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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 182





    THALLIUM











    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 Professor G. Schaub, Institute of Zoology and
    Parasitology, Ruhr University, Bochum, Germany


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


    World Health Organization
    Geneva, 1996

         The International Programme on Chemical Safety (IPCS) is a joint
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    WHO Library Cataloguing in Publication Data

    Thallium

    (Environmental health criteria ; 182)

    1.Thallium -  toxicity  I.Series

    ISBN 92 4 157182 9                 (NLM Classification: QV 618)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR THALLIUM

    PREAMBLE

    1. SUMMARY

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

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

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factor
         2.4. Analytical methods
               2.4.1. Sampling and sample preparation
               2.4.2. Methods of determination
                       2.4.2.1   Atomic absorption spectrometry
                       2.4.2.2   Inductively coupled plasma - mass
                                 spectrometry
                       2.4.2.3   Other methods
               2.4.3. Quality control and quality assurance
               2.4.4. Conclusions

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
               3.2.1. Production levels and processes
               3.2.2. Uses
               3.2.3. Emissions from industrial sources
                       3.2.3.1   Metal production industries
                       3.2.3.2   Power-generating plants
                       3.2.3.3   Brickworks and cement plants
                       3.2.3.4   Sulfuric acid plants

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
               4.1.1. Transport and distribution in air, water
                       and soil
               4.1.2. Soil-vegetation transfer
                       4.1.2.1   Factors affecting soil-vegetation
                                 transfer
                       4.1.2.2   Absorption by plants
                       4.1.2.3   Distribution in plants
         4.2. Biotransformation
         4.3. Interaction with other physical, chemical, or biological
               factors

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
               5.1.1. Air
               5.1.2. Water
                       5.1.2.1   Areas not contaminated by thallium
                       5.1.2.2   Areas contaminated by thallium from
                                 industrial sources
               5.1.3. Rocks, soil and sediment
                       5.1.3.1   Areas not contaminated by thallium
                       5.1.3.2   Areas contaminated by thallium from
                                 industrial sources
               5.1.4. Plants and animals
                       5.1.4.1   Plants
                       5.1.4.2   Animals
         5.2. General population exposure
         5.3. Occupational exposure during manufacture, formulation
               or use

    6. KINETICS AND METABOLISM

         6.1. Absorption
               6.1.1. Animals
                       6.1.1.1   Aquatic animals
                       6.1.1.2   Terrestrial animals
               6.1.2. Humans
         6.2. Distribution
               6.2.1. Animals
                       6.2.1.1   Distribution after administration of
                                 a single dose
                       6.2.1.2   Distribution after long-term sublethal
                                 administration
                       6.2.1.3   Transplacental transfer of thallium

               6.2.2. Humans
                       6.2.2.1   Increased concentrations after lethal
                                 poisoning
                       6.2.2.2   Increased concentrations after
                                 long-term sublethal poisoning
                       6.2.2.3   Transplacental transfer of thallium
         6.3. Metabolic transformation
         6.4. Elimination and excretion
               6.4.1. Animals
               6.4.2. Humans
               6.4.3. Methods to estimate daily intake of thallium
         6.5. Retention and turnover (Biological half-life)
               6.5.1. Animals
               6.5.2. Humans
         6.6. Kinetics at the cellular level

    7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         7.1. Single exposure
               7.1.1. Toxicity and symptoms
               7.1.2. Effects on various organs
         7.2. Short-term exposure
               7.2.1. Toxicity and symptoms
               7.2.2. Effects on various organs
         7.3. Long-term exposure: chronic toxicity
               7.3.1. Toxicity and symptoms
               7.3.2. Effects on various organs
         7.4. Skin and eye irritation
               7.4.1. Skin and hair
               7.4.2. Eye
         7.5. Reproductive toxicity, embryotoxicity and teratogenicity
               7.5.1. Gonadotoxic effects
               7.5.2. Embryotoxicity and teratogenicity
                       7.5.2.1   Chickens
                       7.5.2.2   Mammals
                       7.5.2.3   Delayed effects on development of
                                 offspring
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
         7.8. Neurotoxicity
               7.8.1. Central nervous system
                       7.8.1.1   Histology and ultrastructure
                       7.8.1.2   Electrophysiological and biochemical
                                 investigations
                       7.8.1.3   Behavioural toxicology
               7.8.2. Peripheral nervous system
                       7.8.2.1   Histology and ultrastructure
                       7.8.2.2   Electrophysiological and biochemical
                                 investigations

         7.9. In vitro test systems: cell lines
         7.10. Factors modifying toxicity
               7.10.1. Enhancement of elimination
               7.10.2. Selenium
         7.11. Mechanisms of toxicity - mode of action

    8. EFFECTS ON HUMANS

         8.1. General population exposure
               8.1.1. Acute toxicity
               8.1.2. Effects of long-term exposure: chronic
                       toxicity
         8.2. Occupational exposure
         8.3. Subpopulations at special risk
         8.4. Target organs in intoxicated humans: pathomorphology
               and pathophysiology
               8.4.1. Gastrointestinal tract and renal system
               8.4.2. Cardiovascular system
               8.4.3. Skin and hair
               8.4.4. Nervous system
                       8.4.4.1   Central nervous system
                       8.4.4.2   Peripheral nervous system
               8.4.5. Other organs
         8.5. Special effects
               8.5.1. Reproduction and developmental effects
               8.5.2. Carcinogenicity
               8.5.3. Immunotoxicological effects
         8.6. Factors modifying toxicity: enhancement of
               elimination
         8.7. Protective measures against excessive occupational
               exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
         9.2. Aquatic organisms
               9.2.1. Plants
               9.2.2. Animals
         9.3. Terrestrial organisms
               9.3.1. Plants
                       9.3.1.1   Plant photosynthesis
                       9.3.1.2   Cytotoxic effects
                       9.3.1.3   Growth of plants
                       9.3.1.4   Different sensitivities to thallium(I)
                                 and thallium (III)
                       9.3.1.5   Concentration of trace elements
                       9.3.1.6   Sensitivity of plants
               9.3.2. Wild animals
               9.3.3. Household pets and farm animals

    10. EVALUATION

         10.1. Evaluation of human health risks
               10.1.1. Exposure levels
               10.1.2. Kinetics
               10.1.3. Toxic effects
               10.1.4. Dose-response relationship (animals)
               10.1.5. Dose-response relationship (humans)
         10.2. Evaluation of the effects of thallium on the
               environment

    11. CONCLUSIONS AND RECOMMENDATIONS

    12. FURTHER RESEARCH

    REFERENCES

    RESUME

    RESUMEN
    

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       A detailed data profile and a legal file can be obtained from the
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       This publication was made possible by grant number 5 U01 ES02617-15
    from the National Institute of Environmental Health Sciences, National
    Institutes of Health, USA, and by financial support from the European
    Commission.

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR THALLIUM

    Members

    Professor M. Balali-Mood, Poison Control Centre, Imam Reza Hospital,
       Mashhad University of Medical Sciences, Mashhad, Islamic Republic
       of Iran

    Dr P. Doyle, Chemicals Evaluation Division, Environment Canada,
       Ottawa, Ontario, Canada

    Professor G. Kazantzis, Imperial College of Science, Technology and
       Medicine, Centre for Environmental Technology, Royal School of
       Mines, London, United Kingdom (Joint Rapporteur)

    Dr M. Kiilunen, Department of Industrial Hygiene & Toxicology,
       Institute of Occupational Health, Helsinki, Finland

    Mr H. Malcolm, Institute of Terrestrial Ecology, Monks Wood   
       Experimental Station, Huntingdon, Cambridgeshire, United Kingdom

    Dr G. Nordberg, Department of Environmental Hygiene, Umea University,
       Umea, Sweden  (Chairman)

    Professor G. Schaub, Department of Zoology, Institute for Zoology and
       Parasitology, Ruhr University, Bochum, Germany  (Joint Rapporteur)

    Dr S. Velazquez, Environmental Criteria and Assessment Office, US
       Environmental Protection Agency, Cincinnati, Ohio, USA

     Representatives of other organizations

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

     Observers

    Dr R. Cornelis, Institute for Nuclear Sciences, State University of
       Gent, Gent, Belgium

     Secretariat

    Dr P.G. Jenkins, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland  (Secretary)

    ENVIRONMENTAL HEALTH CRITERIA FOR THALLIUM

         A WHO Task Group on Environmental Health Criteria for Thallium
    met in Geneva from 12 to 16 December 1994.  Dr P.G. Jenkins, 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 thallium.

         The first draft was prepared by Professor G. Schaub, Institute
    for Zoology and Parasitology, Ruhr University, Bochum, Germany.  He
    also prepared the second draft, incorporating comments received
    following circulation of the first draft to the IPCS contact points
    for Environmental Health Criteria monographs.

         Dr P.G. Jenkins, IPCS, was responsible for both the overall
    scientific content and the technical editing.

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

    ABBREVIATIONS

    AAS       atomic absorption spectrometry
    AES       atomic emission spectrometry
    AMP       amperometric titration
    CRMs      certified reference materials
    DPASV     differential pulse anodic stripping voltametry
    EDL       electrode discharge lamp
    EDTA      ethylenediaminetetraacetic acid
    GABA      gamma-aminobutyric acid
    GDMS      glow discharge mass spectrometry
    GFAAS     graphite furnace atomic absorption spectrometry
    GLP       good laboratory practice
    ICP       inductively coupled plasma
    IDMS      isotope dilution mass spectrometry
    LOEL      lowest-observed-effect level
    MED       minimum effective dose
    MIBK      methyl isobutyl ketone
    MS        mass spectrometry
    NAA       neutron activation analysis
    NaDDC     sodium diethyldithiocarbamate
    NADP      nicotinamide adenine dinucleotide phosphate
    NOEL      no-observed-effect level
    PAA       photon activation analysis
    TLV       threshold limit value
    tRNA      transfer ribonucleic acid

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, and analytical
         methods

         Elemental thallium is a soft and malleable metal with a
    bluish-white colour.  When exposed to humid air or water, thallium is
    oxidized rapidly on the surface or the hydroxide is formed,
    respectively.  Thallium has two important oxidation states,
    thallium(I) and thallium(III).  Monovalent (thallous) compounds behave
    like alkali metals, e.g. potassium, whereas the trivalent (thallic)
    compounds are less basic, resembling aluminium.  In contrast to
    inorganic compounds in which the thallium(I) ion is more stable in
    aqueous solutions than the thallium(III) ion, the latter is more
    stable in organic compounds.

         The determination of thallium in environmental samples is
    somewhat difficult as concentrations are in the µg/kg range or less. 
    Generally the limits of determination for minerals, soils and dusts
    are about 20 µg/kg, for aqueous solutions about 0.1 µg/litre, and for
    biological materials a few µg/kg, when no pre-concentration of
    thallium is applied.

         Graphite furnace atomic absorption spectrometry (GFAAS) is an
    analytical method well suited for applications where high sensitivity
    is required from small sample amounts with thallium present at
    concentrations of a few µg/kg. Isotope dilution mass spectrometry
    (IDMS) and inductively coupled plasma-mass spectrometry (ICP-MS),
    possibly combined with isotope dilution, are excellent methods for
    determinations offering good precision and accuracy at the µg/kg
    level.

    1.2  Sources of human and environmental exposure

         Thallium is present in the environment as a result of natural
    processes and from man-made sources.  It is ubiquitous in nature and
    occurs especially in sulfide ores of various heavy metals, but
    normally in low concentrations.  There are only a few areas with a
    naturally very high thallium concentration.

         Thallium is produced industrially only in small quantities (the
    worldwide industrial consumption in 1991 was 10-15 tonnes/year).
    Thallium and its compounds have a wide variety of industrial uses. 
    Its uses as a depilatory agent for humans and as a rodenticide and
    insecticide are now severely restricted.  The main uses are in the
    electrical and electronic industries and in the production of special
    glasses.  Another important field of application is the use of
    radioisotopes in medicine for scintigraphy and the diagnosis of
    melanoma and the use of arylthallium(III) compounds in biochemistry.

         Losses to the environment mainly occur from mineral smelters
    (deposits of waste material and emissions into the atmosphere),
    coal-burning power-generating plants, brickworks, and cement plants
    (all emissions into the atmosphere).  From 2000 to 5000 tonnes/year
    are estimated to be mobilized world-wide by industrial processes. 
    Emissions of thallium from industrial processes vary widely according
    to the type of industry.

         Emissions from coal-fired power-generating plants can contain a
    thallium concentration of 700 µg/m3 exhaust air and those from
    cement plants up to 2500 µg/m3.  The latter value may be reduced to
    < 25 µg/m3 by using other raw materials and changing the production
    process.  Thallium volatilizes during the burning of coal or raw
    material for cement production and recondenses on the surface of ash
    particles in cooler parts of the system. These particles contain up to
    50 mg thallium/kg fly-ash and are often of small size, so that only
    50% of them are held back by filters in cement plants.  Also, about
    one third of emitted particles from power-generating plants are of the
    small particle size which can be deposited in the lower respiratory
    tract.

         Effluent from mine tailing ponds containing up to 1620 and
    36 µg/litre caused elevated levels of 88 and 1 µg/litre, respectively,
    in connecting rivers.  Rainwater ponds around a cement plant contained
    up to 37 µg/litre.  In soil maximal concentrations of 60 mg/kg have
    been found near waste materials from mines; 2, 0.6 and 27 mg/kg have
    been found in the vicinity of base metal smelters, brickworks and
    cement plants, respectively.

         In contaminated areas the majority of vegetables, fruits and meat
    contain less than 1 mg thallium/kg fresh weight.  Concentrations are
    higher in cabbages (Brassicaceae), with up to 45 mg/kg reported in
    green kale.  Concentrations of thallium in the tissues of farm animals
    correlate with concentrations in the fodder.  In the vicinity of some
    cement plants, increased concentrations in fodder (e.g., up to
    1000 mg/kg in rape) and beef and rabbit meat (up to 1.5 and 5.8 mg/kg,
    respectively) have been reported.

    1.3  Environmental transport, distribution and transformation

         Near point sources such as coal-fired power-generating stations,
    some cement plants and metal smelting operations, the major source of
    thallium in air is emission of fly ash.  The results of one study
    indicate that nearly all of the thallium in fly dust from a cement
    plant was present as soluble thallium(I) chloride.

         The fate of thallium added to soil (in deposited fly ash, for
    example) depends largely on soil type.  Retention will be greatest in
    soils that contain large amounts of clay, organic matter and
    iron/manganese oxides.  Incorporation into stable complexes causes
    enhanced thallium concentrations only in the upper levels of soils. 
    The uptake of thallium by vegetation increases as soil pH decreases. 
    In some strongly acid soils significant amounts of thallium can be
    leached to local ground and surface water.

         Most dissolved thallium in freshwater is expected to be in the
    monovalent form.  However, in strongly oxidized fresh water and most
    seawater trivalent thallium may predominate.  Thallium can be removed
    from the water column and accumulate in sediment by various exchange,
    complexation or precipitation reactions.

         Although thallium can bioconcentrate, it is not likely to
    biomagnify in aquatic or terrestrial food webs.

    1.4  Environmental levels and human exposure

         In areas not contaminated by thallium, concentrations in air are
    usually < 1 ng/m3, those in water < 1 µg/litre, and those in water
    sediments < 1 mg/kg.  Mean concentrations in the earth's crust range
    from 0.1 to 1.7 mg/kg, but very high concentrations are possible,
    e.g., in coal up to 1000 mg/kg, and the rarely found minerals of
    thallium consist of up to 60% of the element.  Food of plant and
    animal origin usually contains < 1 mg/kg dry weight and the human
    average dietary intake of thallium appears to be less than 5 µg/day. 
    Uptake via the respiratory system is estimated to be < 0.005 µg
    thallium/day.

         There are only limited data about the actual thallium content of
    workplace air.  The most recent (1980s) concentrations of thallium
    observed were < 22 µg thallium/m3 (in the production of a special
    thallium alloy and in a thallium smelter). Average urinary
    concentrations were determined to be in the range of 0.3-8 µg/litre
    for cement workers and 0.3-10.5 µg/litre for foundry workers.

    1.5  Kinetics and metabolism in laboratory animals and humans

         Thallium is rapidly and well absorbed through the gastro 
    intestinal and respiratory tracts and is also taken up through the
    skin.  It is rapidly distributed to all organs and passes the placenta
    (as indicated by the rapid fetal uptake) and the blood-brain barrier. 
    Because of its rapid accumulation in cells, concentrations of thallium
    in whole blood do not reflect the levels in tissues.  In acute
    poisoning of experimental animals or humans, initially high
    concentrations of thallium appear in the kidney, low concentrations in
    fat tissue and brain, and intermediate concentrations in the other
    organs; later the thallium concentration of the brain also increases.

         Elimination of thallium may occur through the gastrointestinal
    tract (mainly by mechanisms independent of biliary excretion), kidney,
    hair, skin, sweat and breast milk.  Intestinal reabsorption (mainly
    from the colon) may occur with a consequent decrease in total body
    clearance.  In rats, the main routes of thallium elimination are
    gastrointestinal (about two thirds) and renal (about one third), in
    rabbits the contribution of the two routes is about equal.  Thallium
    is also secreted in saliva.

         As with many other substances, the excretion of thallium in
    humans differs from that in laboratory animals, since the rate of
    excretion is generally much lower in humans (rate constant =
    0.023-0.069 day-1) than in laboratory animals (average rate constant =
    0.18 day-1).  Another major difference between humans and animals is
    the relative contribution of the different routes of excretion.  In
    humans, renal excretion seems to be much more important than in
    animals, although its relative contribution to the total body
    clearance has not been definitively established, due principally to
    the lack of sufficient human data.  Moreover, exposure levels,
    duration of exposure, impairment of excretory organ function,
    potassium intake and concomitant treatment of acute poisoning may
    considerably influence the results.

         In one study renal excretion of thallium was reported to be about
    73%, whereas that through the gastrointestinal tract was about 3.7% of
    the daily excreted amount.  Excretion through hair and skin, and sweat
    has been estimated to be 19.5% and 3.7%, respectively.

         The biological half-life of thallium in laboratory animals
    generally ranges from 3 to 8 days; in humans it is about 10 days but
    values up to 30 days have been reported.

         No data on the biotransformation of thallium are available.

    1.6  Effects on laboratory mammals and in vitro test systems

         There are no striking species-specific differences in the
    toxicity of thallium(I) salts.  Usually an oral intake of 20 to 60 mg
    thallium/kg body weight is lethal within one week.  Guinea-pigs are
    slightly more sensitive than other experimental animals.  The
    water-insoluble thallium(III) oxide shows a somewhat lower acute
    toxicity by oral or parenteral administration than thallium(I) salts. 
    Comparison of acute toxicity data indicates a high degree of
    bioavailability from all exposure routes.  Most organs are affected,
    but the signs of poisoning and the sequence in which they occur reveal
    some intra- and interspecies variability.

         The symptoms of acute intoxication generally follow the following
    sequence: firstly anorexia, vomiting and depression, later diarrhoea,
    skin changes (inflammation at body orifices, skin furuncles, hair
    loss), and then dyspnoea and nervous disorders.  Finally, respiratory
    failure leads to death.

         Symptoms of chronic intoxication are similar to those of acute
    intoxication.  Loss of hair regularly occurs.

         Histological examination reveals necrosis or other cell damage. 
    Necrotic changes have been observed in the kidneys, liver, intestine,
    heart and the nervous system.  Swelling of mitochondria and loss of
    cristae, dilatations of smooth endoplasmic reticulum, increased
    numbers of autophagic vacuoles and lipofuscin granules, and loss of
    microvilli have been observed in many cells.  The thallium-induced
    alterations of functional processes may arise from physical disruption
    of the membranes of subcellular organelles.  In the heart,
    arrhythmogenic effects are restricted to the sinus node.

         Thallium intoxication causes selective impairment of certain
    behavioural elements, which are correlated with biochemical effects
    (which indicate cellular damage) in certain regions of the brain. 
    Some neurological effects seem to be caused by direct action, e.g.
    ataxia and tremor by cerebellar alterations or alterations in
    endocrine activity through changes in the hypothalamus.  The autonomic
    nervous system, mainly the adrenergic, may be activated by thallium. 
    In peripheral nerves, thallium seems to interfere presynaptically,
    with the spontaneous release of transmitter, by antagonizing these
    calcium-dependent processes.

         The exact mechanism of thallium toxicity is still unknown. 
    Several, perhaps interconnected, mechanisms have been postulated.  An
    important aspect of thallium intoxication is the significant increase
    in lipid peroxidation and in the activity of the lysosomal enzyme
    ß-galactosidase.  The resulting deficiency of glutathione leads to the
    accumulation of lipid peroxides in the brain and, presumably, finally
    to lipofuscin granules.  The mode of action of thallium seems to be
    mainly due to a disturbance of the function of the mitochondria.

         Sexual activity is usually reduced in chronically poisoned
    animals, and gonadotoxic effects of thallium are evident in the male
    reproductive system.  In the testes of rats given 10 mg thallium/litre
    in the drinking-water for 16 days, the Sertoli cells were most
    sensitive, and desquamation of the spermatogenic epithelium led to
    immature sperm cells in the semen.  This could explain the decreased
    survival rate of embryos or reduced life span of offspring after
    sublethal thallium-poisoning of the fathers.

         Teratogenic effects, growth inhibition and disturbances in the
    development of bones were found to occur in chicken embryos after
    injection of thallium into the egg, but such effects in mammals, even
    at maternotoxic doses, are controversial.  Although transplacental
    transfer has been demonstrated, many strains of mice and rats show no
    or only slight teratogenic effects.

         Two microbiological mutagenicity tests in  Salmonella typhimurium
    were negative and  in vivo tests on sister chromatid exchange were
    controversial.  However, single studies report chromosomal aberrations
    or a significant increase of single-stranded DNA breaks.

         Long-term studies on the carcinogenicity of thallium are lacking.

    1.7  Effects on humans

         Since thallium salts are tasteless, odourless, colourless, highly
    toxic, were easily obtainable in the past and still are in some
    developing countries, thallium has often been used for suicide,
    homicide and attempts at illegal abortion, causing acute thallium
    poisoning.  Indeed, thallium intoxication is considered one of the
    most frequent causes, on a worldwide scale, of purposeful or
    accidental human poisoning.  Knowledge of chronic thallium
    intoxication is limited to occupational exposure, to population groups
    in contaminated areas and to cases of homicide involving multiple low
    doses.

         Symptoms of acute thallium toxicity depend on age, route of
    administration and dose.  Doses which have proved lethal vary between
    6 and 40 mg/kg, being on average 10 to 15 mg/kg.  Without therapy this
    average dose usually results in death within 10 to 12 days, but death
    occurring within 8-10 h has also been reported.

         The triad of gastroenteritis, polyneuropathy and alopecia is
    regarded as the classic syndrome of thallium poisoning, but in some
    cases gastroenteritis and alopecia were not observed.  Several other
    signs and symptoms also occur, varying in order, extent and intensity.

         Symptoms of thallium intoxication are often diffuse and initially
    include anorexia, nausea, vomiting, metallic taste, salivation,
    retrosternal and abdominal pain and occasionally gastrointestinal
    haemorrhage (blood in faeces).  Later, constipation is commonly seen
    and may be resistant to treatment, thus interfering with antidotal
    treatment.

         After 2 to 5 days some of the typical thallium disorders slowly
    develop, irrespective of the route of exposure.  Effects on the
    central and peripheral nervous system vary, but a consistent and
    characteristic feature of thallium intoxication in humans is the
    extreme sensitivity of the legs, followed by the "burning feet
    syndrome" and paraesthesia.  Involvement of the central nervous system
    (CNS) is indicated by symptoms like hallucinations, lethargy,
    delirium, convulsions and coma.  Common circulatory symptoms are
    hypertension, tachycardia and, in severe cases, cardiac failure.  Loss
    of head hair and sometimes body hair occurs after the second week of
    poisoning; dystrophy of the nails is manifested by the appearance of
    white lunular stripes (Mee's lines) 3 to 4 weeks after intoxication. 
    The black regions found in hair papillae are not caused by deposition
    of pigments or thallium but are due to small amounts of air entering
    the shaft.

         In lethal cases the time until death occurs may vary from hours
    to several weeks, but most commonly death occurs within 10 to 12 days. 
    Causes of death are mainly renal, CNS and cardiac failure.

         In sublethal poisonings, recovery often requires months. 
    Sometimes neurological and mental disturbances as well as
    electroencephalographic abnormalities and blindness can remain. 
    Additionally, intellectual functions seem to be adversely affected in
    survivors.

         In cases of chronic poisoning, symptoms are similar but in
    general milder than in cases of acute intoxication.  Sometimes
    permanent blindness occurs.  Complete recovery takes months and can be
    interrupted by relapses.

         In a well-investigated case of thallium emission around a cement
    plant in Lengerich, Germany, thallium concentrations in the hair and
    urine of exposed people did not correlate with certain features which
    are known to be usually associated with chronic thallium poisoning,
    but only with subjective neurological symptoms.

         Postmortem examinations or biopsies following thallium poisoning
    reveal damage of various organs.  For example, after ingestion of
    lethal doses, haemorrhages in the mucosa of the intestine, lung,
    endocrine glands and heart, fatty infiltrations in liver and heart
    tissue, and degenerative changes to glomeruli and renal tubules occur. 
    In the brain, fatty degeneration of ganglion cells, damage to axons
    and disintegration of myelin sheaths can be observed.

         Variations in blood pressure may be caused by direct effects of
    thallium on the autonomic nervous system.  Thallium intoxication
    causes symmetric, mixed peripheral neuropathy.  Distal nerves are
    affected more than proximal nerves, and earlier but lesser degrees of
    damage occur in nerves with shorter axons, e.g., cranial nerves. 
    Axons are swollen and contain vacuoles and distended mitochondria.  In
    lethal poisoning, severe damage of the vagus nerve, denervation of the
    carotid sinus and lesions of the sympathetic ganglia have been
    observed.  In sublethal poisoning, affected nerves may undergo axonal
    degeneration with no or only partial recovery within 2 years.

         Retrobulbar neuritis and resulting visual disorders can develop
    and persist for months after terminating treatment with thallium-
    containing depilatories, and even optic atrophy may occur.

         Limited data are available on the effects of thallium on human
    reproduction.  Menstrual cycle, libido and male potency may be
    adversely affected. Effects on sperm are known to occur following
    chronic intoxication.  As in animal studies, transplacental transfer
    occurs; this was seen following a thallium-induced abortion.  However,
    apart from a relatively low weight and alopecia of newborn babies,
    fetal development was not affected in about 20 cases of thallium
    intoxication during pregnancy.

         No reports of any carcinogenic effects or data on immunological
    effects of thallium are available.  There is no adequate evidence of
    genotoxic effects.

         Therapies of thallium intoxication combine forced diuresis, use
    of activated charcoal and prevention of re-absorption in the colon by
    administration of Prussian blue, potassium ferric hexacyano 
    ferrate(II).

    1.8  Human dose-response relationship

         The mean urinary thallium concentration in unexposed populations
    is 0.3 to 0.4 µg/litre.  As thallium has a short biological half-life,
    measured in days, and assuming steady-state conditions, this urinary
    concentration can be taken as an indicator of total dose following
    inhalation and dietary intake.

         The mean urinary thallium concentration in a population sample
    living near a thallium atmospheric emission source was 5.2 µg/litre. 
    A clear dose-response relationship was found between urinary thallium
    concentration and the prevalence of tiredness, weakness, sleep
    disorders, headache, nervousness, paraesthesia, and muscle and joint
    pain.  A similar dose-response relationship was also reported when
    thallium in hair was used as an indicator of exposure.

         The Task Group considered that exposures causing urinary thallium
    concentrations below 5 µg/litre are unlikely to cause adverse health
    effects.  In the range of 5-500 µg/litre the magnitude of risk and
    severity of adverse effects are uncertain, while exposure giving
    values over 500 µg/litre have been associated with clinical poisoning.

