm abnormality assay exposing
    groups of 10 male B6C3F1 mice to air containing 0, 78, or 272 mg
    methyl bromide/m3 (0, 20, or 70 ppm) for 7 h/day, for 5 days. No
    sperm abnormalities were found at these concentrations.

         Atrophy of seminal epithelium, incomplete spermatogenesis, and
    giant cells in the seminal tubules, were detected unilaterally in one
    rat (group of 10) after inhalation of 778 mg methyl bromide/m3 (200
    ppm) (4 h/day; 5 days/week for 6 weeks) and in six rats (group of 10)
    after inhalation of 1167 mg methyl bromide/m3 (same length of
    exposure). In the tubules of the epididymis adjacent to the atrophied
    testis, necrotic spermatocytes had accumulated in seminal fluid, but
    spermatozoa were not seen (Kato et al., 1986).

         Spermatogenesis and sperm quality were evaluated in the rat
    (F-344/N) following exposure to 778 mg methyl bromide/m3, 6 h/day
    for 5 days (Hurtt & Working, 1988). Although methyl bromide caused a
    transient decrease in plasma testosterone and testicular nonprotein
    sulfhydryl concentrations during acute exposure, no other reproductive
    indices, including testis weight, daily sperm production, cauda
    epididymal sperm count, sperm morphology, percentage motile sperm,
    linear sperm velocity, and epididymal and testicular histology, were
    affected by methyl bromide exposure.

         Testicular degeneration and atrophy occurred in several rats and
    mice following repeated (6 h/day, 5 days/week for up to 6 weeks)
    inhalation exposure to 622 mg methyl bromide/m3 (Eustis et al.,
    1988). In rats, degeneration included separation and sloughing of
    spermatocytes and late stage spermatids and/or formation of
    intratubular multinucleate giant cells. Atrophy was characterized by
    variable loss of all components of the spermatogenic epithelium. In
    exposed mice, degeneration of testes occurred frequently, but it was
    not always severe.

         Thirteen-week inhalation studies on sperm morphology and vaginal
    cytology examinations (SMVCEs) in B6C3F1 mice and F-344 rats were
    carried out by Morrissey et al. (1988). Results from mouse studies
    (inhalation of 39, 156, or 467 mg methyl bromide/m3) showed a
    decrease in terminal body weight, and a relative increase in the
    weight of epididymis and testis. A decrease in sperm density and an
    increase in the percentage of abnormal sperm were also noted. In rats
    that inhaled 117, 233, or 467 mg methyl bromide/m3, a decrease in
    terminal body weight as well as a decrease in the weight of the cauda
    epididymis, and a relative increase in the weight of the testis were
    noted. A decrease in sperm motility was also observed. In females,
    exposure to methyl bromide did not affect the length of the estrous
    cycle (Morrissey et al., 1988).

         Female rats exposed to 272 mg methyl bromide/m3 (70 ppm) for up
    to 40 days survived and reproduced without impairment (Hardin et al.,
    1981; Sikov et al., 1981).

         In a dominant lethal assay carried out in rats (McGregor, 1981),
    groups of 10 male, adult CD rats were exposed to 0, 78, or 272 mg
    methyl bromide/m3 for 7 h/day on five consecutive days, then
    serially mated at weekly intervals for 10 weeks with untreated virgin
    females in the ratio one male: two females. When the females were
    sacrificed, their ovaries were examined for corpora lutea graviditatis
    and the uteri were opened and examined for live implantations, late
    deaths, and early deaths. The frequency of pregnancy was determined by
     (a) females with corpora lutea graviditatis and  (b) females with
    implantations. With either method, methyl bromide did not cause a
    significant decrease in the frequency of pregnancy, and the number of
    corpora lutea per pregnancy and the frequency of early deaths were
    unaffected.

         The effects of inhalation exposure to 0, 12, 117, or 350 mg
    methyl bromide/m3 for 6 h/day, 5 days/week, for around 8 months, on
    the growth, reproduction, and offspring in two consecutive generations
    of CD Sprague-Dawley rats were investigated (American Biogenics
    Corporation, 1986). Body weight depressions were noted in the males in
    the highest concentration group at 5 of the 10 pre-mating collection
    intervals and at final sacrifice. The pre-mating and total weight
    gains were also less than those of the untreated control males. In the
    F1 generation, parental body weight was comparable in exposed and
    control animals. In the F2a litter, a slight body weight depression
    was noted in gestating and lactating dams in the highest concentration
    group compared with controls. Otherwise, maternal body weights were
    comparable with those of the controls.

         There was a marginal reduction in female fertility index in the
    two top dose groups of the F2a litter. The mean numbers of pups
    delivered viable were comparable with controls. Survival of the pups
    was reduced in the 350 mg/m3 dose group in late lactation in the F1a
    generation. Body weights of pups were reduced in both the 350 and 117
    mg methyl bromide/m3 dose groups of the F1a, F2a and F2b
    generations, though no consistent changes were observed in the F1b
    generation.

         No anomalies were noted in the treated progeny that were
    attributed to methyl bromide exposure.

         Gross pathological examination of parent animals from both
    generations and randomly selected F1b and F2b progeny did not reveal
    any treatment-related lesions. A statistically significant decrease in
    the mean brain weight in the F0 males and an increased liver to body
    weight ratio in both sexes were found in the upper concentration
    group. In the F1 generation, both male and female brain weights were
    decreased at 350 mg methyl bromide/m3.

         Statistical analyses of the F1b progeny final body weight and
    organ weight data revealed no significant differences. Statistical
    reductions were found in the final body weight data obtained for the
    F2b males (350 mg methyl bromide/m3) and F2b females (117 and 350 mg
    methyl bromide/m3) compared with untreated control progeny. Analysis
    of F2b progeny organ weight data revealed significant decreases,
    compared with controls, for the female brain, heart, kidney, and liver
    weights (350 mg methyl bromide/m3) and female liver weight (117 mg
    methyl bromide/m3). In these two upper concentration groups, the
    females brain to body weight ratio was increased and the liver to
    brain ratio, decreased. Microscopic examination of the reproductive
    organs and abnormal tissues did not reveal any treatment-related
    lesions.

    8.5.2  Teratogenicity

         Female Wistar rats were exposed for 7 h/day, 5 days/week for 3
    weeks to methyl bromide concentrations of 78 or 272 mg/m3. After
    this time, they were mated. There was a total of 7 different exposure
    groups (Table 48). Female rats whose vaginal smears showed evidence of
    sperm were exposed for 7 h daily from day 1 (=day of finding sperm in
    vaginal lavage) to 19 of gestation. The day before term (gestation day
    21), they were sacrificed and necropsied. The results showed no
    effects of the exposure on the female rats, nor were embryotoxic or
    other teratogenic effects found (Sikov et al., 1981).

         In a further series of studies by Sikov et al. (1981), groups of
    24 female New Zealand white rabbits were exposed for 7 h daily to 78
    or 272 mg methyl bromide/m3 (20 or 70 ppm) from the day of
    artificial insemination. The 78 mg/m3 group was exposed up to day 24
    of gestation; ecause of toxic effects, exposure had to be stopped on
    day 15 for the 272 mg/m3 group, in which all but one pregnant rabbit
    died. The remaining rabbits from the control and 78 mg/m3 exposure
    group were sacrificed on the 30th day of gestation. The low exposure
    group showed no fetotoxic or eratogenic effects. An evaluation of the
    fetotoxicity or teratogenic results from the high dose group was not
    possible because of the high mortality rate in the pregnant rabbits
    (Hardin et al., 1981; Sikov et al., 1981).

         In a preliminary teratology study (Breslin et al., 1990),
    pregnant New Zealand White rabbits were exposed via inhalation for 6
    h/day to 0, 39, 117, 195, 272, or 545 mg methyl bromide/m3 (0, 10,
    30, 50, 70, or 140 ppm). Toxicity was observed in rabbits exposed to
    545 mg methyl bromide/m3 and these were sacrificed before the end of
    the study. No apparent embryotoxic effects were observed at any
    exposure level (Breslin et al., 1990).

         A subsequent study by the same investigators was conducted in two
    parts. In Part I, groups of 26 inseminated New Zealand White rabbits
    were exposed via inhalation to 0, 78, 156, or 311 mg methyl
    bromide/m3 (0, 20, 40, or 80 ppm) on days 7-19 of gestation. In Part

    II, groups of 17 inseminated rabbits were exposed for 6 h/day to 0 or
    311 mg methyl bromide/m3 (0 or 80 ppm) on days 7-19 of gestation. An
    additional group of 16 females, inseminated by a single male, acted as
    controls. On day 28 of gestation, all surviving animals were
    necropsied. Maternal liver, kidney, lung, brain weights, gravid
    uterine weights, and the number of corpora lutea, implantations,
    resorptions, and live/dead fetuses were noted. The fetuses were
    weighed, sexed, and examined for external, visceral, and skeletal
    alterations.

         Rabbits exposed to 311 mg methyl bromide/m3 showed moderate to
    severe maternal toxicity. Decreased body weight and/or body weight
    gain were noted. Clinical alterations included lethargy, right-sided
    head tilt, ataxia, and lateral recumbency. The last three signs were
    associated with significant histopathological lesions of the brain
    (multifocal areas of inflammation of the meninges and/or bilaterally
    symmetrical necrosis or spongiosis in the midbrain) in the
    above-mentioned probe study with 545 mg methyl bromide/m3. At an
    exposure level of 311 mg methyl bromide/m3, developmental effects
    were observed consisting of decreased fetal weights, an increase in
    the incidence of fused sternebrae, and an increase in the incidence of
    malformations [18/23] (mostly missing gallbladder or missing caudal
    lobe of the lung).

         No adverse maternal, embryonal, or fetal effects were observed in
    rabbits exposed to 78 or 156 mg methyl bromide/m3 (Breslin et al.,
    1990).

         Methyl bromide at 0, 0.5, 5, 25, or 50 mg/kg body weight was
    administered in peanut oil, by gavage, to pregnant rats on days 5-20
    of gestation (Peters et al., 1982). Signs of maternal toxicity were
    evident in the two highest dose groups. Total resorption of embryos
    was observed in the highest dose group and was considered to be the
    result of the poor health of the pregnant rats and not a primary toxic
    effect. In the control and 25 mg/kg groups, no effects on the skeleton
    or internal organs were reported. In this study, methyl bromide was
    not considered teratogenic and adverse effects on prenatal development
    only occurred when maternal toxicity was present.

    8.6  Mutagenicity and related end-points

         Table 50 summarizes the results of tests for the genotoxic
    activity of methyl bromide.

    8.6.1  DNA damage

         DNA adducts have been demonstrated in F344 rats, following oral
    or inhalation administration 14C-methyl bromide. The adducts were
    isolated from liver, lung, stomach, and forestomach and identified as
    3-methylguanine, 7-methylguanine, and  0 6-methylguanine. Following
    exposure by either route, the levels of adducts were higher in female
    than in male rats and the guanine adducts were particularly prominent
    in the stomach and forestomach (Gansewendt et al., 1991).

         Alkylation of guanine-N-7 in the DNA of liver and spleen was
    observed after treatment of male CBA mice with 14C-labelled methyl
    bromide (4.9-5.0 mCi/mmol) by inhalation (340 mCi/kg body weight for
    4 h) or i.p. injection (4.4 µmol/kg body weight) (Djalali-Behzad et
    al., 1981). They noted that the extent of DNA alkylation in the liver
    and spleen  in vivo was 200 and 20 times lower, respectively, than
    expected from the extent of the alkylation of haemoglobin and from the
    relative reactivities of DNA and haemoglobin towards methyl bromide
     in vitro.


        Table 50.  Mutagenicity tests with methyl bromide
                                                                                                                                
    Test                Test system              Dose level,         Metabolic      Response                 Reference
                                                 concentration       activation
                                                                     presence/
                                                                     absence
                                                                                                                                
    Reverse mutation     Salmonella                0.02-0.2%           +/-            positive,                Simmon et al. 
                         typhimurium               (in desiccators)                   TA 100                   (1977)
                        TA 100, TA 98,
                        TA 1535, TA 1537,2 h
                        TA 1538

    Reverse mutation     Salmonella                500-5000 mg/m3,     +/-            positive,                Moriya et al. 
                         typhimurium               2 days                             TA 100,                  (1983)
                        TA 100, 1535
                        TA 98, 1537, 1538                                           TA 1535

                         Escherichia coli                                             positive
                        WP 2 hcr

    Reverse mutation     Salmonella                500-50 000 mg/m3    +/-            positive at              Kramers et al. 
                         typhimurium TA 100        (plate), 5 days                    1900 mg/m3               (1985a)
                        TA 98                                                       negative

    SOS-umu (modified    Salmonella                1.5 litre/min for                  positive                 Ong et al. (1987)
    Ames test)           typhimurium TA 1535/      30 min
                        pSK 1002

    Forward mutations    Klebsiella pneumoniae     950-19 000 mg/m3,                  positive at              Kramers et al. 
    streptomycin        ur- pro-                 20 h                               4750 mg/m3               (1985a)
    resistance

    Forward mutation     Escherichia coli          0.5-6 mmol/litre,                  1 mutation/108           Djalali-Behzad et
                        Sd 4                     1 h                                surviving                al. (1981)
                                                                                    bacteria/mmol*h
                                                                                                                                

    Table 50 (continued)
                                                                                                                                
    Test                Test system              Dose level,         Metabolic      Response                 Reference
                                                 concentration       activation
                                                                     presence/
                                                                     absence
                                                                                                                                
    Forward mutation    L5178Y mouse             0.03-30 mg/litre,                  positive                 Kramers et al. 
                                                 24 h                                                        (1985a)

    Sex-linked           Drosophila               78 or 272 mg/m3,                    negative                 McGregor (1981)
    recessive lethal     melanogaster             5 h

    Sex-linked           Drosophila                750 mg/m3 (6 h)                    negative                 Kramers et al. 
    recessive            melanogaster              375 mg/m3 (5 x 6 h)                positive                 (1985a,b)
                                                 200 mg/m3 (15 x 6 h)               positive

    Sister chromatid    Phytohaemagglutinin-     4.3%                               increased SCE            Tucker et al. 
    exchanges (SCE)     stimulated                                                  frequency from           (1985)
                        human whole blood                                           10-16.84/cell
                                                                                    after 100-second
                                                                                    exposures

    SCE                 cultured human           10-4-10-6           +/-            positive                 Garry et al. 
                        lymphocytes              mol/litre                                                   (1990)

    SCE                 bone marrow cells        47-778 mg/m3                       dose response            NTP (1992)
                        of exposed B6C3F1        6 h/day; 5 days/                   observed at 14 days
                        mice                     week; 14 days and                  only;  higher in
                                                 12 weeks                           females than males

                                                 same dose range                    negative
                                                 and exposure

    Unscheduled         DNA  human diploid       up to 70%           +/-            negative                 McGregor (1981)
    synthesis           fibroblasts              3 h
                        (human embryonic
                        intestinal cells)
                                                                                                                                

    Table 50 (continued)
                                                                                                                                
    Test                Test system              Dose level,         Metabolic      Response                 Reference
                                                 concentration       activation
                                                                     presence/
                                                                     absence
                                                                                                                                
    Unscheduled DNA     SPF male Wistar          10-30 mg/litre                     negative                 Kramers et al. 
    synthesis           rats, primary liver                                                                  (1985a)

    Cell                Syrian hamster           3890-31 120 mg/m3                  negative                 Hatch et al. 
    transformation      embryo cells             2-20 h in sealed                                            (1983)
                                                 chambers

    Chromosomal         male and female CD       78 or 272 mg/m3                    negative                 McGregor (1981)
    aberrations         (ex Sprague-Dawley)      single 7 h or
                        rat bone marrow          7 h/day; 5 days
                        cells

    Micronucleus        male and female          600-1712 mg/m3                     polychromatic            Ikawa et al.
                        BDF1 mice                6 h/day;  5 days/                  erythrocytes with        (1986)
                                                 week; 14 days                      micronuclei in the
                                                                                    bone marrow increased
                                                                                    10-fold in males
                                                                                    (778 mg/m3) and
                                                                                    6-fold in females
                                                                                    (600 mg/m3); in 
                                                                                    peripheral blood 
                                                                                    increased 32-fold 
                                                                                    in males (778 mg/m3) 
                                                                                    and 3-fold in females
                                                                                    (600 mg/m3)
                                                                                                                                

    Table 50 (continued)
                                                                                                                                
    Test                Test system              Dose level,         Metabolic      Response                 Reference
                                                 concentration       activation
                                                                     presence/
                                                                     absence
                                                                                                                                
    Micronucleus        male and female          600-1712 mg/m3                     polychromatic            Ikawa et al.
                        F344 rats                6 h/day; 5 days/                   erythrocytes with        (1986)
                                                 week; 14 days                      micronuclei in the
                                                                                    bone marrow increased
                                                                                    10-fold in males 
                                                                                    and 3-fold in females
                                                                                    at 1314 mg/m3

    Micronucleus        in peripheral            47-778 mg/m3                       elevated (only at        NTP (1992)
                        erythrocytes of          6 h/day; 5 days/                   14 days) responses
                        B6C3F1 mice              week; 14 days                      over entire dose
                                                                                    range with greatest
                                                                                    response at 389 and
                                                                                    778 mg/m3 in 
                                                                                    females; males less 
                                                                                    responsive

                                                 same dose range and                negative
                                                 exposure routine;
                                                 13 weeks

    Dominant lethal     rats, male CD            78 or 272 mg/m3                    negative                 McGregor
                        (Sprague-Dawley)         7 h/day; 5 days                                             (1981)
                                                                                                                                
    

         Starratt & Bond (1988a) found that methylation of DNA in maize
    and wheat took place during fumigation using 14C- labelled methyl
    bromide (48 mg/litre for 72 h). They identified 7-methylguanine and
    1-methyladenine as major products and lesser amounts of
    3-methyl-cytosine and 3- methyladenine and 7-methyladenine; 0.5-1% of
    the guanine residues in the DNA were methylated. Methylation of solid
    samples of calf thymus DNA and salmon testes DNA gave similar results,
    except that the quantity of 1-methyladenine exceeded that of
    7-methylguanine (Starratt & Bond, 1988b).

         In contrast, a different pattern of methylated bases was found
    when solutions of DNA were treated with 14C-labelled methyl bromide.
    Here, predominantly 7-methylguanine with a small amount of
    3-methyladenine and only traces of 1-methyladenine and
    3-methyl-cytosine were identified (Starratt & Bond, 1988b). The
    authors noted that these results agreed better with the  in vivo
    studies of Djalali-Behzad et al. (1981).

         An  in vitro assay for unscheduled DNA synthesis (UDS) was
    carried out in human diploid fibroblasts with exposures of 3 h and
    concentrations up to 70% in air. No increase in UDS was found
    (McGregor, 1981).