    1.9  Effects on other organisms in the laboratory and field

         Thallium affects all organisms, but species- and also strain-
    specific differences are evident.  Different inorganic thallium(I) and
    thallium(III) compounds and organothallium compounds can show
    different toxicities.

         The most important effect of thallium on microorganisms seems to
    be inhibition of nitrification by soil bacteria.  Results of one study
    suggest that microbial community structure is disturbed at soil
    concentrations in the range of 1-10 mg/kg dry weight, but the form of
    thallium used in this experiment was not identified.

         Thallium is taken up by all plant parts, but principally by the
    roots.  After uptake into the cell, it is concentrated unevenly in the
    cytosol, probably bound to a peptide.  Thallium concentrations found
    in plants depend on soil properties (especially pH, clay and organic
    matter content), as well as on the developmental stage and on the part
    of the plant.  Thallium accumulates in chlorophyll-containing
    regions, but to a lesser degree in thallium-resistant plants.  Oxygen
    production is reduced by thallium, presumably by direct action on
    electron transfer in photosystem II.  Interference with the pigments
    is indicated by the occurrence of chlorosis. In addition, impaired
    uptake of trace elements seems to be involved in the mechanism of
    toxicity.  Growth is also affected, roots reacting more sensitively
    than leaves or stems.  These effects have been reported at
    concentrations as low as 1 mg thallium/kg of dry plant tissue, after
    exposure to monovalent forms of thallium.

         Most studies of effects on aquatic organisms have used soluble
    monovalent thallium compounds.  The lowest thallium concentration
    reported to affect aquatic species is 8 µg/litre, which caused a
    reduction in growth of aquatic plants.  Invertebrates are often
    affected at lower concentration than fish (96-h LC50 values are
    2.2 mg thallium/litre for daphnids and 120 mg/litre for a freshwater
    fish).  The lowest LC50 value, reported after exposure for about 40
    days, was 40 µg/litre for fish.

         Many cases of thallium intoxication of wildlife have been caused
    by its large scale application as a rodenticide.  In seed-eating
    animals and predators the CNS and/or the gastrointestinal tract are
    most severely affected.  These effects can also be observed in farm
    animals.  In addition, thallium causes a loss of dorsal feathers in
    ducks, salivation from the nose and mouth of cattle, and reduced
    growth in broilers, laying hens, sheep and steers.

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

         Thallium is a soft, malleable, heavy metal with a bluish-white
    colour and the chemical symbol Tl.  The name thallium derives from the
    beautiful green spectral line ( thallos, green shoot), which
    identified the element.

         An overview on the properties, synonyms and chemical formulae of
    pure thallium and some of its compounds is given in Table 1.

    2.1  Identity

         Thallium is the fifth element in Group IIIB of the Periodic
    Table.  It occurs naturally as two isotopes thallium-203 and
    thallium-205 with abundancies of 29.52 and 70.467%, respectively
    (Aderjan et al., in press).  The relative atomic mass of thallium is
    204.383, the atomic number is 81, and the electron configuration is
    (Xe) 4f14 5d10 6s2 6p.  Due to its high specific gravity of
    11.85 g/cm3, thallium belongs to the heavy metal group, which
    comprises all metals with a specific gravity of over 4.5 g/cm3
    (Micke et al., 1983).

    2.2  Physical and chemical properties

         The physical properties of elemental thallium are similar to
    those of lead; it is very soft and malleable.  Thallium exists in both
    the monovalent (thallous) and the trivalent (thallic) form.  Because
    the 6s electrons possess only a low tendency to be released or bound
    covalently, the thallous form is more common and stable and forms
    numerous stable salts.  Thallium(III) is easily reduced to thallium(I)
    by reducing agents at high temperatures (Tl+/Tl3+ = +1.12v) (Micke
    et al., 1983; Schoer, 1984; Stokinger, 1987).

         Below 234°C the metal crystallizes in a hexagonal close-packed
    form (alpha-thallium), while at 234°C it converts to the ß-form, a
    cubic body-centred lattice.  Thallium begins to volatilize at 174°C.
    It has a melting point of 303°C, a boiling point of 1457°C and a
    normal potential of Tl/Tl+ -0.335v (Micke et al., 1983).  Thallium
    is a very reactive metal.  When exposed to air and moisture, it is
    superficially oxidized, forming a coating of thallium(I) oxide
    (Tl2O).  At higher temperatures it reacts with a lovely green flame
    to form thallium(III) oxide (Tl2O3).  Thallium carbonate
    (Tl2CO3) is the only heavy metal carbonate that is very soluble in
    water (Micke et al., 1983; Stokinger, 1987).


        Table 1.  Physical and chemical properties of thallium and some selected thallium compoundsa
                                                                                                                                                

    Name          Chemical           CAS registry   Relative         Specific       Melting          Boiling         Colour          Solubility
                  formula            number         atomic/          gravity        point            point                           in water
                                                    molecular mass   (g/cm3)        (°C)             (°C)                            (g/litre)
                                                                                                                                                

    Thallium      Tl                 7440-28-0      204.38           11.85          303.5            1457            bluish-white,   insoluble
                                                                                                                     metallic

    Thallium(I)   TlC2H3O2           563-68-8       263.43           3.765          131              -               silky white     very
    acetate                                                                                                                          soluble

    Thallium      TlAl(SO4)2*12H2O   52238-56-9     639.66           2.306          91               -               colourless      117.8
    aluminium
    sulfate

    Thallium(I)   TlBr               7789-40-0      284.29           7.557          480              815             pale yellow     0.5
    bromide                                                          (17.3°C)                                                        (25°C)

    Thallium(I)   Tl2CO3             29809-42-5     468.78           7.110          273              -               white           40.3
    carbonate                                                                                                                        (15.5°C)

    Thallium(I)   TlCl               7791-12-0      239.84           7.004          430              720             white           2.9
    chloride                                                         (30°C)                                                          (15.5°C)
                                                                                                                                                

    Table 1 (contd).
                                                                                                                                                

    Name             Chemical      CAS registry    Relative         Specific       Melting          Boiling          Colour          Solubility
                     formula       number          atomic/          gravity        point            point                            in water
                                                   molecular mass   (g/cm3)        (°C)             (°C)                             (g/litre)
                                                                                                                                                

    Thallium(III)    TlCl3         13453-32-2      310.74           -              25               decomposes       colourless,     very
    trichloride                                                                                                      hygroscopic     soluble
                     TlCl3*4H2O    13453-33-3      382.80           -              37               100 (-H2O)       colourless      862

    Thallium         TlOC2H5       20398-06-5      249.44           3.493          -3               130              colourless      -
    ethylate                                                        (20°C)                          (decomposes)

    Thallium(I)      TlF           7789-27-7       223.38           8.23           327              655              colourless      786
    fluoride                                                        (4°C)                                                            (15°C)

    Thallium(III)    TlF3          7783-57-5       261.38           8.36           550              -                olive           decomposes
    trifluoride                                                     (25°C)         (decomposes)                      green           to TlOH

    Thallium         TlOH          1310-83-4       221.39           -              139              -                pale            259
    hydroxide                                                                      (decomposes)                      yellow

    Thallium(I)      TlI           7790-30-9       331.29           7.29           440 (ß)          823 (ß)          yellow          0.006
    iodide (alpha)                                                                                                                   (20°C)
                                                                                                                                                

    Table 1 (contd).
                                                                                                                                                

    Name              Chemical         CAS registry    Relative         Specific      Melting        Boiling         Colour        Solubility
                      formula          number          atomic/          gravity       point          point                         in water
                                                       molecular mass   (g/cm3)       (°C)           (°C)                          (g/litre)
                                                                                                                                                

    Thallium(I)       TlNO3            10102-45-1      266.39           -             206            430             white         95.5
    nitrate (alpha)                                                                                                                (20°C)

    Thallium (III)    Tl(NO3)3*3H2O    13453-38-8      444.44           -             105-107        decomposes      colourless    decomposes
    nitrate
    trihydrate

    Thallium(I)       Tl2O             1314-12-1       424.77           9.52          300            1080 (-O)       black         decomposes
    oxide                                                               (16°C)                                                     to TlOH

    Thallium(III)     Tl2O3            1314-32-5       456.76           10.19         717 ± 5        875 (-O2)       black         insoluble
    oxide                                                               (22°C)

    Thallium(I)       Tl2SO4           7446-18-6       504.82           6.77          632            decomposes      white         48.7
    sulfate                                                                                                                        (20°C)

    Thallium(I)       Tl2S             1314-97-2       440.85           8.46          448.5                                        0.2
    sulfide                                                                                                                        (20°C)
                                                                                                                                                

    a   From: Stokinger (1987); Budavari (1989); Lide (1990)
             In contact with water, thallium(I) hydroxide is formed from the
    metal.  Thallium is very soluble in HNO3 and H2SO4, but only
    slow dissolution takes place in HCl, because of the low solubility of
    the halides.  It is insoluble in alkali bases.  Thallium combines with
    fluorine, chlorine and bromine at room temperature, and reacts with
    iodine, sulfur, phosphorus, selenium and tellurium after heating.  The
    metal does not react with molecular hydrogen, nitrogen or carbon.  It
    forms alloys with other metals and readily amalgamates with mercury
    (Micke et al., 1983).

         The ionic radii and the electronegativity constant of monovalent
    thallium are very similar to those of other alkali metals. 
    Thallium(I) hydroxide, carbonate and sulfate, like the corresponding
    potassium compounds are very soluble in water.  With respect to their
    physical and chemical properties, e.g., poor water solubility,
    thallium(I) oxide, sulfide and halides show similarities to the
    corresponding compounds of silver, mercury and lead
    (Trotman-Dickenson, 1973).  In contrast to inorganic thallium
    compounds, covalent organothallium compounds are only stable in the
    trivalent form (McKillop & Taylor, 1973).  Thallium(I) is not strongly
    complexed by humic acids, whereas thallium(III) forms stable complexes
    of the [TlX4]- or [TlX6]3- type (Schoer, 1984).

    2.3  Conversion factor

    1 g thallium     =  0.0049 mol
    1 mol thallium   =  204.38 g

    2.4  Analytical methods

         Classical analytical methods, the introduction of new techniques
    and a combination of both with enrichment or separation processes
    provide suitable methods for the quantitative detection of thallium in
    various media.  Because thallium concen  trations in environmental
    samples are very low, determination directly from the sample or from
    the digestion solution usually lacks sufficient accuracy.  Therefore,
    preconcentration procedures are necessary (Schoer, 1984; Sager & Tölg,
    1984).

    2.4.1  Sampling and sample preparation

         Thallium losses during sampling, sample preparation and
    determination are a major source of analytical error.  Contamination
    hazards need to be anticipated, as thallium is present in laboratory
    ware and is leached out by solutions (Kosta, 1982).  Glass contains
    about 1-10 µg thallium/kg.  Leaching of polythene containers with 6M
    HCl for 1 week brought 1-10 ng thallium/cm2 into solution.  In

    addition, thallium(I) in 0.1M HNO3 solution adsorbs onto container
    walls made of polyethene, polypropene, glassware or rubber.  This
    effect depends on the chemical properties of the surface of the
    container walls and on the concentration of matrix ions.  At a
    thallium concentration of 1 mg/litre, no losses to borosilicate
    surfaces at pH < 4 were reported, but extensive adsorption occurred
    at pH > 10 (Sager & Tölg, 1984).

         For determinations with spectrophotometric, mass spectrometric,
    voltametric and other methods, digested samples are needed.  With
    respect to the high volatility of the metal and the low boiling points
    of some of its compounds, only closed systems are recommended for the
    digestion of organic matrices to prevent thallium losses.  Fusion, dry
    ashing and fuming with HF and H2SO4 or HClO4 may lead to severe
    losses (up to 40%) of the thallium present (Matthews & Riley, 1969). 
    High-pressure digestion in closed quartz vessels with concentrated
    acids, e.g., HNO3 or HNO3 and HF, at temperatures up to 300°C is
    the most suitable procedure for nearly all matrices (Knapp, 1985).  HF
    interferes with analysis by GFAAS or ICP-AES and needs to be removed
    by heating to dryness with H3BO3 (Han et al., 1982).

         The volatility of thallium and its oxide or chloride makes it
    possible to separate these with a gas stream of O2, H2 or HCl from
    other elements that do not form volatile components under the same
    conditions and subsequently capture them in a cool trap.  This
    procedure can be used as a preconcentration step when large quantities
    of sample are available (Geilmann & Neeb, 1959; Han et al., 1982;
    Sager, 1984).

         Other methods of preconcentration are coprecipitation, anodic
    electrolysis, ion exchange and liquid-liquid extraction. 
    Coprecipitation is not selective, but it leads to a high concentration
    factor and results in a definite matrix, which might be useful in some
    methods (Griepink et al., 1988). For example, coprecipitation with
    Fe(OH)3 leads to separation from a salt matrix (K+, NH4+). 
    Electrolytic deposition or cementation with zinc powder yields an
    excellent separation, although this procedure is time-consuming.  Ion
    exchange, which gives a specific separation in certain cases, is also
    time-consuming.  Liquid-liquid extraction with chelating agents is
    virtually nonspecific, but it is a fast and easy method.  A
    disadvantage is the relatively low concentration factor (Sager & Tölg,
    1984).

         Isotope dilution methods have been applied to avoid ionization
    matrix effects. Thallium is measured as thallium-205; the thallium-203
    isotope can be used as a spike for isotope dilution (Sager, 1986).

    2.4.2  Methods of determination

         Thallium is almost always determined as total metal, rather than
    as specific thallium compounds.  Among the analytical techniques that
    can be used are spectrophotometry, mass spectrophotometry (MS), atomic
    absorption spectrometry (AAS), voltametry, neutron activation analysis
    (NAA), X-ray fluorimetry, and inductively coupled plasma (ICP)
    techniques (Sharma et al., 1986).  A selection of analytical methods
    is summarized in Tables 2 and 3.

    2.4.2.1  Atomic absorption spectrometry

         The most widely used method of thallium determination is atomic
    absorption analysis, using measurement at 276.8 nm with a thallium
    hollow cathode lamp.  The sensitivity can be improved by the use of an
    electrode discharge lamp (EDL), owing to its higher intensity.
    Graphite furnace atomic absorption spectrometry (GFAAS) is a
    well-established technique for the monitoring of trace elements in
    nearly all kinds of matrices.  The technique has sufficiently low
    detection limits and is well-suited to applications where high
    sensitivity is required for small sample amounts.  In Table 3 some
    methods for GFAAS are summarized.

         The platform furnace concept in the temperature-stabilized mode,
    together with Zeeman effect background correction, allows almost
    interference-free determinations of many elements.  Sample
    pretreatment is not necessary, which greatly reduces the risk of
    substance losses or contamination of the sample prior to analysis
    (Minoia et al., 1990).

         Matrix modifiers permit higher pyrolysis temperatures, so that
    the desired element can be isolated from matrix elements and compounds
    in an ideal case.  Letourneau et al. (1987) found that additions of
    H2SO4 as a matrix modifier were inadequate and that interferences
    could not be corrected by Zeeman background compensation.  Modifying
    the matrix with palladium and magnesium nitrate has been suggested to
    be generally applicable, but this is not as effective for thallium as
    it is for other elements (Welz et al., 1988a).  A combination of 6 mg
    palladium with 100 mg ammonium nitrate allows the direct determination
    of thallium in ten-fold diluted blood against matrix-free standards
    (Yang & Smeyers-Verbeke, 1991).

         Paschal & Bailey (1986) determined thallium concentrations in
    urine.  The samples were diluted 1:1 with a matrix modifier consisting
    of magnesium nitrate, HNO3, Triton X-100 and water.  The detection
    limit was calculated to be 0.5 µg/litre.


        Table 2.  Instrumental methods for the determination of thallium
                                                                                                                                                

    Methoda     Matrix       Oxidation       Sample                   Parameters               Interferences      Detection       Reference
                             state           pretreatment             of method                                   limit
                                                                                                                                                

    PAA         metals       -               203Tl (gamma,n) 202Tl    gamma440 keV                                                Segebade &
                                             30 MeV bremsstrahlung                                                                Schmitt (1987)
                                             post-irradiation
                                             separation of Tl
                                             from the matrix

    NAA         biological   post-           drying, 2-M              1013 n/cm2.sec 3-7       other isotopes     1 µg absolute   Itawi &
                material     irradiation                              days 203Tl (n,gamma)     than 204Tl                         Turel (1987)
                             extraction                               204Tl 0.77 MeV ß-
                                                                      measurement

    AMP         water        Tl (I)          Na2CO3, NaHCO3,          -0.47 vs sat. calomel    Mn(VII), Co(II),   -               Agrawal &
                                             thiomalic acid           electrode                Sn(II), Tl(III)                    Khatkar (1988)

    DPASV       urine,       -               Na acetate, HClO4,       -1.0 vs sat. calomel     Cd, Pb             0.2 µg/litre    Vandenbalck &
                saliva                       EDTA                     electrode                                                   Patriarche
                                                                                                                                  (1987)

    ICP-MS      rocks        -               HNO3, HF, H2O2           -                        polyatomic         70 ng/litre     Date et al.
                                                                                               interferences                      (1988)
                                                                                                                                                

    Table 2 (contd).
                                                                                                                                                

    Methoda         Matrix          Oxidation    Sample                Parameters                 Interferences   Detection       Reference
                                    state        pretreatment          of method                                  limit
                                                                                                                                                

    GDMS            indium          -            -                     at pressure 3.10-4 mbar    -               30 µg/kg        Guidoboni &
                                                                       discharge voltage 1 kV                                     Leipziger
                                                                       discharge current 3 mA                                     (1988)
                                                                       accelerating voltage
                                                                       8 kV resolution 4000

    ICP-AES         air             -            HNO3/HClO4 (4:1)      190.9 nm                   F-              17 µg/litre     NIOSH (1984)
                    particulates                                                                                  leachate

    ICP-AES         biological      -            Parr bomb                                        F-              0.05-0.1        Que Hee &
                    material                                                                                      mg/litre        Boyle (1988)

    ICP-MS          water           -            HNO3                  205Tl                      -               0.1 µg/litre    Henshaw et al.
                                                                                                                                  (1989)

    ICP-MS          tissues         -            HNO3                  -                          -               18 µg/kg        Templeton
                                                                                                                                  et al. (1989)

    Spectrometry    environmental   Tl (I)       dithizone, CHCl3,     -                          Ag, Hg          1 µg/litre      Sager (1986)
                                                 EDTA, citrate,
                                                 cyanide
                                                                                                                                                

    a   AMP = amperometric titration; DPASV = differential pulse anodic stripping voltametry; GDMS = glow discharge mass spectrometry;
        ICP-AES =inductively coupled plasma - atomic emission spectrometry; ICP-MS = inductively coupled plasma - mass spectrometry;
        NAA = neutron activation analysis; PAA = photon activation analysis; PPS = proton-induced prompt low energy photon high resolution
        spectrometry

    Table 3.  Methods for determining thallium (Tl) with graphite furnace atomic absorption spectrometry (GFAAS)
                                                                                                                                                

    Sample          Separation                           Injected solution         Detection limit            Interferences    Reference
                                                                                                                                                

    Fly ash, soil   digestion and preconcentration       diluted H2SO4, HNO3       3.3 ng/litre               HBr              De Ruck et
                    by extraction of Tl(III) with                                  including the 400 ×                         al. (1989)
                    diisopropylether evaporation                                   preconcentration step)

    Urine           complex with tri-n-octylamine,       organic layer diluted     0.3 µg/litre               max. charring    Flanjak &
                    extraction with ethanol into 5 mg    with ethanol and H2SO4                               temp. 400°C      Hodda (1988)
                    metallic n-butyl acetate gallium

    Gallium         -                                    gallium                   200 µg/kg                  -                Hiltenkamp &
                                                                                                                               Jackwerth (1988)

    Urine           -                                    spiked urine, diluted     2 µg/litre                 NaCl             Berndt &
                                                                                                                               Sopczak (1987)

    Urine           chelation with NaDDC, extraction     MIBK extract              0.05 µg/litre              -                Apostoli et
                    with MIBK                                                                                                  al. (1988)

    Mineralized     -                                    HNO3, H2SO4, ascorbic     5 µg/litre                 NaCl             Leloux et al.
    faeces and                                           acid, Triton X-100                                                    (1987a)
    tissues
                                                                                                                                                

    Table 3 (contd).
                                                                                                                                                

    Sample          Separation                           Injected solution         Detection limit            Interferences    Reference
                                                                                                                                                

    Blood, serum    -                                    HNO3                      10 µg/litre                                 Leloux et al.
                                                                                                                               (1987a)

    Erythrocytes    -                                    HNO3                      12 µg/litre                                 Leloux et al.
                                                                                                                               (1987a)

    Soil,           extraction with                                                20 µg/kg                   Cu, Zn, Pb       Ebarvia et
    sediments       tri-octyl-methylammonium, MIBK                                                                             al. (1988)

    Coal fly ash    -                                    HNO3                      -                          -                Bettinelli et
                                                                                                                               al. (1988)
                                                                                                                                                

    MIBK = methyl isobutyl ketone; NaDDC = sodium diethyl dithiocarbamate
    
         Chemical interferences due to chloride ions are important.  These
    interferences are caused by volatilization of thallium chloride in the
    pyrolysis stage and, in part, by formation of TlCl(g) during the
    atomization stage.  Even matrix modification gives unsatisfactory
    results.  Welz et al. (1988b) showed that addition of palladium
    nitrate as a modifier and application of argon with 5% H2 as a purge
    gas leads to interference-free determination with, for instance, NaCl
    loads of up to 100 mg.  A special pre-pyrolysis step is necessary to
    reduce palladium to the metal state, thus enabling adsorbed H2 to
    react with the chloride compounds to form volatile HCl.  Similar
    results were obtained by Manning & Slavin (1988).

         De Ruck et al. (1987) reported an oxidation technique for natural
    waters with cerium(IV) sulfate and a subsequent preconcentration step
    on an anion-exchange column.  A preconcentration factor of 400 was
    achieved, and the resultant detection limit was 3.3 ng/litre using
    GFAAS.  Flame atomic absorption is a reliable method for measurement
    of thallium concentrations at the level of mg/litre or more.  The
    determination is easy and free from interference (Welz, 1983; Griepink
    et al., 1988).

    2.4.2.2  Inductively coupled plasma - mass spectrometry

         ICP-MS is a promising method for concentrations in the µg/kg
    range or less, and has good precision and accuracy.  It is a multi-
    element technique with sub-ppb detection limits for many elements. 
    Additional advantages of mass discrimination include its suitability
    for isotope ratio analysis and stable isotope tracer analysis, and the
    extended range of elements that can be studied.  Some ICP-MS methods
    are summarized in Table 2.

         The application of ICP-MS to the analysis of thallium in
    iron-rich ores was described by Date et al. (1988).  No polyatomic
    interferences for iron were detected in acid solutions.  The addition
    of 500 mg iron/litre to a solution of 1 mg thallium/litre in 1% HNO3
    resulted in a 0.1% increase in the thallium peak.  The detection limit
    was found to be 0.07 µg/litre.

         Templeton et al. (1989) examined thallium concentrations in rat
    liver and blood plasma samples which were submitted to acid digestion
    and reported a detection limit of 0.09 µmol/kg (18 µg/kg).

         More than 250 water samples from lakes were analysed for thallium
    (thallium-205) by ICP-MS after acidification with HNO3.  The
    detection limit was found to be 0.1 µg/litre; the recovery of spiked
    analytes amounted to 112 ± 4% (Henshaw et al., 1989).

    2.4.2.3  Other methods

         Methods other than AAS and ICP-MS are summarized in Table 2. 
    Spectrophotometric determination with rhodamin B after liquid/liquid
    extraction is a quick and easy method, but it is less sensitive and
    has a high incidence of interference.  The method is suitable for a
    quick visual test, when a massive intoxication with thallium compounds
    is suspected.  Determinations down to 10 µg/litre are possible in
    environmental matrices (Griepink et al., 1988).

         Inductively coupled plasma - atomic emission spectrometry
    (ICP-AES) is a rapid multi-element technique, but it does not provide
    the detection limits required to measure thallium concentration in
    uncontaminated samples.  The NIOSH method for determining thallium in
    air particulates has a detection limit of 17 µg/litre of leaching
    solution (NIOSH, 1984).

         Differential pulse anodic stripping voltametry (DPASV) is a
    sensitive method for the quantitative determination of thallium in
    water samples or urine.  Voltametric methods also offer the advantage
    of simultaneous determination of several metals from one solution. 
    The lower limit of detection for thallium(I) is 10-100 ng/litre
    (Klahre et al., 1978; Vandenbalck & Patriarche, 1987; Griepink et al.,
    1988).

         Neutron activation analysis (NAA) is applicable for the
    determination of thallium in various environmental samples, but it is
    relatively slow and impractical for the routine analysis of large
    numbers of samples.  The detection limit is determined by the
    irradiation time, neutron flux, the choice of a radiochemical
    separation of the radio-isotope to remove interfering matrix
    radio-isotopes and the measurement time.  Levels down to the absolute
    amount of ng of thallium can be determined (Schoer, 1984).  This
    method can therefore be used for the determination of low thallium
    concentrations in biological samples.  In bovine liver a detection
    limit of 1.5 µg/kg was found after digestion, separation and
    concentration procedures (Henke, 1991).

         Thallium(I)-sensitive electrodes are not sensitive enough for
    trace determinations, and high concentrations of alkali ions reduce
    the selectivity.  Sensitivity problems must also be considered for the
    usual X-ray fluorimetry techniques.  Other methods, like excitation
    with charged particles and photon activation radiochemical isotope
    dilution, are seldom used.

    2.4.3  Quality control and quality assurance

         Sample collection, analysis and data presentation should be
    carried out according to a protocol which ensures adequate validation
    of biological monitoring procedures (Vesterberg et al., 1993).

         There is an urgent need for strict quality control and quality
    assurance of the analytical data on thallium in clinical and
    environmental samples. It is only when proof is given for the accuracy
    of the published data that they become unequivocally useful to
    establish critical concentrations and dose-response relationships in a
    given population or ecosystem.  General considerations of quality
    control and quality assurance have been recommended by WHO (WHO, 1986;
    Aitio, 1988).

         To date, very few of the many  studies on thallium have provided
    the necessary evidence concerning the quality of the data throughout
    the analytical procedure.  The recognized way to control and ensure
    this involves good laboratory practice (GLP), including intra- and
    inter-laboratory analysis of materials with certified concentrations
    of thallium.  Such Certified Reference Materials (CRMs) should have
    the same (or a similar) matrix as the sample to be analysed and be
    certified for thallium concentrations (similar to those in the sample)
    by an internationally recognized body.  This implies suitable levels
    for thallium in serum, whole blood, urine, faeces, animal tissues and
    plants, as well as levels typical for exposed individuals, animal
    studies or eco-systems (Cornelis, 1988).

         Available reference materials with clinical and environmental
    interest are listed in Table 4.  This immediately reveals the very
    poor picture for CRMs certified for thallium.  Whole blood and serum
    samples are totally lacking, while urine of exposed individuals is
    handled by the BI CUM 2 and 3 products with assigned values for
    thallium only.  The BCR milk powders and the NBS liver samples carry a
    reference value.  Thallium has also been reported in some
    environmental samples (fly ash, etc.) without being certified.

         There appears to have been only one inter-laboratory survey on
    thallium in two spiked urine samples (Geldmacher-von Malinckrodt et
    al., 1984).  The 35 participating laboratories used one of the three
    routine methods, AAS, DPASV or photometry, after thallium extraction. 
    The samples were also analysed by IDMS (isotope  dilution mass
    spectrometry) and attributed reference values of 66.3 and 483 µg
    thallium/litre, respectively.  The evaluation of this inter-laboratory
    survey revealed that about 70% of the laboratories met the goal.

    2.4.4  Conclusions

         There are several methods available for the determination of
    thallium in biological and environmental samples.  As routine methods
    these are GFAAS (the most widely used), DPASV, ICP-MS and photometry. 
    They all require a very careful sample pretreatment and, in the case
    of DPASV and photometry, perfect mineralization of the sample without
    losses due to volatilization or adsorption onto the container walls.

    The same remarks apply to the methods including a preconcentration
    step.  In the case of GFAAS and ICP-MS, direct analysis of the diluted
    sample is feasible.  It is strongly recommended that all analyses be
    accompanied by a quality assurance programme.  At present, it is
    possible to determine thallium concentrations of about 0.1 µg/litre or
    0.1 µg/kg.

        Table 4.  Reference materials for thallium determinations in biological and
              environmental materialsa
                                                                                               

    Matrix       Originb     Code           Thallium              Remarks
                                            concentration
                                                                                               

    Liver        NBS         SRM 1577       50 µg/kg              lyophilized bovine liver
                             SRM 1577A      3 µg/kg               lyophilized bovine liver

    Milk         BCR         CRM 63         1.3 µg/kg             natural skim milk powder
    powder                   CRM 150        1.0 µg/kg             spiked milk powder
                             CRM 151        0.8 µg/kg             spiked milk powder

    Urine        BI          CUM 2          93 ± 13 µg/litrec     lyophilized synthetic urine
                             CUM 3          603 ± 78 µg/litrec    lyophilized synthetic urine

    City         BCR         BCR-CRM-       2850 µg/kg            certified; error 6.7%
    waste                    176

    Coal         IRANT       IRANT-ECO      14 000 µg/kg          not certified
    fly ash

    Coal         NIST        NIST-SRM-      5700 µg/kg            certified; error 3.5%
    fly ash                  1633a

    Gas coal     BCR         BCR-CRM-       2200 µg/kg            not certified
                             180

    Steel        IRANT       IRANT-OK       < 3000 µg/kg          not certified
    plant
    flue dust
                                                                                               

    a  According to Muramatsu & Parr (1985) and Cortes Toro et al. (1990)
    b  BCR: Measurement and Testing Programme, DG XII, BCR, Commission of the
       European Union, Wetstraat 200, B-1049 Brussels, Belgium BI: Behring
       Institute, PO box 140, D-3350 Marburg 1, Germany IRANT: Institute of
       Radioecology and Applied Nuclear Techniques (CSSR) NBS (new name NIST):
       Room B 311, Chemistry Building, National Institute for Standardization
       and Testing, Gaithersburg, MD 20899, USA NIST: National Bureau of Standards
       (USA)
    c  assigned values for a particular lot only
    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Thallium is ubiquitous in nature, but occurs at low
    concentrations (< 2 mg/kg) (section 5.1), especially in sulfide ores
    of various heavy metals (zinc, copper, iron and lead) and in minerals
    of potassium, caesium and rubidium (Micke et al., 1983; Kemper &
    Bertram, 1984; Ohnesorge, 1985; Stokinger, 1987; Manzo & Sabbioni,
    1988).  Although the concentration of thallium is low, about 700 000
    tonnes of thallium are contained in worldwide identified resources of
    coal and 19 000 tonnes in zinc resources (US BM, 1989).  There are
    only a few areas with a naturally very high thallium concentration,
    e.g., the Alsar in the Former Yugoslav Republic of Macedonia (Zyka,
    1972).  Minerals of thallium, e.g., lorandite (TlAsS2) and
    crookesite ((Cu,Ag,Tl)2Se), with thallium concentrations of up to
    60%, are rarely found and usually not used for production of thallium
    (Micke et al., 1983; Kemper & Bertram, 1984; Briese et al., 1985;
    Kazantzis, 1986).

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         Since thallium is used only in small amounts by industry,
    worldwide production of pure thallium is low.  In 1975 about 8 tonnes
    were produced in Germany and 2 to 3 tonnes in the USA (Zitko, 1975a),
    while in 1987 and 1988 worldwide production was about 17 tonnes (US
    BM, 1992).  In 1981 the production of thallium in the USA was
    discontinued.  Sources for the production of thallium are zinc, lead
    and sometimes copper or iron smelters and sulfuric acid plants.  Flue
    dust in particular is used as a thallium source (Zitko, 1975a; Smith &
    Carson, 1977; Micke et al., 1983; Briese et al., 1985).  Procedures
    for the separation of thallium from other metals depend on the
    proportions of the different minerals and, therefore, vary
    considerably between the different smelters (Sanderson, 1952; Smith &
    Carson, 1977; Micke et al., 1983; Kemper & Bertram, 1984; Briese et
    al., 1985).

    3.2.2  Uses

         Thallium(I) sulfate was once used in medicine to reduce sweating
    and to cure various infections, e.g., venereal diseases, ringworm of
    the scalp, typhus, tuberculosis and malaria, and as a depilatory
    agent, which caused many intoxications (Munch, 1934b; Smith & Carson,
    1977; Emsley, 1978; Briese & Nessler, 1985a).  However, therapeutic
    uses of thallium have been discontinued because of its toxicity.

    Since 1920, thallium(I) sulfate has been used as a rodenticide, in
    Europe chiefly against rats and in the USA chiefly against ground
    squirrels (Howe, 1971; Smith & Carson, 1977).  Formerly it was used as
    an insecticide (against ants and cockroaches).  However, thallium is
    no longer on sale as a rodenticide in most industrial countries
    (Bruère et al., 1990), but is still used in developing countries
    because of its cheapness.

         Other areas in which thallium is used (Howe, 1971; Smith &
    Carson, 1977; Micke et al., 1983; Briese et al., 1985; Sharma et al.,
    1986; Kazantzis, 1986; Manzo & Sabbioni, 1988; ATSDR, 1992) are as
    follows:

    a)   low temperature thermometers (down to -59°C) made from a  
         mixture of mercury and thallium;

    b)   special glasses with a high resistance and a low melting
         point, containing thallium and selenium;

    c)   mixed crystals for infrared instruments, composed of arsenic 
         or thallium(I) salts and halogenides (TlI-TlBr), and
         Tl3VS4, Tl3NbS4, and Tl3PSe4 for acusto-optic
         and laser equipment;

    d)   electronic devices, e.g. thallium(I) sulfide for
         semiconductors and scintillation counters;

    e)   mercury lamps (addition of thallium(I) halogenids increases
         the yield of light and changes its spectrum);

    f)   alloys with lead, zinc, silver and antimony enhance
         resistance to corrosion;

    g)   catalysing organic reactions, e.g., oxidations of
         hydrocarbons and olefins (thallium compounds are being
         increasingly used for organic synthesis); patents summarized
         by Smith & Carson (1977);

    h)   radioactive isotopes, used in physics for measurement of
         exact time periods (thallium-205), in industry for measuring
         the thickness of material (thallium-204), and in medicine
         for scintigraphy of heart, liver, thyroid and testes, and
         for the diagnosis of melanoma (thallium-201) (Rao et al.,
         1983; Müller-Brand et al., 1984; Urbain et al., 1986);

    i)   other uses, e.g., in the production of imitation jewellery,  
         fireworks, pigments and dyes, the impregnation of wood and  
         leather against bacteria and fungi, and in mineralogical  
         analysis;

    j)   minor amounts of thallium are used in biochemistry, e.g.,
         arylthallium(III) compounds for modification of proteins and 
         tRNA (Douglas et al., 1990).
         Worldwide industrial consumption in 1991 was estimated to be 10
    to 15 tonnes.  Between 1940 and 1980 consumption in the USA varied
    considerably between 0.5 and 11 tonnes/year (Schoer, 1984), and
    between 1984 and 1988 it was 1.1-1.5 tonnes/year (US BM, 1985, 1989). 
    In the USA it is used mainly in the electrical and electronic
    industries and the 650 kg used in 1983 in the German Democratic
    Republic was mainly for making special glass (Smith & Carson, 1977;
    Micke et al., 1983; Briese et al., 1985; Kazantzis, 1986; Kemper &
    Bertram, 1991).

    3.2.3  Emissions from industrial sources

         There is an enormous difference between the amount of thallium
    mobilized (released into air, water or disposed of on land) and the
    thallium consumption of 12 tonnes/year (section 3.2.2).  Worldwide a
    total of 2000-5000 tonnes of thallium is estimated to be mobilized per
    year, especially through the combustion of fossil fuels, refinement of
    oil fractions, the smelting of ferrous and non-ferrous ores, and also
    by some other industrial processes such as cement production (Gorbauch
    et al., 1984; Ewers, 1988; Nriagu & Pacyna, 1988).  Smith & Carson
    (1977) estimated that about 15% (240 tonnes) of total mobilized
    thallium is transferred annually to the atmosphere.  However, only a
    small fraction is released into the atmosphere or wastewater during
    production processes or from waste materials (Table 5).  Summarizing
    estimations for the USA by Smith & Carson (1977), Schoer (1984)
    emphasized that in the USA each year nearly 1000 tonnes of thallium
    are released into the environment, of which 350 tonnes are emitted in
    vapours and dusts, 60 tonnes bound to non-ferrous metals, and more
    than 500 tonnes contained in fluid and solid wastes.

    3.2.3.1  Metal production industries

         It has been estimated that worldwide over 600 tonnes of thallium
    are processed per year during the smelting of lead, copper and zinc
    ores (Micke et al., 1983).  Thallium emissions from smelters can vary
    greatly from plant to plant, depending upon the thallium content of
    the raw materials and the technology used.  For this reason, and
    because of the lack of recent emission data, global releases can be
    only roughly quantified.  On the basis of the data in Table 5, a total
    of about 90 tonnes of thallium may be released each year into the
    atmosphere from non-ferrous metal production operations in the USA,
    Canada and Germany.  Dust in one zinc smelter was reported to contain
    380-3700 mg thallium/kg before and 60-9700 mg/kg after starting the
    production of thallium (Briese et al., 1985).  Although it is not
    possible to estimate the losses of thallium from mineral waste
    materials, releases from these materials are generally expected to be
    small.

        Table 5. Estimated emissions of thallium (tonnes/year) into the environment
                                                                                             

    Emission source                 USA       Canada    Germany   Europe     World
                                                                                             

    Coal combustion
      into air                      180a                7.5b      7c        54d
                                    140e                4f        80e       600e
                                                        6g
      into soil/water               170a
      into total environment                                      240c

    Coal combustion (into air)
      from electric utilities                                               155-620h
      from industry and domestic                                            495-990h

    Ferroalloy production
      using manganese ores
      into air                      140a
      into soil/water               220a

    Raw iron production and
      related coal combustion
      into air                      6a                  35g                 30d
      into total environment        205a

    Production of nonferrous
    metals
      into air                      38a       44i       11g
      total emission                496a

    Potash-derived fertilizers
      into total environment        5a

    Cement plants
      into air                                          25g                 2670-5340h

    Brick works                                         28b
                                                                                             

    Table 5. (cont'd).
                                                                                             

    Emission source                 USA       Canada    Germany   Europe     World
                                                                                             

    Oil fuel combustion, mining
    and processing of oil shales
      into soil/water               8a
      total emission                8a

    Waste combustion                                    < 1g
                                                                                             

    a   Smith & Carson (1977)             f   Brumsack et al. (1984)
    b   Brumsack (1977)                   g   Davids et al. (1980)
    c   Sabbioni et al. (1984b)           h   Nriagu & Pacyna (1988)
    d   Bowen (1979)                      i   Kogan (1970)
    e   Schoer (1984)
    
         Data from the USA (Smith & Carson, 1977) indicate that relatively
    large amounts of thallium are present in waste materials from
    non-ferrous metal (mainly copper) and iron and steel production
    (Table 5).  Although no precise data were available on thallium levels
    in waste from ferroalloy production using manganese ores, Smith &
    Carson (1977) suggested that emissions from this source could be
    significant.  Atmospheric releases resulting from the production of
    iron and steel in the USA were estimated to be relatively small (about
    5 tonnes from steelmaking and 1 tonne in iron blastfurnace gases).  In
    the main area of iron and steel production in Germany, annual thallium
    emissions into air have been estimated to be about 0.8 tonnes (Ewers,
    1988).

    3.2.3.2  Power-generating plants

         Power-generating plants represent a major source of thallium
    emissions, especially those using some brown coal or coal of the
    Jurassic period.  Most coals contain only about 0.5 to 3 mg/kg, mainly
    incorporated in sulfide inclusions.  Some of these impurities can be
    removed by washing and mechanical cleaning.  It has been estimated
    that about half of the thallium content of coal is emitted into the
    atmosphere and represents the biggest anthropogenic source (Smith &
    Carson, 1977) (Table 5).  In such estimations, losses from collected
    fly ash are not taken into consideration, because its use may vary. 
    Only a minor amount is used in cement making.  If it is used as a soil
    stabilizer, contami  nation of the environment is much higher (Smith &
    Carson, 1977).

         Natusch et al. (1974) found that coal-fired power-generating
    plants emitted about 700 µg thallium/m3 flue gases, resulting in a
    local level of air emission of about 700 ng/m3.  This would result
    in an estimated daily absorbed amount of 4.9 µg airborne thallium per
    person (US EPA, 1980).  In the European Union, coal-fired
    power-generating plants were estimated to have caused a total
    mobilization of 240 tonnes of thallium during 1990, about one third of
    this being concentrated in the smallest particles, and atmospheric
    emissions of 7 tonnes (Sabbioni et al., 1984b).

         In coal burners, thallium volatilizes and recondenses onto the
    surface of ash particles in cooler parts of the system.  As a result,
    2 to 10 times higher concentrations of thallium may occur in the
    fly-ash than was present in the coal (Galba, 1982).  Fly-ash thallium
    content is negatively correlated with particle size (Manzo & Sabbioni,
    1988).  Thus, thallium and other toxic trace elements are concentrated
    in the smallest particles, which pass through conventional
    power-generating plant filters, remain suspended in the atmosphere for
    long periods and are respirable.  For instance, particles with a
    diameter of 1.1-2.1 µm contain 76 mg thallium/kg fly-ash, those with a
    diameter of 2.1-7.3 µm contain 62-67 mg/kg and those with a diameter
    of 7.3-11.3 and > 11.3 µm contain 40 and 29 mg/kg, respectively. 
    Particles with a diameter of less than 74 µm contain only 7 mg
    thallium/kg (Natusch et al., 1974).  These particles are highly toxic,
    since thallium and other heavy metals are preferentially concentrated
    on the particle surfaces and therefore are relatively bioavailable
    (Linton et al., 1976; Natusch, 1982).

    3.2.3.3  Brickworks and cement plants

         Total thallium emissions from brickworks in Germany have been
    estimated to be 28 tonnes/year. This compares with emissions of
    7.5 tonnes/year from the burning of coal (Brumsack, 1977).

         The emission potential of cement plants was not recognized until
    1979.  The first effects on vegetation around a cement plant in
    Lengerich, Germany were observed in 1977 (Pielow, 1979; LIS, 1980),
    but only the gradual hair-loss in a rabbit led to the suspicion that
    thallium was the cause of the toxic effects (LIS, 1980; Brockhaus et
    al., 1981b; Dolgner et al., 1983).  The source of thallium was found
    to be residues of pyrite roasting added as a ferric oxide additive to
    powdered limestone in order to produce special qualities of cement and
    the addition of the filter fly-dust (LIS, 1980).  Studies at other
    plants showed much lower emission levels, so that the emission at
    Lengerich was caused by the exceptional circumstances.  Production
    alterations in Lengerich caused a reduction in the emissions of more
    than 99% (Pielow, 1979; Prinz et al., 1979; LIS, 1980).

         Like power-generating plants, cement plants emit thallium mainly
    bound to particles with a diameter of 0.2-0.8 µm (LIS, 1980). 
    Thallium concentrations in fly-dust emitted by the cement plant in
    Lengerich were about 2.5 mg/m3 air, of which nearly all was
    water-soluble thallium(I) chloride.  Whereas the filter efficiency was
    99% with respect to cement dust, it was only 50% with respect to the
    thallium-containing particles.  As a result, about 140 to 200 g
    thallium/hour was emitted (Pielow, 1979; Prinz et al., 1979;
    Weisweiler et al., 1985).  Changing the production process reduced the
    thallium content to less than 25 µg/m3 (< 200 mg/kg dust).  In
    other cement plants the concentrations in the filter dust were reduced
    from 3066 mg/kg to about 100 mg/kg, and after this reduction only 13%
    of the thallium was soluble in water (LIS, 1980).

    3.2.3.4  Sulfuric acid plants

         The sulfuric acid plant which had been the source of the roasted
    pyrite used in the cement plant in Lengerich used pyrite containing
    about 400 mg thallium/kg.  However, in the roasted pyrite about 7% of
    the thallium was water-soluble.  During production of sulfuric acid, a
    100-fold enrichment of thallium was found (LIS, 1980).  As a
    consequence, increased levels of thallium were found in Duisburg,
    Germany around the sulfuric acid plant but never such high
    concentrations as around the cement plant (Gubernator et al., 1979).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Transport and distribution in air, water and soil

         Near point sources such as coal-fired power-generating stations,
    cement plants using pyrite and some metal smelting operations, the
    major source of thallium in air is emission of fly-ash (section
    5.1.1).  Although data on the forms of thallium in these emissions are
    limited, results of one study indicate that nearly all of the thallium
    in fly dust from a cement plant (in Lengerich, Germany) was present as
    soluble thallium(I) chloride (LIS, 1980).  No data on the amounts or
    forms of thallium transported from soil into air during the dry season
    were identified.

         Assuming that 4 × 1012 kg of crustal rocks weather each year,
    Bowen (1979) calculated that 2.4 × 106 kg thallium/year become
    available to plants.  However, as Smith & Carson (1977) have noted,
    thallium tends to be retained during rock weathering, and
    concentrations in soils tend to be somewhat enriched in soils compared
    to the original bedrock.

         The fate of thallium added to soil in deposited fly-ash probably
    depends greatly on soil type (Crössmann, 1984).  Data from Smith &
    Carson (1977) suggest that retention should be greatest in soils that
    contain large amounts of clay, organic matter and iron/manganese
    oxides.  According to McCool (1933) significant amounts of thallium
    can be removed from solution in soils by ion exchange.  Thallium can
    also be incorporated into stable humus complexes (Crössmann, 1984),
    which are resistant to rapid "wash-out" (Schoer, 1984).

         Results of studies in several areas indicate that thallium
    deposited from the atmosphere tends to accumulate in the surface
    layers of soils (Smith & Carson, 1977; Heinrichs & Mayer, 1977; LIS,
    1980).  For example, after prolonged emissions from a cement plant in
    Germany (LIS, 1980), thallium was found to remain in the upper levels
    of soil (Schoer, 1984); material from depths 0-10, 40-50 and 60-70 cm
    contained 4.2, 1.3 and 0.1 mg thallium/kg, respectively (Schoer,
    1984).  Retention processes will, however, be less effective in acidic
    soil.  For example, results of studies by Heinrichs & Mayer (1977)
    indicate that about 40% of the thallium deposited from the atmosphere
    onto relatively uncontaminated acidic (pH = 3.9-4.3) forest soil in
    Germany was leached from the top 50 cm to lower soil horizons. 
    Elevated concentrations of thallium in groundwater (up to 40 µg/litre)
    and in an irrigation canal (up to 96 µg/litre) in China, near a site
    where waste materials from the mining of mercuric ore and coal
    containing 25 to 106 mg thallium/kg were deposited (Zhou & Liu, 1985),
    indicate that under some circumstances significant amounts of thallium
    can move from soil into local water.

         Although there is little information on the forms of thallium in
    natural water, most dissolved thallium in fresh water is expected to
    be present as the monovalent Tl+ ion (Smith & Carson, 1977).  In
    strongly oxidizing fresh water and in most seawater (Sager & Tölg,
    1984), however, trivalent thallium is probably the predominant
    dissolved form.  Both forms of thallium can be removed from solution
    by exchange and complexing reactions with suspended solid phases. 
    Trivalent thallium is also susceptible to reduction and precipitation
    processes.  According to Cotton & Wilkinson (1988), trivalent thallium
    is extensively hydrolysed to form the colloidal oxide over the pH
    range of natural water.  Depending upon the relative kinetics of
    reduction and hydrolysis, precipitation of thallium(III) hydroxide may
    be an effective mechanism for removing thallium from solution.  When
    thallium(III) (precipitated as the oxide or hydroxide) settles into
    organic-rich anaerobic sediment, it will be reduced to the monovalent
    form, which can in turn be fixed in the sediment by reaction with
    sulfide to form insoluble Tl2S (US EPA, 1978).  Thallium is thus
    relatively depleted in seawater where thallium(III) predominates and
    can be enriched in sediments where organic matter accumulates under
    undisturbed, anaerobic conditions (Smith & Carson, 1977).

         The partitioning of thallium among the water, sediment and biotic
    compartments of aquatic systems has rarely been investigated.  In one
    study, however, in which thallium (100 µg/litre as thallium(I)
    nitrate) was added to a 7-litre glass aquarium containing washed sea
    sand, goldfish and submergent aquatic angiosperms, thallium was
    distributed among all of the compartments.  Concentrations in water
    decreased gradually, while those in the fish and vegetation increased,
    throughout the 9-day duration of the experiment, indicating that
    thallium was being exchanged among these media (Wallwork-Barber et
    al., 1985).  Concentrations in the sand increased rapidly to a
    relatively low value (0.05 mg thallium/kg), and remained relatively
    stable thereafter, suggesting that there was little exchange between
    the sediment and the other compartments.  The limited accumulation of
    thallium in the sediment was attributed in part to the short duration
    of the study and to the absence of organic matter and clay in the
    sand.

    4.1.2  Soil-vegetation transfer

    4.1.2.1  Factors affecting soil-vegetation transfer

         In general, the solubility of thallium compounds governs the
    availability of the metal to vegetation (discussed in detail by
    Cataldo & Wildung, 1978).  Crössmann (1984) mentioned that so far no
    method had been developed to quantify the amount of thallium in soil
    that is easily available for plants. However, Schoer & Nagel (1980)
    emphasized the good correlation between soil-vegetation transfer and
    the concentration determined following ammonium acetate extraction
    from soil.  Other authors favour an EDTA/ammonium acetate extraction
    (Scholl & Metzger, 1982).

         Transfer is influenced by various factors, e.g., pH (section
    5.1.3.2) and the type of the contaminated soil.  Green rape, bush
    beans and rye grass were found to take up less thallium from weakly
    acidic soil (pH 6.2) than from more acidic soil (pH 5.6), and thallium
    supplied by cement factory dust was more available to plants than
    thallium in soil (Makridis & Amberger, 1989a).  Rape plants grown on
    two samples of soil from a contaminated area, one sample (A)
    containing a 3-fold higher concentration of thallium than the other,
    showed identical concentrations of thallium, while other vegetables
    grown on sample A even showed a lower thallium content.  It was
    concluded, that plant availability cannot be correlated to total soil
    thallium content as determined after extraction with concentrated
    nitric acid (Hoffmann et al., 1982).  Only 4.4% (± 2.7%) of the
    thallium content of soil from a lead-zinc mining waste material area
    was available to vegetation, compared to 17.5% (± 10.7%) in soil from
    a cement plant area (Schoer & Nagel, 1980).  In a similar study with
    soil from a cement plant and with stream sediments from a mining
    district (Wiesloch, Germany), rape plants took up about 20% of soil
    thallium from the cement plant sample but only 1.4 to 5.1% from the
    stream sediments, although the latter contained 2- to 3-fold higher
    thallium concentrations; 8- to 80-fold higher concentrations of
    plant-available thallium were calculated for the soil from the cement
    plant (Scholl & Metzger, 1982).  Comparing the uptake of thallium by
    rape seedlings from soil contaminated by emissions from a cement plant
    (mainly with thallium(I) chloride or iodide) with that from
    uncontaminated soil (traces of thallium(I) sulfide), a 7.5-fold higher
    uptake from the contaminated soil was found (Lehn & Bopp, 1987).

         At lower thallium concentrations, some plant species took up a
    higher percentage of the available thallium than at higher
    concentrations, perhaps in part because of the stronger toxic effects
    at higher concentrations.  However, the total amount of thallium found
    in the plants and the thallium content of the artificial soil
    solutions were correlated, reaching up to 1000 mg/kg dry weight in
    green kale following one week's exposure to a concentration of
    10 mg/litre (Schweiger & Hoffmann, 1983).

         The transfer from soil to plant also depends on a number of
    factors relating to the plant, e.g., root system, kinetics of membrane
    transport, metabolism of thallium (Cataldo & Wildung, 1978), so that
    the total amount of thallium taken up is species-specific (section
    5.1.4.2).  This is shown by the bioconcentration factor (concentration
    of thallium in the plant (fresh or dry weight) in relation to its
    concentration in dry soil) found for different plants grown in soil
    contaminated by mining waste materials or collected from sites with
    naturally high concentrations (Table 6) (Schoer & Nagel, 1980; Lehn &
    Bopp, 1987).  Calculations based on the concentrations in plant ash

    and dry soil show that the concentration factor is usually less than
    20 (Smith & Carson, 1977).  The concentrations of thallium in
    vegetables reported by these authors are one to two orders of
    magnitude higher than those found by Geilmann et al. (1960) in
    vegetation grown on uncontaminated soil (Schoer & Nagel, 1980)
    (sections 5.1.4.1 and 5.1.4.2).  Trees can be a long-term reservoir of
    thallium.  As a result of emission by cement plants, the bark and
    lichens of several trees contained 2-23.8 mg thallium/kg dry weight. 
    The use of ground-up bark from these trees for mulching can lead to
    considerable uptake of thallium by other plants (Arndt et al., 1987).

    4.1.2.2  Absorption by plants

         Uptake of thallium(I) ions occurs via all parts of the plant,
    presumably by using the uptake mechanisms for potassium.  However,
    uptake of fly-dust by the leaves of sunflowers is minimal (Schweiger &
    Hoffmann, 1983). Although the majority of the thallium-containing
    particles have a diameter less than 2 µm, they cannot be absorbed by
    transpiration through the stomata (Pallaghy, 1972; LIS, 1980).  In
    numerous laboratory studies using nutrient solutions, a positive
    correlation between plant uptake and thallium concentration in the
    solution has been demonstrated (e.g., Al-Attar et al., 1988). 
    Comparable results have been obtained from the cultivation of mycelium
    of higher fungi in thallium-enriched agar medium (Seeger & Gross,
    1981).

         According to Cataldo & Wildung (1978), absorption of thallium by
    plants seems to be under metabolic regulation, and potassium is a
    non-competitive inhibitor.  Sunflowers with a deficiency of potassium
    and supplied with 1 or 10 mg thallium nitrate/litre possessed a 2 to 3
    times higher concentration of thallium per gram dry weight than those
    supplied with potassium (Schweiger & Hoffmann, 1983).  Metabolically
    controlled uptake seemed to occur only with thallium(I), supplied as
    the acetate, while thallium(III), supplied as the chloride, was
    presumably taken up by passive processes such as cation exchange
    (Logan et al., 1983, 1984).  Since increasing concentrations of
    potassium decrease the uptake of thallium(I), this uptake was
    postulated to be mediated by the (Na+/K+) ATPase system.  During a
    3-h exposure to a solution concentration of 5 mg/litre, excised barley
    seed roots took up about 6009 (± 185) mg thallium(I)/kg dry weight and
    only 870 (± 44) mg thallium(III)/kg.  Thallium(III) ions were easily
    desorbed, presumably because of a large extracellular component,
    whereas the thallium(I) ions were unavailable for exchange.  The
    different uptake mechanisms are also reflected in the sensitivity of
    thallium(I), but not of thallium(III), towards temperature and
    metabolic inhibitors.  Using whole plants (maize), the differences in
    uptake could not be confirmed, but the authors suggested that, prior
    to the uptake, thallium(III) may be reduced in the soil to thallium(I)
    (Logan et al., 1984).