         As measured by autoradiography, methyl bromide (tested at 10-30
    mg/litre) did not induce unscheduled DNA synthesis in primary cultures
    of rat hepatocytes treated in air-tight bottles (Kramers et al.,
    1985a).

    8.6.2  Mutation

         Methyl bromide has been tested in various  in vitro and  in vivo
    test systems (Table 50).

         Methyl bromide was mutagenic to  Salmonella typhimurium TA 100
    when tested at concentrations of 0.02-0.2%, in desiccators, in the
    absence of an exogenous metabolizing system (Simmon et al., 1977).

         Positive results were also obtained in strain TA 100 in a liquid
    assay (tested at 10-1000 mg/litre) and a plate assay (tested in closed
    containers at concentrations of 500-50 000 mg/m3). Methyl bromide
    was mutagenic at concentrations of 1900 mg/m3 and higher (plate
    tests), and concentrations of 285 mg/litre (medium) and higher
    (suspension test). The activity in the plate assay was unaffected by
    the presence of liver homogenates from Aroclor(R)-induced rats
    (Kramers et al., 1985a).

         Methyl bromide (tested at 0.5-5 g/m3 in a closed container) was
    mutagenic to  S. typhimurium TA 1535 and TA 100 and to  E. coli WP2
    her, in the absence of an exogenous metabolic system (Moriya et al.,
    1983).

         An aqueous solution of methyl bromide (tested at 0.5-6 µmol/
    litre) induced mutations to streptomycin independence in  E. coli
    Sd-4 (Djalali-Behzad et al., 1981).

         Methyl bromide showed no mutagenic activity in a modified Ames
    test using the impingement  (in situ) test system, but, with the SOS
     umu-test, this compound induced a significant SOS response, even
    with only 30 min impingement (Ong et al., 1987). The SOS function
    induced by genotoxic agents was detected by a colorimetric measurement
    of beta-galactosidase activity encoded by the  1acZ gene, which is
    regulated by the Umu operon.

         Mutations to streptomycin resistance were induced in the
    fluctuation test with  Klebsiella pneumoniae at concentrations of
    4750 mg methyl bromide/m3 and higher (tested at 950- 19 000 mg/m3)
    (Kramers et al., 1985a).

         In barley, a few mutations were induced after treatment of
    kernels with 1.4 mmol methyl bromide/litre for 24 h, in closed vessels
    (Ehrenberg et al., 1974).

         A sex-related recessive lethal assay was carried out on
     Drosophila melanogaster (McGregor, 1981). Male strain Oregon K
     Drosophila were exposed to 78 or 272 mg methyl bromide/m3 for 5 h
    and were mated on days 1,3, or 8 following exposure. The F1 progeny
    from these matings were then mated brother to sister, 1-4 days after
    emergence from pupae and the F2 generation was ex-amined for the
    absence of wild-type males. At 78 mg methyl bromide/m3, the
    frequencies of lethal mutations in the F2 generations from one of the
    stocks were elevated, but this was not thought by the authors to be
    compound-related as these were higher than those at the higher
    concentration range.

         In a sex-linked recessive lethal test on  Drosophila
     melanogaster , flies of the Berlin K strain were exposed to methyl
    bromide at concentrations of 70-750 mg/m3 for increasing periods;
    mutation frequencies were significantly increased at the highest
    nontoxic concentrations. At a concentration of 600 mg/m3, all flies
    died within a short time during the fourth day of exposure (Kramers et
    al., 1985a). Prolongation of the exposure time permitted lower
    concentrations to be detected as mutagenic; 487 mg/m3 for 5 x 6 h
    and 200 mg/m3 for 15 x 6 h were effective exposures whereas
    treatment with up to 750 mg/m3 for 6 h was not sufficient to produce
    significantly increased mutation frequencies. The mutagenic effect of
    methyl bromide was most pronounced in postmeiotic germ cell stages
    (Kramers et al., 1985b).

         Treatment of L5178Y mouse lymphoma cells with 0.03-30 mg methyl
    bromide/litre, in air-tight bottles, resulted in a dose-related
    increase in 6-thioguanine- and bromodeoxyuridine-resistant mutants
    (Kramers et al., 1985a).

    8.6.3  Chromosomal effects

    8.6.3.1  In vitro studies

    Exposure of human lymphocyte cultures to 4.3% methyl bromide for 100
    seconds increased the frequency of sister chromatid exchanges (SCEs)
    from 10.0 to 16.8 per cell (Tucker et al., 1985, 1986).

         Human G0 lymphocytes were treated with methyl bromide (0-24
    µg/ml) for 30 min with, and without, addition of rat liver homogenate.
    After culture, the prepared slides were studied and dose-related
    sister chromatid exchanges (SCEs) and chromosome aberrations (CAs)
    were found. Methyl bromide significantly induced chromosome
    aberrations in the presence of S-9 (Garry et al., 1990).

         Inhalation of methyl bromide gas induced mitotic recombination in
    somatic cells (somatic wing-spot assay) of  Drosophila melanogaster
    (Katz, 1985, 1987). Third instar larvae trans-dihybrid for two
    recessive wing-hair mutations were exposed via inhalation to methyl
    bromide (0-20 000 mg/m3) for 1 h. Wings of surviving adults were
    scored for the presence of clones of cells possessing malformed wing-
    hairs. Small and large, single (indicating a variety of genetic
    alterations) as well as twin spots (from mitotic recom bination) were
    found.

    8.6.3.2   In vivo studies

         The results of  in vivo mammalian tests for chromosomal
    aberrations in rat bone marrow were negative (McGregor, 1981).

         Micronuclei formation was studied on F-344 rats and BDF1 mice
    exposed to 0, 600, 778, 1011, 1314, or 1712 mg methyl bromide/m3 (0,
    154, 200, 260, 338, or 440 ppm) for 6 h/day and 5 days/week for 14
    days (Ikawa et al., 1986). In the surviving mice, poly-chromatic
    erythrocytes with micronuclei in the bone marrow increased 10-fold in
    males (778 mg/m3) and 6-fold in females (600 mg/m3) and those in
    peripheral blood increased 32-fold in males (778 mg/m3) and 3-fold
    in females (600 mg/m3). In rats, poly-chromatic erythrocytes
    containing micronuclei in the bone marrow increased 10-fold in males
    and 3-fold in females (both 1314 mg/m3).

         Increases in SCEs and micronuclei were observed in the bone
    marrow cells of male and female B6C3F1 mice exposed via inhalation to
    a concentration of 778 mg methyl bromide/m3 (200 ppm) for 14 days (6
    h/day, 5 days/week), the increases were more pronounced in female
    mice. In contrast, no significant increases in either SCEs or
    micronuclei were observed in male or female mice exposed via
    inhalation to a concentration of 467 mg methyl bromide/m3 (120 ppm)
    for 13 weeks (NTP, 1992).

    8.6.4  Cell transformation

         Transformation in Syrian hamster embryo cells by SA/adenovirus
    was not enhanced by exposure to 4000-16 000 mg methyl bromide/m3
    (1000-4000 ppm) for 2 or 20 h, in sealed chambers (Hatch et al.,
    1983).

    8.7  Carcinogenicity and related end-points

    8.7.1  Gavage studies

         Danse et al. (1984) administered methyl bromide, by gavage, to
    groups (10 male + 10 female) of weanling Wistar rats for 90 days at
    doses of 0.4, 2, 10, or 50 mg/kg body weight. At the highest dose
    level of 50 mg/kg, squamous cell carcinomas of the forestomach
    developed in 13 out of 20 animals. A marked diffuse hyperplasia of the
    epithelium of the forestomach was seen in all animals in this group.
    However, from subsequent examination of the slides from this study it
    was concluded that the forestomach lesions reported at 50 mg
    represented inflammation and hyperplasia rather than malignant lesions
    (Pesticide & Toxic Chemical News, 1984).

         Boorman et al. (1986) administered methyl bromide in peanut oil
    (50 mg/kg body weight), by gavage, to groups of 15 male Wistar rats
    for 13 weeks (five times a week) with a 12 week recovery period; other
    groups were exposed for 17, 21, or 25 weeks to methyl bromide;
    necropsies were performed at 13, 17, 21, and 25 weeks. At week 13,
    inflammation, acanthosis, fibrosis, and pseudo- epitheliomatous
    hyperplasia in the forestomach were observed microscopically in dosed
    animals. At week 25, all rats had hyperplastic lesions of the
    forestomach that were more severe than those at 13 weeks. Evidence of
    malignancy, seen in one rat, was considered to be a very early
    carcinoma. In the stop treatment group that had received methyl
    bromide for 13 weeks, there was regression of the stomach lesions, but
    at the 12-week final sacrifice, adhesions, fibrosis, and mild
    acanthosis remained (Table 43).

    Hubbs & Harrington (1986) reported similar results. Gross and
    microscopic alterations were most pronounced in the non-glandular part
    of the stomach of the treated rats. Histological change in the
    squamous epithelial portion of the stomach included ulceration and
    pseudoepitheliomatous hyperplasia characterized by hyperkeratosis,
    acanthosis, and epithelial peg formation. Fibrosis, foreign material
    (hair) and subacute to chronic inflammation were found in the
    muscularis mucosa, submucosa, and tunica muscularis of some rats. A
    30-60 day recovery period was accompanied by marked, but incomplete,
    regression of lesions. No evidence of malignancy was seen in the
    stomachs of treated rats (Hubbs & Harrington, 1986).

         A two-year, oral, carcinogenicity study was carried out on 60
    male and 60 female F-344 rats fed on diets fumigated with methyl

    bromide (Mitsumori et al., 1990). Diets contained 80, 200, or 500 mg
    total bromide/kg, respectively, (methyl bromide concentration being
    <20 mg/kg), the controls were fed commercial basal diet (containing
    30 mg bromide/kg) and a diet containing 500 mg potassium bromide
    (KBr)/kg. No carcinogenic effects were observed (see also section
    8.4.1.2).

    8.7.2  Inhalation studies

         In lifetime, inhalation, carcinogenicity studies (Table 49),
    groups of 90 male and 80 female Wistar rats were exposed to methyl
    bromide concentrations of up to 350 mg/m3 for 6 h/day, 5 days/ week,
    for up to 130 weeks (Dreef-van der Meulen et al., 1989; Reuzel et al.,
    1991). Methyl bromide was a mild nasal irritant at all exposure
    concentrations. There was no increased incidence of neoplasms.

         In a 2-year inhalation study (NTP, 1992) on male and female
    B6C3F1 mice exposed to 39, 128, or 389 mg methyl bromide/m3 (Table
    49), there was no evidence of carcinogenic activity in either male or
    female mice.

    8.8  Special studies

    8.8.1  Target organ effects

    8.8.1.1  Inhalation studies

         Studies on laboratory animals have shown that, following
    inhalation exposure, the primary target organs are the brain, kidney,
    nasal cavity, heart, adrenal gland, lung, liver, and testis (Irish et
    al., 1940; Hurtt et al., 1987; Eustis et al., 1988) and lung (Bond et
    al., 1985; Kato et al., 1986; Jaskot et al., 1988) (Table 48).

         Extensive target organ studies have been carried out by Eustis et
    al. (1988) on B6C3F1 mice and F-344 rats after inhalation of 622 mg
    methyl bromide/m3 for 6 h/day, 5 days/week for 6 weeks. The
    histopathological changes observed were as follows:

     Brain: neuronal necrosis in the internal granular layer of the
    cerebellar folia (mice); neurosis and loss of neurons in the cerebral
    cortex, hippocampus, and thalamus (rats).

     Kidney: nephrosis, which occurred in all treated mice, was
    charac-terized by degeneration, necrosis, and sloughing of the
    epithelium of convoluted tubules in the renal cortex. In rats, there
    was dilatation of tubules with atrophy of the epithelium, hyaline and
    granular casts in the tubules, and increased cytoplasmic basophilia,
    indicative of epithelial regeneration. There was minimal nephrosis in
    one female rat. 

     Testes: degeneration of the testes occurred frequently in exposed
    mice and mild bilateral atrophy was present in two. Degeneration and
    atrophy of seminiferous tubules of the testes was noted in several
    exposed rats.

     Nasal cavity: exposed male mice had various levels of degeneration
    and atrophy of the nasal olfactory epithelium. Minimal degeneration of
    the olfactory epithelium was seen in only one female mouse. In male
    and female rats killed after three exposures to methyl bromide, there
    was moderate to marked degeneration of the olfactory epithelium of the
    ethmoturbinates and posterior dorsal nasal septum. There was no
    inflammatory response. In rats, killed or dying after 10 or more
    exposures, actual degeneration of the olfactory epithelium was minimal
    or mild, but there was focal or multifocal loss of olfactory sensory
    cells.

     Heart: degeneration of the myocardium primarily occurred in treated
    males with minimal myocardial degeneration in two female mice.
    Degeneration of the myocardium occurred more frequently and with
    greater severity in treated than in control male and female rats.
    There were increased numbers of mononuclear and fusiform nuclei that
    may represent interstitial cells, the foci showing a relative increase
    in fine reticular fibres, and scattered clear vacuoles.

     Adrenal gland: exposed female mice showed diminished cellularity of
    the x-zone of the adrenal cortex and the affected cells contained less
    cytoplasm and smaller, more hyperchromatic nuclei than normal cells.
    Minimal to mild cytoplasmic vacuolation occurred in the adrenal cortex
    of exposed rats.

     Liver: individual cell necrosis was noted in the liver of several
    treated rats and was generally more severe in affected males than
    females. In three males and one female, an inflammatory reaction
    occurred. There were no data for mice.

     Thymus and spleen: thymic atrophy and lymphoid depletion of the
    spleen was noted in mice and rats of both sexes.

    8.8.2  Neurotoxicity

         Irish et al. (1940) examined the effects of a wide range of
    inhalation exposure conditions in rats, rabbits, guinea- pigs, and
    monkeys, using visual inspection to assess behavioural deficits. They
    observed that nearly 60% (34 out of 58) of the rabbits surviving
    exposure to 128 mg/m3 (33 ppm) developed hindlimb paralysis during
    the 6-month exposure period. This was the lowest concentration at
    which definite neurobehavioural effects could be detected in the
    rabbit, the other species being unaffected at this concentration.

         Anger et al. (1981) studied the neurobehavioural effects of long-
    and short-term methyl bromide inhalation exposure on Sprague-Dawley
    rats and New Zealand White rabbits using more sensitive tests than
    those available in 1940 when the study of Irish et al., was performed.
    Exposure to 252 mg/m3 (65 ppm) for weeks caused sig-nificantly
    reduced eye blink responses and nerve conduction velocity in rabbits,
    but not in rats. No effect on nerve conduction velocity, open-field
    activity, or coordination in rats could be seen after extended
    exposure at 214 mg/m3 (55 ppm) for 36 weeks. In further studies
    (Russo et al., 1984), rabbits did not show any neurobehavioural
    effects after inhalation exposure to 105 mg methyl bromide/m3 (27
    ppm) for 7.5 h per day, 4 days per week over 8 months. A separate
    group of rabbits exposed to 252 mg/m3 exhibited severe neuromuscular
    effects followed by partial recovery, 6-8 weeks after exposure ceased.

         Behavioural effects in rats following repeated exposure to methyl
    bromide at concentrations of 778 or 1167 mg/m3 (200 or 300 ppm) for
    3 weeks were investigated by Ikeda et al. (1980). Relatively prolonged
    (12 days) motor incoordination (rotarod) was observed.

         Conditioned taste aversion induced by inhalation exposure to
    methyl bromide in rats has been reported (Miyagawa, 1982). Rats kept
    under a water restriction schedule for 7 days, were permitted access
    to 0.3% (w/v) sodium saccharin, and were exposed to 0, 97, 195, or 389
    mg methyl bromide/m3 (0, 25, 50, or 100 ppm) for 4 h. Three days
    after exposure, saccharin preference tests were carried out, revealing
    dose-dependent saccharin aversion in the exposure group (Miyagawa,
    1982).

         Male Swiss-Webster mice exposed to methyl bromide concentrations
    up to 3500 mg/m3 showed no effects on single-task passive avoidance
    but had significantly lower rotarod performance (Alexeeff et al.,
    1985).

         Effects of methyl bromide on locomotor activity were observed in
    five groups of three rats after exposure to 245, 486, 731, or 972
    mg/m3 (63, 125, 188, or 250 ppm) for 8 h. The locomotor activity was
    measured in an activity cage before, and immediately after, the
    exposure, shown as an average count per hour in 12-h blocks (day -2
    (before exposure) and day 1) or 4-h blocks (day 0). In the 245 mg/m3
    group, the activity was the same as that in the control group. The
    activity was decreased by 731 mg/m3 and in-hibited strongly by 972
    mg methyl bromide/m3 for up to 6 h after exposure (Honma et al.,
    1985).

         The effects of methyl bromide exposure on the thiopental-induced
    reduction of righting reflex of rats was investigated. Three groups of
    eight rats were exposed to 0, 245, or 486 mg/m3 (63 or 125 ppm) and
    then were injected i.p. with 60 mg thiopental/kg to induce a loss of
    righting reflex. The time of loss of righting reflex was measured and
    group means were calculated. In the control group, two out of eight

    rats lost the righting reflex, while in the 245 and 486 mg methyl
    bromide/m3-exposure groups, the loss of righting reflex was observed
    in all rats and was considerably more prolonged (Honma et al., 1985).

         Kato et al. (1986) described neurological signs in rats, such as
    paralysis and ataxia, after exposure to 1167 or 1556 mg methyl
    bromide/m3, for 4 h/day over 6 weeks (section 8.4).

         The acute effects of methyl bromide on electroencephalographic
    activity and on sleep-wakefulness and circadian rhythms have been
    investigated in rats (Tanaka et al., 1988). Slowing of the EEG
    frequency in the wakefulness (W) stage and spike-wave activity
    appeared at a single subcutaneous dose of 135 mg methyl bromide/kg
    body weight. These abnormal EEG activities did not occur at lower dose
    levels. Administration of methyl bromide at doses of 45, 15, or 5
    mg/kg produced dose-related changes in amounts of W, non-REM sleep,
    and REM sleep and in their circadian rhythms. Pretreatment with
    glutathione effectively lessened the detrimental effects of methyl
    bromide on sleep-wakefulness and its circadian rhythms and increased
    the LD50 (Tanaka et al., 1988).

         The effects were studied on regional brain glutathione- S-
    transferase (GST) activity and the concentrations of glutathione
    (GSH), monoamines, and amino acids in F-344 rats exposed to methyl
    bromide (Davenport et al., 1992). Exposure to 584 mg/m3 was for 6
    h/day for five days. While no histological evidence of brain lesions
    was noted, there was GSH depletion and GST inhibition in the frontal
    cortex, caudate nucleus, hippocampus (examined for GSH only), brain
    stem, and cerebellum. No significant changes were observed in the
    concentrations of monoamines (only measured in males), but there were
    increases in the concentrations of aspartic acid and glycine in the
    frontal cortex and of aspartic acid only in the cerebellum (only
    measured in males).

         Honma et al. (1982) exposed groups of 5-6 SD rats to methyl
    bromide concentrations of 39-467 mg/m3 for 24 h or to 4-40 mg/m3
    for 3 weeks. After sacrifice (microwave), the brain was dissected and
    analysed for monoamines. A reduction in the norepinephrine (NE)
    contents of the hypothalamus and cortex + hippocampus was found at
    concentrations of 390 mg/m3 and above (24-h study) or 39 mg/m3
    (3-week study), whereas levels of dopamine (DA), sero-tonin (5HT), and
    acetylcholine (ACh), were only slightly affected by exposure. In more
    detailed studies, rats were exposed to 120, 240, 486, or 973 mg/m3
    for 8 h (Honma, 1987; Honma et al., 1987). Decreases in DA and NE and
    increases in the metabolites homovanillic acid (HVA) and
    3-methoxy-4-hydroxyphenylglycol (MHPG) were observed in various
    regions of the CNS in rats exposed to 319 mg/m3. The maximal effects
    were obtained 0 or 2 h after exposure with the largest changes in DA
    (-24%) and NE (-34%) seen in the striatum. HVA and MHPG levels were
    increased primarily in the frontal cortex (81%) and striatum (38%).
    The tyrosine hydroxylase (TH) activity in the striatum, hypothalamus,

    frontal cortex, midbrain, and medulla oblongata was measured in brain
    homogenates from rats exposed to 62-973 mg/m3 (16-250 ppm) for 8 h
    (Honma et al., 1991). The rats were sacrificed serially (decapitation)
    between 0 and 16 h after exposure. TH was also measured  in vivo
    following administration of decarboxylase inhibitor. Exposure to
    methyl bromide dose-dependently inhibited both TH activity in vitro
    and  in vivo . TH activity in the hypothalamus was most sensitive to
    methyl bromide compared with the other brain areas. The authors
    suggested that methyl bromide reduces catecholaminergic neuronal
    activity in the brain via inhibition of TH activity.

         The direct effects of methyl bromide on the rat brain have been
    investigated using a two-probe (right striatum and left ventricle)
    microdialysis method (Honma, 1992). Methyl bromide (1 µg or 0.5
    µg/µlitre) dissolved in 10% ethanol/90% artificial cerebrospinal fluid
    was perfused through the ventricle probe at a rate of 2.5 µlitre/min
    and changes in 3,4-dihydroxyphenylacetic acid (DOPAC), HVA, and
    5-hydroxyindoleacetic acid, a serotonin metabolite, (5HIAA) content in
    the striatum perfusate were measured. DOPAC and HVA increased
    following the initiation of ventricle perfusion but the 5HIAA content
    of the striatum perfusate was reduced. The increases in DOPAC and HVA
    persisted after perfusion and the decreased 5HIAA level returned to
    normal. A concentration of 0.1 µg methyl bromide/µlitre had no effects
    on DOPAC and HVA levels, though the 5HIAA level was reduced. These
    findings support the findings of an increase in DOPAC and HVA in the
    brain homogenate of rats exposed to methyl bromide (Honma, 1987; Honma
    et al., 1987) indicating that dopamine metabolites in the
    extracellular, and, probably, intracellular, regions of dopamine nerve
    terminals were increased by methyl bromide itself. The extracellular
    level of the 5HIAA in microdialized perfusate was reduced by
    intraventricularly administered methyl bromide (Honma, 1992).

         Systematic neuropathological studies of their central and
    peripheral nervous systems were carried out on male Wistar rats
    exposed to methyl bromide (1128 or 1945 mg/m3) for 6 h/day, 3
    days/week for 3-8 weeks (Furuta et al. 1993). Among the rats exposed
    to 1945 mg methyl bromide/m3 for 10-18 days, the following
    neuropathological changes were noted: axonal degeneration of
    myelinated fibres at the cervical level of the fasciculus gracilis and
    the necrosis and atrophy of neurons in the caudate-putamen, thalamus,
    and cingulate cortex. Rats exposed to a concentration of 1128 mg
    methyl bromide/m3 for 8 weeks did not show any abnormalities.

    8.8.3  Immunotoxicity

         No data on the immunotoxicity of methyl bromide are available.

    8.9  Factors modifying toxicity; toxicity of metabolites

         Cysteine has been shown to reduce the toxicity of methyl bromide,
    when administered to rats, mice, and rabbits, orally or s.c., 30 min

    before, or s.c. within 5 min following, acute poisoning (Mizyukova &
    Bakhishev, 1971). Cysteine treatment prevented the death, paralysis,
    paresis, and spasms that developed on the 3rd-4th days after methyl
    bromide inhalation in other animals.

    8.10  Mechanisms of toxicity - mode of action

         The mode of action of methyl bromide is still not understood.
    Proposed mechanisms of toxicity include the direct cytotoxic effect of
    the intact methyl bromide molecule or toxicity due to one of its
    metabolites. The bromide ion concentrations are insufficient to
    explain methyl bromide toxicity, but it may be related to its
    alkylating ability.

         Honma et al. (1985) concluded that the CNS toxicity seems to be
    due to the methyl bromide molecule itself or the methyl moiety
    incorporated into the tissue and does not appear to be attributable to
    inorganic bromide or methyl alcohol (Honma et al., 1985). In humans
    showing medium or severe toxic symptoms of the CNS, methanol
    concentrations in the blood ranged between 200 and 3000 mg/litre
    (Swartz et al., 1981).

         The direct cytotoxic effect of methyl bromide on HeLa cells  in
     vitro has been shown, whereas bromide appeared not to cause cell
    damage (Nishimura et al., 1980).

         Methyl bromide reacted  in vitro with a number of SH enzymes and
    caused progressive and irreversible inhibition (Lewis, 1948). DNA and
    protein alkylation by methyl bromide have previously been discussed
    (section 6.3).

         The role of glutathione (GSH) in reducing toxicity is also not
    clear. Studies on the possible role of glutathione are given in
    section 6.3. One hypothesis for the toxicity of methyl bromide
    proposes the formation of a reactive species through a methyl
    bromide-glutathione conjugation process, but it is more probable that
    glutathione acts as a detoxifying agent.  

    9.  EFFECTS ON HUMANS

         Humans can be exposed to methyl bromide via inhalation, by skin
    contact with the compound, or through residues in food that has been
    fumigated with the gas to control pests. Exposure is also possible
    through drinking- water from wells contaminated with leaching water.

         In this section, only direct exposure to gaseous or liquid methyl
    bromide is considered.

         Since the first case reported by Schuler in 1899, there have been
    hundreds of cases of methyl bromide poisoning involving fatalities,
    systemic poisoning, skin and eye injuries, and damage to the central
    nervous system (von Oettingen, 1946, 1964; Hine, 1969; Torkelson &
    Rowe, 1981; Weller, 1982; Alexeeff & Kilgore, 1983).

         Table 51 shows acute cases up to 1983 reported throughout the
    world. Up to 1955, most cases were from chemical manufacture or fire
    extinguisher incidents. Since this date, cases of poisoning from its
    use as a fumigant have predominated.

    9.1  Clinical findings

         It is important to note that the manifestations of methyl bromide
    poisoning may be delayed. The latent period may vary from 2 to 48 h
    (Holling & Clarke, 1944).

         The acute and long-term effects of methyl bromide can be divided
    broadly into two categories: neurological and non-neurological.

         The principal non-neurological symptoms reported after acute
    inhalation of methyl bromide are associated with the respiratory
    system. Chest pain or difficulty in breathing have been reported,
    which is consistent with pathological findings at autopsy including
    pulmonary oedema, bronchopneumonia, congestion, and haemorrhage
    (Holling & Clarke, 1944; Hine, 1969).

         In fatal poisoning, the early symptoms and signs are headache,
    visual disturbances, nausea and vomiting, smarting of the eyes,
    itching of the skin, listlessness, vertigo, and tremor. Progression is
    usually rapid, with the development of convulsions, often with a
    Jacksonian-type of progress, fever, tachypnoea associated with signs
    of severe pulmonary oedema, cyanosis, pallor, and death. Several
    neuropsychiatric signs and symptoms, such as mental confusion, mania,
    muscular twitches, and slurring of speech, may precede death (Wyers,
    1945; Sax et al., 1984; Gosselin et al., 1984).


        Table 51.  Methyl bromide poisoning incidents up to 1955 and between 1955 and 1983a
                                                                                                                                
    Resulting from:           Fatalities      Systemic Poisoning   Skin Injuries   Eye Injuries     Other or unspecified injuries
                              up to  1955-    up to    1955-       up to   1955-   up to   1955-    up to           1955-
                              1955   1983     1955     1983        1955    1983    1955    1983     1955            1983
                                                                                                                                
    Chemical manufacture,     16      1       108       45         26        4     0b               0b
    filling, storage, 
    transportation, or 
    disposal

    Use or leaking fire       24     11        38       28         10        0     0b               0b
    extinguishers

    Uses as a fumigant        44     16         3      298          0      145     0b      57       0b              78
                                                                                                                                

    a Adapted from: Alexeeff & Kilgore (1983).  Data up to 1955 were taken from von Oettingen (1955).
    b No cases known.
    

         The clinical picture in non-fatal poisoning is extremely
    variable. Fatigue, blurred or double vision, nausea, and vomiting are
    frequent; incoordination, tremors, convulsions, exaggeration of the
    patellar reflexes, and a positive Babinski's sign may develop. Nearly
    every type of nervous disturbance has been reported. The pulmonary
    symptoms are comparatively slight (Sax et al., 1984). Low-level,
    short-term exposures to the vapour have produced a syndrome of
    polyneuropathy without overt central manifestations, characterized by
    persistent numbness in the hands and legs, impaired superficial
    sensation, muscle weakness, unsteadiness of gait, and absent or
    hypoactive distal tendon reflexes (Kantarjian & Shaheen, 1963). Victor
    & Adams (1980) stated that the signs and symptoms of chronic bromide
    poisoning intoxication consisted of dizziness, drowsiness,
    irritability, emotional lability, impairment of thought or memory,
    and, in severe cases, delirium and mania or stupor or coma.

         Locally, methyl bromide is an intense vesicant on human skin. The
    blisters produced by methyl bromide are enormous, but rarely deep
    enough to destroy the entire skin layer, even though it may produce
    severe burns (Watrous, 1942; Butler et al., 1945; Wyers, 1945).

         Both central and peripheral neurological deficits may persist;
    organic brain syndrome has occurred (Greenberg, 1971; Goulon et al.,
    1975). Profound psychological depression can occur during prolonged
    convalescence (Hine, 1969). Late sequelae include bronchopneumonia
    after severe pulmonary lesions, renal failure, and severe weakness
    with, or without, evidence of paralysis.  Renal failure due to tubular
    necrosis may be a late sequela, but this is uncommon and usually of
    mild proportions (Benatt & Courtney, 1948; Prain & Smith, 1952). There
    have been occasional reports of jaundice, elevations of liver enzyme
    activity in serum, and abnormal liver function tests suggestive of
    mild hepatotoxicity after exposure to methyl bromide (Verberk et al.,
    1979). In a 6- year-old boy, signs of liver involvement in conjunction
    with encephalopathy after exposure to methyl bromide vapour were at
    first mistaken for Reye's syndrome (Shield et al., 1977).

         Recovery is frequently prolonged and there may be permanent
    injury, commonly characterized by sensory disturbances, weakness,
    disturbances of gait, irritability, and blurred vision.

         The effects of methyl bromide on the nervous system, based on
    case histories, showed that dysfunction affected the peripheral and
    optic nerves, cerebellar connections, and certain spinal cord tracts
    (Carter, 1945). Brain stem damage was described in a man who died
    after 30 days of unconsciousness following methyl bromide exposure
    (Cavanagh, 1992; Squier et al., 1992). Serum bromide levels, 2 days
    after admission, were 160 mg/litre (normal 3-4 mg/litre). At
    post-mortem examination, the brain showed mild generalized swelling,
    normal ventricles, and well- defined symmetrical lesions, including
    loss of neurones, in the mammilary bodies and inferior colliculi. The
    cerebellar dentate nuclei had occasional foci of neuronal loss; other

    brain stem regions were normal. The spinal cord was normal, but dorsal
    root ganglia had scattered nodules of neuronal loss. Nerve roots and
    thoracic peripheral nerve showed sparse chronic inflammatory exudate
    and patchy axonal and myelin loss. The thyroid gland was densely
    infiltrated with lymphocytes, plasma cells were rare, and there was no
    significant fibrosis. The lungs were slightly oedematous and
    congested. In another case of methyl bromide poisoning, a woman
    remained in a coma for 4 years and 8 months before death. At
    post-mortem, there was necrosis of both colliculi, with gliosis in the
    upper brainstem, reticular formation, and moderate changes in the
    dentate and pontine nuclei (Goulon et al., 1975).

         Various visual disturbances have been reported following acute
    methyl bromide poisoning. These include blurring of vision, diplopia,
    lacrimation from eye irritation, accommodative disturbance, and
    central scotomata for shades of green (Grant, 1974). Ocular findings
    in a case of chronic methyl bromide poisoning included persistent
    bilateral decrease in vision, temporal optic nerve head pallor, marked
    attenuation of visual evoked response amplitude with normal latencies,
    normal electro-retinogram but abnormal electro-oculogram, and
    deuteranomalous (green) defect (Chavez et al., 1985).

         Electrophysiological studies have been performed on patients as
    part of a clinical investigation of the neurological effects of methyl
    bromide poisoning (Goulon et al., 1975; Verberk et al., 1979; Audry et
    al., 1985; Lopez et al., 1986a, b; Uncini et al., 1990; Mazzini et
    al., 1992; Hustinx et al., 1993). Abnormal findings included
    epileptiform patterns in electroencephalograms, enlarged and
    asymmetric somatosensory evoked potentials, and evidence of axonal
    neuropathy in peripheral nerves.

    9.1.1  Bromide levels in body tissues and fluids

         In cases of methyl bromide poisoning, methyl bromide itself has
    been detected in human tissue on only one occcasion. This may be due
    to the absence of methyl bromide or, more probably, to its very short
    half-life in tissues, as well as difficulties in analysis. There is an
    inconsistency in the data as to whether there is a correlation between
    bromide levels and the symptoms of methyl bromide poisoning. Some
    authors have suggested a direct correlation between blood bromide
    levels and the degree of intoxication (Rathus & Landy, 1961; Hine,
    1969): 400 mg/litre (ppm) - severe disability and death in some cases;
    250 mg/litre (ppm) - convulsive seizure and sometimes death; 176
    mg/litre (ppm) - slight residual ataxia; 135 mg/litre (ppm) - moderate
    disability; 100 mg/litre (ppm) or less -recovery, but symptoms of
    poisoning have been reported at bromide levels as low as 28 mg/litre
    blood and severe symptoms at blood bromide levels of 120 mg/litre
    (Rathus & Landy, 1961). Brenner (1978) and Bowers & Onoreski (1990)
    considered that the toxic threshold level for bromide in serum in
    humans was 500 mg/kg, though effects were observed in patients with
    lower levels.

         However, Weller (1982) disputed a correlation between the bromide
    levels in serum and the severity of poisoning. In workers in a methyl
    bromide manufacturing plant, no definite association was found between
    symptoms and urine bromine concentrations (Kishi et al., 1991). A
    direct association between serum bromine concentrations and the
    severity of neurological symptoms was not found in a poisoning
    incident involving greenhouse workers (Hustinx et al., 1993).

    9.1.2  Dermal exposure

         Dermal exposure can result from direct contact with liquid methyl
    bromide, e.g., from accidental splashing, or through contact with
    contaminated boots, clothing, bandages, or gloves (Alexeeff & Kilgore,
    1983). These articles are often made of rubber, which can absorb
    methyl bromide (Watrous, 1942). Direct eye injury or irritation can
    also occur. Dermal exposure to gaseous methyl bromide can also cause
    poisoning.

         When liquid methyl bromide is spilled on the skin, it evaporates
    rapidly producing a cool, but not a cold, or burning sensation
    (Watrous, 1942). Repeated application of the liquid caused a burning
    or tingling sensation in the skin, which, in more severe cases, led to
    a sense of numbness, followed later by aching. In the early stages,
    the skin appeared red and slightly swollen, with blisters and
    second-degree burns appearing after 2-12 h in severe cases. In less
    severe cases, an itching dermatitis may develop after a latent period
    of about seven days (Watrous, 1942).

         Cases of skin burns have been reported during fumigation (Bruhin,
    1942) and from methyl bromide fire extinguishers (Butler et al.,
    1945). Bruhin (1942) reported three cases of dermal exposure during
    bulk fumigation of a mill. Methyl bromide poisoning occurred due to
    percutaneous absorption; the men were using breathing apparatus. All
    three men were exposed to the same conditions, they suffered first or
    second degree skin burns and one died as a consequence of the
    exposure.

         Skin lesions occurred in 6 patients who were exposed to methyl
    bromide during the fumigation of a castle (Zwaveling et al., 1987;
    Hezemans-Boer et al., 1988). They had adequate airway protection, so
    poisoning was by dermal exposure and not by inhalation. Exposure to
    high concentrations of methyl bromide (about 40 g/m3) for 40 min led
    to redness and blistering of the skin. Standard protective clothing
    (overalls - 35% cotton/65% polyester), worn over normal clothing, PVC
    gloves, and working shoes did not prevent this. Redness, oedema, and
    blistering of the skin were limited to areas where perspiration is
    relatively high, i.e., armpits, groin, genitals, and the skin under
    the waistbelt. The authors suggested that methyl bromide absorption
    might be increased in this partly lipophilic (sebaceous glands),
    partly hydrophilic (sweat glands) environment, perhaps leading to
    increased absorption through the skin as well. The skin in these parts

    is also thinner, favouring absorption. Plasma bromide levels were
    highest about 13 h after exposure (mean 9.0± 1.4 mg/litre) and fell in
    subsequent hours (mean 6.8±2.3 mg/litre; 25 h after exposure),
    suggesting absorption of methyl bromide through the skin. Since the
    published half-life of bromide is about 100 h, the falls in plasma
    levels must be due almost exclusively to the distribution of bromide
    in tissues. No systemic effects were noted.

    9.1.3  Inhalation

         Inhalation is the primary route of exposure. Poisoning has
    occurred following acute, short-, and long-term exposures. Acute cases
    have occurred involving spilling or leaks while handling methyl
    bromide or where the persons were unaware of its presence (Alexeeff &
    Kilgore, 1983).

         In spite of stronger regulations for the safe and licensed use of
    methyl bromide, cases of poisoning still occur. Cases have been
    reported in California (Edmiston & Maddy, 1987; Maddy et al., 1990)
    and incidents of poisoning have been reported with occupational
    exposure (Cantineau et al., 1988; Herzstein & Cullen, 1990), in
    members of the general public (Goldman et al., 1987; Polkowski et al.,
    1990), and in burglars entering fumigated premises (Marraccini et al.,
    1983; O'Neal, 1987).