        Table 6.  Bioconcentration factor for plants grown on contaminated soils
                                                                                             

    Plant                             Bioconcentration factora      Reference
                                    Fresh weight     Dry weight
                                                                                             

    Barley (Hordeum vulgare)                         0.14           Lehn & Bopp (1987)

    Cabbage species:
    Green kale                      < 0.1                           Schoer & Nagel (1980)
    Brussels sprouts                < 0.1                           Schoer & Nagel (1980)

    Celeriac (Apium graveolens)     < 0.1                           Schoer & Nagel (1980)

    Cress (Lepidium sativum)                         33             Lehn & Bopp (1987)

    Cress (Lepidium sativum)        0.45-0.59                       Schoer & Nagel (1980)

    Horse-radish (Armoracia)        0.33                            Schoer & Nagel (1980)

    Maize (Zea mays)                                 0.05           Lehn & Bopp (1987)

    Mushrooms                       2.9                             Schoer & Nagel (1980)

    Mustard (Sinapis alba)                           1.07           Lehn & Bopp (1987)

    Parsley (Petroselinum           0.15-0.21                       Schoer & Nagel (1980)
    crispum lapathifolia)

    Rape (Brassica napus)                            66             Lehn & Bopp (1987)

    Rape (Brassica napus)           0.26-0.29                       Schoer & Nagel (1980)

    Spinach                                          594            Maier-Reiter et al.
                                                                    (1987)

    Wheat (Triticum aestivum)                        0.05           Lehn & Bopp (1987)
                                                                                             

    a    Concentration of thallium in fresh or dry weight of the plant in relation
         to its concentration in dry soil
    
    4.1.2.3  Distribution in plants

         Thallium distribution at the cellular level has been investigated
    with rape grown both on uncontaminated soil and on soil spiked with
    non-toxic amounts of thallium (Günther & Umland, 1989).  At each test
    concentration about 70% of the thallium was concentrated in the
    cytosol (comparable to human data in section 6.6).  In the exposed
    plants nearly all the thallium was in the form of free thallium(I)
    ions; no thallium(III) ions or dimethylthallium compounds were
    detected.  However, in all the rape grown on uncontaminated soil, the
    cytosolic thallium was bound, probably to a peptide. This native
    thallium-complexing agent lacked sulfur-containing amino acids and
    could not be induced in rape by the application of thallium (Günther &
    Umland, 1989).

         In addition to its varied distribution at the subcellular level,
    thallium distribution in green plants depends on the developmental
    stage and the part of the plant. Only in mushrooms was no specific
    distribution pattern found to exist (Seeger & Gross, 1981).  Rape
    seedlings grown on soil contaminated by a cement plant (1 to 3 mg
    thallium/kg dry soil) contained 3 to 5 times higher concentrations of
    thallium than full-grown plants. The concentrations in different parts
    of full-grown rape (leaf, 47 mg/kg dry weight; shoot, 5.5 mg/kg; seed,
    2.1 mg/kg) (Lehn & Bopp, 1987) indicate that thallium concentrations
    are higher in the chlorophyll-containing regions, a fact also known
    from plants grown on uncontaminated soils (Weinig & Zink, 1967).  In
    rape grown on artificially contaminated soil (1 mg thallium
    nitrate/plant), yellowing leaves showed higher concentrations (up to
    200 mg/kg dry weight) than green leaves, while the seeds contained
    only about 1 to 2% of the concentration found in the yellow leaves. 
    However, in rape grown in the field near a cement plant, the leaves
    contained up to 85 mg thallium/kg dry weight and the seeds about
    20 mg/kg (Arndt et al., 1987).

         Experimentally, thallium concentrations of 0.0001 to 2.5 mg/litre
    substrate increased the concentration in the shoots of the grass
    Lolium perenne from < 0.075 mg/kg dry weight to 144.05 mg/kg and in
    the roots from 0.42 to 576 mg/kg (Al-Attar et al., 1988).

         The distribution of thallium also varies in different vegetables. 
    For instance, in gardens around Lengerich, leaves of kohlrabi
    contained a 350-fold higher concentration than the tubes, while in
    other vegetables the differences in concentrations between leaves and
    other parts ranged from 3 to 45 times (see Table 13) (Hoffmann et al.,
    1982).  In studies with bush beans and green rape, differences in
    thallium accumulation in the plants were evident (Makridis & Amberger,
    1989b): after incubation in a liquid culture medium (1 mg
    thallium(III) trichloride/litre) for 10 days, roots and shoots of

    beans contained 742 and 62 mg/kg and those of rape 57 and 244 mg/kg,
    respectively.  At higher concentrations the difference between roots
    and leaves disappeared in both species, the concentration in the roots
    of rape increasing more strongly than in the shoots, which, in part,
    was an effect of reduced growth.  Kaplan et al. (1990), using
    thallium(I) sulfate (0.55 and 1 mg/litre), observed at least 4-fold
    higher concentrations of thallium in the roots of soya beans than in
    the pods or the lower or higher leaves.

         These data indicate that plants which are more resistant to
    thallium do not have a reduced uptake, but a reduced transport of
    thallium to the leaves (section 9.3.1.6).

    4.2  Biotransformation

         Laboratory experiments indicate that organothallium derivates may
    originate from the biomethylation processes of anaerobic bacteria in
    lake sediments (Manzo & Sabbioni, 1988).  However, according to Craig
    (1980), there is no firm evidence for environmental methylation.  The
    methylation of thallium and other heavy metals is a vitamin
    B12-(cobalamin-)dependent reaction (Hill et al., 1970; Agnes et al.,
    1971).  Due to its reduction potential, thallium(III) is methylated by
    methylcobalamin (Ridley et al., 1977).  Transfer of the methyl group
    to thallium(III) seems to occur by electrophilic attack of the Co-C
    bond (Wood et al., 1978; Wood, 1984, 1987).

         Monovalent thallium seems to be simultaneously oxidized and
    methylated by specific anaerobic microorganisms to methylthallium(III)
    moieties which are stabilized by complexation (Huber et al., 1978).

         Oxidation of thallium(I) ions to thallium(III) oxide in yeast
    mitochondria (Lindegren, 1971; Lindegren & Lindegren, 1973b) confirms
    an  in vivo oxidation, but specific culture conditions are necessary
    to obtain this detoxification phenomenon in which thallium oxide is
    deposited between cell wall and plasma membrane.

    4.3  Interaction with other physical, chemical, or biological factors

         In the atmosphere, chemical reactions involving thallium are not
    very likely to occur (Schoer, 1984).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

         Because of the limited industrial uses of thallium, emission on a
    global scale resulting from the production and use of thallium
    compounds is unlikely.  However, thallium is present in relatively
    large amounts in the raw materials used in various industrial
    processes (e.g., smelting of sulfide ores, power generation using
    coal, brick and cement manufacturing) (Table 5), which when released
    can significantly increase environmental exposure to thallium on both
    a local and regional scale.

    5.1.1  Air

         Bowen (1979) reported mean values of 0.06 ng particulate
    thallium/m3 air for Europe and 0.22 ng/m3 for North America, and
    Arnold (1986) a range of 0.1 to 30 ng/m3.  The air of six large
    American cities contained < 0.04 to 0.1 ng thallium/m3 (Ohnesorge,
    1985).  In a detailed study at Chadron, Nebraska, USA, Struempler
    (1975) found yearly mean values for thallium of 0.22 ± 0.08 (range
    0.07 to 0.48 ng/m3) and of 0.15 ± 0.04 ng/m3 during the summers of
    1973 and 1974, respectively.

         In industrial and urban areas of Genoa, Italy, the geometric mean
    concentrations of thallium have been found to be 15 and 14 ng/m3
    air, respectively, with maximal values of 58 ng/m3, but often values
    were below 1 ng/m3 (Valerio et al., 1988, 1989).  In London, levels
    of 0.07 to 6 mg thallium/kg dust were measured (Bowen, 1979).

         Air emission by thallium is mainly caused by mineral smelters,
    power-generating plants and cement plants (ATSDR, 1992).  Thallium
    compounds are volatile at high temperatures and are not efficiently
    retained by most emission control facilities.  In consequence, large
    amounts of thallium are released into the atmosphere if the raw
    material (coal or ores) is not selected for a low thallium content.

         In fly-ash from a power plant, only 0.08% of particles were
    < 5 µm in diameter with a thallium concentration of 45 mg/kg ash
    (Natusch et al., 1974).

    5.1.2  Water

         In the majority of reports, the authors did not specify whether
    they determined dissolved and/or particulate thallium in samples of
    water.  This information was included if possible, according to the
    methodology used in the study.

    5.1.2.1  Areas not contaminated by thallium

         Seawater contains < 0.01 to 0.02 µg/litre, and river water
    < 0.01 to 1 µg/litre (Mason, 1966; Smith & Carson, 1977; Bowen, 1979;
    Kemper & Bertram, 1984; Wachs, 1988).

         In volcanic springs, low concentrations have been found
    (0.25 µg/litre) (Arnold, 1986) and in three samples of hydrothermal
    water it was below the detection limit of 0.6 µg/litre (Korkisch &
    Steffan, 1979). Although, in these and the wastewater investigation,
    dissolved and particulate thallium were not determined separately,
    Henshaw et al. (1989) found concentrations of up to 0.41 µg
    thallium/litre in filtered water from freshwater lakes.  In three
    wastewater treatment facilities in Massachusetts, USA, that had no
    major industrial waste inputs, the thallium concentration in the
    influent was below the detection limit of 5 µg/litre (Aulenbach et
    al., 1987).

         However, wastewater from oilfields (oil-well brines) in the USA
    contained 12.9 to 672 µg thallium/litre, 5 out of 13 samples
    containing > 400 µg thallium/litre (Korkisch & Steffan, 1979).

    5.1.2.2  Areas contaminated by thallium from industrial sources

         Data on thallium emission in water are available for areas with
    oilfields, mineral industry and cement plants (Table 7).

         Increased concentrations of thallium in well water and in water
    from an irrigation canal in China resulted from old waste materials
    from the mining of mercury and coal (Zhou & Liu, 1985) (section
    5.1.3.2).  Effluents from tailing ponds of base-metal mining
    operations in New Brunswick, Canada contained 27 and 1620 µg dissolved
    thallium/litre and up to 88 µg/litre was found in connecting rivers
    (Zitko et al., 1975; Zitko, 1975b).

         Raw wastewater from a pyrite ore mine at Lennestadt, Germany
    (which was the source of the pyrite roasting residues used by the
    cement plant in Lengerich, Germany) showed a thallium concentration of
    160 µg/litre (LIS, 1980).  Treatment in sedimentation ponds and with
    lime and chlorine, reduced the concentration to 2-35 µg/litre.  In a
    stream, used as main drainage channel, the thallium concentration rose
    from < 1 µg/litre (detection limit) to 1 µg/litre after the inlet. 
    This level is similar to that found in the River Rhine, Germany (0.5
    and 2.5 µg/litre) (LIS, 1980).

        Table 7.  Concentrations of thallium in water from contaminated areasa
                                                                                                

    Locality                   Source           Concentration of           Reference
                                                thallium (µg/litre)
                                                                                                

    Underground water,       zinc smelter          13-820               BGA (1979)
    Düsseldorf, Germany

    Wastewater, different    smeltersb             < 0.1-2400           Smith & Carson
    locations, USA                                                      (1977)

    Tailing ponds, New       mining                27; 1620             Zitko et al. (1975)
    Brunswick, Canada

    Rivers, different        mining                21-30                US EPA (1980)
    locations, USA

    Rivers, New              mining                1-88                 Zitko et al. (1975)
    Brunswick, Canada

    River,                   mining                < 1-1                LIS (1980)
    Lennestadt, Germany

    Wastewater,              mining                2-160                LIS (1980)
    Lennestadt, Germany

    Well, China              mining                17-40                Zhou & Liu (1985)

    Irrigation canal,        mining                6-96                 Zhou & Liu (1985)
    China

    Wells, Lengerich         cement plant          < 1                  LIS (1980)
    Germany

    Surface water,           cement plant          < 1-1                LIS (1980)
    Lengerich, Germany

    Water,                   cement plant          7.3                  Mathys (1981)
    Lengerich, Germany       (distance 1 km)

    Wastewater,              cement plant          < 1-37               LIS (1980)
    Lengerich, Germany

    Wells, Erwitte           cement plant          < 5-< 50             LIS (1980)
    etc., Germany
                                                                                                

    Table 7 (contd).
                                                                                                

    Locality                   Source           Concentration of           Reference
                                                thallium (µg/litre)
                                                                                                

    Surface water,           cement plant          < 50-130             LIS (1980)
    Erwitte etc., Germany

    Wastewater,              cement plant          800                  LIS (1980)
    Erwitte etc., Germany    (flue dust)

    Wastewater,              oil drilling          12.9-672             Korkisch & Steffan
    USA                      (natural brines)                           (1979)

    Wastewater,              iron and steel        mean = 60            MISA (1991a)
    Canada                   plants

                             pulp and paper        230;                 MISA (1991b)
                             mills                 mean = 52

                             petroleum             310;                 MISA (1989)
                             refineries            mean = 19
                                                                                                

    a   Further literature summarized by Schoer (1984)
    b   Detailed data of sulfide mineral processors in Smith & Carson (1977)
    
         Groundwater directly below a depot for pyrite roasting residues
    in Duisburg, Germany contained 17 µg thallium/litre, and, at a
    distance of some 100 m, up to 6 µg/litre (LIS, 1980).

         In the vicinity of the cement plant in Lengerich, Germany (see
    section 4.2.1.4) thallium levels were monitored in wells, rivers and
    wastewater (LIS, 1980).  In rivers, levels of 7.3 µg/litre 1 km from
    the plant decreased to 1.8 µg/litre at a distance of 5 km and to
    1.0 µg/litre at a distance of 10 km (Mathys, 1981).  In all private
    wells and water works, thallium concentrations were below the
    detection limit of 1 µg/litre.  At the purification plant of the
    cement plant in Lengerich, the water from the inlet showed a
    concentration of 17 µg/litre and that from the outlet of the rainwater
    collection pond 37 µg/litre.  A rainwater pond used for watering
    cattle contained 3 µg thallium/litre.

         Around other cement plants, thallium concentrations in private
    wells, water works and surface water were below the detection limit
    (< 5 and < 50 µg/litre).  Pond water from the vicinity contained
    130 µg/litre.  In drip-water from the storage of flue dust, a
    concentration of 800 µg/litre was determined (LIS, 1980).

         The elimination of thallium from wastewater varies.  Only 28% of
    the thallium could be removed by conventional wastewater treatment
    (liming) (Zitko et al., 1975) whereas 80 to 98% was removed in
    Lennestadt (LIS, 1980).  It has been suggested that Prussian Blue
    could be used to eliminate thallium from wastewater (Rauws & Canton,
    1976).  Wool cannot be used as a filter to remove thallium from
    contaminated water, since, in contrast to other metallic ions, only
    minor amounts of thallium are adsorbed (Masri, 1976).

    5.1.3  Rocks, soil and sediment

    5.1.3.1  Areas not contaminated by thallium

         Mean concentrations in the earth's crust range from 0.1 to
    1.7 mg/kg.  Higher values (up to 3 mg/kg) have been determined for
    granite and shale; intermediate values for basalt, limestone,
    sandstone and most coals, and lowest values for dunite (Table 8)
    (Mason, 1966; Bowen, 1966, 1979; Brumsack, 1977; Smith & Carson, 1977;
    Kemper & Bertram, 1984, 1991; Schoer, 1984; Arnold, 1986).  Much
    higher concentrations can occur in organic-rich shales such as the
    Pierre Shale in the USA (25 mg/kg) and in coals of the Jurassic period
    in Tadzhikistan (100 to 1000 mg/kg) (Smith & Carson, 1977).

         Total thallium concentrations in soil typically range from 0.1 to
    about 1.0 mg/kg (Geilmann et al., 1960; Bowen, 1966, 1979;
    Chattopadhyay & Jervis, 1974; Brumsack, 1977; Smith & Carson, 1977;
    Schoer, 1984; OMEE, 1994), but in China are around 0.011 mg/kg in
    garden soil (range 0 to 0.02 mg/kg) (Zhou & Liu, 1985).  Higher
    concentrations (up to 5 mg total thallium/kg) have been reported,
    however, in Poland (Staszyc et al., 1986), in soil on shale (Hoffmann
    et al., 1982) and near some metallic ore deposits (Smith & Carson,
    1977).

         Marine sediments have been found to contain 0.95 mg thallium
    per kg (Bowen, 1979) or, according to McLaren et al. (1987), using
    isotope dilution inductively coupled plasma mass spectrometry, 0.6 to
    0.7 mg/kg.  Data summarized by Smith & Carson (1977) show a range of
    0.14 to 1.13 mg/kg and in manganese nodules up to 614 mg/kg.

        Table 8.  Concentrations of thallium in uncontaminated geological samplesa
                                                                                             

    Source                     Concentration of               Reference
                               thallium (mg/kg)
                             Mean          Range
                                                                                             

    Basalt                                 < 0.2-0.7      Smith & Carson (1977)
    Basalt                   0.08                         Bowen (1979)
    Basalt                                 0.02-0.06      Arnold (1986)
    Clay                                   0.3            Smith & Carson (1977)
    Clay                                   440-470b       Smith & Carson (1977)
    Clay                     0.9                          Bowen (1979)
    Coal                     0.38          < 0.2-1.4      Smith & Carson (1977)
    Coal                     0.2           0.01-2         Bowen (1979)
    Coal                     0.6           0.12-1.3       Gluskoter et al. (1977)
    Brown coal (18% ash)     0.027                        Brumsack et al. (1984)
    Hard coal (8.7% ash)     0.51                         Brumsack et al. (1984)
    Hard coal (13.9% ash)    0.72                         Brumsack et al. (1984)
    Dunite                   0.0005                       Bowen (1979)
    Granite                  3.1           0.3-6.4        Smith & Carson (1977)
    Granite                  1.1                          Bowen (1979)
    Limestone                1.7                          Smith & Carson (1977)
    Limestone                0.14                         Bowen (1979)
    Limestone                              0.1-0.9        Arnold (1986)
    Sandstone                0.8                          Smith & Carson (1977)
    Sandstone                0.36                         Bowen (1979)
    Sandstone                              0.05-0.4       Arnold (1986)
    Shale (low in
    organic carbon)          0.68                         Brumsack et al. (1984)
    Shale                    1.2                          Bowen (1979)
    Shale                    3.1                          Smith & Carson (1977)
    Black shale (rich
    in organic carbon)       25                           Smith & Carson (1977)
                                                                                             

    a   Selected data; detailed data summarized in Smith & Carson (1977);
        Bowen (1966, 1979); Schoer (1984)
    b   Very fine inclusions of plant matter
    
         Uncontaminated sediments from lakes and small streams in various
    parts of Canada typically contain about 0.35 mg thallium per kg (range
    0.02 to 3.2 mg/kg) (G. Bonham-Carter, Geological Survey of Canada,
    Applied Geochemistry Subdivision, personal communication to the IPCS),
    with lowest values occurring in areas with underlying basaltic rock. 
    Thallium levels in the sediment of small streams in an uncontaminated
    area of Münsterland, Germany contained from 0.03 to 0.1 mg/kg (LIS,
    1980).  In another investigation of small rivers in the same area and
    in Sauerland, Germany, concentrations of 0.01 to 0.07 mg/kg dry weight
    were determined (Mathys, 1981).  This is also in the range of the data
    summarized by Smith & Carson (1977).

    5.1.3.2  Areas contaminated by thallium from industrial sources

         Cases of contamination of sediment and soil by thallium are
    mainly caused by mineral mining and smelters and by dust fall-out from
    emissions of power-generating plants, brickworks and cement plants
    (ATSDR, 1992) (Table 9).

         Emissions from the cement plant in Lengerich, Germany caused a
    remarkable increase in thallium concentrations in sediments of rivers
    and brooks (Mathys, 1981).  Sediment levels of 18 mg thallium/kg dry
    weight found in a brook 1 km from the plant decreased to 8.7 mg/kg
    within 4 km and then to 7.5 mg/kg in the River Glane into which the
    brook flowed.  Sediments of the following River Ems contained 5.0, 2.7
    and 0.8 mg/kg at distances of 30, 70 and 100 km, respectively. In
    comparison, river sediments from industrialized areas contained 0.05
    to 1.8 mg/kg dry weight.  Very high thallium levels were detected in
    sediments from areas with zinc mining or iron ore industry, e.g.,
    40.0 mg/kg in the River Lenne.  After transport to the River Ruhr,
    sediment thallium levels were 3 mg/kg dry weight (Mathys, 1981).

         Large amounts of contaminated waste materials from the mining of
    mercuric ore and coal containing 25 to 106 mg thallium per kg resulted
    in chronic thallium poisoning in China.  As a result of dispersal of
    the waste materials, the garden soil of poisoned owners showed levels
    from 28 to 61 mg/kg (mean: 43 mg/kg), whereas the soil levels in
    gardens of unaffected families contained 6 to 11 mg/kg (mean,
    8 mg/kg); this was still much higher than in other villages (mean,
    0.011 mg/kg).  In the affected village, the concentration of soluble
    thallium salts decreased with increasing pH, with 8.0, 2.0 and
    < 0.15 mg/kg at soil pH values of 1-2, 3-4 and 6-7, respectively. 
    The lower soil pH in the dry season (3.5-4.5 compared to pH 6-7 in the
    rainy season) correlated with an increase in the number of
    intoxications during these months, presumably due to an increase in
    the thallium concentration in cabbage.  After the experimental
    addition of lime to contaminated soil, the thallium concentration in
    cabbage was reduced (Zhou & Liu, 1985).

        Table 9.  Concentrations of thallium in soil from the vicinity of factories in Germany
                                                                                             

    Locality            Source           Distance      Concentration of     Reference
                                         (m)           thallium (mg/kg)
                                                                                             

    Göttingen           lead-zinc        -a            1.07                 Brumsack
                        smelter                                             (1977)

    Duisburg            copper smelter   500-1400      < 0.2-2.1            LIS (1980)

    Leimen, Wiesloch    mining and       -a            5.5-21               Hoffmann
                        cement plant                                        et al. (1982)

    Lengerich           cement plant     500-5000      < 0.1-6.9            LIS (1980)

    Erwitte             cement plant     350-1800      0.1-10.5             LIS (1980)

    Schelklingenb       cement plant     < 3200        0.1-0.5              Arndt et
                                                                            al. (1987)

    Mergelstettenb      cement plant     < 800         0.1-0.5              Arndt et
                                                                            al. (1987)

    Duisburg            sulfuric acid    0-1000        < 0.2-10.5           LIS (1980)
                        plant

    Duisburg            sulfuric acid    350-1100      < 0.2-2.3            LIS (1980)
                        plant

    Göttingen           brickwork        -a            0.6                  Brumsack
                                                                            (1977)
                                                                                             

    a   No data given;

    b   The investigation was performed 6 years after a ban on the use of iron pyrite
        residues with high thallium contaminations. Owing to the method used (acid
        digestion with concentrated nitric acid for 2 h at 90-95°C and addition of 10%
        sulfuric acid), the concentrations measured correspond to the extractable soluble
        emitted thallium and not the total thallium in the soil.
    
         Sabbioni et al. (1984b) calculated the emissions from a
    hypothetical coal-fired power-generating plant for a period of 40
    years.  They deduced an air-borne deposition of thallium around the
    power-generating plants of 0.005 mg/kg, and the factor of increase
    over the background level was estimated to be 0.001.

         Around four small brickworks, samples of soil were digested by
    strong acids and analysed for total concentration of thallium
    (Brumsack, 1977).  The proportion that was bioavailable is unknown. 
    Compared to a soil background level of 0.2 mg/kg, the contaminated
    samples of soil showed a maximum accumulation factor of 3, while for
    samples taken directly around the factory the factor was about 5. 
    Clear effects were found when the weather side of a hill was just
    opposite the smoke stack.  (Interestingly, shale from uncontaminated
    areas showed a similarly high content (0.99 mg/kg)).

         Thallium emission by the cement plant in Lengerich, Germany
    caused an increase of thallium concentrations in the soil over an area
    of 1 to 2 km radius from the plant, with a maximal level of 6.9 mg/kg
    dry soil (LIS, 1980). Up to 4 mg/kg soil was determined in
    agricultural soil and up to 6 mg/kg in the soil of house gardens
    (Crössmann, 1984).  Samples of soil taken at different depths always
    showed highest thallium contaminations in the upper layers, decreasing
    with increasing depth (LIS, 1980).  Only small amounts of the thallium
    in the upper layers were washed out (section 4.1) (Scholl & Metzger,
    1982).  The soil around the two plants that had produced the residues
    from pyrite roasting was also highly contaminated, with maximal levels
    of up to 10.5 and 2.3 mg/kg, respectively (LIS, 1980).

         Soil from the vicinity of two other cement plants in Germany
    contained only slightly elevated concentrations of thallium, up to
    0.5 mg/kg soil, in the upper layers (see section 3.2.3.3 and 5.1.4.2)
    (Table 9) (Arndt et al., 1987).

    5.1.4  Plants and animals

         Thallium occurs in low amounts in almost all living organisms,
    including humans (Mason, 1966) (Tables 10 and 14).  It seems to be a
    non-essential cation in animals and plants (Yopp et al., 1974).  Some
    species accumulate this element.

    5.1.4.1  Plants

    a)  Areas not contaminated by thallium

         Usually thallium concentrations in plants are much less than
    0.1 mg/kg dry weight (Geilmann et al., 1960) or 1 mg/kg ash (Dvornikov
    et al., 1973, 1976), and levels exceeding 2 mg/kg ash are unusual
    (Smith & Carson, 1977) (Table 10).  However, such high thallium
    concentrations have been found in plants from areas with a naturally
    very high thallium concentration, e.g., the Alsar in Macedonia,
    Yugoslavia (Zyka, 1972) (Table 11).  Data from this area are
    considered in sections 5.1.4.2 and 9.3.1.

         No thallium could be detected in cabbage or grain from areas of
    China not contaminated by thallium (Zhou & Liu, 1985).  Plants used
    for teas (e.g., Anisi, Betulae, Hibisci and Menthae) contained very
    low concentrations of thallium (< 0.01 mg/kg), whereas higher
    concentrations of other heavy metals and pesticides often occurred
    (Ali & Blume, 1983).  The majority (85%) of 421 investigated species
    of wild mushrooms, which often accumulate heavy metals, contained
    concentrations below the detection limit of < 0.25 mg/kg dry weight
    (range < 0.25 to 5.5 mg/kg).  A transfer factor of < 0.1
    (concentration of thallium in the mushroom (fresh or dry weight) in
    relation to its concentration in dry soil) indicates that no
    accumulation took place (Seeger & Gross, 1981).  However, in other
    plants and using soil from a contaminated area, a much higher transfer
    factor of 2.9 was determined (Schoer & Nagel, 1980).  The thallophilic
    Brassicaceae can contain higher amounts of thallium (1.5 mg/kg fresh
    weight) than other plants, which usually contain 0.007 (detection
    limit) to 0.1 mg/kg wet weight (Crössmann, 1984).

         Wild plants normally contain only traces of thallium, whereas the
    levels in garden plants can be increased by repeated use of sewage
    sludge or potash fertilizers, which can contain 100 to 210 µg/kg
    sludge or 15 to 310 µg/kg fertilizer (Geilmann et al., 1960;
    Heinrichs, 1982). Also phosphate and copper fertilizers may contain up
    to 400 µg thallium/kg (Boysen, 1992).