    9.2  General population exposure

    9.2.1  Poisoning incidents

         Earlier poisoning incidents involving the general public were
    mainly from the methyl bromide in fire extinguishers. More poisoning
    incidents have involved unauthorized entry into fumigated buildings or
    persons living near fumigated buildings, greenhouses, or fields being
    fumigated with methyl bromide.

    9.2.1.1  Poisoning associated with fire extinguishers

         Incidents involving fire extinguishers filled with methyl bromide
    often involved exposure to the gas by inhalation and severe burns when
    the liquid was inadvertently squirted on the feet or clothing. Butler
    et al. (1945) described two cases where drivers suffered burns after
    extinguishing a fire in an armoured car. Both recovered after 2 and 8
    weeks, respectively. Twenty-two cases of methyl bromide poisoning in
    incidents involving fire extinguishers in ships, including 6
    fatalities, were reported between 1939 and 1945 (Holling & Clarke,
    1944; Clarke et al., 1945). In another incident, 8 boys, 6 of whom
    died, were exposed accidentally to methyl bromide from a fire
    extinguisher (Prain & Harvey Smith, 1952). Longley & Jones (1965)
    described an accident during methyl bromide filling where there was
    massive skin contamination. Although the victim removed the
    contaminated clothing and washed himself thoroughly, symptoms and

    signs of poisoning, commencing with severe nausea appeared within 2 h,
    and CNS effects 5 h after the exposure. The CNS effects persisted and
    6 months later there was still some disability. There were no dermal
    effects apart from oedema and itching of the eyelids with subsequent
    peeling of the skin and no evidence of pulmonary or renal involvement.

         Goulon et al. (1975) reported a detailed study of three cases
    where one patient died after 5 years in a stuporous state with
    myoclonus. Two of these were females who had slept in bedrooms
    containing fire extinguishers filled with methyl bromide; one of these
    patients died, still in coma, 4 years and 8 months later. The other
    case was a male lorry driver, who was found in a coma after spending
    a night in his lorry cab, which contained a leaking fire extinguisher;
    4 years later he showed only partial recovery with persisting lack of
    coordination, ataxia, and dysarthria. Behrens & Dukes (1986) described
    the case of a scrap-dealer who was poisoned by methyl bromide from
    fire extinguishers in obsolete aircraft engines.

         A case of poisoning and the resulting death of a man (and his
    dog) from methyl bromide leaking from an old corroded fire
    extinguisher has been reported (Cavanagh, 1992; Squier et al., 1992).

         Since methyl bromide is no longer in general use for fire
    extinguishers, the occurrence of such cases is now extremely rare.

    9.2.1.2  Poisoning associated with bulk or house fumigation

         In May 1978, severe methyl bromide poisoning occurred in 4 people
    living above a warehouse in Japan (Ishizu et al., 1988). The
    warehouse, containing herbs, was accidentally fumigated with a greater
    quantity of methyl bromide than normal giving an estimated
    concentration of 38 900-58 350 mg/m3 (10 000-15 000 ppm). Three days
    later, one member of the family, a girl aged 12 years, developed
    severe convulsions and then 2 others had severe convulsions and the
    fourth had marked mental confusion. The serum or plasma bromide ion
    levels ranged from 280 to 600 mg/litre. Clinical laboratory tests
    showed that GOT exceeded the normal level in 3 out of 4 cases.
    Moreover, the LDH activity was above the normal range in three cases
    and CPK activity was increased in all the cases (Ishizu et al., 1988).

         In California, the most frequent cause of death from
    non-occupational exposure, in recent years, has been unauthorized
    entry into structures under fumigation with methyl bromide. Most often
    the entry was by burglars, transients, or intoxicated persons who
    broke into buildings that were covered with gas resistant sheeting,
    locked, and posted with warning signs. During 1982-87 there were 13
    such fatalities (Maddy et al., 1990).

         In Florida, where homes are fumigated to destroy termites by
    placing a huge coloured tent over the house, the methyl bromide being
    released by trained technicians, 27 non-fatal cases and four

    fatalities following unauthorized entry were reported between 1957 and
    1982 (Marraccini et al., 1983). The intervals between exposure and
    death ranged between 2.5 and 36 h. Three of these deaths together with
    three additional hospitalizations followed burglaries of tented houses
    during a nine-month period.

         O'Neal (1987) reported that, at one hospital in Florida, 15-25
    patients a year, including fatalities, were treated for methyl bromide
    poisoning. Proper diagnosis and therapy were hampered by the latency
    period (4-48 h before onset of symptoms) and the fact that the toxic
    state also mimics other diseases.

         Even after apartments have been cleared for habitation, deaths
    due to methyl bromide poisoning have been reported. The fumigant can
    be absorbed by furniture, water beds, and walls, and can sequester in
    enclosed spaces, with subsequent desorption (Dempsey et al., 1992).

         Prockop & Smith (1986) reported a case in which a house fumigator
    wearing a faulty protective face mask was exposed briefly on one day.
    This was followed by malaise, although he continued to work, and then
    again, ten days later, when tremor and increasing malaise resulted in
    admission to hospital. On the next day, he was comatose with
    generalized major motor convulsions, and myoclonic limb movements
    between convulsions. On admission, the serum bromide level was 350
    mg/litre (falling to 30 mg/litre 29 days later). Five years later, the
    patient still exhibited dysarthria, impaired arm coordination, and
    disturbance of gait.

         A fatal case of methyl bromide poisoning was reported after
    fumigation of a restaurant. Although the methyl bromide levels were
    checked, for some reason the apparatus showed a reading of "no
    detectable levels" and, without putting the ventilation system on, the
    premises were declared safe. A restaurant employee, who then entered
    the building, was found dead 2.5 h later; the post-mortem inorganic
    bromide level in serum was 48 mg/litre. Four other workers who were in
    the building for 45 min had blood bromide concentrations ranging from
    40 to 51 mg/litre. Another worker who was in the restaurant for 1 h 15
    min, had a blood bromide concentration of 101 mg /litre. These 5
    workers had immediate symptoms of malaise and fatigue, but no chronic
    symptoms (Fuortes, 1992).

         A 13-year-old girl accidentally exposed to excessive methyl
    bromide concentrations after a warehouse fumigation had early symptoms
    of headache, dizziness, and nausea, followed a few hours later by
    unconsciousness, from which she recovered three days later. At that
    time, myoclonic jerks developed, the intensity of which progressed and
    was unresponsive to treatment over a two-month period. In a two-year
    follow-up, treatment with clonazepam and phenobarbitol decreased the
    intensity of myoclonus and she was able to return to school.
    Electrophysiological findings suggested that the methyl bromide

    exposure had induced a type of cortical reflex myoclonus (Uncini et
    al., 1990).

    9.2.1.3  Poisoning associated with soil fumigation

         Goldman et al. (1987) reported four episodes of community
    exposure to methyl bromide and chloropicrin soil fumigation in
    California in 1973, 1980, and two in 1984. A total of over sixty cases
    were involved, and, in all episodes, either evacuation of homes or
    cessation of fumigation was the outcome. In one episode, a strawberry
    field was fumigated preplanting with a methyl bromide/ chloropicrin
    formulation (dosage and % composition not given). Local weather
    conditions included a temperature of 30 °C with an inversion; 32
    adults and 4 children were treated with incident-related symptoms,
    such as eye irritation, sore throat, headache, shortness of breath,
    and cough. One child was hallucinating. Fumigant-related symptoms
    dropped off sharply with distance, 30% within 1 km compared with 4.5%
    more than 2 km from the field. It should be noted that these symptoms
    could be attributed to either methyl bromide or chloropicrin.

         A nurseryman was poisoned after glasshouses near his house had
    been fumigated with methyl bromide (Bishop, 1992). The symptoms were
    delayed. By day 3 after the fumigation, he had convulsions and became
    comatose. There was a long recovery period and persistence of
    neurological signs and symptoms.

    9.2.1.4  Miscellaneous incidents

         Inhalation of methyl bromide from leaking canisters caused acute
    methyl bromide poisoning. Two grandparents and a child showed various
    levels of poisoning. The man showed predominantly mental disturbances,
    with only mild neurological signs and no convulsions; initial euphoria
    and lack of concern progressed to a florid psychosis. His mental state
    was normal 6 months later. The woman was severely affected and
    remained in status epilepticus for 7 days. The boy had an upper
    respiratory illness 24 h before methyl bromide poisoning, which might
    have increased his susceptibility to the toxic agent. He developed an
    acute encephalopathy with fluctuating conscious state, hypotonia,
    araflexia, and extensor plantar responses. Before methyl bromide was
    identified as the cause of the illness, Reye's syndrome had been
    diagnosed (Shield et al., 1977).

         A tractor trailer-truck overturned and a cylinder (max. capacity
    680 kg) was punctured.  Although people were warned of the risk, ten
    were admitted to hospital. The symptoms included nausea, vomiting,
    breathing difficulty, headache, dizziness, burning throat, coughing,
    and chest tightness. The primary route of exposure was inhalation for
    seven patients, dermal for two, and both dermal and inhalation for
    one. All patients recovered without neurological sequelae (Polkowski
    et al., 1990).

         Leakage from a compressed gas cylinder caused unconsciousness and
    status epilepticus in a man (Mazzini et al., 1992). After awaking, he
    suffered from severe myoclonic jerks and major epileptic convulsions.
    Six months later, he still had severe action myoclonus of the limbs.
    A standardized neuropsychological evaluation revealed severe cognitive
    impairment.

    9.3  Controlled human studies

         Raabe (1988) carried out an inhalation study using [14C]-
    labelled methyl bromide up to 0.1 mg/m3 to determine the percentage
    of methyl bromide absorbed by the human body from air containing
    ambient concentrations of the gas. The uptake was 55.4% nasal and
    52.1% oral (section 6.1.1.2 and Fig. 6).

    9.4  Occupational exposure

         Up to 1955, the majority of methyl bromide poisoning incidents
    resulted from chemical manufacture and filling operations, followed by
    fire extinguishers and fumigation (von Oettingen, 1955). Since 1955,
    fumigation has become the major source of fatalities (Alexeeff &
    Kilgore, 1983).

    9.4.1  Occupational exposure during manufacture

         Incidents of methyl bromide poisoning in industry have been
    described by Watrous (1942) and Wyers (1945). The main incidents were
    dermatological cases occurring principally among those who filled the
    small cylinders for distribution from the larger ones. Other sources
    of danger were defects in the plant, such as ill-fitting joints and
    bursting of cylinders by an undue rise in temperature. Carelessness
    with handling was also a cause.

         Kishi et al. (1991) carried out a questionnaire survey to
    determine the symptoms of workers exposed to methyl bromide in the
    manufacturing process. Seventy five male workers (exposure length:
    1-25 years) were compared with a reference group of railway workers.
    The questionnaire covered acute symptoms during workshift (16
    questions), and general symptoms (61 questions). Acute and general
    symptoms were statistically higher in frequency among the exposed
    workers (sign test of pairwise comparison). Methyl bromide
    concentrations in the air in the workers' breathing zone were measured
    every 6 months, and were normally less than 4 mg/m3, but, during
    some accidental events, they exceeded 20 mg/m3. The mean bromide ion
    concentration in the urine of men working in the manufacture of methyl
    bromide was 18.9 mg/litre± 10.4 (range 3.2-54.0 mg/litre), with no
    correlation with the symptoms reported.

         Previous studies had shown that urinary bromide concentrations
    were an index of relatively acute exposure, correlating with the air
    concentration of the working site. The concentration in the work-place

    air sometimes accidently exceeded 58 mg/m3. There were some cases of
    sub-acute poisoning with lethargy, ataxia, and retrobulbar optic
    neuritis. In one incident, the mean urine concentration of 20 workers
    exposed to methyl bromide was 277 mg/litre. On that occasion, 14 of
    the 21 exposed workers had abnormally accelerated tendon reflexes, 8
    had paraesthesia, and 4 showed disturbance of the convergence reflex
    of the eyes (Kishi et al., 1991).

    9.4.2  Occupational exposure due to methyl bromide fumigation

         In many countries, the use of methyl bromide is restricted to
    trained and licensed personnel.

         Occupational exposure to methyl bromide can occur during the
    manufacturing, filling, and packaging processes, as well as during its
    use as a fumigant. As described in section 3.2.2, methyl bromide is
    used mainly for soil fumigation as well as for the fumigation of
    buildings and commodities, to prevent pest infestation. The various
    occupations involved are given in section 5.3.

         Methyl bromide was used as a fumigant in the USA by an estimated
    105 000 workers between 1972 and 1974 (NIOSH, 1984) and 75 000 workers
    in 1980 (Anger et al., 1981).

    9.4.2.1  Incidents involving bulk fumigation

         A poisoning incident in a mill where three fumigators were
    poisoned through dermal exposure to gaseous methyl bromide has been
    described in section 9.1.2 (Bruhin, 1942).

         Johnstone (1945) and Ingram (1951) reported incidents in
    data-processing factories where over 200 employees were taken ill,
    with over 50 cases of frank methyl bromide poisoning, including two
    workers suspected of insanity. All 34 packers, described by Johnstone
    (1945), had visual disturbances and there was a high incidence of
    speech difficulties, mental confusion, hallucinations, and
    paraesthesia. Four workers claimed permanent and six temporary
    disabilities. The main factor in these poisonings was that the workers
    ignored the necessary precautionary measures (Johnstone, 1945).
    Kantarjian & Shaheen (1963) described 8 cases of polyneuropathy in
    date factory workers who suffered repeated exposure to the vapour due
    to faulty working techniques over a period of three months. Within 6
    months all had recovered. Only 8 out of 14 employees developed
    symptoms, suggesting a variation in susceptibility in different
    individuals.

         Seven workers employed in the bulk fumigation of houses were
    poisoned by methyl bromide (Rathus & Landy (1961). The cause was the
    insufficient absorption properties of the canisters in their
    respirators. Three of the men were burned on the area of the face
    covered by the respirators. 

         Drawneek et al. (1964) described a case of irreversible brain
    damage in a methyl bromide fumigator. Seven other workers, without any
    recognisable illness, were found to have serum bromide levels of over
    50 mg/litre, at which level mild euphoria may develop and lead to
    carelessness in the handling of methyl bromide, and, therefore, to
    possible acute exposure.

         Hine (1969) reported two acute and eight chronic cases of
    fumigation-related poisoning in California from 1957 to 1966. Four of
    the patients died. The most common symptoms were malaise, weakness,
    and dyspnoea. The deaths were preceded by convulsions and coma. All
    cases could be traced to a failure in preventative procedures.

         A few hours after exposure, during the fumigation of cocoa beans,
    a dock worker developed status epilepticus, coma, and pulmonary oedema
    (Greenberg, 1971).

         Ten cases of methyl bromide poisoning occurred in the hold of a
    ship whilst a rice cargo was being fumigated in port (Brodniewicz,
    1967). The accident was the result of several circumstances: sealing
    of the crew's quarters was forgotten, some of the crew remained on the
    ship during, and after, fumigation, and the port fumigating team
    lacked experience and proper qualifications. One victim died following
    convulsions, acute pulmonary oedema, and heart failure. In the other
    cases, the main complaints were dizziness and nausea.

         In a fatal case of methyl bromide poisoning of a ship's boy who
    slept in the crew's quarters, the levels of methyl bromide measured
    after fumigation had not exceeded 40 mg/m3, but the boy was
    poison-ed by a high concentration of the gas leaking from the
    fumigated commodity, because of large temperature differences (Weller,
    1982).

         An employee habitually not wearing a mask in a fumigating plant
    spraying fruits and vegetables was initially treated for psychosis, as
    the early symptoms of methyl bromide poisoning are similar (Zatuchni
    & Hong, 1981).

         Cases of dermal exposure occurring during the fumigation of a
    castle have been reported (Zwaveling et al., 1987; Hezemans-Boer et
    al., 1988). Details are given in section 9.1.2.

         Systemic and neuro-ophthalmic manifestations of methyl bromide
    poisoning including increased serum bromide level (66 mg/litre),
    paraesthesia and burning dysesthesia on hands and feet, and visual
    impairment, were described in an assistant fumigator who had been
    exposed acutely, twice, during the year previous to examination
    (Chavez et al., 1985).

    9.4.2.2  Incidents involving soil fumigation

     (a)  Field workers

         Table 52 shows occupational poisoning incidents, reported in
    California, due to methyl bromide exposure in the years 1950, 1986,
    and 1987, and analysed according to work activity (Edmiston & Maddy,
    1987; Maddy et al., 1990).

         Seven deaths through occupational exposure were reported in
    California between 1951 and 1965. The distribution of cases was: 1952
    (1), 1956 (2), 1958 (1), 1959 (2), and 1965 (1) (Maddy et al., 1990).

         Methyl bromide poisoning of four field workers occurred during
    the removal of soil fumigation sheets under cool weather conditions
    (Herzstein & Cullen, 1990). Ten days after injection of methyl bromide
    into the soil, the polyethylene sheets covering the soil were removed.
    The 4 field workers developed fatigue and light-headedness and 3 had
    progressive respiratory, gastrointestinal, and neurological symptoms.
    The acute systemic symptoms improved over several days, but
    neuropsychiatric symptoms that developed later persisted for several
    weeks. The 2% chloropicrin was not enough to warn the workers of the
    presence of methyl bromide.

     (b)  Greenhouse workers

         Methyl bromide has been used extensively in the USA since the
    1950s, and, in Western Europe, since the 1960s, in the fumigation of
    soils in greenhouses. This can be hazardous to the health of the
    workers because of the enclosed area in which methyl bromide is
    applied (Roosels et al., 1981). Poisoning incidents have occurred in
    operators and other people entering fumigated areas. An analysis of
    eight severe cases was made by Van den Oever et al. (1978). The signs
    and symptoms followed the usual pattern. Nearly all incidents were
    associated with professional fumigation workers using the injection
    method.

         In a case of acute occupational methyl bromide intoxication, a
    27-year-old man, using methyl bromide in a greenhouse, suffered
    continuous epileptic convulsions for 3 weeks, followed by repeated
    generalized convulsions. Myoclony of the face and the fingers
    accompanied by a complete motor deficiency persisted; there was also
    bilateral deafness (Cantineau et al., 1988).

         In an accident involving nine greenhouse workers (2 women, 7 men;
    aged 21-40 years), exposed to an inadvertent spread of methyl bromide
    during fumigation, two patients needed intensive care for several
    weeks because of severe reactive myoclonus and tonic-clonic
    generalized convulsions (Hustinx et al., 1993).