         Thallium concentrations of up to 17 g/kg ash have been found in
    plants from Alsar in Macedonia, Yugoslavia (Table 11), an area with
    very high geogenic thallium levels (Zyka, 1972).

    b)  Areas contaminated by thallium from industrial sources

         Soils contaminated through mineral smelters, power-generating
    plants, brickworks or cement plants can greatly increase the
    concentrations of thallium found in food of plant origin (Tables 12
    and 13), which are the major route of entry of thallium into the food
    chain.  Data on bioconcentration factors are listed in Table 6.  In
    the contaminated area of Lengerich, Germany, consumption of home-grown
    food was correlated with high levels of thallium in urine and hair,
    and possibly with thallium-related health disorders among local people
    (Brockhaus et al., 1981b; Dolgner et al., 1983).  The importance of
    these findings is underlined by the similarly elevated levels of
    thallium found in the urine of family members consuming the home-grown
    vegetables (Ewers, 1988).

        Table 10.  Concentrations of thallium in plants from uncontaminated areasa
                                                                                                

    Sourceb                         Concentration of thallium          Reference
                                 (µg/kg dry weight)    (mg/kg ash)
                                                                                                

    Achillea millefolium                               0.01-0.04       Dvornikov et al. (1973)
    Achillea setacea                                   0.04-0.9        Dvornikov et al. (1976)
    Alpine fir (L)                                     2-100           Shacklette et al. (1978)
    Alpine fir (S)                                     2-70            Shacklette et al. (1978)
    Anthemis tinctoria                                 < 0.1-0.5       Dvornikov et al. (1976)
    Artemisia absinthum                                0.03            Dvornikov et al. (1973)
                                                       0.02-0.6        Dvornikov et al. (1976)
    Artemisia campestris                               0.057           Dvornikov et al. (1973)
                                                       0.04-0.8        Dvornikov et al. (1976)
    Asperula humifusa                                  0.1-1.0         Dvornikov et al. (1976)
    Clover                            8-10                             Geilmann et al. (1960)
    Echium vulgare                                     0.1-0.3         Dvornikov et al. (1976)
    Endive                            80                               Geilmann et al. (1960)
    Engelmann's spruce (L)                             2-10            Shacklette et al. (1978)
    Engelmann's spruce (S)                             15              Shacklette et al. (1978)
    Euphorbia virgata                                  0.022-0.027     Dvornikov et al. (1973)
                                                       0.03-0.3        Dvornikov et al. (1976)
    Festuca sulcata                                    0.2             Dvornikov et al. (1973)
                                                       0.2-0.6         Dvornikov et al. (1976)
    Green cabbage                     125                              Geilmann et al. (1960)
    Hay                               20-25                            Geilmann et al. (1960)
    Head-lettuce                      21                               Geilmann et al. (1960)
    Herbaceous vegetables             30-300                           Bowen (1979)
    Kale                              150                              Bowen (1979)
    Leek                              75                               Geilmann et al. (1960)
    Limber pine (L)                                    2-5             Shacklette et al. (1978)
    Limber pine (S)                                    3-5             Shacklette et al. (1978)
    Lodgepole pine (L)                                 2-5             Shacklette et al. (1978)
    Lodgepole pine (S)                                 3-7             Shacklette et al. (1978)
    Mushrooms                         < 0.25-5.5                       Seeger & Gross (1981)
    Myrtle blueberry (L, S)                            2-7             Shacklette et al. (1978)
    Ponderosa pine (S)                                 15              Shacklette et al. (1978)
    Potato (L, S)                     25-30                            Geilmann et al. (1960)
    (T)                               5                                Geilmann et al. (1960)
    Rape (L)                          25-30                            Geilmann et al. (1960)
    Red cabbage                       40                               Geilmann et al. (1960)
                                                                                                

    Table 10 (contd).
                                                                                                

    Sourceb                         Concentration of thallium          Reference
                                 (µg/kg dry weight)    (mg/kg ash)
                                                                                                

    Salvia nemorosa                                    0.04            Dvornikov et al. (1973)
                                                       0.04-0.8        Dvornikov et al. (1976)
    Stinging nettle (L)               28.8                             Weinig & Zink (1967)
    Tanacetum vulgare                                  0.06-0.2        Dvornikov et al. (1976)
    Tobacco (L)                       24-100                           Geilmann et al. (1960)
    Verbascum ovalifolium                              0.01-0.7        Dvornikov et al. (1976)
    Woody gymnosperms                 50                               Bowen (1979)
                                                                                                

    a   Further data summarized by Dvornikov et al. (1973, 1976), Gough et al. (1979) and
        Smith & Carson (1977)
    b   L = leaves, needles; S = stems; T = tubers


    Table 11.  Concentrations of thallium in plants from the Alsar region in Yugoslavia
               possessing a high natural concentration of thallium in the soil
                                                                                             

    Source                                  Concentration of thallium
                                            (mg/kg ash weight)
                                                                                             

    Campanula sp. (L, S, F)                           5990
    Centaurea sp. (P)                                   75
    Centaurea sp. (L, S)                               105
    Dianthus sp. (F)                                  5200
    Echinops sp. (L)                                    15
    Eryngium sp. (L)                                     3
    Eryngium sp. (F)                                    10
    Galium sp. (F)                                  17 000
    Lavatera sp. (L, S)                                125
    Lavatera sp. (F)                                    45
    Linaria triphylla                                 3000
    Linaria triphylla                                 3800
                                                                                             

    According to Zyka (1972)
    F = flowers; L = leaves, needles; P = pods and seeds; S = stems
    
         Waste materials from the mining of mercuric ore and coal in China
    (section 5.1.3.2) increased the concentration of thallium in cabbage
    and grain.  Cabbage from gardens of affected families contained
    42 mg/kg fresh weight (range 39 to 49), whereas cabbage eaten by
    healthy families contained 5.6 mg/kg (range 3 to 11). Other vegetables
    from the gardens of affected families usually contained less than
    10 mg/kg (Zhou & Liu, 1985).

         An accumulation in vegetables of the genus Brassica was also
    observed in Lengerich. In the area with the highest contamination, the
    majority of plants and fruits contained < 0.1 to 0.4 mg/kg fresh
    weight.  Higher thallium levels were sometimes found in strawberries,
    potatoes, beans, tomatoes, carrots and leeks, while in parsley,
    celery, red currants, and all Brassicaceae high levels were usual
    (LIS, 1980).  Within this genus uptake of thallium varied: the
    bioconcentration factor of white and red cabbage was relatively low;
    it was 5- to 10-fold higher in the stems of kohlrabi.  Savoy cabbage
    and green kale were found to contain the highest thallium
    concentrations, exceeding those of the soil (Crössmann, 1984). The
    maximal value of 45.2 mg/kg fresh weight was found in green kale (LIS,
    1980).  Most forage plants, e.g., turnips, hay, grass and fodder corn,
    contained < 5 mg/kg dry weight, but 46% of rape plants contained >
    100 mg/kg (up to 1095 mg/kg dry weight) and 22% of the maize 10 to
    50 mg/kg (LIS, 1980).  Vegetables from Lengerich, grown in soil with
    4.5 mg thallium/kg dry weight, could be classified according to their
    mean thallium concentration (mg/kg fresh weight) into five groups. 
    These were I: green cabbage (22.6 mg/kg) and savoy cabbage
    (8.5 mg/kg); II: turnip, broccoli, kohlrabi and white cabbage
    (3.1 mg/kg); III: stock beet and other vegetables (1.4 mg/kg); IV: red
    beet, rhubarb and spinach (0.7 mg/kg); V: the majority of fruits and
    vegetables (0.5 mg/kg), e.g., red cabbage, Brussels sprouts, onion,
    salad, carrot, bean, tomato, cucumber and potato (Scholl & Metzger,
    1982).

         The accumulating capacity of rape also became evident in an
    investigation at cement factories in Schelklingen and Mergelstetten,
    Germany, 6 years after the use of the same iron pyrite residues that
    had been used in Lengerich was banned.  The soil contained only
    slightly elevated concentrations of thallium (section 5.1.3.2), and in
    the majority of the plants, four of them Brassicaceae, no thallium was
    detectable (Arndt et al., 1987).  However, rape contained increased
    levels of 2.4 to 679.6 mg thallium/kg dry weight at Mergelstetten and
    1.8 to 19.1 mg/kg dry weight at Schelklingen (Table 12).  The highest
    levels detected in single rape plants were found within an area
    extending 150-400 m downwind from the cement plant.  The majority of
    the rape grown in that area contained more than 5 mg thallium/kg dry
    weight and could not be used as animal feed.


        Table 12.  Concentrations in plants from thallium-contaminated areas
                                                                                                                                

    Organism       Concentration of thallium (mg/kg)      Source of               Localitya            Reference
                                                          emission
                   Dry weight       Fresh weight
                                                                                                                                

    Algae          9.5-43.4                               mining                  New Brunswick        Zitko et al. (1975)
    Algae                           0.665                 cement plant            Lengerich            LIS (1980)
    Berula         100.3                                  cement plant            Lengerich            Mathys (1981)
    Berula                          0.585; 0.654          cement plant            Lengerich            LIS (1980)
    Caltha         187.3                                  cement plant            Lengerich            Mathys (1981)
    Elodea         87.4                                   cement plant            Lengerich            Mathys (1981)
    Elodea                          0.29; 6.5             cement plant            Lengerich            LIS (1980)
    Grass          52.0                                   sulfuric acid plant     Duisburg             LIS (1980)
    Moss           125; 162                               mining                  New Brunswick        Zitko et al. (1975)
    Rape                            29.2                  cement plant            Lengerich            LIS (1980)
    Rape                            23.7                  cement plant            Lengerich            Kemper & Bertram (1984)
    Rape           1095                                   cement plant            Lengerich            LIS (1980)
    Rape           679.6                                  cement plant            Mergelstetten        Arndt et al. (1987)
    Rape           19.1                                   cement plant            Schelklingen         Arndt et al. (1987)
    Sparganium                      0.265                 cement plant            Lengerich            LIS (1980)
                                                                                                                                

    a   All the localities are in Germany, except for New Brunswick (Canada)

    Table 13.  Concentrations in vegetables and fruits from thallium-contaminated areas
                                                                                                                                     

    Plant                 Part          Concentration of thallium (mg/kg)a    Source of              Reference
                                                                              emission
                                        Dry weight        Fresh weight
                                                                                                                                     

    Apple                 fruit                           0.2                 cement plant           LIS (1980)
    Bean                  fruit                           0.7                 cement plant           LIS (1980)
    Blackberry            fruit                           0.5                 cement plant           LIS (1980)
    Black-currant         fruit                           0.527               cement plant           Kemper & Bertram (1984)
    Brussels sprout       leaf                            0.5                 cement plant           LIS (1980)
    Carrot                root                            1.0                 cement plant           LIS (1980)
    Carrot                leaf          0.30                                  mining and             Hoffmann et al. (1982)
                          root          0.10                                  cement plant
    Celeriac              stem                            0.8                 cement plant           LIS (1980)
    Cucumber              leaf          0.70                                  mining and             Hoffmann et al. (1982)
                          fruit         0.10                                  cement plant
    Green cabbage         leaf                            14.9                cement plant           Kemper & Bertram (1984)
    Green cabbage         leaf                            45.2                cement plant           LIS (1980)
    Green cabbage         leaf                            22.6b               cement plant           Scholl & Metzger (1982)
    Kohlrabi              leaf          35.00                                 mining and             Hoffmann et al. (1982)
                          stem          0.10                                  cement plant
    Kohlrabi              stem                            3.1b                cement plant           Scholl & Metzger (1982)
    Kohlrabi              stem                            4.9                 cement plant           LIS (1980)
    Onion                 stalk         0.10                                  mining and             Hoffmann et al. (1982)
                          bulb          0.01                                  cement plant
    Onion                 stalk                           0.4                 cement plant           LIS (1980)
    Parsley               leaf                            1.2                 cement plant           LIS (1980)
    Pear                  fruit                           0.5                 cement plant           LIS (1980)
                                                                                                                                     

    Table 13 (contd).
                                                                                                                                     

    Plant                 Part          Concentration of thallium (mg/kg)a    Source of              Reference
                                                                              emission
                                        Dry weight        Fresh weight
                                                                                                                                     

    Potato                tuber                           0.8                 cement plant           LIS (1980)
    Radish                leaf          5.90                                  mining and             Hoffmann et al. (1982)
                          root          0.40                                  cement plant
    Red beet              leaf          2.40                                  mining and             Hoffmann et al. (1982)
                          root          0.60                                  cement plant
    Red beet              root                            0.7                 cement plant           LIS (1980)
    Red-currant           fruit                           1.1                 cement plant           LIS (1980)
    Savoy cabbage         leaf                            8.5b                cement plant           Scholl & Metzger (1982)
    Strawberry            fruit                           0.9                 cement plant           LIS (1980)
    Tomato                fruit                           0.6                 cement plant           LIS (1980)
    White cabbage         leaf                            3.1b                cement plant           Scholl & Metzger (1982)
    Zucchini              leaf          0.90                                  mining and             Hoffmann et al. (1982)
                          stem          0.02                                  cement plant
                                                                                                                                     

    a   Individual value, unless otherwise stated
    b   Mean value
        5.1.4.2  Animals

    a)  Areas not contaminated by thallium

         Investigations of three species of freshwater fish, the
    omnivorous white sucker  (Catostomus commersoni) and the more
    carnivorous yellow perch  (Perca flavescens) and brook trout
     (Salvelinus fontinalis), show them to have similar average
    concentrations of thallium in their axial muscle (< 0.07 to 3.0 mg/kg
    dry weight), which were independent of water pH (Heit, 1985)
    (Table 14).  Extensive studies of different marine shellfish and fish
    revealed average concentrations of 0.14 mg/kg; only in three species
    (occasionally  Clupanodon punctatus and  Trachurus japonicus and
    often  Penaeus japonicus) were concentrations above 1 mg/kg found
    (Hamaguchi, 1960).

         In marine invertebrates concentrations were even lower, but,
    owing to the low concentration in the seawater, the concentration
    factor (concentration in the organism divided by the concentration in
    the seawater) calculated by Smith & Carson (1977) was > 700.

         Thallium concentrations in marine mammals have rarely been
    investigated.  In the blubber, liver, kidney, spleen and muscle of
    bowhead whales, concentrations are nearly always below 0.01 mg/kg
    fresh weight (Byrne et al., 1985).

         Meat from farm animals contains very low levels of thallium
    (Table 14).

    b)  Areas contaminated by thallium from industrial sources

         Different animals as well as different organs vary with respect
    to their accumulation capacity for thallium (Table 15).

         In a case of fish poisoning, three species were found to contain
    77 to 96 mg/kg muscle (Palermo et al., 1983).  The liver and kidneys
    of fish from a pond contaminated by a cement plant contained 1.6 and
    1.3 mg/kg fresh weight, respectively (LIS, 1980).  In the same area,
    fish from other ponds and waters usually contained < 0.1 mg/kg
    muscle.


        Table 14.  Concentrations of thallium in animals from uncontaminated areas
                                                                                                                                                

    Source                            Part          Number of        Concentration of thallium       Reference
                                                    measurements                              
                                                                     µg/kg wet       mg/kg dry
                                                                     weight          weight
                                                                                                                                                

    Invertebrates

    Colorado beetle                   whole         1                                18              Geilmann et al. (1960)

    Different marine invertebrates                                                   0.001-0.03      Noddack & Noddack (1939)

    Echinoderms (hard parts)                                         110                             Bowen (1979)

    Molluscs (soft parts)                                            340                             Bowen (1979)

    Fish

    Various fish species                                             80                              Bowen (1979)

    Various marine                                  139              < 2930                          Hamaguchi (1960)
    shellfish and fish

    Brook trout                       muscle        5                                < 3.0           Heit (1985)
    (Salvelinus fontinalis)
                                                                                                                                                

    Table 14 (contd).
                                                                                                                                                

    Source                            Part          Number of        Concentration of thallium       Reference
                                                    measurements                              
                                                                     µg/kg wet       mg/kg dry
                                                                     weight          weight
                                                                                                                                                

    White sucker                      muscle        28                               < 2.0           Heit (1985)
    (Catostomus commersoni)

    Yellow perch                      muscle        27                               < 3.0           Heit (1985)
    (Perca flavescens)

    Birds

    Ducka                             kidney        15               0.03                            Holm et al. (1987)
    Duckb                             kidney        10               0.129                           Holm et al. (1987)
    Ducka                             liver         15               0.022                           Holm et al. (1987)
    Duckb                             liver         10               0.207                           Holm et al. (1987)

    Hen                               liver         2                < 50                            LIS (1980)
    Hen                               muscle        2                < 50                            LIS (1980)

    Mammals

    Cattle                            hair          1                                20              Geilmann et al. (1960)
    Cattle                            hoof          1                                16              Geilmann et al. (1960)
    Cattle                            horn          1                                10              Geilmann et al. (1960)
                                                                                                                                                

    Table 14 (contd).
                                                                                                                                                

    Source                            Part          Number of        Concentration of thallium       Reference
                                                    measurements                              
                                                                     µg/kg wet       mg/kg dry
                                                                     weight          weight
                                                                                                                                                

    Fox                               intestine     25               < 2.7                           Munch et al. (1974)
    Fox                               kidney        27               0.01-1.5                        Munch et al. (1974)
    Fox                               liver         27               0.01-1.6                        Munch et al. (1974)

    Goat                              hair          1                                7               Geilmann et al. (1960)
    Goat                              hoof          1                                9               Geilmann et al. (1960)

    Hare                              hair          1                                17              Geilmann et al. (1960)

    Horse                             hair          1                                7               Geilmann et al. (1960)
    Horse                             hoof          1                                4               Geilmann et al. (1960)

    Marten                            brain         7                < 0.1-0.7                       Clausen & Karlog (1974)
    Marten                            intestine     13               < 0.01-0.57                     Clausen & Karlog (1974)
    Marten                            kidney        17               < 0.01-3.5                      Clausen & Karlog (1974)
    Marten                            liver         36               < 0.01-1.4                      Clausen & Karlog (1974)
    Pig                               hair          1                                9               Geilmann et al. (1960)
    Pig                               hoof          1                                11              Geilmann et al. (1960)
    Pig                               muscle        1                                0.028           Kemper & Bertram (1984)
    Pig                               muscle        43               < 70                            Konermann et al. (1982)
    Pig                               kidney        43               < 70                            Konermann et al. (1982)
                                                                                                                                                

    Table 14 (contd).
                                                                                                                                                

    Source                            Part          Number of        Concentration of thallium       Reference
                                                    measurements                              
                                                                     µg/kg wet       mg/kg dry
                                                                     weight          weight
                                                                                                                                                

    Pig                               kidney        6                < 50                            LIS (1980)
    Pig                               liver         43               < 70                            Konermann et al. (1982)
    Pig                               liver         6                < 50                            LIS (1980)

    Rabbit                            hair          1                                60              Geilmann et al. (1960)
    Rabbit                            hair          1                                < 1.5           LIS (1980)

    Roe deer                          liver         19               approx. 30                      Holm et al. (1987)
    Roe deer                          kidney        19               approx. 30                      Holm et al. (1987)

    Sheep                             hair          1                                9               Geilmann et al. (1960)
    Sheep                             hoof          1                                12              Geilmann et al. (1960)
    Sheep                             kidney        3                50-60                           Hapke et al. (1980)
    Sheep                             liver         3                < 50                            Hapke et al. (1980)
    Sheep                             muscle        3                50-60                           Hapke et al. (1980)
                                                                                                                                                

    a   Cuxhaven, Germany (coast)
    b   Cuxhaven, Germany (inland)
    
         In farm animals intake of thallium mainly occurs through
    contaminated feed.  In broilers and laying hens, tissue thallium
    concentrations were linearly correlated with feed levels for
    concentrations between 2 to 40 mg/kg fresh weight of feed (Ueberschär
    et al., 1986).  The accumulation factor (concentration of thallium in
    the tissue in relation to its concentration in the feed) was 2 to 3
    times higher for the tissues of broilers than for those of hens (Table
    16).  In contrast to the situation in sheep, cattle and pigs, thallium
    accumulates in hens to a greater degree in the muscle than in the
    liver.  The concentration in the kidneys is about 90% lower than in
    the egg shell.  Thallium half-life is about 2 to 4 days for the
    various hen tissues (Ueberschär et al., 1986).

         Whereas maximal permitted concentrations of lead, mercury,
    arsenic and fluoride in animal fodder have been established in
    Germany, this has not been done for thallium (Crössmann, 1985). 
    Thallium poisoning in cattle has been caused by silage (41 mg
    thallium/kg fresh weight) bought from a farm in a contaminated area
    (Frerking et al., 1990).  Thallium mainly accumulates in the kidneys,
    liver and bones (section 6.2).  Steers fed for at least 6 months with
    fodder originating from the thallium-contaminated area around
    Lengerich, Germany, containing about 1.25 mg/kg dry weight (daily
    uptake: 0.025 mg/kg body weight), contained 0.10 ± 0.02, 1.66 ± 0.55,
    0.52 ± 0.28 and 0.40 ± 0.15 mg thallium/kg fresh weight, respectively,
    in muscles, kidneys, livers and testes (Hapke et al., 1980).  In pigs
    fed with 1.45 mg thallium/kg food (dry weight) for 5 months, muscle,
    kidneys and liver contained 0.18 ± 0.04, 0.44 ± 0.06 and 0.31 ±
    0.09 mg thallium/kg fresh weight, respectively.  Feeding with 2.71 mg
    thallium/kg dry weight resulted in 0.39 ± 0.07 (muscle), 0.7 ± 0.2
    (kidney) and 0.53 ± 0.1 (liver) mg thallium/kg fresh weight.  Since
    0.5 mg/kg fresh weight is the limit set by the federal state of North
    Rhine-Westphalia for thallium concentrations in human food, a critical
    level for pigs seems to be a daily intake corresponding to 1.9 mg
    thallium/kg dry matter of food (Konermann et al., 1982).

         Exposure of farm animals to thallium in the vicinity of the
    cement plant in Lengerich, Germany, resulted in increased thallium
    levels in the liver and kidneys of various animals (LIS, 1980): 0.8%
    of the samples of internal organs contained > 10 mg/kg fresh weight,
    1.3% contained 5 to 10 mg/kg, 12.6% contained 1 to 5 mg/kg and 14.5%
    contained 0.5 to 1 mg/kg.  In 0.2%, 3% and 4.4% of meat from various
    farm animals, 5-10, 1-5 and 0.5-1 mg/kg were found, respectively. 
    Concentrations above 0.5 mg/kg fresh weight were sometimes also found
    in eggs and chicken meat (up to 0.8 mg/kg), rabbit meat (up to
    5.8 mg/kg) and roe deer (1.6 mg/kg) (Table 15) (LIS, 1980).  In whole
    eggs with a concentration of 1.26 mg/kg fresh weight, the
    concentration in albumin and yolk was 0.394 mg/kg, while in the shell
    it was 4.94 mg/kg (Kemper & Bertram, 1984).

        Table 15.  Concentrations in animals from thallium-contaminated areas
                                                                                                                                                

    Animal           Organ         Source         Locality              na              Concentration of thallium              Reference
                                                                                        (mg/kg fresh weight)b

                                                                                Mean       Range            Highest value
                                                                                                                                                

    Fish

    Morone           muscle       -d              Taranto, Italy       -        77                                             Palermo et al.
    labraxc                                                                                                                    (1983)
    Eelc             muscle       -               Taranto, Italy       -        96                                             Palermo et al.
                                                                                                                               (1983)
    Salmon           muscle       mining          New Brunswick,       3-4                 5.1e; 14.6f                         Zitko et al.
                     liver                        Canada               3-4                 6.8; 23.5                           (1975)
                     gill                                              3-4                 1.2; 30.0

    Salmon           muscle       mining          New Brunswick,       3-4                 3.6-34g                             Zitko et al.
                     liver                        Canada               3-4                 5.7-46                              (1975)
                     gill                                              3-4                 7-89

    Silver-scaled    liver        cement plant    Lengerich, Germany   1        1.6                                            LIS (1980)
    fish             kidney                                            1        1.3
                     brain                                             1        0.46

    Mugil            muscle       -               Taranto, Italy       -        84                                             Palermo et al.
    cephalusc                                                                                                                  (1983)
                                                                                                                                                

    Table 15 (contd).
                                                                                                                                                

    Animal           Organ         Source         Locality              na              Concentration of thallium              Reference
                                                                                        (mg/kg fresh weight)b

                                                                                Mean       Range            Highest value
                                                                                                                                                

    Trout            liver        cement plant    Lengerich, Germany   4                                    0.13               LIS (1980)
                     kidney                                            4                                    0.885
                     muscle                                            3                                    0.09
    Birds

    Duck             liver        industry        Harburg, Germany     30       0.191      < 0.075-0.86                        Holm et al.
    Duck             kidney       industry        Harburg, Germany     30       0.076      < 0.075-0.43                        (1987)
    Duck             liver        industry        Stade, Germany       24       0.072                                          Holm
    Duck             liver        industry        Stade, Germany       10       0.186                                          et al.
    Duck             kidney       industry        Stade, Germany       10       0.042                                          (1987)
    Duck             liver        cement plant    Lengerich, Germany   4                                    0.4                LIS (1980)
                     muscle                                            4                                    0.4

    Geesec           muscle       poison          USA                  17       29         4-57                                Shaw (1932)

    Hen              egg          cement plant    Lengerich, Germany   24       1.26                                           Kemper &
                                                                                                                               Bertram (1984)
    Hen              egg          cement plant    Lengerich, Germany   26                                   1.6                LIS (1980)
                     liver                                             17                                   0.8
                     muscle                                            26                                   0.8
                     heart                                             5                                    0.7
                     stomach                                           9                                    0.9
                                                                                                                                                

    Table 15 (contd).
                                                                                                                                                

    Animal           Organ         Source         Locality              na              Concentration of thallium              Reference
                                                                                        (mg/kg fresh weight)b

                                                                                Mean       Range            Highest value
                                                                                                                                                

    Pigeon           liver        cement plant    Lengerich, Germany   1                                    0.6                LIS (1980)
                     kidney                                            3                                    0.6
                     muscle                                            5                                    0.4
                     heart                                             1                                    0.3

    Mammals

    Cattle           kidney       cement plant    Lengerich, Germany   58                                   2.2                LIS (1980)
                     muscle                                            61                                   1.5

    Cattle           kidney       not specified   Germany              2                                    24.0               Frerking et al.
                     liver        (presumably                          2                                    2.3                (1990)
                     muscle       cement plant)                        1                                    0.4
                     urine                                             3                                    1.35h

    Foxc             liver        poison          Denmark              27                                   64.0               Munch et al.
                     kidney                                            16                                   34                 (1974)
                     intestine                                         7                                    55

    Martenc          liver        poison          Denmark              15                                   57                 Clausen &
                     kidney                                            16                                   92                 Karlog (1974)
                     intestine                                         9                                    42
                     brain                                             5                                    8.2
                                                                                                                                                

    Table 15 (contd).
                                                                                                                                                

    Animal           Organ         Source         Locality              na              Concentration of thallium              Reference
                                                                                        (mg/kg fresh weight)b

                                                                                Mean       Range            Highest value
                                                                                                                                                

    Pig              liver        cement plant    Lengerich, Germany   3                                    1.2                LIS (1980)
                     kidney                                            296                                  1.3
                     muscle                                            300                                  0.6

    Rabbit           liver        cement plant    Lengerich, Germany   49                                   5.8                LIS (1980)
                     kidney                                            44                                   29.0

    Roe deer         liver        cement plant    Lengerich, Germany   1                                    2.6                LIS (1980)
                     kidney                                            3                                    14.0
                     muscle                                            2                                    1.6
                     heart                                             3                                    2.9

    Sheep            liver        cement plant    Lengerich, Germany   4                                    0.6                LIS (1980)
                     kidney                                            10                                   1.1
                     muscle                                            14                                   1.1
                                                                                                                                                

    a   Number of measurements (animals)               e,f  The two thallium concentrations of 45e and 100f µg/litre water are in the range
    b   mg/kg fresh weight unless otherwise stated          of the natural concentrations at that locality; thallium concentration in the
    c   Fatal poisoning                                     gill was higher (25.6 mg/kg fresh weight) at a lower concentration in water
    d   No data given                                       (17.9 µg/litre)
                                                       g    Lethal dose of 100 to 10 000 µg/litre
                                                       h    mg/litre
        5.2  General population exposure

         The US Environmental Protection Agency calculated the typical
    value for the exposure of the general population to be 0.48 ng
    thallium/m3 air (US EPA, 1980). US EPA (1980) calculated an absorbed
    amount of 3.4 ng/day assuming an inspired volume of 20 m3/day and
    35% deposition in the lungs. BGA (1979) calculated the daily uptake
    via the respiratory system to be < 5 ng thallium per day.