        Table 52.  Summary of occupational cases of methyl bromide poisoning in California
    as reported by physicians, listed according to work activity and type of illness/injury a
                                                                            
    Year      Work activity                 Systemic  Eye  Skin  Eye/   Total
                                                                 skin   cases
                                                                            
    1950      all occupational              3         0    0     0      3
              exposures

    1986      chamber fumigator             2         0    1     0      3
    1987      chamber fumigator             2         0    0     0      2

    1986      field fumigator               0         1    5     0      6
    1987      field fumigator               1         1    4     0      6
    1987b     field fumigator               6         2    1     0      9

    1986      "tarp" cover fumigator        4         0    1     1     6
    1987      "tarp" cover fumigator        1         0    1     0     2
    1987b     "tarp" cover fumigator        1         0    0     0     1

    1986      coincidental exposure         0         1    0     0     1
    1987      coincidental exposure         4         0    0     0     4
    1987b     coincidental exposure         2         0    0     0     2

    1987      emergency response            2         1    0     0     3
    1987b     personnel                     1         0    0     1     1
                                                                            

    a 1950 and 1987 figures taken from Maddy et al. (1990); 
      1986 figures taken from Edmiston & Maddy (1987)
    b A methyl bromide/chloropicrin formulation was used.
    

    9.4.3  Studies measuring the levels of bromide ion in biological
           fluids and tissues

         There have been a number of studies to investigate whether there
    is a correlation between methyl bromide exposure levels and bromide
    ion concentrations, but the results are conflicting.

    9.4.3.1  Manufacturing

         Ohmori & Hirata (1982), using radioactivation analysis, reported
    mean bromine concentrations in serum (66 µg/g) and hair (11 µg/g) from
    14 methyl bromide workers, and mean bromine concentrations in serum
    (40 µg/g) and hair (4 µg/g) in controls. A worker suspected of methyl
    bromide poisoning had a level of 412 µg/g serum, 13 days after
    exposure.

         Average bromide ion concentrations detected in 36 urine samples
    of workers exposed to methyl bromide were 13.3±7.7 mg/litre compared
    with 7.1±2.1 mg/litre in a non-exposed group (Koga et al., 1991). The
    atmospheric methyl bromide concentrations of exposed workers were
    monitored with passive samplers during their work shifts (8 h). No
    significant correlation was found between these methyl bromide
    readings and the bromide ion concentrations in urine.

    9.4.3.2  Fumigation

         Routine monitoring of bromide levels in the blood of a group of
    fumigators, undertaking both bulk and soil fumigation, was carried out
    in England between 1971 and 1979 (Cornwell, 1979). It was found that
    the plasma bromide levels between January and the end of the year were
    correlated with the number of gas applications, irrespective of the
    type of fumigation work undertaken (Fig. 10). 

    The plasma bromide level was thought to rise as a result of repeated
    exposure to low concentrations of methyl bromide with small amounts
    accumulating in the body faster than the rate of elimination. During
    the Christmas period, when all the men took a break at the same time,
    the plasma bromide levels were substantially reduced. Results from
    October 1974 to January 1978 indicated that average plasma levels
    increased from 15 mg/litre in January to 25 mg/litre in October. Some
    fumigators carried out disproportionally more treatments of stacks,
    containers, and lighters, and reached plasma bromide levels of 30-60
    mg/litre. A relationship between plasma bromide levels and the number
    of fumigation applications was found (Fig. 11).

    FIGURE 10


         Blood bromide levels, EEGs, and transaminases were measured in 33
    methyl bromide workers engaged in soil disinfection inside
    greenhouses. Blood bromide varied between 4 and 23 mg/litre (Verberk
    et al., 1979).

         In a study of the bromide ion concentration in the plasma of 39
    methyl bromide workers, a mean level of 6.9 mg/litre was measured
    compared with controls (100 workers) who had a mean of 3.7 mg/ litre
    (Yamano et al., 1987).
    FIGURE 11


         Tanaka et al. (1991) measured ambient methyl bromide
    concen-trations and urinary bromine concentrations at various plant
    quarantine fumigation sites in Japan. The geometric mean for exposed
    workers was 9.0±1.85 mg/litre while the arithmetic mean for a matched
    control population was 6.3±2.5 mg/litre. The authors found a
    statistically significant positive correlation between the ambient
    methyl bromide concentrations collected with a personal sampling
    device and the urinary concentrations.

    9.4.4  Haemoglobin adducts as a biological index to methyl bromide
           exposure

         Iwasaki et al. (1989) determined the haemoglobin adduct
    (haemoglobin MeCys) in methyl bromide manufacturing workers, and
    examined its effectiveness as a biological index of exposure to methyl
    bromide. Methyl bromide reacts with cysteine to form
     S-methylcysteine (MeCys) in haemoglobin (Djalali-Behzad et al.,
    1981). It was suggested that determination of MeCys in haemoglobin
    could detect previous methyl bromide exposure levels so low that they
    were not detected by a special medical check-up (Iwasaki et al.,
    1989). Haemoglobin adducts have a life span of about 2 months, so
    workers only intermittently exposed to methyl bromide would also be
    detected in such a survey. Previous studies by the same authors showed
    individual differences in mice in the levels of MeCys within each dose
    and time series group (Iwasaki, 1988a,b). These individual differences
    may be caused by the differential susceptibility of haemoglobin in red
    blood cells or individual differences in methyl bromide metabolism.
    These differences were found to be minor in the human study (Iwasaki
    et al., 1989).

         Results from animal studies (Xu et al., 1990) supported the
    suggestion of Iwasaki et al. (1989) that the Hb adduct of methyl
    bromide might be a useful parameter in the biological exposure
    monitoring of methyl bromide workers.

    9.4.5  Neurobehavioural and other studies

         Anger et al. (1986) carried out a neurobehavioural study on soil
    fumigators who were exposed to 9 mg methyl bromide/m3 over an 8-h
    day and structural fumigators who were exposed to 0-9 mg/m3 for 1.5
    h per day. The fumigators, who reported a significantly higher
    prevalence of 18 symptoms, consistent with methyl bromide toxicity,
    than the controls, did not perform so well on 23 out of 27 behavioural
    tests, and were significantly lower on one test of finger sensitivity
    and one of cognitive performance.

         EEGs and transaminases were measured in 33 methyl bromide workers
    engaged in soil disinfection inside greenhouses in the Netherlands.
    Symptoms of methyl bromide intoxication were determined by means of a
    specially designed questionnaire. A general neurological examination
    was performed. No differences compared with controls were found, with
    the exception of slight electro-encephalographic changes in 10 workers
    involving diffuse increase of beta and theta activity. Workers with
    abnormal EEGs had higher blood bromide levels (geometric mean 10.9
    mg/litre compared with a mean of 8.2 mg/litre in the other workers;
    the difference was statistically significant ( P <0.05) (Verberk et
    al., 1979).

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

    10.1  Human exposure

         Human exposure to methyl bromide occurs predominantly as an
    occupational hazard, particularly during soil or bulk fumigation, but
    also during manufacture. Individuals in the vicinity of fumigated
    fields or buildings may also be exposed. Methyl bromide has widespread
    use for fumigating post-harvest foods, such as cereals, spices,
    dried-fruits, and nuts, as well as fresh fruits and vegetables. The
    determination of levels of methyl bromide and inorganic bromide in the
    fumigated food is important for the assessment of possible risks for
    human and animal health. Methyl bromide levels in food commodities
    usually decrease rapidly after aeration, but may be detected for some
    weeks after treatment. Fumigation with methyl bromide results in
    increased levels of inorganic bromide in food commodities and,
    equally, in produce grown on fumigated soils. Fumigant dosage
    standards should be adhered to, so that the bromide levels do not
    exceed the recommended limits.

         The major health concern is from acute exposure.

         Delayed onset of symptoms may occur. Fatal poisoning has resulted
    from exposures to relatively high concentrations (from 33 000 mg/m3
    or 8600 ppm onwards) of methyl bromide vapours. Non-fatal poisoning
    has resulted from exposure to concentrations as low as 390-1950
    mg/m3 (100- 500 ppm). Organs affected by exposure include the
    nervous system, lung, nasal mucosa, kidney, eye, and skin. There are
    no epidemiological data on reproductive toxicity and carcinogenicity
    in humans. There are no data on any human health effects of methyl
    bromide residues in food or drinking-water.

    10.1.1  Relevant animal studies

         Methyl bromide is very toxic for all animal species by all routes
    of administration studied. Deaths from exposure follow a steep
    dose-response curve. LC50 (1-h) values for mice and rats are 4680
    and 7300 mg/m3, respectively.

         Deaths and neurotoxicity occur within hours or days after a
    single inhalation exposure at high concentrations. Studies on mice
    show that more prolonged exposure at low concentrations (6 h/day; 389
    mg/m3) may also produce neurotoxicity or deaths, appearing with a
    delayed onset of several months.

         Absorption and distribution to various tissues is rapid, as is
    elimination. The metabolic pathways and mode of action are unknown.

         The principal toxic effects associated with lethality occur in
    the brain and kidney. Histopathology of the brain shows necrosis of
    granular cells of the cerebellum in mice and rats and neuronal

    necrosis in the cerebral cortex, hippocampus, and thalamus, in rats.
    The lowest doses at which these lesions were observed were 250
    mg/m3, 6 h/day, for 2 years, in mice, and, 622 mg/m3, 6 h/day, for
    5 weeks, in rats. In the kidney, necrosis of the convoluted tubule
    epithelium occurs at doses of 599 mg/m3, 6 h/day, for 2 weeks, in
    mice, and 1712 mg/m3, 6 h/day, for 2 weeks, in rats. Other effects
    are observed in the heart (degeneration of focal necrosis), nose
    (necrosis of olfactory epithelium), testis (degeneration of
    seminiferous tubules), and other organs. In non-lethal exposure, nasal
    irritation and neuro-toxicity (including histopathological lesions)
    are the major toxic effects.

         No teratogenic effects have been observed in rats or rabbits.
    Embryotoxicity occurred in rats and rabbits only at doses that were
    also maternally toxic. In a rat multigeneration study, there were
    reductions in the fertility index in the second generation, when the
    animals were exposed to 117 or 350 mg/m3 (30 or 90 ppm) for 6 h/
    day, but effects were not observed following exposure to 12 mg/m3 (3
    ppm) for 6 h/day.

         Methyl bromide was mutagenic in several  in vivo and  in vitro
    assays.

         Long-term inhalation studies on rats and mice did not reveal any
    evidence of carcinogenicity. Lesions originally interpreted as
    carcinomas of the forestomach in rats, following gavage
    administration, were shown in a subsequent study to regress after
    termination of treatment, and were considered not relevant for human
    risk assessment.

    10.2  Environment

         Methyl bromide is predominantly a naturally occurring compound.
    Oceans are believed to be a major natural source of methyl bromide.
    Another source(s) may exist in the tropics, which is yet to be
    explained. Anthropogenic sources from fumigation and, to a much lesser
    extent, motor vehicles (from the combustion of organic bromine
    additives in leaded petrol) add to these. Present data indicate that
    the globally averaged atmospheric abundance of methyl bromide is
    between 9 and 13 pptv, equivalent to a total atmospheric loading of
    150-220 thousand tonnes. If the atmospheric lifetime is two years
    (assuming only atmospheric removal processes are significant),
    anthropogenic sources of methyl bromide represent about 25% (±10%) of
    the total emissions. The world production of methyl bromide in 1990
    was 69 000 tonnes, having increased at a rate of 6% per year from 1984
    to 1990. About 50% of the methyl bromide produced is released into the
    atmosphere during, or after, use. Although methyl bromide reacts with
    the hydroxyl radical in the troposphere, some methyl bromide is
    transferred by upward diffusion to the stratosphere, where it
    photolyses. Active bromine species react with ozone in the lower
    stratosphere and are partly responsible for the depletion of the ozone

    layer. It is estimated that anthropogenic releases of methyl bromide
    cause about 3% of the present total stratospheric ozone loss.

         Methyl bromide is used for soil fumigation (about 77%), for
    quarantine, commodity fumigation (12%), for structural fumigation
    (5%), and for chemical intermediates (6%).

         In soil, methyl bromide is degraded by hydrolysis and microbial
    activity. The remainder (about 50%) eventually dissipates into the
    atmosphere. The degradation product, principally as inorganic bromide,
    remains as a residue in soil.

         Methyl bromide has herbicidal properties. In the vicinity of
    greenhouses and fumigated structures, phytotoxic effects may occur.
    Visible damage to the leaves of lettuce (a sensitive test plant) was
    noticed at 400 mg/m3.

         Soil fumigation using methyl bromide (with 2% chloropicrin)
    affects both target and non-target organisms: various soil microflora
    and fauna are adversely affected, at least temporarily, by fumigation.
    High mortality of non-target insects has been noticed from fumigation
    under plastic sheeting. Methyl bromide could be detected in different
    soil types up to 3 weeks after the treatments, the highest levels
    being found in the upper layers (0-40 cm) of the soil.

         Methyl bromide is highly toxic for aquatic organisms, though it
    is generally of no risk to the aquatic environment. The lowest EC50
    or LC50 values reported are 2.8 mg/litre for algae, 1.7 mg/litre for
    daphnids, and 0.3 mg/litre for fish. NOEC levels, derived from
    long-term studies, as low as 0.06 mg/litre have been reported for
    daphnids and fish. Toxic concentrations are not expected to be reached
    under normal circumstances, because most of the methyl bromide applied
    on soil is degraded or lost, due to evaporation, before it reaches
    surface water via run-off. Only in very special situations (leaching
    of greenhouse soils to reduce inorganic bromide residues), can levels
    of methyl bromide in the mg/litre range occur in water. Concentrations
    of up to 9.3 mg methyl bromide/litre were measured in drainage water.

         Similarly, relatively high levels of bromide (up to 72 mg/litre)
    that could adversely affect aquatic organisms were measured in
    drainage water from greenhouses. Long-term exposure to bromide ion
    resulted in an EC50 value of 27 mg bromide/litre for daphnia and the
    lowest NOEC for different fish species was 25 mg bromide/litre.

    11.  RECOMMENDATIONS FOR THE PROTECTION OF HUMAN HEALTH AND THE
         ENVIRONMENT

    11.1  Human health protection

         In most countries, methyl bromide is strictly regulated for
    application as a fumigant for soil, commodities, and structural
    purposes. Adherence to good practices and guidelines should ensure no
    adverse effects on persons exposed occupationally. Considerable care
    should be taken by manufacturers in the production process of methyl
    bromide and by suppliers in its transfer and use.

         Methyl bromide does not pose a significant risk for the general
    population. It is, however, a very toxic substance and precautions
    have to be taken: exposure of the general public should be avoided
    through adequate precautions in fumigated buildings, greenhouses, and
    stores used for commodity fumigation. Fumigated premises should be
    clearly marked, in order to prevent accidental exposure of
    individuals.

    11.2  Environmental protection

         Emission of methyl bromide from anthropogenic sources should be
    reduced as far as possible. It is, therefore, desirable to reduce
    emissions from soil, commodity, and structural fumigation.
    Improvements should be sought in these areas:

         (1)  improved injection methods;

         (2)  better barrier films;

         (3)  better measurement of the efficacy of methyl bromide, with
              the goal of lower dosage rates where possible.

         For commodity and, possibly, for structural fumigation,
    techniques should be developed to:

         (1)  seal fumigation chambers more tightly;

         (2)  capture and recycle fumigation gas.

    11.3  Recommendations for further research

         There is a need for:

         -    study of the metabolism and toxic mechanisms of methyl
              bromide;

         -    a postnatal behavioural study;

         -    a human epidemiological study including exposure  
              assessment;

         -    development of a treatment protocol for cases of human
              poisoning.

         Effects of methyl bromide on the depletion of the ozone layer are
    not yet entirely understood, indicating a need for:

         -    studies quantifying the distribution sources of methyl  
              bromide and other organic bromine compounds.

         There is also a need for:

         -    a study of the impact of sea spray on the formation of
              organic bromine compounds;

         -    a study on the degradation products of methyl bromide in the
              troposphere;

         -    further study of the rate constant for the reaction with
              OH-;

         -    studies on soil fumigation with the aim of reducing  
              emissions while keeping efficacy.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    12.1  FAO/WHO

         The toxicology of methyl bromide was evaluated by the FAO/WHO
    Joint Meeting on Pesticide Residues in 1965 and 1966 (FAO/ WHO, 1965
    a,b; WHO, 1967, a,b). In 1965, no acceptable daily intake (ADI) was
    allocated, but, in 1966, an ADI of 1 mg/kg body weight, as bromide
    ion, was established. In 1988, the JMPR evaluated the toxicology of
    the bromide ion (FAO/WHO 1988a,b) and concluded that the level causing
    no toxicological effect was:

         Rat:         240 ppm, equivalent to 12 mg bromide/kg body weight
                      per day

         Human:       9 mg bromide/kg body weight per day 

         The acceptable daily intake (ADI) of 1 mg/kg body weight was
    confirmed.

    12.2  IARC

         The carcinogenic risks for humans were evaluated by an
    International Agency for Research on Cancer ad hoc expert group in
    1986. The evaluation was updated in 1987 and it was concluded that
    there was inadequate evidence for carcinogenicity to humans and
    limited evidence for carcinogenicity to animals; the overall
    evaluation of carcinogenicity to humans was "not classifiable" [group
    3] (IARC, 1986, 1987).

    12.3  UNEP

    In 1992, the United Nations Environment Programme evaluated methyl
    bromide on behalf of the Contracting Parties to the Montreal Protocol
    (UNEP, 1992). The executive summary of the evaluation reads:

                "The report covers the current understanding of the impact
         of methyl bromide on the ozone layer and on the uses of, and
         alternatives to, methyl bromide." 

    It was requested by the United Nations Environment Programme on behalf
    of the Parties to the Montreal Protocol. The report includes
    information presented and discussed at the International Methyl
    Bromide Science Workshop held in Washington, DC, on 2-3 June 1992, and
    at the International Workshop on Alternatives and Substitutes to
    Methyl Bromide held in Washington, DC, on 16-18 June 1992.

         The current state of scientific knowledge concerning bromine
    compounds in the atmosphere is considerably less developed than the
    corresponding understanding of chlorine compounds. In addition, the
    evaluation of the alternatives and substitutes to methyl bromide as a

    fumigant is in an earlier stage than that for chlorofluorocarbons
    (CFCs), methylchloroform, carbon tetrachloride, and halons.

         Methyl bromide is used as a fumigant for soils, commodities, and
    structures. It is currently vital for the economic viability of
    certain agricultural production (especially strawberries, tomatoes,
    peppers, tobacco, eggplants, nursery stock, vines, and turf) and for
    the quarantine treatment of certain products in international trade.
    Many developing countries are particularly dependent on the export of
    products currently fumigated using methyl bromide, before shipment and
    at ports of entry.

         Total annual production and sales of methyl bromide for
    fumigation have increased from about 42 000 tonnes to about 63 000
    tonnes between 1984 and 1990. Combining the approximate methyl bromide
    use-pattern data with the currently estimated fraction that escapes to
    the atmosphere from each use (soils: 80% of use, 50 % emitted;
    commodities: 15 % of use, <80 % emitted; and structural: 5 % of use,
    80% emitted) indicates that about half of the methyl bromide used as
    a fumigant is emitted into the atmosphere. Based on current
    understanding, this implies an anthropogenic emission from fumigation
    applications of about 30 thousand tonnes in 1990, which represents
    25±10 % of the total (natural and anthropogenic) emissions.

         Ozone destruction by bromine is more efficient on a per molecule
    basis than destruction by chlorine by a factor of 30-60. Therefore, 1
    part per trillion by volume (pptv) of bromine is equivalent to
    0.03-0.06 parts per billion by volume (ppbv) of stratospheric
    chlorine.

         The current best estimate of the steady-state value of the Ozone
    Depletion Potential (ODP) for methyl bromide is 0.7. Because of the
    short atmospheric lifetime of methyl bromide, its relative impact on
    ozone is expected to be much greater over the next decade (when
    chlorine abundances and ozone losses are predicted to reach their
    maximum) than is indicated by its steady-state ODP.

         There are significant uncertainties in the atmospheric budget and
    ODP of methyl bromide, especially the quantification of possible
    oceanic and terrestrial surface removal processes and the rate of
    formation of unreactive bromine in the stratosphere.

         Model calculations suggest that anthropogenic emissions of methyl
    bromide used for fumigation applications could have accounted for
    about one-twentieth to one-tenth of the current observed global ozone
    loss of 4-6% and could grow to about one-sixth of the predicted ozone
    loss by the year 2000, if methyl bromide emissions continue to
    increase at the present rate of about 5-6% per year.

         The anthropogenic contribution to the current atmospheric
    abundance of methyl bromide from fumigation applications is about 3

    pptv, which is equivalent to 0.09-0.18 ppbv of stratospheric chlorine.
    An advance of the CFC and carbon tetrachloride phaseout schedule by
    three years would reduce the peak chlorine loading by 0.18 ppbv. 

         Therefore, elimination of methyl bromide used as a fumigant could
    provide an ozone-layer protection equivalent to that of an advance of
    the CFC and carbon tetrachloride phaseout schedule by about 1.5-3
    years.

         There is no single alternative to methyl bromide in the broad
    spectrum of applications for which it is currently used. There are,
    however, many alternative chemicals and procedures for specific
    applications. The introduction of some chemical alternatives may
    require government approval, which could be a lengthy process.

         Rough estimates indicate that a significant fraction (from as low
    as 30% to as high as 90%), albeit uncertain, of methyl bromide used
    for soil fumigation could be replaced by chemical substitutes during
    the 1990s; that a substantial proportion of emissions from fumigation
    chambers could be captured and recycled or destroyed; that a small
    fraction (1-2%) of methyl bromide emissions could be eliminated by
    better procedures during tank filling; and that significant reductions
    in emissions could be made using other alternatives or techniques,
    alone, or in combination. However, there are some applications for
    which there are limited or no alternatives, including some
    agricultural situations that have developed a dependence on methyl
    bromide, quarantine treatments, and some structural fumigation uses.

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    RESUME

    1  Propriétés physiques et chimiques, méthodes d'analyse

         A la température ambiante et sous la pression normale, le bromure
    de méthyle est un gaz incolore dont le point d'ébullition est
    d'environ 4 °C. Il est plus lourd que l'air et on peut facilement le
    liquéfier en-dessous du point critique. Il est inodore sauf à fortes
    concentrations auquel cas il dégage une odeur chloroformique. Il est
    ininflammable à l'air, sauf aux concentrations comprises entre 10 et
    16%, mais brûle dans l'oxygène. Le bromure de méthyle n'est que
    légèrement soluble dans l'eau mais facilement soluble dans les autres
    solvants courants. Il peut pénétrer dans de nombreuses substances
    comme le béton, le cuir, le caoutchouc et certaines matières
    plastiques.

         Le bromure de méthyle s'hydrolyse en méthanol et acide brom-
    hydrique en solution aqueuse, la vitesse d'hydrolyse dépendant du pH.
    C'est un agent de méthylation efficace qui réagit sur les amines et
    les composés soufrés. La plupart des métaux sont inertes au bromure de
    méthyle pur et sec mais des réactions de surface peuvent avoir lieu
    sur le zinc, l'étain, l'aluminium et le magnésium en présence
    d'impuretés ou d'humidité. Des réactions explosives ont été observées
    avec l'aluminium et le diméthylsulfoxyde.

         Le bromure de méthyle existe dans le commerce sous forme de gaz
    liquéfié. Les formulations destinées à la fumigation des sols
    contiennent de la chloropicrine (2%) ou de l'acétate d'amyle (0,3%)
    comme agents d'alerte. D'autres formulations peuvent contenir jusqu'à
    70% de chloropicrine ainsi que d'autres fumigants ou hydrocarbures
    comme diluants. Pour la fumigation des marchandises, on utilise du
    bromure de méthyle à 100%.

         Il existe des méthodes d'analyse pour le dosage du bromure de
    méthyle dans l'air, l'eau, le sol, les produits alimentaires et la
    nourriture pour animaux. Parmi les méthodes directes de dosage du
    bromure de méthyle dans l'air sur le terrain, on peu citer les
    analyseurs de gaz par conductivité thermique, les tubes de détection
    colorimétrique, les analyseurs à infrarouge, et les détecteurs par
    photo-ionisation. Pour les dosages de routine, on recommande la
    chromatographie en phase gazeuse avec détection par capture
    d'électrons, éventuellement couplée à la spectrométrie de masse pour
    la confirmation au laboratoire.

         Pour le dosage par chromatographie en phase gazeuse du bromure de
    méthyle dans l'eau, on peut utiliser diverses techniques d'injection
    (purge, piégeage, espace de tête par exemple). Pour le dosage en
    routine du bromure de méthyle dans les produits alimentaires, on
    recommande de procéder à une extraction par un mélange d'acétone et
    d'eau puis à une chromatographie en phase gazeuse sur colonne

    capillaire selon la technique de l'espace de tête avec détection par
    capture d'électrons. Etant donné que le bromure de méthyle se
    transforme en partie en bromure dans le sol, les denrées alimentaires
    et les produits biologiques, l'ouvrage étudie également les méthodes
    de recherche et de dosage des bromures. Parmi les méthodes utilisées
    pour le dosage des bromures dans diverses matrices, on peut citer les
    méthodes colorimétriques, la spectroscopie de rayons X, la
    potentiométrie, l'analyse par activation neutronique, la
    chromatographie en phase gazeuse ainsi que la chromatographie en phase
    liquide à haute performance (HLPC).

    2  Sources d'exposition humaine et environnementale

         On pense que les océans sont la source essentielle de bromure de
    méthyle. La principale source d'origine humaine en est la fumigation
    des sols et de l'intérieur des habitations. Les véhicules à moteur qui
    utilisent de l'essence au plomb émettent également une petite quantité
    de bromure de méthyle.

         En 1990, la consommation mondiale de bromure de méthyle a dépassé
    67 millions de kg soit une augmentation de 46% depuis 1984. On produit
    généralement le bromure de méthyle par action du méthanol sur l'acide
    bromhydrique et, dans certains procédés, on l'obtient à côté du
    tétrabromobisphénol A. Le bromure de méthyle est généralement stocké
    et transporté à l'état liquide sous pression dans des récipients
    d'acier.

         Le bromure de méthyle est utilisé à environ 77% pour la
    fumigation des sols, à 12% pour la fumigation des marchandises et
    notamment des marchandises soumises à quarantaine, à 5% pour la
    fumigation des construction et à 6% comme intermédiaire dans
    l'industrie chimique.

         Sous forme gazeuse, il est utilisé comme fumigant des sols, soit
    en plein champ, soit sous serre pour la destruction des ravageurs.
    Sous forme liquide, on l'applique avant la plantation, soit par
    injection dans le sol, soit en plaçant des jattes pleines de bromure
    de méthyle sous une couverture en plastique et en laissant le produit
    s'évaporer sur place (méthode à froid) ou par chauffage (méthode à
    chaud). Les méthodes autorisées varient selon le pays. Le type de
    matière plastique utilisé est également important.

         Les doses de bromure de méthyle à appliquer dépendent égale-ment
    des normes légales en vigueur dans les différents pays, de l'espèce de
    ravageur à détruire (type, ampleur de l'infestation), de la récolte
    suivante, du type de sol et de la couverture plastique utilisée (durée
    de couverture et nature de la matière plastique). Le bromure de
    méthyle est généralement épandu sur le sol à des doses comprises entre
    50 et 100 g/m2.

         En fumigation spatiale, le bromure de méthyle est utilisé sur les
    produits agricoles (par exemple fourrage, céréales, noix, etc.) ainsi
    que pour la destruction des termites et des rongeurs. Pour la plupart
    des denrées stockées dans des pièces et des silos fermés ou sous une
    couverture étanche au gaz, on utilise des doses de 16 à 30 g de
    bromure de méthyle par m3. Après la fumigation, il faut aérer les
    locaux pendant un certain temps. Cette fumigation est également
    importante dans le cas des légumes et des fruits frais soumis à
    quarantaine.

         Parmi les utilisations industrielles du bromure de méthyle, on
    l'emploie en synthèse organique, généralement en tant qu'agent de
    méthylation, ou comme solvant à bas point d'ébullition, par exemple
    pour l'extraction de l'huile de noix et de différentes graines ou
    celle des huiles essentielles. L'emploi du bromure de méthyle comme
    réfrigérant ou comme produit extincteur à usage général, n'a plus
    qu'un intérêt historique.

    3  Transport, distribution et transformation dans l'environnement

         Le bromure de méthyle est naturellement présent dans l'atmosphère
    et les quantités qui résultent de l'activité humaine viennent s'y
    ajouter. Le bromure de méthyle réagit en petites quantités sur les
    radicaux hydroxyles de la troposphère mais il en passe une certaine
    proportion dans la stratosphère par diffusion verticale. Là, c'est la
    photolyse qui gagne en importance, puisqu'elle devient le mécanisme
    dominant d'élimination du bromure de méthyle dans la partie basse de
    la stratosphère. Il en résulte la formation de brome actif qui réagit
    sur l'ozone stratosphérique et pourrait être en partie responsable de
    la destruction de la couche d'ozone.

         Dans le sol, le bromure de méthyle est partiellement hydrolysé en
    ion bromure. Après fumigation au bromure de méthyle, on peut lessiver
    le sol à l'eau afin d'éviter que les ions bromure formés ne soient
    fixés par les végétaux plantés après stérilisation du sol. Cet
    accroissement de la concentration en bromure peut poser des problèmes
    si l'on utilise pour cela des eaux de surface. Le bromure de méthyle
    peut diffuser à travers les canalisations d'eau potable en
    polyéthylène si le sol environnant a subi une fumigation avec ce
    produit.

         Dans le sol, le bromure de méthyle peut diffuser jusqu'à une
    profondeur de 0,8 m selon le type de sol, la dose d'emploi, le mode
    d'épandage et la durée de fumigation, la couche supérieure du sol en
    retenant la majeure partie. Le transport du gaz s'effectue par
    écoulement ou diffusion moléculaire, mais il est également influencé
    par le présence de processus simultanés de piégeage comme une sorption
    ou une dissolution, et qui peuvent être irréversibles comme
    l'hydrolyse. La quantité de bromure de méthyle transformée en bromure
    dépend principalement de la teneur du sol en matières organiques. Les

    bromures ainsi produits sont largement solubles dans l'eau et peuvent
    être fixés par les plantes ou descendre plus profondément dans le sol
    par lessivage.

         La quantité de bromure qui s'accumule dans les plantes dépend de
    divers facteurs comme la dose d'emploi, la durée d'exposition, le
    débit d'aération, les propriétés physiques et chimiques du sol, la
    climatologie (température et précipitations), l'espèce végétale et la
    nature du tissu végétal. En particulier, les légumes-feuilles comme la
    laitue et les épinards, peuvent fixer des quantités relativement
    importantes d'ions bromure sans présenter de symptômes de
    phyto-toxicité. En revanche, d'autres plantes cultivées comme les
    oeillets, les plants d'agrumes, le coton, le céleri, les poivrons ou
    les oignons sont particulièrement sensibles à la fumigation par le
    bromure de méthyle.

         Le bromure de méthyle et ses produits de réaction, dont on n'a
    considéré jusqu'ici que les bromures, peuvent pénétrer dans la chaîne
    alimentaire de deux manières; soit par consommation de plantes
    cultivées dans des serres ou dans des champs traités par fumigation
    avant la plantation, soit par consommation de produits alimentaires
    traités au bromure de méthyle pendant l'entreposage. A partir d'une
    certaine concentration, les bromures peuvent être dangereux pour la
    santé et il existe un seuil de tolérance pour le bromure présent dans
    les denrées alimentaires. La concentration des autres produits de
    réaction n'a pas été étudiée.

         Dans le sol, le bromure de méthyle subit une dégradation par
    hydrolyse et décomposition microbienne. La constante de vitesse
    d'hydrolyse varie avec la température et le pH et augmente avec
    l'intensité de la lumière.

         Le coefficient de partage octanol/eau (log Pow) du bromure de
    méthyle est égal à 1,19, ce qui indique que sa bioaccumulation est
    faible.

         Le bromure de méthyle qui n'est pas décomposé lors de la
    fumigation pénètre dans la troposphère et gagne la stratosphère par
    diffusion verticale. Il ne semble pas qu'il existe un important
    gradient de concentration vertical du bromure de méthyle dans la
    troposphère, mais sa concentration diminue rapidement dans la basse
    stratosphère où il subit une photolyse.

    4  Concentrations dans l'environnement et exposition humaine

         La concentration du bromure de méthyle mesurée dans l'air de
    zones inhabitées, varie de 40 à 100 ng/m3 (10 à 26 pptv), les
    valeurs pour l'hémisphère nord étant supérieures à celles à celles que
    l'on trouve dans l'hémisphère sud. La plupart des valeurs vont de 9 à
    15 pptv. Des différences saisonnières ont été constatées à l'occasion
    d'un certain nombre d'études. Dans les zones urbanisées et

    industrialisées, les concentrations sont beaucoup plus élevées avec
    des valeurs moyennes allant jusqu'à 800 ng/m3 voire jusqu'à 4 µg de
    bromure de méthyle par m3. A proximité des champs et des serres, on
    constate, lors de la fumigation et de l'aération, des concentrations
    de bromure de méthyle beaucoup plus élevées, des valeurs de 1 à 4
    mg/m3 ayant été mesurées dans une étude à des distances allant
    jusqu'à 20 m d'une serre, quelques heures après l'injection du
    produit; quatre jours plus tard, la concentration était tombée au
    dixième de cette valeur.

         Dans un échantillon d'eau de mer prélevé en surface, on a trouvé
    une concentration de bromure de méthyle de 140 ng/litre. Dans des
    échantillons d'eau littorales de la Mer du Nord, la concentration
    moyenne en ions bromure était de 18,4 mg/litre; dans les cours d'eau
    de l'arrière pays, cette concentration était beaucoup plus faible,
    sauf là où l'on pratiquait la fumigation par le bromure de méthyle ou
    dans les zones polluées par les rejets industriels. Dans les eaux de
    drainage d'une serre hollandaise, on a signalé des concentrations de
    9,3 mg de bromure de méthyle par litre et de 72 mg d'ions bromure par
    litre. Dans les eaux rejetées par une serre belge, on a trouvé après
    fumigation une concentration de 280 mg de bromure par litre.

         La teneur naturelle du sol en bromure dépend du type de ce sol
    mais elle est généralement inférieure à 10 mg/kg. La teneur en résidus
    de bromure dans les sols traités dépend du traitement, de la dose
    d'emploi, du type de sol, des précipitations, du lessivage par l'eau
    et de la température.

         Il peut y avoir de fortes concentrations de bromure de méthyle ou
    d'ions bromure dans les cultures vivrières poussant sur des sols
    préalablement traités au bromure de méthyle ou qui ont subi une
    fumigation après récolte.

         Plus rarement, on a constaté que les concentrations de bromure
    dans les légumes frais cultivés sur des sols qui avaient traité avec
    du bromure de méthyle, dépassaient les teneurs en résidus autorisées.
    Dans certains pays, il est interdit de cultiver des légumes sur des
    sols traités de cette manière.

         On utilise largement le bromure de méthyle pour la fumigation des
    denrées alimentaires après récolte, par exemple les céréales et
    notamment le froment, les épices, les noix, les fruits secs ou frais
    et le tabac. La concentration en bromure de méthyle diminue en général
    rapidement après aération et au bout de quelques semaines on ne peut
    plus déceler de résidus. Certains produits comme les noix et les
    graines ou des aliments gras comme le fromage ont tendance à retenir
    le bromure de méthyle et le brome minéral.

         Il peut y avoir exposition humaine au fumigant lui-même comme aux
    résidus d'ions bromure. Il pourrait également y avoir un risque
    d'accroissement de la concentration du bromure de méthyle ou des

    bromures dans l'eau des puits peu profonds situés à proximité de
    terrains où l'on pratique la fumigation par le bromure de méthyle.

         Les personnes qui vivent à proximité immédiate des champs, des
    serres ou des entrepôts traités au bromure de méthyle pourraient
    courir le risque d'une exposition au gaz. Il existe également un
    risque individuel pour les personnes qui pénètrent accidentellement ou
    délibérément dans une maison traitée contre la vermine avant que l'on
    ait annoncé qu'il n'y a plus de danger. 

         L'exposition professionnelle au bromure de méthyle est le risque
    le plus probable pour les travailleurs lors de la production, du
    remplissage des récipients et des opérations de fumigation. Seuls les
    fumigateurs sont désormais considérés comme constituant un groupe à
    haut risque étant donné que, sur les lieux de production, des mesures
    de sécurité très strictes sont appliquées. Ceux qui sont employés au
    traitement des constructions peuvent être exposés à des concentrations
    beaucoup plus élevées que les valeurs-seuil après 24 heures d'aération
    (80 à 2000 mg/m3). Cependant, un ouvrier expérimenté utilisera un
    équipement protecteur approprié. Les travailleurs agricoles qui
    procèdent à la fumigation du sol peuvent être exposés pendant de
    longues durées à des doses transitoires élevées de bromure de méthyle.
    De par la nature même du processus, le traitement d'une serre peut
    exposer les travailleurs à d'importantes concentrations de bromure de
    méthyle (100-1200 mg/m3). Il est vrai cependant, que pour combattre
    des risques inhérents aux diverses opérations de fumigation, on a
    établi des règles de sécurité très strictes qui impliquent notamment
    le port d'un équipement protecteur. Cela n'empêche pas des accidents
    de se produire par suite d'une exposition excessive.