    Table 16.  Bioconcentration factora of thallium in broilers and
               laying hensb and half-life in the tissues of laying hens
                                                                        

                                Bioconcentration factor

    Organ             Broiler       Laying hen       Half-life
                                                     (days)
                                                                        

    Bone              0.54            0.26             2.0

    Egg yolk          -               0.26             4.1

    Egg albumen       -               0.14             1.6

    Egg shell         -               3.72             2.5

    Fat               0.006           0.001            -

    Feather           0.074           0.006            -

    Kidney            0.77            0.38             3.6

    Liver             0.19c           0.1              4.0
                      0.11d

    Muscle            0.46            0.18             3.8

    Skin              0.2             0.08             -
                                                                        

    a   Concentration of thallium in the respective tissue divided by
        the concentration of thallium in the food
    b   From: Ueberschär et al. (1986)
    c   After 3 weeks
    d   After 6 weeks

         More than 99% of samples of drinking-water in the USA contained
    no thallium (detection limit, 0.3 µg/litre), and the positive samples
    contained about 0.89 µg/litre.  With a water consumption of
    2 litre/day, this would result in an intake of < 1 µg thallium/day
    for most adults (US EPA, 1980).  The thallium concentration in 17
    bottled mineral waters ranged between < 0.6 and 3.5 µg/litre, but
    only 4 contained > 2 µg/litre (Korkisch & Steffan, 1979).

         In the United Kingdom, Sherlock & Smart (1986) reported the total
    dietary intake of thallium, based on the analysis of 13 diets.  Four
    (meat, fish, fats and green vegetables) out of nine food groups
    contained samples with concentrations of thallium above the limit of
    determination, ranging from 10 to 50 µg/kg fresh weight depending on
    the food commodity.  The average dietary intake of thallium for adults
    was estimated to be 0.005 mg/day with a range of 0-0.01 mg/day,
    assuming that concentrations less than the limit of determination were
    equal to zero.  The daily intake of thallium from vegetables alone is
    estimated to be about 3.8 µg for an average adult in the USA (US EPA,
    1980).  Food of plant origin often contains more thallium than food of
    animal origin, a 4-fold higher concentration of thallium being
    eliminated in the urine of vegetarians than in that of humans eating
    food of varying origin (Ohnesorge, 1985).

         A minor route of thallium uptake can be sodium-free dietetic salt
    (KCl), which contains up to 420 µg thallium/kg salt (Toots & Parker,
    1977), but not sodium chloride, which only contains 0.08 µg/kg
    (Geilmann et al., 1960).  Wine has also been found to contain small
    amounts of thallium (0.056 to 0.684 µg/litre) (Geilmann et al., 1960).

    5.3  Occupational exposure during manufacture, formulation or use

         Few data on occupational exposure to thallium are available.  An
    industrial plant in the USA used concentrated thallium salt solutions
    for separations by centrifugation. Considerable variations in the
    thallium content of the air occurred during the day, depending on the
    emission potential of the different steps of the procedure (Hill &
    Murphy, 1959), although no exact data were reported.  In a plant in
    the United Kingdom manufacturing special alloy anodes for use in
    magnesium seawater batteries, air samples from two working areas
    contained a maximum level of 0.022 mg thallium/m3 and 0.014 mg/m3
    (Marcus, 1985).  Detailed data are available from a Russian plant
    producing thallium before and after changes in processes.  The air
    concentration varied from 0.12 to 0.18 mg thallium/m3, but peak
    concentrations of 13.5 to 17.4 mg/m3 during the smelting process
    were observed. During dissolving and packing of thallium salts, the
    air thallium concentrations were 0.117 and 0.274 mg/m3, respectively.
    After changes in the smelting process were instituted, the air
    thallium content decreased to 0.0036-0.0072 mg/m3 (Tikhova, 1964). 
    Floating dust in a German thallium smelter contained 60 to 9700 mg
    thallium/kg dust; the air-suspended dust concentration was 6-50 µg/m3
    (Briese et al., 1985).

         Working with thallium causes dust contamination of the hands,
    this increasing with the duration of work (Tikhova, 1964).  The dust
    concentration on the hands has been reported to be in the range of
    0.04 to 10.6 mg/m2 (Shabalina & Spiridonova, 1979).

    6.  KINETICS AND METABOLISM

         Investigations into the kinetics and metabolism of thallium in
    aquatic and terrestrial animals have mainly made use of radioactive
    compounds, especially thallium-201. The investigations cited in this
    chapter have been performed with various thallium salts, but to
    facilitate comparison concentrations have been generally expressed as
    µg (or mg) thallium/litre.

    6.1  Absorption

    6.1.1  Animals

    6.1.1.1  Aquatic animals

         Clams and mussels reached equilibrium within 12 to 19 days when
    exposed to 50 or 100 µg thallium/litre.  Depending on the exposure
    level, the clams contained 5 or 9 mg/kg dry weight and the mussels 3
    or 5 mg/kg (Zitko & Carson, 1975).

         Very poor absorption of thallium salts from water containing
    0.1 mg thallium/litre was found in isolated gill preparations of the
    mussel Mytilus galloprovincialis (Nolan et al., 1984).  In the first
    10 min about 10% of the dose was absorbed.

         Accumulation of thallium in juvenile salmon exposed for 300 h to
    different concentrations of thallium (17.9 to 200 µg thallium/litre)
    varied in different organs (Table 15).  In muscle, thallium levels
    increased almost linearly with the water thallium concentration from
    2.3 to 27.0 mg/kg tissue (wet weight).  Data on the liver show no
    consistent trend, but in gills an obvious maximal accumulation
    capacity of about 30 mg/kg was reached even at the lowest
    concentration of 17.9 µg/litre water (Zitko et al., 1975).  The mean
    accumulation factor (mg thallium per kg tissue wet weight divided by
    mg thallium per litre water) of the gills (up to 1430) is about three
    to ten times higher than that of muscle or liver.

    6.1.1.2  Terrestrial animals

         Using different routes of administration of thallium(I) nitrate
    solution (oral, intratracheal, subcutaneous, intraperitoneal,
    intramuscular and intravenous), thallium was rapidly and almost
    completely absorbed in rats (Lie et al., 1960).  High concentrations
    of thallium were detected in the blood within just 1-2 h after oral
    administration of thallium(I) malonate and thallium(I) sulfate
    (Aoyama, 1989), and as little as 1 h after oral or parenteral
    administration of thallium(I) sulfate it was found in the urine and
    faeces of rats (Lund, 1956a).

         Only a few experimental studies on intestinal absorption are
    available.  In sheep and cows about 2% of the thallium ingested with
    contaminated food was retained, while about 98% was eliminated
    (Crössmann, 1984).  Sabbioni et al. (1980b) found no obvious
    differences using various doses of thallium(I) or thallium(III)
    sulfate or bromide, but, after oral uptake of dimethyl thallium(III)
    bromide in rats, the organs contained only 1 to 10% of the
    concentrations found after the uptake of inorganic thallium,
    indicating reduced absorption.  In rats the absorptive capacity of
    different ligated regions of the intestinal tract varies strongly:
    201thallium (sulfate) was rapidly absorbed from the colon, but more
    slowly from the ileum and jejunum and slowest from the stomach
    (Sabbioni et al., 1984a).  Within 60 min the ligated colon absorbed
    about 75%.  Lower values were obtained for the other regions.  Voltage
    clamp experiments on the mucosa of rat descending colon showed
    exclusive transport by diffusion to the serosal side (Schäfer et al.,
    1981).

         Absorption of thallium through the skin of rats is indicated by
    the determination of a cutaneous LD50 of 117 mg/kg for thallium(I)
    carbonate (Shabalina et al., 1980).

    6.1.2  Humans

         Increased levels of thallium have been observed in the lungs of
    coal miners, but no data are available concerning the absorption of
    thallium salts after inhalation exposure (section 6.2.2.2) (Weinig &
    Zink, 1967).  Generally it is assumed that about 35% of respirable
    dust is deposited in the lung (Ohnesorge, 1985; IPCS, 1992) and that
    up to 100% of the deposited thallium is absorbed (Gubernator et al.,
    1979).  The rate of deposition and absorption is high because thallium
    concentrations increase markedly with decreasing particle size
    (sections 3.2.3.2 and 5.1.1.2), and small particles become deposited
    in the lung whereas larger particles are deposited in the upper
    respiratory system (Natusch & Wallace, 1974).  In addition, nearly all
    the thallium chloride in the dust emitted from the cement plant in
    Lengerich was water-soluble (LIS, 1980).  In human broncho-alveolar
    lavage fluids, 0.258 ng thallium per 1000 cells was found in a
    silicosis patient, but only 0.009-0.05 ng in patients suffering from
    other lung diseases (Maier et al., 1986).

         From several intoxication cases, e.g., after oral and topical
    application of thallium(I) sulfate during depilatory treatment
    (Barckow & Jenss, 1976; Schmidbauer & Klingler, 1979), it can be
    assumed that both percutaneous and gastrointestinal absorption occur,
    but no data on absorption are available. High blood thallium
    concentrations have been reported following human poisoning (see
    Table 20).

    6.2  Distribution

    6.2.1  Animals

         No effect of the route of administration (oral, intratracheal,
    subcutaneous, intraperitoneal, intramuscular and intravenous) on
    distribution was observed by Lie et al. (1960).  After intravenous
    injection, an initial increase in the thallium concentration of the
    blood is followed by a steep decrease within 5 to 15 min (Gehring &
    Hammond, 1967; Lameijer & van Zwieten, 1977a,b).  A similar trend is
    observed when concentrations are compared 1.5 and 24 h after oral
    administration of 10 mg thallium/kg body weight to rats or intravenous
    injection into rabbits (Careaga-Olivares & Morales-Aguilera, 1993). 
    Thallium is distributed by the blood stream to all organs.

         Data on the distribution of thallium in the main blood
    compartments, e.g., serum and erythrocytes, have been reported.  In
    vitro measurements by Lund (1956a) and Witschi (1965) indicate that
    thallium is distributed equally in blood plasma and red cells,
    presumably without any direct binding, while Gregus & Klaassen (1986)
    found that 2 h after intravenous injection of 1 to 30 mg/kg more than
    80% of blood thallium was in the plasma.  According to Ducket et al.
    (1983), 24 h after intraperitoneal injection of a very low dose of
    thallium, nearly 90% was located in the red blood cells and only about
    10% in the plasma.  An intermediate result was obtained by Ulrich &
    Long (1955): after intraperitoneal injection of about 20 µg
    radioactive thallium, about one third of the thallium concentration in
    the whole blood was located in the plasma.  This ratio did not change
    over the period 0.5 h to 96 h after injection, although the
    concentration in the blood decreased with time.  Similar results were
    obtained in human whole blood  (in vitro) and in rabbit whole blood
    ( in vitro and  in vivo) (Careaga-Olivares & Morales-Aguilera,
    1990).  A slightly higher concentration in the erythrocytes was also
    found by Leloux et al. (1987), but during redistribution phases the
    concentrations in erythrocytes were increased, suggesting that
    erythrocytes may be involved in thallium uptake.

    6.2.1.1  Distribution after administration of a single dose

         The distribution of thallium after administration of single doses
    of thallium compounds has been investigated in a number of studies,
    using either subtoxic doses (0.2 µg/kg to 8 mg thallium/kg body
    weight) (e.g., Ulrich & Long, 1955; Lie et al., 1960; Bradley-Moore et
    al., 1975; Edel Rade et al., 1982; Ziskoven et al., 1983; Ducket et
    al., 1983) or toxic doses (e.g., Lund, 1956a; Fitzek & Henning, 1976;
    Achenbach et al., 1980; Leloux et al., 1987b; Aoyama, 1989).

    Comparisons of dose-dependent distribution (Emara & Soliman, 1950;
    Gehring & Hammond, 1967; Sabbioni et al., 1980a,b, 1982; Talas &
    Wellhöner, 1983; Gregus & Klaassen, 1986; Ríos et al., 1989) revealed
    only slight differences in the distribution pattern, even at
    intraperitoneally administered concentrations as different as 0.00004,
    2, 20 and 2000 µg thallium/rat (Sabbioni et al., 1980a).

         The distribution of thallium in the organs is a time-dependent
    process (Tables 17 and 18).  Summarizing the investigations on rats,
    rabbits, dogs and goats, in an initial phase after a single dose of an
    inorganic thallium compound, e.g., thallium sulfate or thallium
    chloride, maximal concentrations occurred in the kidneys and nearly
    equal levels were found in the testes, myocardium, salivary glands,
    muscle, liver, intestines, adrenals and thyroid; fat and brain
    contained very low levels of thallium (Lund, 1956a; Gehring & Hammond,
    1967; Bradley-Moore et al., 1975; Sabbioni et al., 1982; Talas &
    Wellhöner, 1983).  About 24 h after administration, the relative
    thallium content of all organs, with the exception of the kidneys,
    decreased and that of brain, muscle and testes increased.  In
    guinea-pigs administered lethal doses of thallium, kidney and liver
    finally contained about equal levels, presumably due to kidney damage
    (Weinig & Walz, 1971).  With respect to the affinity and
    redistribution of thallium in rat organs, Leloux et al. (1987b)
    distinguished three compartments according to affinity and
    redistribution which are not completely in agreement with the
    experimental data shown in Table 17.

         Intraperitoneal application of 16, 32 and 48 mg thallium
    sulfate/kg body weight to male rats resulted in peak levels occurring
    in various regions of the brain 24 h after injection, except in the
    hypothalamus where the peak was reached earlier.  After 24 h, the
    regional concentrations decreased in the following order:
    hypothalamus, midbrain, hippocampus, thalamus, pons, cerebellum,
    corpus striatum and cerebral cortex.  In the hypothalamus, a region
    with low blood-brain barrier protective mechanisms, thallium
    concentration was significantly higher than in the corpus striatum,
    whereas in the cerebral cortex it was significantly lower than in all
    other regions (Ríos et al., 1989).  Whereas weanling rats showed a
    region-dependant distribution of thallium after a single sublethal
    intraperitoneal injection (16 mg thallium/kg body weight), thallium
    concentrations were similar in different brain regions of newborn rats
    (Galvan-Arzate & Ríos, 1994).


        Table 17.  Alterations in the distribution of thallium in different organs of experimental animals at different times after
               administration (mean ± standard deviation)a
                                                                                                                                                

                                     Rats (4; intraperitoneal)b                                           Syrian hamsters (5; oral)c

    Experiment No.:            1                                  2                                    3                            4

                     2 h               40 h             4 h               24 h                 1 h           24 h           1 h          24 h

                          (% of dose)             (% of dose of thallium/g wet weight)                  (mg thallium/kg wet weight)
                                                                                                                                                

    Blood        0.05 ± 0.01d     0.08 ± 0.05d    0.023 ± 0.001     0.027 ± 0.017         1.5 ± 0.6      1.0 ± 0.1     1.7 ± 0.6     0.8 ± 0.1

    Bone         -                -               0.239 ± 0.036     0.216 ± 0.064         -              -             -             -

    Brain        0.027 ± 0.003    0.28 ± 0.05     0.047 ± 0.009     0.090 ± 0.023         < 0.1          3.7 ± 0.3     0.6 ± 0.1     3.0 ± 0.3

    Heart        0.57 ± 0.07      0.33 ± 0.03     0.546 ± 0.064     0.337 ± 0.006         11.4 ± 1.7     7.2 ± 0.7     21.0 ± 3.4    6.6 ± 0.7

    Intestine    1.1 ± 0.26       -               -                 -                     -              -             -             -

    Kidney       5.65 ± 0.35      9.75 ± 0.97     3.354 ± 0.535     1.899 ± 0.253         58.5 ± 8.4     51.3 ± 14.0   88.4 ± 21.8   41.5 ± 0.9

    Liver        4.44 ± 0.55      0.95 ± 0.19     0.373 ± 0.040     0.228 ± 0.028         14.3 ± 7.6     6.6 ± 2.1     39.7 ± 6.2    5.8 ± 0.4

    Lung         0.55 ± 0.35      0.45 ± 0.04     0.289 ± 0.076     0.230 ± 0.081         -              -             -             -

    Muscle       0.6 ± 0.02e      0.54 ± 0.2e     0.168 ± 0.031     0.234 ± 0.091         < 0.1          9.1 ± 2.4     1.2 ± 0.5     9.1 ± 1.2
                                                                                                                                                

    Table 17 (contd).
                                                                                                                                                

                                     Rats (4; intraperitoneal)b                                           Syrian hamsters (5; oral)c

    Experiment No.:            1                                  2                                    3                            4

                     2 h               40 h             4 h               24 h                 1 h           24 h           1 h          24 h

                          (% of dose)             (% of dose of thallium/g wet weight)                  (mg thallium/kg wet weight)
                                                                                                                                                

    Pancreas     0.86 ± 0.34      0.57 ± 0.13     0.505 ± 0.163     0.310 ± 0.206         -              -             -             -

    Salivary     0.76 ± 0.06      0.7 ± 0.32      0.595 ± 0.078     0.370 ± 0.090         -              -             -             -
    gland

    Spleen       0.32 ± 0.03      0.18 ± 0.02     0.338 ± 0.039     0.249 ± 0.054         -              -             -             -

    Testes/      0.56 ± 0.04      0.93 ± 0.34     0.388 ± 0.077     0.200 ± 0.010         < 0.1          14.7 ± 0.7    1.0 ± 0.1     14.0 ± 1.0
    Ovary
                                                                                                                                                

    a   - = no data given
    b   No. 1: Sabbioni et al. (1980b) and No. 2: Edel Rade et al. (1982): injection of thallium(I) sulfate (2 µg thallium/rat)
    c   Nos. 3 and 4: Aoyama (1989): administration of 12.5 mg thallium(I) sulfate/kg (No. 3) or 12.35 mg thallium(I) malonate/kg (No. 4)
    d   % dose/ml
    e   % dose/g wet weight

    Table 18.  Distribution of thallium in different organs of experimental animals after different
               periods of exposurea
                                                                                                                     

    Experiment no:b    1a          1b          2          3           4a          4b          5

                       72 h        72 h        4 h        24 h        48 h        48 h        48 h
                                                                                                                     

    Blood             0.007       0.001       0.02        0.02        0.02        0.02        -

    Bone              0.016       0.028       0.37        0.42        0.23c       0.23c       0.67

    Brain             0.006       0.008       0.05        0.13        0.17        0.14        0.32

    Fat               0.0008      0.001       -           0           0.01        0.02        -

    Heart             0.027       0.030       0.55        0.20        0.34        0.25        0.63

    Intestine         0.012d      0.017d      -           0.51        0.49e       0.76e       0.50

    Kidney            0.205       0.210       3.35        2.15        2.58        0.53        5.36

    Liver             0.019       0.026       0.37        0.33        0.19        0.16        0.53

    Lung              0.016       0.018       0.29        0.55        0.25        0.24        0.51

    Muscle            0.014       0.025       0.17        0.49        0.25f       0.27f       0.76
                                                                                                                     

    Table 18 (contd).
                                                                                                                     

    Experiment no:b    1a          1b          2          3           4a          4b          5

                       72 h        72 h        4 h        24 h        48 h        48 h        48 h
                                                                                                                     

    Pancreas          0.010       0.014       0.51        -           0.44        0.33        -

    Salivary gland    -           -           0.59        -           0.42        0.44        1.06

    Skin              -           -                       0.20        -           -           0.32

    Spleen            0.016       0.021       0.34        0.20        0.24        0.21        0.51

    Testes/           0.023       0.024       0.39        0.39        0.53        0.53        0.81
    Ovary
                                                                                                                     

    a   Thallium content in % of dose per kg wet weight; - = no data given
    b   No. 1: Talas & Wellhöner (1983): mean of 2 rabbits after intravenous injection of < 2 µg
        (No. 1a) or 1.1 mg thallium/kg (No. 1b); No. 2: Sabbioni et al. (1982): mean of 4 rats
        after intraperitoneal injection of 2 µg/rat; No. 3: Lund (1956a): data of 1 rat after
        intraperitoneal injection of 10 mg/kg; No. 4: Barclay et al. (1953): mean of 4 rats after
        intravenous injection of 23 µg thallium nitrate (No. 4a) or mean of 3 rats after
        intravenous injection of 10.023 mg thallium sulfate (No. 4b); No. 5: Lie et al. (1960):
        mean of 18 rats after injection of thallium by various routes
    c   Femur
    d   Mean of values of small and large intestine
    e   Lower bowel
    f   Abdominal muscle
             Although the endocrine organs were thought to be involved in the
    mechanism of toxicity, no accumulation was observed in
    autoradiographic studies of low-dosed adult mice and rats (Barclay et
    al., 1953; André et al., 1960).  Leloux et al. (1987b) found no
    obvious deviation from the levels found in other organs 5 days after
    subacute or acute intoxication with 4 or 20 mg thallium nitrate/kg,
    respectively.  Thyresson (1951), however, reported a high
    concentration of thallium (96.9 mg/kg wet weight) in the thyroid gland
    of rats 24 h after administration of 40 mg thallium nitrate/kg body
    weight.  According to Ulrich & Long (1955), treatment of rats with
    thyrotropic hormone subsequent to the administration of thallium did
    not affect the uptake of thallium by the thyroid, whereas pretreatment
    (2 days prior to administration) significantly increased the initial
    uptake.  In addition, the authors reported that adrenals, thyroid and
    pituitary contained similar concentrations of thallium.

         Different modes of application and different thallium compounds
    hardly affect the distribution pattern, as shown by Sabbioni et al.
    (1980b) with intravenous or oral administration of thallium(I),
    thallium(III) and dimethyl thallium(III) in rats.  Another
    investigation showed that after administration of thallium(I) malonate
    and thallium(I) sulfate the distribution pattern between different
    organs varied only initially.  Later, both patterns were similar
    (Aoyama, 1989).

    6.2.1.2  Distribution after long-term sublethal administration

         The distribution pattern of thallium in chronically poisoned rats
    shows a strong similarity to the final pattern after a single dose,
    there being wide distribution throughout the body.  Lameijer & van
    Zwieten (1977a,b) determined thallium concentrations in urine, blood
    and 19 different tissues of rats exposed to thallium (10 mg/litre) in
    drinking-water for 9 or 24 weeks.  No statistically significant
    differences in the concentration of thallium were observed for any
    tissues except kidney. The thallium concentration in the renal medulla
    was about 7 times higher than in the heart, liver, muscle, brain or
    skin.  If rats received 30 mg/litre in drinking-water, they died
    within 9 to 11 days, but after 7 days this administration had not
    affected the rapid decline of the thallium blood level following
    administration of an additional intravenous dose of 1 mg/kg (Lameijer
    & van Zwieten, 1977a).

    6.2.1.3  Transplacental transfer of thallium

         Mice were gavaged with thallium(I) sulfate (8 mg thallium/kg body
    weight) on gestation day 9 and tissue concentrations were determined
    0.5 to 24 h later.  Thallium levels in fetuses and maternal kidneys
    rose during the first hour, then levelled off to a plateau which did
    not change during the following 22 h.  No indication of a specific
    placental barrier was detected (Ziskoven et al., 1980).  Ziskoven et

    al. (1983) repeated the study, additionally including rats.  After 10,
    20 and 30 min, increasing thallium concentrations were found in the
    maternal kidneys, reaching a plateau after 30 to 60 min, which was
    stable for at least 50 h (last measurement).  A similar time course of
    thallium uptake was observed in the fetal tissues: the initial uptake
    was comparable to that of the maternal kidney, but the resultant
    concentrations were 10-fold lower.  There were no specific differences
    between mice and rats.

         A slightly delayed transfer to fetuses was observed in an
    autoradiographic study with mice (gestation day 15), dosed with an
    intraperitoneal injection of thallium sulfate.  After just 15 min,
    thallium was observed in the fetuses, but the maximum level was
    reached within 2 to 4 h, when some thallium elimination took effect. 
    During the whole observation period, fetal thallium levels were lower
    than those of the placenta (Olsen & Jonsen, 1982).  The authors also
    reported on the influence of the stage of gestation.  Thallium crossed
    the placenta throughout gestation; during the early stages it was
    concentrated in the visceral yolk sac placenta and during late
    gestation additionally in the chorioallantoic placenta and amnion.

         When near-term mice and rats (gestation day 17-18) were given
    subcutaneous injections of 204thallium sulfate, thallium
    concentrations in the mouse fetuses rose during the following 8 h and
    in the rat fetuses during the following 16 h.  Thereafter, the
    fetal/maternal ratios in tissues remained constant at 0.84 in rats and
    considerably lower (0.46) in mice (Gibson et al., 1967).

         Intra-arterial infusion of 0.2 to 6.4 mg 204thallium
    sulfate/min per kg body weight on day 20 of pregnancy in rats resulted
    in an initially restricted transplacental transfer. In the lowest and
    highest dosage groups, 32 min after administration, thallium levels in
    fetal tissues corresponded to only about 7% of those in the maternal
    plasma, perhaps because two-thirds of the whole blood thallium was
    located in the erythrocytes and did not pass the placental barrier
    (Gibson & Becker, 1970).

         Sabbioni et al. (1982) compared placental transfer in rats after
    intraperitoneal injection of a low dose (2 µg thallium-201/rat;
    gestation day 13) with that after administration of a toxic dose by
    gavage (10 mg thallium/kg body weight; gestation day 16).  Thallium
    concentrations in maternal and fetal brain were similar 4 h after
    injection of the low dose.  In fetal liver they were 80% lower than in
    the maternal liver, and in the placenta and fetal organs they were
    higher than in the blood of the dams and fetuses.  Very low
    concentrations were found in the amniotic fluid.  After 8 days,
    concentrations in most of the maternal organs were about 10 times
    lower than the initial levels, while in muscle, cerebellum and brain
    of the dams, reductions of only 60, 40 and 5%, respectively, were
    found during the same period.  In contrast to the variable decline in
    maternal organs, a 10-fold decline was observed in the whole fetus and

    its liver, brain and blood.  Preliminary results of the authors
    indicated that this was due to a much stronger thallium accumulation
    in the mitochondria of the adult rat brain than in those of the fetal
    brain.  Furthermore, identical low-dose experiments (2 µg/rat) also
    showed a faster decline of thallium concentrations in fetal than in
    maternal brain, after an initially more rapid entry into the fetal
    brain, whereas declines in the liver levels were nearly identical
    (Edel Rade et al., 1982).  Administering a toxic dose of 10 mg/kg to
    the dams resulted in 60% lethality within the following 3 days. After
    3 days, concentrations in the liver and brain of the surviving dams
    were similar and about 2-fold higher than in the corresponding fetal
    organs.  Therapeutic oral dosing with Prussian Blue (100 mg/kg body
    weight, twice daily) starting 8 h after administration of thallium,
    significantly reduced the thallium concentrations in maternal and
    fetal tissues and only 1 of 12 adult rats died (Sabbioni et al.,
    1982).