    5  Cinétique et métabolisme

         Des études au cours desquelles on a fait inhaler du bromure de
    méthyle à des rats, des chiens beagle et des volontaires humains ont
    révélé que le produit était rapidement résorbé au niveau pulmonaire.
    La résorption est également rapide chez le rat après administration
    par voie orale.

         Une fois résorbé, le bromure de méthyle ou ses métabolites se
    répartissent rapidement dans de nombreux tissus, notamment les
    poumons, les surrénales, les reins, le foie, les fosses nasales, le
    cerveau, les testicules et les tissus adipeux. Lors d'une étude par
    inhalation sur des rats, on a constaté que la concentration tissulaire
    du bromure de méthyle passait par un maximum une heure après
    l'exposition puis diminuait rapidement, aucune trace n'étant plus
    décelable au bout de 48 heures. On n'a pas encore élucidé le
    métabolisme du bromure de méthyle inhalé mais le glutathion pourrait
    jouer un rôle.

         Dans les tissus de plusieurs espèces, notamment l'homme, on a
    observé une méthylation des protéines et des lipides après exposition
    au bromure de méthyle par voie respiratoire. On a également mis en
    évidence la présence d'adduits méthylés de l'ADN après exposition de
    rongeurs ou de cellules de rongeurs  in vivo ou  in vitro.

         Lors d'études d'inhalation avec du bromure de méthyle marqué par
    du [14C], on a observé que la principale voie d'élimination du
    radiocarbone était l'exhalation de 14CO2. La quantité de
    radiocarbone retrouvée dans le urines a été moindre. Après
    administration par voie orale de bromure de méthyle, on a constaté que
    c'était par la voie urinaire que le 14C était principalement
    excrété.

         Le système nerveux central est également est un organe cible
    important du bromure de méthyle. La neurotoxicité de ce composé est
    sans doute liée à une modification de la teneur en monoamines, en
    acides aminés et éventuellement en catécholamines.

    6  Effets sur les êtres vivants dans leur milieu naturel

         L'une des utilisations commerciales du bromure de méthyle
    consiste dans la destruction des nématodes, des mauvaises herbes et
    des champignons terricoles qui causent des maladies chez les plantes
    comme la fonte des semis, et divers types de pourritures et de
    verticillioses.

         Peu d'études ont été consacrées aux effets du bromure de méthyle
    sur les organismes aquatiques car ce composé n'est lui-même que peu
    soluble dans l'eau. Les valeurs de la CL50 vont de 17 mg/litre pour
     Cyprinus carpio L. sur 4 heures, à 1,2 mg/litre pour  Poecilia
     reticulata sur 48 heures. Aux concentrations mortelles, il est
    probable que la mort est causée par des lésions au niveau des
    branchies et de l'épithélium buccal.

         Après fumigation par le bromure de méthyle, il se forme des ions
    bromure que l'on retrouve dans l'eau après lessivage. Ces ions bromure
    ont été à l'origine d'intoxications aiguës chez différents organismes
    dulçaquicoles à des concentrations allant de 44 à 5800 mg de
    Br-/litre; la concentration sans effets observables lors d'épreuves
    à long terme allant de 7,8 à 250 mg de Br-/litre. Les ions bromure
    ont également un effet perturbateur marqué sur la reproduction des
    crustacés et des poissons.

         En fumigation, on peut appliquer du bromure de méthyle
    directement sur les semis, sur les boutures ou sur les plantes après
    récolte, pour les débarrasser des parasites pendant le transport et
    l'entreposage. Si le taux d'humidité ou la température sont trop
    élevés, il peut y avoir retard à la germination, voire perte de la
    capacité germinative. 

         Certains végétaux, en particulier les légumes-feuilles, sont
    sensibles à la fumigation par le bromure de méthyle, soit par excès de
    bromure dans le sol, soit indirectement en raison des effets de ce
    composé sur la microflore terricole. Quelquefois, le bromure de
    méthyle a au contraire un effet positif sur les végétaux car il peut
    stimuler leur croissance et améliorer le rendement des cultures.

         La fumigation par le bromure de méthyle détruit non seulement les
    parasites visés mais également une partie de la flore, des
    gastéropodes, des arachnides et des protozoaires terricoles.

         On l'utilise de préférence à d'autres insecticides en raison de
    son aptitude à pénétrer rapidement et profondément dans la masse des
    produits traités et dans les sols. Les doses d'emploi pour traiter les
    marchandises entreposées vont essentiellement de 16 à 100 g/m3
    pendant deux à trois jours, selon la température. La dose nécessaire
    pour la destruction des oeufs et des pupes est plus élevée que pour
    les insectes adultes. La tolérance varie selon les diverses espèces
    d'insectes, selon leurs divers stades de développement et chez une
    même espèce, en fonction de la souche.

         On ne dispose d'aucune donnée relative aux effets directs du
    bromure de méthyle sur les oiseaux et les mammifères sauvages.

    7  Effets sur les animaux d'expérience

         Des études d'inhalation effectuées sur divers espèces de
    mammifères montrent que la sensibilité au bromure de méthyle varie
    nettement selon l'espèce et le sexe. La droite dose-mortalité présente
    une pente accentuée chez toutes les espèces animales étudiées.

         Chez le rat et la souris, les principaux signes cliniques
    d'intoxication sont des manifestations neurologiques avec, à fortes
    concentrations, une irritation des muqueuses.

         Ces manifestations neurologiques consistent notamment en
    fasciculations et paralysie. Divers auteurs ont également fait état à
    doses plus faibles, de modifications dans l'activité locomotrice,
    d'anomalies de la fonction nerveuse périphérique, de modifications du
    rythme circadien et d'aversion gustative conditionnée.

         On a également décrit des altérations histo- pathologiques au
    niveau du cerveau, des reins, des muqueuses nasales, du coeur, des
    surrénales, du foie et des testicules chez des rats et des souris
    exposés à diverses concentrations de bromure de méthyle.

         Une exposition de brève durée au bromure de méthyle provoque des
    lésions au niveau des cellules de soutien de l'épithélium olfactif et
    des cellules sensorielles matures mais la réparation et la
    récupération sont rapides.

         Les études d'inhalation de longue durée (jusqu'à deux ans)
    effectuées sur des rats, ont révélé la présence de lésions de la
    muqueuse nasale et du myocarde. Lors d'une étude à long terme analogue
    chez la souris, les lésions primitives ont été observées au niveau du
    cerveau, du coeur et de la muqueuse nasale. Aucun signe de
    cancérogénicité n'a été observé chez l'une ou l'autre espèce.

         L'administration par voie orale de 50 mg de bromure de méthyle
    par kg de poids corporel à des rats pendant des périodes allant
    jusqu'à 25 semaines a entraîné une inflammation et une hyperplasie
    grave au niveau de l'épithélium de la portion cardiaque de l'estomac.
    Après une période de récupération, qui a suivi l'exposition au bromure
    de méthyle, la principale lésion observée était une fibrose de la
    portion cardiaque de l'estomac. Chez des rats traités quotidiennement
    pendant 25 semaines, on a également constaté la présence d'un cancer
    précoce à ce niveau.

         Des souris B6C3F et des rats F344 exposés à des concentrations de
    bromure de méthyle allant jusqu'à 467 mg/m3 pendant 13 semaines, ont
    présenté de légères anomalies morphologiques des spermatozoïdes, la
    durée du cycle oestral n'étant pas affectée.

         Deux générations consécutives de rats CD Sprague- Dawley ont été
    soumis par la voie respiratoire à des concentrations de bromure de
    méthyle allant jusqu'à 350 mg/m3 sans que l'on constate d'effets
    notables sur leur croissance, les divers processus de la reproduction
    ni sur leur descendance. Il y avait diminution des indices de
    fécondité des mâles et des femelles aux deux doses les plus élevées,
    chez les rats de la génération F1 et de la génération F2b.

         On a étudié les effets toxiques du bromure de méthyle sur le
    développement de lapins blancs de Nouvelle-Zélande, exposés à 311 mg
    de bromure de méthyle par m3 (6 heures/jour, du 7ième au 19ième jour
    de la gestation). Les effets toxiques relevés chez les mères étaient
    modérés à graves. Les effets sur le développement observés aux doses
    toxiques pour les mères, consistaient en une réduction du poids du
    foetus, une augmentation de la fréquence des modifications
    squelettiques mineures ainsi qu'en malformations (essentiellement
    absence de la vésicule biliaire ou du lobe inférieur du poumon).
    Toutefois à la dose de 272 mg/m3, la toxicité maternelle était moins
    marquée et il n'y avait plus d'effets embryotoxiques.

         Aucun effet nocif maternel, embryonnaire ou foetal n'a été
    observé chez des lapins exposés à des doses de bromure de méthyle
    égales à 78 ou 156 mg/m3. Pour les lapins blancs de
    Nouvelle-Zélande, on a fixé à 156 mg/m3 la dose sans effets
    observables pour la toxicité maternelle et les effets toxiques sur le
    développement.

         Le bromure de méthyle s'est révélé mutagène dans plusieurs
    systèmes d'épreuve  in vitro et  in vivo. Il provoque des mutations
    létales récessives liées au sexe chez  Drosophila melanogaster ainsi
    que des mutations dans des cellules mammaliennes en culture. Il ne
    provoque pas de synthèse anarchique de l'ADN (non programmée) ni de
    transformation cellulaire dans les cultures de cellules mammaliennes.
    Chez des souris à qui on avait administré du bromure de méthyle par
    diverses voies, on a observé une méthylation de l'ADN au niveau des
    cellules hépatiques et spléniques. Chez des rats et des souris, on a
    observé la formation de micro-noyaux dans les cellules de la moelle
    osseuse et les leucocytes périphériques.  On ignore le mécanisme de la
    toxicité du bromure de méthyle.

    8  Effets sur l'homme

         Il peut y avoir exposition humaine au bromure de méthyle, soit
    par inhalation du gaz, soit par contact avec le liquide. L'exposition
    peut également se produire par la voie digestive à la suite de
    l'ingestion d'eau de boisson contaminée par des eaux de lessivage
    polluées.

         Une étude contrôlée sur l'homme a révélé que, après inhalation,
    environ 50% de la dose administrée étaient absorbés.

         Le bromure de méthyle provoque des lésions au niveau du système
    nerveux, des poumons, des muqueuses nasales, du rein, de l'oeil et de
    la peau. Les effets sur le système nerveux central consistent en
    troubles visuels, confusion mentale, engourdissement, tremblements, et
    troubles de l'élocution. Une contamination topique peut entraîner une
    irritation et des brûlures cutanées ainsi que des lésions oculaires.

         L'exposition à de fortes concentrations de bromure de méthyle
    provoque un oedème pulmonaire. Dans les cas d'intoxication par le
    bromure de méthyle, la cause immédiate de la mort est généralement une
    dépression du système nerveux central entraînant une paralysie
    respiratoire et/ou une défaillance circulatoire, précédées par des
    convulsions et un coma.

         Lors d'intoxications aiguës ou chroniques par le bromure de
    méthyle, on a observé différents symptômes neuro- psychiatriques. Une
    exposition de brève durée à de faibles concentrations de vapeurs de
    bromure de méthyle peut produire un syndrome polyneuropathique sans
    manifestations centrales évidentes.

         Parmi les séquelles tardives de l'intoxication on peut noter une
    broncho-pneumonie consécutive à de graves lésions pulmonaires, une
    insuffisance rénale avec anurie et une très importante faiblesse avec
    ou sans signes de paralysie. Généralement ces symptômes tendent à
    disparaître en quelques semaines à quelques mois. Toutefois, on a
    observé des déficits permanents généralement caractérisés par des

    troubles sensoriels, de la faiblesse, une baisse de l'acuité visuelle
    et des troubles de la démarche.


         L'exposition au bromure de méthyle s'accompagne d'une
    augmentation du taux sanguin de bromure. Chez les fumigateurs, il
    existe une relation entre le nombre d'opérations auxquelles ils ont
    participé et le taux plasmatique moyen de bromure.

    RESUMEN

    1  Propiedades físicas y químicas y métodos analíticos

         El bromuro metílico es un gas incoloro a la temperatura ambiente
    y a la presión atmosférica normal, con un punto de ebullición de 4 oC
    aproximadamente. Es más pesado que el aire y se licúa con facilidad
    por debajo de sus puntos críticos. Es inodoro, excepto en
    concentraciones altas, en las que tiene un olor parecido al
    cloroformo. No es inflamable en el aire, excepto en la gama de
    concentraciones del 10-16%, pero arde en oxígeno. El bromuro metílico
    es ligeramente soluble en agua, pero fácilmente soluble en otros
    disolventes corrientes. Puede penetrar a través de numerosas
    sustancias, como cemento, cuero, caucho y ciertos plásticos.

         El bromuro metílico se hidroliza dando metanol y ácido
    bromhídrico en solución acuosa, con una velocidad de hidrólisis que
    depende del pH. Es un agente metilante eficaz que reacciona con las
    aminas y con los productos que contienen azufre. La mayoría de los
    metales son inertes ante el bromuro metílico seco y puro, pero se
    producen reacciones de superficie sobre el zinc, el estaño, el
    aluminio y el magnesio en presencia de impurezas o humedad. Se han
    señalado reacciones explosivas con el aluminio y el sulfóxido
    dimetílico.

         El bromuro metílico se comercializa en forma de gas licuado. Las
    formulaciones par la fumigación del suelo contienen cloropicrina (2%)
    o acetato amílico (0,3%) como agentes de aviso. Otras formulaciones
    incluyen hasta el 70% de cloropicrina o de otros fumigantes o
    hidrocarburos como diluyentes inertes. Para la fumigación de
    mercancías se utiliza bromuro metílico al 100%.

         Se han descrito métodos analíticos para la determinación del
    bromuro metílico en el aire, el agua, el suelo, los alimentos y los
    piensos. Entre los aparatos para la determinación directa del bromuro
    metílico en el aire, en condiciones prácticas, figuran los
    analizadores de gases por conductividad térmica, los tubos de
    detección colorimétrica, los analizadores en infrarrojos y los
    detectores por fotoionización. Se recomienda la cromatografía de gases
    (CG) con detección por captura de electrones (DCE) para las mediciones
    corrientes, seguida a veces de la confirmación por espectrometría de
    masa (EM) en el laboratorio.

         Para la determinación por CG del bromuro metílico en el agua se
    utilizan técnicas de purga y captura, así como de muestreo en el
    espacio superior. Se recomienda la extracción con acetona y agua
    seguida de la cromatografía capilar de gas del espacio superior con
    DCE para la determinación ordinaria del bromuro metílico en los
    alimentos. Teniendo en cuenta que una parte del bromuro metílico se
    convierte en bromuro en el suelo, los alimentos y los productos
    biológicos, se examinan también los métodos de determinación del

    bromuro. Entre los utilizados para esa determinación en distintas
    matrices figuran métodos colorimétricos, la espectroscopia de rayos X,
    la potenciometría, el análisis por activación neutrónica, la
    cromatografía de gases y la cromatografía de líquidos de alto
    rendimiento.

    2  Fuentes de exposición humana y ambiental

         Se estima que los océanos son la fuente más importante de bromuro
    metílico. La principal fuente antropogénica de bromuro metílico es la
    fumigación de suelos y locales. Los vehículos de motor que utilizan
    gasolina con plomo emiten una pequeña cantidad de bromuro metílico.

          En 1990, el consumo mundial de bromuro metílico fue superior a
    67 millones de kg, con un aumento del 46% respecto a 1984. Se fabrica
    corrientemente por reacción entre el metanol y el ácido bromhídrico y
    en algunos procedimientos es un coproducto que acompaña al
    tetrabromobisfenol A. El bromuro metílico se almacena y transporta
    habitualmente como gas licuado a presión en recipientes de acero.

         El 77% aproximadamente del bromuro metílico fabricado se emplea
    para la fumigación del suelo, el 12% para la fumigación de cuarentena
    y de mercancías, el 5% para la fumigación de edificios y el 6% para
    obtener intermediarios químicos.

         El gas se emplea como fumigante del suelo en los campos o los
    invernaderos en la lucha contra las plagas. Se aplica en forma de
    líquido antes de la plantación, por inyección en el suelo o por
    evaporación en recipientes colocados bajo las cubiertas de plástico,
    dejando que el producto se evapore  in situ (método frío) o por
    calentamiento (método caliente). Hay diferencias en los métodos
    utilizados en los distintos países. También es importante el tipo de
    cubierta de plástico empleada.

         Las dosis de bromuro metílico que se han de aplicar dependen de
    las normas reglamentarias de los distintos países, el parásito vegetal
    que se ha de eliminar (tipo, amplitud de la infestación), el cultivo
    siguiente, el tipo de suelo y la cubierta de plástico empleada (tiempo
    de recubrimiento y tipo de plástico). El bromuro metílico se aplica
    habitualmente al suelo en concentraciones comprendidas entre 50 y 100
    g/m2.

         En la fumigación espacial se emplea el bromuro metílico para el
    tratamiento de productos agrícolas (por ej., alimentos, cereales,
    nueces, etc.) y la lucha contra las termitas y los roedores. Se
    emplean concentraciones de 16-30 g de bromuro metílico por m3 para
    la mayor parte de los productos almacenados en naves y silos cerrados
    herméticamente y bajo cubiertas impermeables a los gases. La
    fumigación debe ir seguida de un periodo de aireación. También es
    importante la fumigación de hortalizas y frutas frescas en donde han
    de observarse reglamentos de cuarentena.

         Entre los usos industriales del bromuro metílico figuran la
    síntesis orgánica, habitualmente como agente metilante, y el empleo
    como disolvente de baja temperatura de ebullición, por ejemplo, para
    la extracción de aceites de nueces, semillas y flores. La utilización
    del bromuro metílico como refrigerante y como agente general de
    extinción de incendios sólo tiene ahora impor-tancia histórica.

    3  Transporte, distribución y transformación en el medio ambiente

         El bromuro metílico se halla presente de modo natural en la
    atmósfera. Se suman a esa presencia las fuentes antropogénicas. Aunque
    una pequeña cantidad del bromuro metílico reacciona con el radical
    hidroxilo en la troposfera, parte del bromuro metílico pasa a la
    estratosfera por difusión ascendente. En esa capa adquiere importancia
    creciente la fotólisis del bromuro metílico, siendo el mecanismo
    predominante de desaparición en la estratosfera baja. El bromo activo
    reacciona con el ozono en la estratosfera y se cree que es en parte
    responsable de la destrucción de la capa de ozono.

         En el suelo, el bromuro metílico se hidroliza parcialmente para
    dar ion bromuro. Después de la fumigación con bromuro metílico, el
    suelo puede ser lixiviado con agua para evitar que los iones bromuro
    formados sean captados por los vegetales plantados después en el suelo
    esterilizado. Este aumento de las concen- traciones de bromuro puede
    producir problemas cuando se utilizan aguas superficiales para la
    lixiviación. El bromuro metílico puede difundirse a través de las
    tuberías de polietileno de conducción de agua potable, si el suelo que
    las rodea ha sido fumigado con bromuro metílico.