         Transplacental transfer of thallium has also been observed in a
    cat (Fitzek & Henning, 1976).  The cat showed signs of a strong
    thallium intoxication and was killed after abortion of approximately
    5-week-old fetuses.  Thallium levels in maternal blood and fetal
    tissues were similar, but the concentrations in fetal heart and lungs
    were two to three times higher than in the corresponding maternal
    organs.

    6.2.2  Humans

         Background thallium concentrations found in human body fluids and
    tissues are given in Table 19.  After poisoning, thallium
    concentrations ranging up to nearly 36 mg/litre in blood, 25 mg/litre
    in urine and 8 mg/kg in hair have been found (Table 20).

    6.2.2.1  Increased concentrations after lethal poisoning

         In reports of postmortem examinations after suicide or homicide,
    data on the distribution of thallium in different organs are rarely
    included with data on dose and application routes (Table 20).  The
    distribution pattern shows no consistent trend.  In a single
    individual, concentrations in bones, fat and muscles from different
    parts of the body may vary, e.g., in vertebrae (12.7 mg/kg), sternum
    (7.0 mg/kg), femur (16.4 mg/kg) and tibia (9.0 mg/kg) (case 7 in
    Table 21) (Arnold, 1986).  The distribution of thallium differs
    considerably from that reported for potassium in humans (Davis et al.,
    1981).  Endocrine glands, kidneys, liver and intestine (without
    content) showed the highest concentrations (Table 21).

         With respect to the total amount per organ, liver or lung were
    found to contain 2 to 6 times and the brain about 1.5 to 2 times more
    thallium than the kidneys (Curry et al., 1969; Arnold, 1986).

         A comparison between the white and grey matter of the brain
    revealed that in the latter the concentration was three times higher
    (Cavanagh et al., 1974).  Detailed data of thallium concentrations in
    different regions of the nervous system were given by Davis et al.
    (1981).  The authors showed that areas of the brain rich in neurons
    tend to accumulate twice as much thallium as areas devoid of neurons,
    and that the grey matter contains some of the highest thallium levels
    of any body organ.

    6.2.2.2  Increased concentrations after long-term sublethal poisoning

         Thallium levels in urine (Table 22), blood or saliva of
    chronically exposed people offer better indications of the actual
    burden than those derived from hair samples, since elevated levels in
    hair can be caused by exogenous dust (Bertram et al., 1985).

         People consuming food grown in private gardens and living at a
    distance of more than 3 km from the cement plant at Lengerich, Germany
    showed significantly higher concentrations of thallium in their urine,
    decreasing with increasing distance from the plant, than people who
    did not consume food from their gardens.  Thallium concentrations in
    the urine of people living near the plant (< 1 km) and consuming food
    grown in private gardens were about five times higher (3.95 µg/litre)
    (Brockhaus et al., 1980).  Peak values were 76.5 µg/litre in urine and
    565 µg/kg in hair (Ewers & Brockhaus, 1982).  In this area a medical
    survey was carried out immediately after the occurrence of thallium
    emissions had been recognized; urine thallium levels in about 80% of
    the population were found to exceed the upper normal limit of
    1 µg/litre (Brockhaus et al., 1980; Dolgner et al., 1983).  The
    recommendation to avoid home-grown vegetables was followed by many
    people and resulted in a significant decrease in urine thallium
    levels.  However, in some residents, even 8 years later, increased
    levels of > 20 µg/litre urine could be found.  Probably there was
    still a significant contamination of soil and thus of home-grown
    vegetables (Ewers, 1988).

         Subsequent studies were carried out at other cement factories. 
    About 70% of employees at two cement plants in Middle and Lower
    Franconia, Germany were found to have normal thallium concentrations
    in their urine.  However, at a third factory in the same area only 30%
    of employees showed normal thallium urine levels, presumably because
    of the higher thallium content in the raw material used (Schaller et
    al., 1980).  The population around the three cement plants showed
    normal urine thallium levels: of 238 people tested, 194 had thallium
    concentrations below 2 µg/litre, 36 were in the range of 2 to
    5 µg/litre, and 5 were between 5 and 10 µg/litre.  Higher
    concentrations were found in the urine of three people (11.5, 14.5 and
    19.5 µg/litre) (Steuer, 1980).


        Table 19.  Background concentrations of thallium in humans
                                                                                                                                      

    Material        Number of            Concentration of thallium          Concentration unit        Referencef
                    measurements
                                         Mean ± SD       Range
                                                                                                                                      

    Blood,          2                                    0.33-0.59          µg/litre                  Weinig & Zink (1967)
    whole                                                < 20                                         Bowen (1966)
                    13                                   0.47-9                                       Iyengar et al. (1978)
                    320                                  < 5-80                                       Singh et al. (1975)
                                                         0.05                                         Kemper (1979)
                    418                  0.39 ± 0.05     0.1-1.1                                      Minoia et al. (1990)
                                                         0.5-2                                        Kemper & Bertram (1991)
    plasma                                               < 2.5                                        Bowen (1966)
                    1                                    < 2.5                                        Iyengar et al. (1978)

    Bone            2                                    0.84-2.51          µg/kg fresh weight        Weinig & Zink (1967)
                    1                                    2                                            Iyengar et al. (1978)
                    5                                    < 0.1-0.1                                    Goenechea & Sellier (1967)

    Bonea           1                                    0.7; 0.9                                     Goenechea & Sellier (1967)

    Brain                                                < 0.5              mg/kg dry weight          Bowen (1966)
                                                                                                                                      

    Table 19 (contd).
                                                                                                                                      

    Material            Number of        Concentration of thallium          Concentration unit        Referencef
                        measurements
                                         Mean ± SD       Range
                                                                                                                                      

    Bronchoalveolar     1b                               0.258              ng/1000 cells             Maier et al. (1986)
    lavage fluids       1c                               0.009
                        1c                               0.011
                        1d                               0.016
                        1d                               0.050

    Faeces              5                                < 0.02-3.0         µg/kg fresh weight        Goenechea & Sellier (1967)

    Hair                7                18.6 ± 14.9     7-51               µg/kg fresh weight        Geilmann et al. (1960)
                        6                10.4 ± 4.3      4.8-15.8                                     Weinig & Zink (1967)
                        1                                < 20                                         Ziegler & Ziegler (1984)

    Heart                                                < 0.4              mg/kg dry weight          Bowen (1966)

    Kidney                                               < 0.4              mg/kg dry weight          Bowen (1966)
    Kidney              6                2.7 ± 1.1       1.44-4.1           µg/kg fresh weight        Weinig & Zink (1967)
                        8                                < 3                                          Iyengar et al. (1978)
                        259                              0.03-8.6                                     Bösche & Magureanu (1983)

    Liver                                                0.4                mg/kg dry weight          Bowen (1966)
                        11               0.47 ± 0.13     < 0.4-0.9                                    Johnson (1976)
                                                                                                                                      

    Table 19 (contd).
                                                                                                                                      

    Material        Number of            Concentration of thallium          Concentration unit        Referencef
                    measurements
                                         Mean ± SD       Range
                                                                                                                                      

    Liver           6                    1.1 ± 0.9       0.55-2.85          µg/kg fresh weight        Weinig & Zink (1967)
                    1                                    0.4                                          Goenechea & Sellier (1967)
                    6                                    1-9                                          Iyengar et al. (1978)
                                                         0.5-3                                        Kemper & Bertram (1991)

    Lung                                                 < 0.3              mg/kg dry weight          Bowen (1966)
    Lung            4                    1.1 ± 0.7       0.36-1.8           µg/kg fresh weight        Weinig & Zink (1967)

    Muscle                                               < 0.4              mg/kg dry weight          Bowen (1966)
    Muscle          6                    2.1 ± 2.1       0.52-7.05          µg/kg fresh weight        Weinig & Zink (1967)
                    3                                    15-100                                       Iyengar et al. (1978)

    Musclee         1                                    0.4                µg/kg fresh weight        Goenechea & Sellier (1967)

    Nail            6                    51.2 ± 12.1     40-74              µg/kg fresh weight        Geilmann et al. (1960)
                    6                    2.6 ± 1.4       0.72-4.93                                    Weinig & Zink (1967)

    Skin                                                 < 0.2              mg/kg dry weight          Bowen (1966)
                                                                                                                                      

    Table 19 (contd).
                                                                                                                                      

    Material        Number of            Concentration of thallium          Concentration unit        Referencef
                    measurements
                                         Mean ± SD       Range
                                                                                                                                      

    Urine           10                                   < 0.02-1.0         µg/kg fresh weight        Goenechea & Sellier (1967)

    Urine                                                0.05-0.1           µg/litre                  Geilmann et al. (1960)
                    14                   0.7 ± 0.5       0.07-1.69                                    Weinig & Zink (1967)
                                                         0.05-20                                      Kemper (1979)
                    31                   0.4 ± 0.2       < 0.1-1.2                                    Brockhaus et al. (1981b)
                    10                   0.3 ± 0.2       < 0.1-0.9                                    Brockhaus et al. (1981b)
                    149                  0.3 ± 0.14      0.02-0.7                                     Dolgner et al. (1983)
                    72                   0.22 ± 0.14     0.06-0.61                                    Apostoli et al. (1988)
                    496                  0.42 ± 0.09     0.06-0.82                                    Minoia et al. (1990)
                                                         0.05-1.5                                     Kemper & Bertram (1991)

    Urine           20                                   < 0.3-1.1          mg/kg creatinine          Schaller et al. (1980)
                    10                   2.2 ± 1.6                                                    Briese et al. (1985)
                                                                                                                                      

    a   1.5 months after death
    b   silicosis patient
    c   saw setters suffering pneumoconiosis
    d   welders suffering emphysema
    e   6 months after death
    f   Additional values for other tissues have been compilated by Iyengar et al. (1978)

    Table 20.  Concentrations of thallium in cases of poisoning
                                                                                                                                     

    Material                Number of       Range of thallium       Concentration unit      Reference
                            cases           concentrations
                                                                                                                                                

    Blood, whole                            50-6000a                µg/litre                Kemper (1979)
    Blood                   2               29; 7700                                        Alarcón-Segovia et al. (1989)
    Blood, whole            3               350-36 000                                      Heath et al. (1983)
    Blood, plasma           2               300; 1500                                       Heath et al. (1983)
    Blood, erythrocyte      2               400; 2300                                       Heath et al. (1983)

    Bone                    1b              0.9-2.1                 µg/kg fresh weight      Goenechea & Sellier (1967)

    Faeces                  1               6500-38 400                                     Paulson et al. (1972)

    Hair                    1               650                                             Geilmann et al. (1960)
    Hair                    1b              6.8                                             Goenechea & Sellier (1967)
    Hair                    1               420-1800                                        Hagedorn-Götz & Stoeppler (1975)
    Hair                                    250-8000a                                       Kemper (1979); Kemper & Bertram (1984)

    Heart                   1               3600                                            Munch et al. (1933)

    Intestine               1               3600                                            Munch et al. (1933)
    Intestine               1               0.8; 4.0                                        Goenechea & Sellier (1967)
                                                                                                                                                

    Table 20 (contd).
                                                                                                                                                

    Material                Number of       Range of thallium       Concentration unit      Reference
                            cases           concentrations
                                                                                                                                                

    Kidney                  5               2700-11 600                                     Munch et al. (1933)
    Kidney                  1               106 000                                         Heath et al. (1983)

    Liver                   1               75 000                                          Heath et al. (1983)
    Liver                   2               3700; 5500                                      Munch et al. (1933)

    Lung                    2               3300; 7700                                      Munch et al. (1933)

    Muscle                  1b              < 0.02; 1.3                                     Goenechea & Sellier (1967)

    Nails                   1               2400                                            Geilmann et al. (1960)

    Spleen                  3               2900-6600                                       Munch et al. (1933)

    Urine                                   50-25 000a              µg/litre                Kemper (1979)
    Urine                   15              500-20 400                                      Klöppel & Weiler (1978)
    Urine                   1               3100                                            Gastel (1978)
    Urine                   3               10-13 800                                       Alarcón-Segovia et al. (1989)
    Urine                   2               2700-30 000             µg/litre fresh weight   Heath et al. (1983)
    Urine                   1               0.65                    mg/kg creatinine        Hagedorn-Götz & Stoeppler (1975)
                                                                                                                                                

    a   Concentrations indicative for poisoning
    b   3 years after death

    Table 21.  Concentrations of thallium in individual cases of human poisoning
                                                                                                                                   

                                           Thallium concentration (mg/kg wet weight or mg/litre)
    Case no:a          1               2             3             4               5               6             7
    Durationb:     > 14 days        > 21 days      9 days        8 days         11 days         12 days       13 days
    Dose:              -c              -           5-10 g        0.75 gd           -               -             -
                                                                                                                                   

    Adrenal           -              -              83.6           -              -              -              -
    Blood             5.1            3.4            5.1            -              -              3.0            -
    Bone              -              5.0            -              0.92           1.9            8.0            7.0-16.4
    Brain             8.5            -              62-140         0.15           -              -              -
    grey              -              10.0           -              -              -              -              -
    white             -              3.0            66.1           -              -              -              -
    cerebellum        -              -              103.3e         -              1.5            5.0            -
    cerebrum          -              -              102.0e         -              1.0            -              -
    Fat               -              -              < 1.0          -              0.4-1.2        -              -
    Heart             -              13.3           -              0.19           1.5            13.0           6.2
    left              -              -              26.8           -              -              -              -
    right             -              -              131.6          -              -              -              -
    Intestine         -              -              -              0.20           -              -              -
    small             4.4f           -              -              -              0.5-0.9        8.0f           6.4
    colon             71.0f          120.0f         126.0          -              2.0            500.0f         8.5
    Kidney            26.7           20.0           74.1           0.26           3.0            28.0           12.5
    Liver             8.6            5.0            77.3           0.82           1.8            15.0           14.7
                                                                                                                                   

    Table 21 (contd).
                                                                                                                                   

                                           Thallium concentration (mg/kg wet weight or mg/litre)
    Case no:a          1               2             3             4               5               6             7
    Durationb:     > 14 days        > 21 days      9 days        8 days         11 days         12 days       13 days
    Dose:              -c              -           5-10 g        0.75 gd           -               -             -
                                                                                                                                   

    Lung              -              1.8            -              0.15           0.9            4.0            -
    Muscle            10.1           5.0            26.8           0.21           0.4-2.0        -              3.6
    Pancreas          -              -              71.7           -              -              -              -
    Parathyroid       -              -              38.1           -              -              -              -
    Pituitary         -              -              114.5          -              -              -              -
    Salivary gland    -              -              32.1           -              -              -              -
    Skin              -              6.0            32.1           -              0.3            -              -
    Spleen            -              -              -              0.35           1.9            -              -
    Testes/Ovaries    -              -              152.0          -              -              -              -
    Thyroid           -              -              33.5           -              4.6            -              -
    Urine             15.6           5.9            3.3            -              -              3.0            -
                                                                                                                                   

    a   Case no. 1: Curry et al. (1969); no. 2: Cavanagh et al. (1974); no. 3: Davis et al. (1981); no. 4: Graben et al.
        (1980); nos. 5-7: Arnold (1986); nos. 3-7: poisoning by one uptake of thallium
    b   Period of time from uptake of thallium to death or determination of concentrations
    c   - = no data given
    d   15-week-old embryo; dose of mother
    e   Cortex
    f   Content

    Table 22.  Concentrations of thallium following environmental or occupational exposure
                                                                                                                                                

    Material      Number of       Concentration of thallium            Concentration unit        Source of               Reference
                  people                                                                         thallium
                                 Mean ± SD          Range
                                 (Median)
                                                                                                                                                

    Hair           1163          20.3 ± 42.7        0.6-565            µg/kg fresh weight        cement plant        Brockhaus et al. (1981b)

    Urine          50            (0.6)              < 0.3-4.9          mg/kg creatinine          cement plant        Schaller et al. (1980)
                   47            (1.65)             0.4-6.3            mg/kg creatinine          cement plant        Schaller et al. (1980)
                   21            (0.34)             < 0.3-2.9          mg/kg creatinine          cement plant        Schaller et al. (1980)
                   10            7.1 ± 6.0                             mg/kg creatinine          zinc smelter        Briese et al. (1985)
                   1265          5.2 ± 8.3          < 0.1-76.5         µg/litre                  cement plant        Brockhaus et al. (1981b)
                   82            2.4 ± 4.3          < 0.1-35.8         µg/litre                  cement plant        Dolgner et al. (1983)
                   117           3.0 ± 5.6          0.2-37.7           µg/litre                  cement plant        Dolgner et al. (1983)
                   34a           3.4 ± 3.5          0.4-14.8           µg/litre                  cement plant        Dolgner et al. (1983)
                   30            0.38 ± 0.30        0.08-1.22          µg/litre                  cement plant        Apostoli et al. (1988)
                   20            0.40 ± 0.34        0.08-1.22          µg/litre                  cement plant        Apostoli et al. (1988)
                   10            0.33 ± 0.16        0.09-0.60          µg/litre                  cement plant        Apostoli et al. (1988)
                                                                                                                                                

    Table 22 (contd).
                                                                                                                                                

    Material      Number of       Concentration of thallium            Concentration unit        Source of               Reference
                  people                                                                         thallium
                                 Mean ± SD          Range
                                 (Median)
                                                                                                                                                

    Urine
    (contd)        9             0.38 ± 0.29        0.10-1.04          µg/litre                  iron smelter        Apostoli et al. (1988)
                   74b           16.0 ± 16.9        0.2-76.5           µg/litre                  cement plant        Brockhaus et al. (1981a)
                   74            7.9 ± 8.8          0.2-42.6           µg/litre                  cement plant        Dolgner et al. (1983)
                   21            0.33 ± 0.27        0.06-1.04          µg/litre                  iron smelter        Apostoli et al. (1988)
                   12            0.29 ± 0.21        0.06-0.70          µg/litre                  iron smelter        Apostoli et al. (1988)
                                                                                                                                                

    a   children
    b   Data of people with high concentrations of thallium or possibly thallium-related disorders determined in the first survey and about
        1 year later in the following line
             Only a few cases resulting from industrial exposure have been
    reported and seem to be mainly a result of skin contact or inhalation
    (Kazantzis, 1986; Ewers, 1988).

         At a zinc smelter in eastern Germany, increased thallium levels
    were not only found in the urine of men working in the production
    process, but also in men working in the administration.  During the
    production of thallium in this plant, the levels were further
    increased (maximal value: 28.6 µg/litre) (Briese et al., 1985).

         High concentrations of thallium were found in lung tissue from
    two coal miners (20.2 and 29.5 µg/kg wet weight).  Concentrations in
    most other tissues were normal (Weinig & Zink, 1967).

         In Italy, slight but significant increases in thallium levels
    were found in the urine of cement workers (0.4 µg/litre) and cast iron
    workers (0.3 µg/litre), compared with a non-exposed group
    (0.2 µg/litre).  There was no correlation with age or the duration of
    exposure (Apostoli et al., 1988).

         Weinig & Zink (1967) reported a slight elevation of urine
    thallium levels of vegetarians (and smokers) compared to controls. 
    However, it should be noted that each group comprised only three
    people and the levels were far below those of thallium-affected
    people.  Geilmann et al. (1960) estimated that more than 60% of the
    thallium content of a cigarette (62 µg/kg) is inhaled, but no data are
    available on the amount absorbed.  Assuming an absorption of 50% and a
    consumption of 20 cigarettes/day, 375 ng/day would be absorbed (BGA,
    1979).  Based on data of the thallium concentration in urine of about
    120 people, non-exposed individuals and workers with suspected
    industrial exposure to thallium, Apostoli et al. (1988) found no
    evidence of a difference between smokers and non-smokers, all about 40
    years old.

         Comparing a total of 128 men, no correlation was found between
    duration of employment at a cement plant (1 to 42 years) or age (16 to
    62 years) and thallium concentrations in the urine (< 0.3 to 6.3 µg
    thallium/g creatinine) (Schaller et al., 1980).  Therefore, it can be
    concluded that the uptake of low amounts of thallium does not cause
    accumulation in the body.

    6.2.2.3  Transplacental transfer of thallium

         Abortion was produced in the fourth month of pregnancy 8 days
    after ingestion of approximately 750 mg thallium sulfate.  Starting 2
    days after the ingestion, the mother was treated (haemodialysis,
    forced diuresis, Prussian Blue) for 92 h and survived.  Before the
    start of the therapy, the blood of the mother and of the fetus
    contained 0.07 and 0.01 mg/litre and the urine 0.4 and 0.1 mg/litre,
    respectively.  One day after the end of the treatment, the bones,

    liver and kidney of the fetus contained 0.9, 0.8 and 0.3 mg
    thallium/litre, respectively, and the blood of the mother
    0.08 mg/litre (Graben et al., 1980).   Additional evidence for the
    transplacental transfer of thallium is provided by studies
    demonstrating effects in infants exposed in utero (section 8.5.1).

    6.3  Metabolic transformation

         Data on the transformation and the equilibrium between the two
    oxidation states of thallium ions(I and III) in body fluids and
    tissues of mammals are not available.  The two ions show a similar
    intracellular distribution (Sabbioni et al., 1980b).

    6.4  Elimination and excretion

    6.4.1  Animals

         In a study on the accumulation and excretion of thallium in
    mussels and clams (section 6.1.1.1), the bivalves needed 7 and 30
    days, respectively, to excrete all absorbed thallium.  This is rapid
    in comparison to other heavy metals, such as cadmium, copper, lead and
    mercury, so that no significant amounts of thallium should enter the
    food web in this way (Zitko & Carson, 1975).

         Within 25 days after parenteral administration of 10 mg thallium
    sulfate/kg body weight, rats eliminated 26% in the urine and 51% in
    the faeces (Lund, 1956a).  Elimination via urine started within hours
    after oral application and persisted for up to 3 months.  Faeces were
    not found to contain thallium until the fourth day, and thallium was
    still present after 1 month (Oehme, 1978).  After injections of low
    doses of 204thallium nitrate by different routes, the ratio of
    faecal to urinary elimination of rats increased with time from 2 to 5
    (Lie et al., 1960).  Gregus & Klaassen (1986) reported that faecal
    elimination is always greater than renal elimination.  Biliary
    elimination is of minor importance (Schäfer & Forth, 1980; Gregus &
    Klaassen, 1986).  Within 4 h after an intravenous injection, less than
    0.3% of the injected thallium was eliminated in the bile of rats, but
    up to 8% into the gut (Sabbioni et al., 1984a).  An even lesser degree
    of elimination occurred in tears, sweat, and milk (Oehme, 1978).

         In contrast to absorption, secretion of thallium into the gut of
    rats (given as 201thallium sulfate intravenously or directly into
    the individual ligated gastrointestinal segments) is highest in
    segments of the jejunum, followed by the ileum, colon and stomach
    (Sabbioni et al., 1984a).  Similar results were obtained after
    intravenous administration to rats:  in situ, the jejunum showed the
    highest excretory activity, followed by the ascending colon (Henning &
    Forth, 1982).  The ileum and descending colon each excreted about half

    of the amount of the jejunum; excretion into the stomach was
    negligible.  An increased dose (4 to 400 µg of thallium(I) sulfate/kg
    body weight) caused increased excretion into the jejunum and
    descending colon (Henning & Forth, 1982).  Since thallium is also
    absorbed in the colon (section 6.1), only a proportion of the secreted
    thallium appears finally in the faeces.

         Thallium ions are secreted against an electrochemical or
    concentration gradient by an active transport mechanism, as shown in
    experiments on the isolated mucosa of the descending rat colon
    (Schäfer et al., 1981; Schäfer & Forth, 1987).  Thallium(I) ions use,
    at least in part, the same transport systems as potassium (Henning &
    Forth, 1977; Schäfer & Forth, 1987), and thallium secretion is reduced
    when the concentration of potassium is increased on the serosal side
    (Henning et al., 1982).

    6.4.2  Humans

         The normal daily total elimination in humans is estimated to be
    in the range of 1.64 µg thallium (urine: 1.2 µg; hair: 0.32 µg;
    faeces: 0.06 µg; skin and sweat: 0.06 µg) (US EPA, 1980).  About 50%
    of total urinary elimination occurs within 9 to 11 days (Weinig &
    Schmidt, 1966).

         In lethal cases of human poisoning, postmortem examination has
    always demonstrated high concentrations of thallium, especially in the
    contents of the colon (Table 21).  Thallium levels in human saliva are
    up to 15 times higher than in the urine during the initial 2 weeks
    (Richelmi et al., 1980).  Minor amounts are eliminated via hair and
    nails, both of which show the highest thallium concentrations of any
    tissue among human populations in uncontaminated areas (Table 19). 
    Usually mother's milk is not an important route of elimination for
    heavy metals (Hapke, 1988).  However, 2 weeks after a suicide attempt
    using thallium sulfate following the birth of her child (about 500 mg
    thallium), the milk of a mother contained 0.25 mg thallium/litre,
    while her blood only contained 0.07 mg/litre (Graben et al., 1980).

    6.4.3  Methods to estimate daily intake of thallium

         There are two ways to estimate daily intake of thallium, one
    based on total daily excretion and the other on the total amount of
    thallium in the body.  In the former case, the total amount of
    thallium excreted daily under steady-state conditions (a model which
    may be reasonably applied to long-term exposure to low doses of
    thallium) should reflect accurately the daily intake of thallium. 
    Using a mean urinary concentration of 0.4 µg/litre (which has been
    frequently reported in unexposed populations), a daily urinary
    excretion of 0.6 µg may be calculated assuming a urinary volume of
    1.5 litre per day.  Since we have assumed that renal excretion may

    account for about 70% of the total daily excretion of thallium,
    another 0.3 µg/day would be excreted by other routes, giving a value
    for total thallium daily intake of about 0.9 µg.  A similar procedure
    leads to an estimated thallium daily intake of about 11 µg in
    chronically exposed populations (using a mean urinary concentration of
    5 µg/litre).

         The other method for estimating daily intake assumes that the
    following relationship exists between the total amount of thallium in
    the body (Ab), the daily intake of thallium (Ad) and the
    elimination rate constant (K):

         Ad = KAb

         Since the total amount of thallium in the body has been estimated
    to be 100 µg per 75 kg body weight in an unexposed population (Weinig
    & Zink, 1967), a daily intake of 2.3 µg may be calculated, assuming an
    elimination rate constant of 0.023 day-1.

    6.5  Retention and turnover (biological half-life)

    6.5.1  Animals

         The biological half-life of thallium in experimental animals is 3
    to 8 days.  Accordingly, the elimination of 70 to 90% of the
    administered dose takes about 4 weeks (Oehme, 1978).

         Using different routes of administration of thallium-204 in rats,
    Lie et al. (1960) found a biological half-life of 3.3 days during the
    first 21 days or until about 1% of the administered dose remained in
    the body.  This body clearance was not affected by the route of
    administration and did not differ between various organs, except for
    the hair, which contained up to 60% of the body burden after 21 days. 
    A biological half-life of 24 h was determined in pregnant mice and
    rats (Gibson et al., 1967).

         Durbin et al. (1957) determined a biological half-life in rats of
    5.2 days and calculated half-lives of 7 and 6 days for removal from
    the kidney and muscle, respectively.  The half-lives in various organs
    (brain, spinal cord, sciatic nerve, kidney, liver and spleen) were
    lower in young rats than in adult rats and varied in different organs
    of young and adult rats.  Ducket et al. (1983) found that half-life
    values in young rats ranged from 1.2 days for the sciatic nerve to 5.1
    days for the liver (average for all tissues: 2.6 days) and in adult
    rats from 2.7 days for the brain to 6.0 days for the spleen (average:
    3.8 days).