         En el suelo, el bromuro metílico puede difundirse hasta una
    profundidad de 0,8 m, en función del tipo de suelo, la dosis, el
    método de aplicación y la duración de la fumigación; la mayor
    concentración de bromuro metílico se alcanza en la parte superior del
    suelo. El transporte del gas se produce por flujo de masas y difusión
    molecular, pero también influyen los procesos de desa-parición que se
    produzcan simultáneamente, como la absorción y la disolución, y los
    procesos de desaparición irreversible, como la hidrólisis. La cantidad
    de bromuro metílico convertido en bromuro depende principalmente del
    contenido en materias orgánicas del suelo. El bromuro producido es
    principalmente hidrosoluble y puede ser captado por las plantas o
    desplazado a niveles inferiores del suelo por lixiviación con agua.

         En las plantas, la cantidad de bromuro acumulado depende de
    distintos factores, como la concentración, el tiempo de exposición, la
    tasa de aireación, las propiedades físicas y químicas del suelo, las
    tendencias climáticas (temperatura y pluviosidad), las especies
    vegetales y el tipo de tejido de las plantas. En particular las
    hortalizas de hoja, como la lechuga y la espinaca, pueden captar
    cantidades relativamente altas de ion bromuro sin síntomas
    fitotóxicos. Por el contrario, otros cultivos, como los claveles, los

    planteles de cítricos, el algodón, el apio, los pimientos y las
    cebollas, son especialmente sensibles a la fumigación con bromuro
    metílico.

         El bromuro metílico y sus productos de reacción, entre los cuales
    sólo se ha considerado hasta ahora el bromuro, pueden entrar en la
    cadena alimentaria de dos modos: consumo de alimentos cultivados en
    invernaderos o en campos fumigados antes de la plantación o
    alimentación con productos fumigados con bromuro metílico en el curso
    del almacenamiento. En determinadas concentraciones, el bromuro puede
    ser peligroso para la salud; se han indicado niveles de tolerancia
    para el bromuro contenido en los alimentos. No se han investigado los
    niveles de otros productos de reacción.

         El bromuro metílico se degrada en el suelo por hidrólisis y
    descomposición microbiana. La constante de hidrólisis varía con la
    temperatura y el pH, y aumenta con la luz.

         El coeficiente de partición octanol/agua (log Pow) del bromuro
    metílico es de 1,19, lo que sugiere la existencia de una
    bio-acumulación baja. 

         El bromuro metílico que no se ha degradado en el curso de la
    fumigación pasa a la troposfera y por difusión ascendente a la
    estratosfera. No parece que haya un gradiente vertical importante del
    bromuro metílico en la troposfera, pero las concentraciones disminuyen
    con rapidez en la estratosfera baja por acción de la fotólisis.

    4  Niveles ambientales y exposición humana

         Las concentraciones de bromuro metílico, medidas en el aire en
    zonas sin habitar, varían entre 40 y 100 ng/m3 (10 a 26 pptv),
    siendo los valores en el hemisferio Norte superiores a los del
    hemisferio Sur. La mayoría de las concentraciones se hallan en la gama
    de 9-15 pptv. En algunos estudios se han observado diferencias
    estacionales. En las zonas urbanas e industriales, las concentraciones
    son mucho mayores, con valores medios de hasta 800 ng/m3, llegando
    a veces hasta 4 µg de bromuro metílico por m3. En el curso de la
    fumigación y la aireación, las concentraciones de bromuro metílico son
    apreciablemente más altas cerca de los campos y los invernaderos,
    habiéndose medido valores de 1-4 mg/m3 en un estudio a distancias de
    hasta 20 m de un invernadero, algunas horas después de la inyección en
    el suelo; cuatro días más tarde se observó la décima parte de ese
    valor.

         La concentración de bromuro metílico en una muestra de agua del
    mar de superficie fue de 140 ng/litro. En muestras de agua costera
    cerca del mar del Norte, el valor medio de las concentraciones de ion
    bromuro fue de 18,4 mg/litro; la concentración de ion bromuro en los
    ríos de tierra adentro fue mucho más baja, excepto en las regiones
    donde se practicaba la fumigación con bromuro metílico o en las zonas

    de contaminación industrial. En el agua de drenaje de un invernadero
    de los Países Bajos se señalaron concentraciones de 9,3 mg de bromuro
    metílico/litro y de 72 mg de ion bromuro/litro. En el agua evacuada de
    un invernadero belga se registró un valor de 280 mg de bromuro/litro
    después de la fumigación.

         El contenido de bromuro natural del suelo depende del tipo de
    suelo, pero suele ser inferior a 10 mg/kg. La presencia de restos de
    bromuro en el suelo fumigado depende del tratamiento, la dosis, el
    tipo de suelo, la cantidad de lluvia o de agua de lixiviación y la
    temperatura.

         Las concentraciones de bromuro metílico o bromuro pueden ser
    altas en los alimentos que se han cultivado en suelos tratados
    previamente con bromuro metílico o que se han fumigado después de la
    recolección.

         En hortalizas frescas cultivadas en suelos previamente fumigados
    con bromuro metílico se han observado excepcional-mente
    concentraciones de bromuro que rebasaban el nivel autori-zado de
    residuos. En algunos países no se permite cultivar hortalizas en los
    suelos tratados.

         El bromuro metílico se utiliza ampliamente para la fumigación de
    productos alimenticios después de la recolección, como trigo y
    cereales, especias, nueces, frutas frescas y desecadas, y tabaco. Las
    concentraciones de bromuro metílico suelen descender con rapidez
    después de la aireación y no se detectan residuos al cabo de unas
    semanas. Algunos alimentos, como las nueces, las semillas y productos
    grasos como el queso, tienden a retener el bromuro metílico y el
    bromuro inorgánico. 

         Las personas pueden estar expuestas al fumigante y a restos de
    ion bromuro. También existe el riesgo de que haya bromuro metílico o
    un aumento del contenido de bromuro en el agua de pozos situados cerca
    de lugares en donde se ha fumigado bromuro metílico.

         Las personas que viven cerca de campos, invernaderos o almacenes
    fumigados con bromuro metílico pueden estar expuestos al gas. Los
    seres humanos pueden también correr peligro si accidental o
    deliberadamente penetran en locales que han sido fumigados para
    erradicar plagas antes de declararlos seguros.

         La exposición profesional al bromuro metílico es el riesgo más
    probable de los operarios en el curso de la fabricación, el llenado y
    la fumigación. Dadas las medidas de seguridad aplicadas estrictamente
    en las fábricas, sólo se considera actualmente como grupo de alto
    riesgo a los fumigadores. Los fumigadores que realizan el tratamiento
    de edificios pueden tener una exposición muy superior al valor umbral
    límite (VUL) después de 24 horas de aireación (80-2000 mg/m3). Sin
    embargo, los operarios convenientemente capacitados utilizarán equipo

    protector apropiado. Los obreros que trabajan en el campo durante la
    fumigación del suelo pueden estar expuestos durante periodos más
    prolongados a dosis pasajeras de bromuro metílico. Dada la naturaleza
    de la fumigación de los invernaderos, los operarios pueden también
    encontrar concentraciones más altas (100-1200 mg/m3). Así pues, la
    gestión del riesgo provocado por los distintos aspectos de la
    fumigación exige medidas de seguridad estrictas y el empleo de equipo
    protector. Pese a ello se producirán todavía casos aislados de
    sobreexposición accidental.

    5  Cinética y metabolismo

         Los estudios de inhalación efectuados en ratas, perros sabuesos
    y seres humanos han mostrado la absorción rápida del bromuro de metilo
    por los pulmones. También se absorbe con rapidez en las ratas después
    de la administración oral.

         Tras la absorción, el bromuro metílico o sus metabolitos se
    distribuyen con rapidez en numerosos tejidos, comprendidos los
    pulmones, las glándulas suprarrenales, los riñones, el hígado, los
    cornetes nasales, el cerebro, los testículos y el tejido adiposo. En
    un estudio de inhalación efectuado en ratas, la concentración tisular
    de bromuro metílico alcanzó el valor máximo una hora después de la
    exposición, pero descendió con rapidez, no encontrándose indicios 48
    horas más tarde. Todavía no se ha esclarecido el metabolismo del
    bromuro metílico inhalado, pero parece que interviene el glutatión.

         Se ha observado la metilación de proteínas y lípidos en los
    tejidos de varias especies, incluidos los seres humanos, expuestos a
    través de la inhalación. También se han detectado aductos de ADN
    metilado después de la exposición  in vivo e  in vitro de roedores
    o células de roedores.

         En los estudios de inhalación con bromuro metílico marcado con
    [14C], la expiración de 14CO2 fue la principal vía de
    eliminación de 14C. Por la orina se eliminó una cantidad menor de
    14C. Tras la administración oral de bromuro metílico, la excreción
    urinaria fue la principal vía de eliminación del 14C.

         El sistema nervioso central es un importante destinatario del
    bromuro metílico. En la neurotoxicidad provocada por el bromuro
    metílico pueden intervenir modificaciones del contenido de monoaminas
    y aminoácidos y tal vez de catecolaminas.

    6  Efectos en los seres vivos del medio ambiente

         El bromuro metílico se utiliza comercialmente en la lucha contra
    los nematodos, las malas hierbas y los hongos transmitidos por el
    suelo que provocan trastornos tales como el resecamiento, la
    putrefacción de la copa o las raíces y el marchitado.

         Se han realizado escasos estudios sobre los efectos del bromuro
    metílico en los seres acuáticos, pues el propio bromuro metílico sólo
    es ligeramente soluble en agua. Los valores de la CL50 van de un
    valor a las cuatro horas de 17 mg/litro para  Cyprinus carpio L. a
    otro a las 48 horas de 1,2 mg/litro para  Poecilia reticulata. En
    concentraciones letales, las lesiones de las agallas y el epitelio
    oral son la causa probable de la muerte.

         El ion bromuro se forma a partir del bromuro metílico después de
    la fumigación y se halla en el agua tras la lixiviación. Se observó
    una toxicidad aguda por iones bromuro en distintos seres de agua dulce
    en concentraciones comprendidas entre 44 y 5800 mg de Br-/litro; la
    concentración de efecto no observado (NOEC) en las pruebas de larga
    duración varió entre 7,8 y 250 mg de Br-/litro. Los iones bromuro
    produjeron una marcada alteración de la reproducción de crustáceos y
    peces.

         El bromuro metílico puede aplicarse directamente como fumigante
    a las semillas o los esquejes de las plantas o a los productos
    alimenticios después de la recolección para la desin-festación en el
    curso del transporte y el almacenamiento. Puede producirse el retraso
    de la germinación o la pérdida de la capacidad germinativa si la
    humedad o la temperatura son demasiado altas.

         Algunos cultivos, en particular las hortalizas de hoja, son
    sensibles a la fumigación con bromuro metílico debido a la presencia
    de bromuro en exceso en el suelo o indirectamente por los efectos en
    la microflora del suelo. El bromuro metílico tiene a veces un efecto
    positivo sobre las plantas, favoreciendo su crecimiento y el
    rendimiento de los cultivos.

         La fumigación con bromuro metílico erradica no sólo los seres
    vivos a los que se aplica sino también una parte de la flora del
    suelo, los gastrópodos, los arácnidos y los protozoos.

         El bromuro metílico se utiliza a menudo de preferencia a otros
    insecticidas por su capacidad para penetrar con rapidez y profundidad
    en productos no envasados y en los suelos. Las dosis de bromuro de
    metilo utilizado como fumigante en almacenes se sitúan sobre todo
    entre 16 y 100 g/m3 durante 2-3 días, dependiendo la dosis de la
    temperatura. Para matar los huevos y las pupas se necesita una dosis
    más alta que en el caso de los insectos adultos. Existen variaciones
    en la tolerancia de las distintas especies y fases de insectos y entre
    las distintas estirpes del mismo insecto.

         No existen datos sobre los efectos directos del bromuro metílico
    en las aves y los mamíferos silvestres.

    7  Efectos en los animales de experimentación

         Los estudios de inhalación realizados en varias especies de
    mamíferos han mostrado que existen claras diferencias relacionadas con
    la especie y el sexo en lo que se refiere a la susceptibilidad al
    bromuro metílico. No se observó una respuesta dosis-mortalidad muy
    marcada en ninguna de las especies animales ensayadas.

         Las manifestaciones neurológicas son los principales signos
    clínicos de toxicidad en las ratas y los ratones y, en concentraciones
    más altas, se ha observado también la irritación de las mucosas.

         Entre las manifestaciones neurológicas destacan los espasmos y la
    parálisis. Con dosis más altas varios autores han señalado
    modificaciones de la actividad locomotriz, disfunción de los medios
    periféricos, cambios del ritmo circadiano y aversión gustativa
    condicionada.

         Se han descrito lesiones histopatológicas en el cerebro, el
    riñón, la mucosa nasal, el corazón, las glándulas suprarrenales, el
    hígado y los testículos de ratas y ratones expuestos a distintas
    concentraciones de bromuro metílico.

         Las células de soporte olfativas y las sensoriales maduras sufren
    lesiones por la exposición a corto plazo al bromuro metílico, pero la
    reparación y la recuperación son rápidas.

         Los estudios de inhalación de larga duración (hasta 2 años) en
    ratas mostraron lesiones de la mucosa nasal y el miocardio. En un
    estudio análogo de larga duración en ratones se observaron los efectos
    tóxicos primarios en el cerebro, el corazón y la mucosa nasal. En
    ninguna de ambas especies se registraron signos de carcinogenicidad.

         La administración oral de 50 mg de bromuro metílico/kg de peso
    corporal a ratas durante un periodo de hasta 25 semanas produjo
    inflamación e hiperplasia intensa del epitelio del antro cardial. Tras
    un periodo de recuperación postexposición, la principal lesión
    observada fue la fibrosis del antro cardial. En la rata tratada
    diariamente durante 25 semanas se observó un carcinoma inicial del
    antro cardial.

         Los ratones B6C3F y las ratas F344 expuestos a dosis de hasta 467
    mg de bromuro metílico/m3 durante 13 semanas mostraron cambios
    ligeros de la morfología del esperma sin que se afectara la duración
    del ciclo estral.

         La exposición por inhalación a dosis de hasta 350 mg de bromuro
    metílico/m3 no produjo ningún efecto digno de mención sobre el
    crecimiento, los procesos reproductivos y las crías de dos

    generaciones consecutivas de ratas CD Sprague-Dawley. Los índices de
    fecundidad de machos y hembras se redujeron con dos niveles máximos de
    concentraciones en la camada F2B de la generación F1.

         En los estudios sobre la toxicología del desarrollo efectuados en
    conejos blancos de Nueva Zelandia, la exposición a 311 mg de bromuro
    metílico/m3 (6 h/día; días 7-19 de la gestación) mostró una
    toxicidad materna moderada a intensa. Los efectos en el desarrollo
    observados con dosis tóxicas para la madre consistieron en
    dis-minución del peso del feto, aumento de la incidencia de
    variaciones óseas ligeras y presencia de malformaciones
    (principalmente ausencia de la vesícula biliar o del lóbulo caudal del
    pulmón). Sin embargo, con dosis de 272 mg/m3 la toxicidad materna
    fue menos marcada y no se produjeron efectos embriotóxicos.

         No se observaron efectos maternos, embrionarios o fetales
    adversos en conejos expuestos a 78 ó 156 mg de bromuro metílico/m3.
    En conejos blancos de Nueva Zelandia se indicó un nivel sin efectos
    observados (NOEL) de 156 mg de bromuro metílico/m3 en lo que
    respecta a la toxicidad materna y del desarrollo.

         Se ha observado que el bromuro metílico es mutagénico en varios
    sistemas de ensayo  in vitro e  in vivo. Provoca mutaciones letales
    recesivas ligadas al sexo en  Drosophila melanogaster y mutaciones en
    células de mamífero cultivadas. No induce la síntesis no programada
    del ADN ni la transformación celular en células de mamífero
    cultivadas. En ratones a los que se administró bromuro metílico por
    distintas vías se observó la metilación del ADN en el hígado y el
    bazo. Se indujo la formación de micronúcleos en las células de la
    médula ósea y de la sangre periférica de ratones y ratas.

         Se desconoce el mecanismo de la toxicidad del bromuro metílico.

    8  Efectos en la especie humana

         La exposición humana al bromuro metílico puede producirse por
    inhalación del gas o por contacto con el líquido. También se produce
    exposición por ingestión de agua de bebida contaminada con agua de
    lixiviación.

         Un estudio en la especie humana con testigos mostró que la
    captación del producto después de la exposición por inhalación es del
    50% aproximadamente de la dosis administrada.

         El bromuro metílico es nocivo para el sistema nervioso, los
    pulmones, la mucosa nasal, los riñones, los ojos y la piel. Entre los
    efectos en el sistema nervioso central figuran la visión enturbiada,
    la confusión mental, la pérdida de sensibilidad, el temblor y los
    defectos del habla. La exposición tópica puede provocar irritación
    cutánea, quemaduras y lesiones oculares.

         La exposición a altas concentraciones de bromuro metílico causa
    edema pulmonar. La depresión del sistema nervioso central con
    parálisis respiratoria e insuficiencia respiratoria es a menudo la
    causa inmediata de la muerte, que va precedida de convulsiones y coma.

         Se han observado distintos signos y síntomas neuropsiquiátricos
    en el curso de las intoxicaciones agudas y prolongadas producidas por
    bromuro metílico. Las exposiciones de corta duración a dosis bajas de
    vapores han producido un síndrome de polineuropatía con
    manifestaciones centrales patentes.

         Entre las secuelas tardías figuran la bronconeumonía consecutiva
    a lesiones pulmonares graves, la insuficiencia renal con anuria y la
    debilidad extrema, con o sin signos de parálisis. Por lo general esos
    síntomas tienden a remitir después de un periodo de unas semanas o
    meses. Sin embargo, se han observado deficiencias sin recuperación,
    caracterizadas habitualmente por trastornos sensoriales, debilidad,
    alteraciones del carácter y enturbiamiento de la visión.

         La exposición al bromuro metílico va acompañada de un aumento de
    la concentración de bromuro en la sangre. En los fumigadores se
    observa una relación entre el número de aplicaciones del gas y la
    concentración plasmática media de bromuro.




    See Also:
       Toxicological Abbreviations
       Methyl bromide (ICSC)
       Methyl bromide (PDS)
       Methyl bromide (PIM 340)
       Methyl bromide (FAO Meeting Report PL/1965/10/2)
       Methyl bromide (FAO/PL:CP/15)
       Methyl bromide (FAO/PL:1967/M/11/1)
       Methyl bromide (FAO/PL:1968/M/9/1)
       Methyl bromide (WHO Pesticide Residues Series 1)
       Methyl bromide (SIDS)
       Methyl Bromide (IARC Summary & Evaluation, Volume 71, 1999)