    6.5.2  Humans

         Several investigators have reported on the half-life of thallium
    in plasma and whole blood of humans acutely poisoned. Hologgitas et
    al. (1980) reported the half-life in the blood of one patient to be
    1.9 days.  Heath et al. (1983) reported a half-life in the blood of
    one patient of 1.9 days and a range of 21-24 h for the half-life in
    blood for three patients.  Treatment for thallium toxicosis has been
    found to decrease the half-life of thallium in blood.  In a review by
    de Groot & van Heijst (1988), the half-life in blood decreased as
    follows:

    Treatment                          Thallium half-life in blood

    No treatment (n=2)                 9.5; 15 days
    Prussian Blue (PB) (n=5)           3.0 ± 0.7 days
    PB + forced dialysis (FD) (n=7)    2.0 ± 0.3 days
    PB + FD + haemoperfusion (n=3)     1.4 ± 0.3 days

         In cases of poisoning, the half-life of thallium in blood is
    found to increase somewhat with time.  Starting measurements at 42
    days after toxic ingestion of thallium, Chandler et al. (1990)
    reported a blood half-life of 3.7 days in a patient treated with PB
    and intravenous potassium.  The Gauss-Newton optimization model was
    used in this calculation.  Wainwright et al. (1988) and Schwartz et
    al. (1988) presented data showing similar half-lives for thallium in
    urine and in serum, but no quantitative analysis was performed.

         There has only been one study of the whole-body half-life of
    thallium in normal (i.e. unpoisoned) humans.  In an investigation into
    the use of radiolabelled thallium for medical imaging, Atkins et al.
    (1977) administered thallium-200 to three volunteers.  Using a
    whole-body counter, the biological half-life for thallium was found to
    be 9.8 days (range = 7.4-12.4 days).  This determination is of much
    greater value than the determinations of plasma or whole blood
    half-lives for evaluating total excretion of thallium from the body.

    6.6  Kinetics at the cellular level

         The cellular uptake of thallium has been investigated in various
    systems.  Due to the similarity in ionic radius of thallium(I) and
    potassium, thallium can substitute for potassium in a variety of
    potassium-dependent transport processes, as indicated by studies with
    microorganisms and frog skin (Norris et al., 1976; Zeiske & van
    Driessche, 1986).  In rats and dogs, data indicate that "the mechanism
    involved in the active transport of potassium cannot differentiate
    between potassium and thallium" (Gehring & Hammond, 1967)
    (section 7.11).

         The cytosol contains most of the intracellular thallium.  In
    rats, autoradiography revealed the presence of thallium in the
    cytoplasm of nervous tissues during the first few days after injection
    (Ducket et al., 1983), a phenomenon also evident in kidney, liver and
    testis homogenates of rats treated with oral or intraperitoneal doses
    of 0.00004, 2, 20, 2000 or 3150 µg thallium(I) per rat (Sabbioni et
    al., 1980a,b) and in mussels (Nolan et al., 1984).

         In a postmortem examination of a fatal case of thallium
    poisoning, 87% of the thallium was present in the cytosol (Davis et
    al., 1981) (for data on plants see section 4.1.2.3).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         The reported toxic effects of thallium are not always comparable,
    since no standardized procedure is used by the different authors and
    the duration of the experiments is not always stated.  However, the
    effective dose (ED) of thallium at which minimal adverse effects
    (LDmin) occur, or at which 50% or all organisms are killed (LD50 and
    LD100, respectively), are clearly correlated with the duration of
    the experiment.  This correlation also exists for the period of time
    at which, for example, 50% of the organisms are killed.

         The sections on single exposure (section 7.1.2), short-term
    exposure (section 7.2.2) and long-term exposure (section 7.3.2) cover
    the effects on various organs, except those on skin and eye (section
    7.4) and the nervous system (section 7.8).

    7.1  Single exposure

    7.1.1  Toxicity and symptoms

         The acute toxicity data for thallium compounds are listed in
    Table 23.  They vary considerably with observation time, e.g., a
    7-fold higher LD50 value (2000 mg/kg) for mice is obtained if the
    period of observation is reduced from 24 h to 1 h (Achenbach et al.,
    1980).

         There exist only insignificant differences in the toxicity of
    various water-soluble thallium(I) salts to mice, rats, rabbits and
    dogs.  In general, for most laboratory species and an observation
    period of 1 week, the LD50 or minimum effective dose (MED) values
    range between 20 and 60 mg/kg body weight for thallium(I) salts,
    independent of the application route, with the exception of
    guinea-pigs (5 to 15 mg/kg).  The toxicity of water-soluble thallium
    compounds is similar for oral and parenteral routes of administration,
    indicating a high degree of gastrointestinal absorption (Table 23).
    The toxicity of water-insoluble thallium(III) oxide in rats and
    rabbits is 2 to 4.5 times higher following oral administration than
    following parenteral administration (Downs et al., 1960).

         Acute toxicity is characterized by severe symptoms and/or death,
    which may be caused by single exposure or by multiple lower doses
    administered within 24 h.  These symptoms are associated with
    disorders of the digestive (vomiting, diarrhoea) and nervous system,
    inflammation at body orifices, skin furuncles, tremor, loss of hair, a
    necrotizing renal papillitis, and death by respiratory failure (BGA,
    1979; Hapke, 1984; Kazantzis, 1986; Bruère et al., 1990).


        Table 23.  Toxicity of different thallium compounds in experimental animals after single exposure
                                                                                                                                                

    Species          Thallium compound    Route of           Toxicitya     Period of              Dose               Referenceb
                                          administration                  observation       (mg/kg body weight)
                                                                                          Thallium      Thallium
                                                                                          compound      ion
                                                                                                                                                

    Mouse             (I) carbonate       subcutaneous       LDmin         14 day         18             15.7        Sanotskii (1961)
    Mouse             (I) chloride        intraperitoneal    LD50          -c             24             20.5        Luckey & Venugopal (1977)
    Mouse             (I) sulfate         oral               LD50          1 h            2470           2000        Achenbach et al. (1980)
    Mouse             (I) sulfate         oral               LD50          2 h            1358           1100
    Mouse             (I) sulfate         oral               LD50          4 h            988            800
    Mouse             (I) sulfate         oral               LD50          12 h           432            350
    Mouse             (I) sulfate         oral               LD50          24 h           370            300
    Mouse             (I) sulfate         oral               LD50          36 h           235            190
    Mouse             (I) sulfate         oral               LD50          -              30             24.3        IPS (1982)
    Mouse             (I) sulfate         intraperitoneal    LD50          10 days        47.5           38.5d       Stavinoha et al. (1959)
    Mouse             (I) sulfate         intraperitoneal    LD10          10 days        37             30

    Rat               (I) acetate         oral               LDmin         14 days        37.4           29          Downs et al. (1960)
    Rat               (I) acetate         oral               LD50          7 days         41.2           32
    Rat               (I) acetate         intraperitoneal    LDmin         14 days        25.8           20
    Rat               (I) acetate         intraperitoneal    LD50          7 days         29.6           23
    Rat               (I) nitrate         intravenous        LD50          -              16.3           12.5e       Gehring & Hammond (1967)
    Rat               (I) nitrate         intravenous        LD50          -              18.9           14.5e       Gehring & Hammond (1967)
                                                                                                                                                

    Table 23 (contd).
                                                                                                                                                

    Species          Thallium compound    Route of           Toxicitya     Period of              Dose               Referenceb
                                          administration                  observation       (mg/kg body weight)
                                                                                          Thallium      Thallium
                                                                                          compound      ion
                                                                                                                                                

    Rat               (III) oxide         oral               LDmin         14 days        22.3           20          Downs et al. (1960)
    Rat               (III) oxide         oral               LD50          7 days         43.6           39
    Rat               (III) oxide         intraperitoneal    LDmin         14 days        103            92
    Rat               (III) oxide         intraperitoneal    LD50          7 days         80.5           72
    Rat               (I) sulfate         oral               LD50          -              10-25          8.1-20.2    IPS (1982)
    Rat               (I) sulfate         dermal             LD50          7 days         500            405         IPS (1982)
    Rat               (I) sulfate         intraperitoneal    LD100         2-6 days       33.3           27          Nachman & Hartley (1975)
    Rat (R.           (I) sulfate         oral               LD50          -              15             12.1        Wegler (1970)
    norvegicus)
    Rat (R. rattus)   (I) sulfate         oral               LD50          -              76             61.5        Wegler (1970)

    Hamster           (I) malonate        oral               LD50          > 7 days       50             40          Aoyama et al. (1988)
    Hamster           (I) malonate        oral               LD100         5-7 days       62.5           50

    Rabbit            (I) acetate         oral               LDmin         14 days        24.5           19          Downs et al. (1960)
    Rabbit            (I) acetate         intravenous        LDmin         14 days        25.8           20
    Rabbit            (I) acetate         intraperitoneal    LDmin         14 days        16.8           13
    Rabbit            (III) oxide         oral               LDmin         14 days        33.5           30          Downs et al. (1960)
    Rabbit            (III) oxide         intravenous        LDmin         14 days        43.6           39
    Rabbit            (III) oxide         intraperitoneal    LDmin         14 days        67             60
                                                                                                                                                

    Table 23 (contd).
                                                                                                                                                

    Species          Thallium compound    Route of           Toxicitya     Period of              Dose               Referenceb
                                          administration                  observation       (mg/kg body weight)
                                                                                          Thallium      Thallium
                                                                                          compound      ion
                                                                                                                                                

    Guinea-pig        (I) acetate         subcutaneous       LD100         5-9 days       19.3           15          Kaeser & Lambert (1962)
    Guinea-pig        (I) acetate         oral               LDmin         14 days        15.5           12          Downs et al. (1960)
    Guinea-pig        (I) acetate         intraperitoneal    LDmin         14 days        9.0            7
    Guinea-pig        (III) oxide         oral               LDmin         14 days        5.6            5           Downs et al. (1960)
    Guinea-pig        (III) oxide         intraperitoneal    LDmin         14 days        33.5           30

    Dog               (I) acetate         oral               LDmin         14 days        25.8           20          Downs et al. (1960)
    Dog               (III) oxide         oral               LDmin         14 days        33.5           30          Downs et al. (1960)
                                                                                                                                                

    a   LDmin = minimal dose at which lethality was observed; LD10 = dose at which 10% of the animals were killed; LD50 = dose at which 50%
        of the animals were killed; LD100 = dose at which all animals were killed
    b   Selected data; detailed data summarized in Negherbon (1959), Christensen et al., (1973), Zitko (1975a, b),Smith & Carson (1977),
        Venugopal & Luckey (1978), Schoer (1984), Nessler (1985a), Manzo & Sabbioni (1988), ATSDR (1992)
    c   No data given
    d   Graphical determination based on data of authors
    e   Rats fed a low or high potassium diet. An increase in dietary potassium had a small protective effect.
    
         In rats oral administration of a toxic dose of thallium sulfate
    (10 mg thallium/kg) caused reduced food intake, diarrhoea, lethargy
    and ocular haemorrhage regardless of whether or not the animal
    survived the first 72 h (Sabbioni et al., 1982).

         Summarizing 34 cases of canine thallotoxicosis, Zook & Gilmore
    (1967) emphasized the variability of the sequence and the severity of
    symptoms, partly due to the intoxication stage.  Frequent symptoms
    were vomiting (82%), cutaneous alterations (71%), depression (62%),
    anorexia (53%), nervous disorders (47%), diarrhoea (44%), respiratory
    difficulty (44%), conjunctivitis (41%), dehydration (24%) and
    oesophageal paralysis (6%).  The sequence in which the symptoms of
    intoxication occurred was generally as follows: first anorexia,
    vomiting and depression, then skin changes, dyspnoea and nervous
    disorders.  Usually, rectal temperature was not elevated but was later
    often subnormal.  After 3 to 7 days of illness, erythematous lesions
    occurred, which were most severe near mucocutaneous junctions and on
    the foot pads.  The haematological findings were leukocytosis
    (neutrophilia, lymphopenia, eosinopenia) and haemoconcentration. 
    Proteinuria and bilirubinuria were commonly observed.  Autopsy and
    histo  pathological examination of 15 and 12 dogs, respectively,
    revealed increased heart weight (presumably caused by systemic
    hypertension), myocardial necrosis, congestion of the kidney with
    tubular nephrosis, pulmonary oedema, enlarged spleen, enlarged or
    oedematous lymph nodes, dilatation and areas of erosion of the
    oesophagus and necrosis of skeletal muscles.  Some myelinated nerves
    showed focal distensions of their myelin sheaths, and lesions of the
    cerebrum and cerebellum were evident in dogs with neurological
    disorders (Zook & Gilmore, 1967).  In addition, alopecia, anorexia,
    emesis and tenesmus (Coyle, 1980) and haematemesis (Waters et al.,
    1992) have been reported in cases of acute poisonings in dogs.

         In cats similar signs of thallium poisoning have been found,
    e.g., skin alterations, apathy, lack of appetite, vomiting and signs
    of peripheral and central neuropathy (Zook et al., 1968; Fitzek &
    Henning, 1976).  Haematological and histopathological findings were
    similar to those obtained with dogs.  In older cats that died early,
    haemorrhagic gastroenteritis and hepatic or renal damage were evident
    (Zook et al., 1968).

         Implantation of a pellet of pure thallium (3 to 5 mm diameter)
    into the motor cortex of a monkey,  Macaca mulatta, resulted in death
    within 6 days (Chusid & Kopeloff, 1962).

    7.1.2  Effects on various organs

         Effects on the various organs have been summarized by Sabbioni &
    Manzo (1980) and ATSDR (1992).  In nearly all affected organs direct
    cytotoxic effects as well as indirect effects due to damage of the
    nervous system have been found.

         In acutely poisoned rats (single subcutaneous injection of 20 to
    50 mg thallium acetate/kg), there was mild to moderate enteritis,
    including oedema of the submucosa and muscularis layers, and moderate
    to severe colitis (Herman & Bensch, 1967).  Ultra  structural
    degenerative changes in the liver were frequently present, especially
    in the mitochondria.  These were also indicated by increased numbers
    of autophagic lysosomes and lipid droplets (Herman & Bensch, 1967) and
    were evident 16 h after intraperitoneal injection of 50, 100 or 200 mg
    thallium(III) chloride/kg into rats (Woods & Fowler, 1986).  It was
    concluded that "thallium-induced alteration of hepatic functional
    processes may arise from physical disruption of the membranal
    integrity of subcellular organelles with which those processes are
    functionally associated" (Woods & Fowler, 1986).  In an extreme case
    of a poisoned dog, all the parenchymal hepatocytes were necrotic and
    the adrenals, thyroid, pituitary and pancreas had degenerated (Larson
    et al., 1939).

         The kidney is considerably affected in poisoned animals (section
    9.3.3).  Since the concentration of thallium in the kidney is higher
    than in other organs, it would seem to be a specific target organ.
    Light microscopy of rat and mouse kidney tissue up to 48 h after
    administration of lethal doses of thallium (30 to 40 mg thallium
    sulfate/kg body weight) showed stromal oedema, necrosis of the loops
    of Henle and hydropic degeneration, as well as swelling and focal
    necrosis of the epithelium of proximal convoluted tubules (Danilewicz
    et al., 1979, 1980).  Electron microscopy revealed degenerative
    changes in the epithelial cells of the glomeruli and tubules.  The
    same changes in the kidneys of acutely poisoned rats have been
    described by Herman & Bensch (1967) (section 7.1.2).

         Oral and intravenous administration of thallium sulfate (20 to
    40 mg/kg) to the dog, cat, rabbit, goat and pigeon also caused direct
    effects on the respiratory apparatus, in addition to decreasing
    vasomotor reactivity (Rossi et al., 1981).

         In  in vitro studies, addition of 30 to 50 µg thallium sulfate
    reduced the beat frequency in isolated frog hearts (Buschke &
    Jacobsohn, 1922).  Over a range of thallium concentrations, from those
    encountered after uptake from a contaminated environment (2 µg/litre)
    to those seen after suicide or homicide (and also higher levels of up
    to 204 mg/litre), the contractility of sheep interventricular cordis
    muscles exhibited three types of response, but they were not

    correlated to the thallium concentrations or period of incubation
    (Ziskoven et al., 1982).  Using guinea-pig papillary muscles and low
    concentrations (0.02 to 2 mg thallium/litre), positive inotropic
    transients were followed by an inotropic decay (Ziskoven et al.,
    1982).  In contrast, thallium produced concentration- and
    time-dependent positive inotropic effects in guinea-pig atrial
    preparations, but also inhibition of the sodium pump in ventricular
    slices (Ku et al., 1978).  However, there is no discrepancy between
    these two effects, assuming that thallium inactivates the already
    fully activated pump and stimulates the inactivated pump (Ziskoven et
    al., 1982).  The authors suggested that at low concentrations the
    effects of thallium are not associated with changes of membrane
    activity but with energy supply.  Parameters of the slow inward
    current at the membrane level were not specifically altered by
    thallium (Wiemer et al., 1982).  Another investigation involving
    guinea-pig papillary muscles and sheep Purkinje fibres indicated that
    the arrhythmogenic effects of thallium are restricted to the sinus
    node (Achenbach et al., 1982).  High concentrations (200 mg/litre)
    depolarize the muscle fibre membrane and lead to irreversible damage
    (Mullins & Moore, 1960).  Within the muscle, thallium seems to compete
    for the adsorption sites normally occupied by potassium, being
    adsorbed on to myosin and thus being localized primarily in the A band
    (Ling, 1977).

    7.2  Short-term exposure

    7.2.1  Toxicity and symptoms

         In mice the daily supplementation of food with 400 µg thallium
    acetate induced alopecia after about 14 days, followed by increasing
    apathy and death within 16 to 18 days after the beginning of the
    treatment (Buschke, 1900).

         Daily intraperitoneal injection of thallium(I) acetate (5 mg/kg)
    for 7 days in rats caused anorexia, reduced growth, irritability and
    tenderness during handling, lethargy, diarrhoea, dragging of the hind
    limbs, fits of abnormal rotation of head and neck and curving of the
    body.  About 15% of the rats died (Hasan et al., 1977c).

    7.2.2  Effects on various organs

         In subacutely poisoned rats (2 to 3 injections of 10 to 15 mg
    thallium acetate/kg at intervals of 1 week), only slight colitis and
    enlargements of mitochondrial granules in the liver occurred (Herman &
    Bensch, 1967).  Electron microscopy of the kidney revealed similar
    changes to those observed in acutely poisoned animals (section 7.1).

    7.3  Long-term exposure: chronic toxicity

    7.3.1  Toxicity and symptoms

         The chronic toxicity data on thallium compounds are listed in
    Table 24.


        Table 24.  Toxicity of different thallium compounds in experimental animals after several administrations
                                                                                                                                                

    Species    Thallium compound    Route of            Toxicitya    Period of                   Dose               Reference
                                    administration                   observation          (mg/kg body weight)
                                                                                        Thallium       Thallium
                                                                                        compound       ion
                                                                                                                                                

    Mouse      (I) chloride         intraperitoneal     LD50         30 days            1.2            0.1          Bienvenu et al. (1963)b
    Mouse      (III) chloride       intraperitoneal     LD10         30 days            6.0            4.0          Hart & Adamson (1971)b;
                                                        LD50         30 days            6.9            4.5          Adamson et al. (1975)
    Mouse      (I) nitrate          intraperitoneal     LD50         14 days            37.5           28.6         Williams et al. (1982)b

    Rat        (III) chloride       intraperitoneal     LD10         30 days            4.85           3.2          Hart & Adamson (1971)b;
                                                        LD50         30 days            5.66           3.7          Adamson et al. (1975)
    Rat        (I) sulfate          oral                LD20         15 days            1.25           1.0          Tikhova (1964)
                                                        LDmin        15 days            0.6

    Rabbit     (I) carbonate        oral                LDmin        180 days           0.25           0.2          Tikhova (1967)c
    Rabbit     (I) carbonate        subcutaneous        LDmin        180 days           0.25           0.2
    Rabbit     (I) sulfate          oral                LDmin        180 days           0.25           0.2          Tikhova (1967)c
    Rabbit     (I) sulfate          subcutaneous        LDmin        180 days           0.25           0.2
                                                                                                                                                

    a   LDmin = minimal dose at which lethality was observed; LD10 = dose at which 10% of the animals were killed; LD50 = dose at which 50%
        of the animals were killed; LD100 = dose at which all animals were killed
    b   Daily injection for 10 consecutive days 
    c   Value in winter was lower than in summer
    
         In rabbits daily administration of thallium(I) sulfate or
    carbonate (0.25 mg/kg) for 6 months caused disturbed behaviour,
    aggressiveness, diarrhoea, and loss of hair (Tikhova, 1967).  In rats
    daily ingestion of 7.5 mg thallium was lethal (Bowen, 1966).

         In a study of weanling albino rats (50-80 g) fed  ad libitum for
    1 month on a diet containing 2, 10, 50, 100, 500 or 5000 mg
    thallium(I) acetate per kg diet (5 rats/group), dietary levels of 2
    and 10 mg/kg diet caused no effects on growth and survival within the
    feeding period, whereas the other concentrations resulted in
    mortalities of 60 to 100% within 10 days.  When rats were fed for 15
    weeks with 5, 15, 30 or 50 mg thallium acetate/kg diet (5 males and 5
    females/group), the two lowest doses did not affect growth of males or
    females.  The 15 and 30 mg/kg doses caused hair loss starting after 2
    weeks, and after 15 weeks the rats were almost free of hair.  Within
    the fourth and eighth week and after intakes of 30 mg/kg diet, 80% of
    males and 60% of females died.  At 50 mg/kg all males died within 2
    weeks and all females within 8 weeks.  No specific pathological
    alterations were found in any organ.  A dose of 30 mg/kg diet resulted
    in moderate growth depression in males but not in females, while in
    both sexes increased mortality was observed.  For thallium(III) oxide
    the effective concentrations were similar, and males also reacted more
    sensitively than females.  No specific pathological alterations were
    found in any organ except the skin, where atrophy of hair follicles
    and sebaceous glands were seen at both higher dose levels.  The exact
    concentration of thallium ingested by the rats could not be determined
    but was estimated to be in the range of 1 to 3 mg thallium acetate/kg
    body weight per day for the diet containing 15 mg thallium acetate/kg
    food (Downs et al., 1960).

         US EPA (1986) conducted a 90-day study in which male and female
    Sprague-Dawley rats (20 of each sex per group) were administered
    aqueous thallium sulfate by gavage at doses of 0.01, 0.05 or
    0.25 mg/kg body weight per day.  Both untreated controls and vehicle
    (water) treated controls were included.  Clinical observations were
    recorded daily and neurotoxicological examinations were performed 3
    times per week on selected animals.  Haematological and clinical
    chemistry parameters were measured on days 0, 30 and 90, and
    ophthalmological examinations were performed on days 0 and 90.  Upon
    necropsy, selected organs were weighed.  No significant differences
    were seen in any group for body or organ weights.  Several changes
    were reported for blood chemistry parameters.  Statistics were
    reported for male and female rats at 30 and 90 days for each dose
    group compared with both untreated controls and vehicle-treated
    controls.  In both males and females, small increases were seen for

    serum glutamic-oxaloacetic transaminase, lactic acid dehydrogenase and
    sodium levels, with statistical significance at many points.  At the
    lowest dose, statistically significant changes were seen in male rats
    for all three of these parameters, but only when compared with
    untreated controls.  Higher doses resulted in statistical significance
    when compared with vehicle controls.  Similar patterns were seen in
    female rats.

         In addition, there was a dose-related increase in the incidence
    of alopecia, lacrimation and exophthalmos.  No treatment-related
    changes were seen in the eye.  Gross necropsy revealed only alopecia;
    this occurred in a dose-related manner for females and was apparent at
    the lowest dose level.  In males, alopecia was also apparent in all
    dose groups but was not strictly dose-related.

         In a study with female Sprague-Dawley rats (180-200 g), thallium
    sulfate was given via the drinking-water (10 mg thallium/litre) over a
    period of 40 weeks and with a total intake of about 80 mg thallium/rat
    (Manzo et al., 1983).  First symptoms, i.e. poor hair lustre,
    periorbital redness and irritability, were observed on days 20 to 25. 
    Hair loss first appeared after 32 days in some rats, and in several
    rats was almost complete by the end of the 36-week period of
    treatment.  However, in other rats no hair loss occurred.  Starting
    from day 40 the number of rats showing mild or severe cutaneous
    disorders increased strongly.  After 40 days and a total ingestion of
    about 10 mg thallium/rat, lethality amounted to 15%, and the surviving
    rats showed no electrophysio  logical abnormalities.  After 240 to 280
    days and the ingestion of about 70 to 80 mg/rat only an additional 6%
    of the rats died; about two-thirds of the rats showed
    electrophysiological effects and reduced motor and sensory action
    potentials.

    7.3.2  Effects on various organs

         In chronically poisoned rats (initial injection of 10 to
    20 mg/kg, followed by weekly subcutaneous injections of 5 mg/kg for 4
    to 26 weeks), only slight colitis sometimes occurred (Herman & Bensch,
    1967), but degeneration in the liver was similar to the severe effects
    in acutely poisoned rats (section 7.1.2) and liver enzymes were also
    affected (Bulavintseva & Bulavintsev, 1982).  In the stomach of rats
    the production of hydrochloric acid was reduced (Buschke, 1929). 
    Kidney weight was increased (Downs et al., 1960) and ultrastructure
    affected in the same way as in acutely poisoned animals (Herman &
    Bensch, 1967) (section 7.1.1).  The greater accumulation of thallium
    in the renal medulla than in the renal cortex of chronically poisoned
    rats indicates a firmer binding of thallium, which might impede
    thallium elimination (André et al., 1960; Lameijer & van Zwieten,
    1977a).

         Intratracheal administration of 0.5 or 5 mg thallium(I) salts
    (iodide, bromide and chloride or mixtures of them) caused dose- and
    time-dependent changes in the lungs of rats, iodide being the most
    toxic salt (Spiridonova et al., 1978).

         In chronically poisoned guinea-pigs, the adrenaline and lipoid
    contents of the adrenal glands were considerably, sometimes totally,
    reduced. Examination of chronically poisoned rats revealed a reduction
    in the size of the thyroid gland, follicular atrophy and some pycnotic
    nuclei (Buschke & Peiser, 1922a,b; Buschke, 1929).

    7.4  Skin and eye irritation

    7.4.1  Skin and hair

         Thallium intoxications in dogs caused striking effects in all
    layers of the skin.  The dermal changes were characterized by oedema
    and disruption of collagen bundles.  In erythematous patches massive
    parakeratosis (much more pronounced than in other dermatoses) and
    occasionally a granular layer were found.  In the follicles, of which
    only 60% contained hairs, the external root sheath was hyperplastic,
    showing an excess of parakeratotic horny material.  Follicular
    plugging was prominent (Schwartzman & Kirschbaum, 1962).  The progress
    of the erythematous lesions towards scaling and crusting included
    varying degrees of necrolysis and, characteristically for thallium
    intoxications, spongiform abscesses, the latter occurring also in the
    hair follicles (Schwartzman & Kirschbaum, 1962) where thallium binds
    strongly to melanin (Tjälve et al., 1982).

         The mechanism of depilation is unclear.  According to Truhaut
    (1960), this major sign of thallium intoxication, alopecia, is caused
    by its antimitotic activity, since hair follicles (and testes) are
    normally characterized by marked mitotic activity.  This adverse
    effect is prevented by glutathione and cysteine.  Counting the mitotic
    rate per hair follicle after a subcutaneous injection of 30 mg
    thallium(I) sulfate into young rats at 4 and 7 days of age, Cavanagh &
    Gregson (1978) observed an initial decline in mitotic rate followed by
    cell deaths in the matrix zone.

         On the basis of results from early experiments on mice, rats,
    guinea-pigs, cats and rabbits performed by Buschke (1900, 1903, 1911),
    Buschke & Peiser (1922b,c, 1926) and Buschke et al. (1928), the
    authors put forward the hypothesis that the depilatory effect is
    mediated by the activation of sympathetic nerves, since light
    microscopy never revealed a direct effect on the hair follicles and
    since sensory hairs, innervated by cerebrospinal nerves, were never
    affected, in contrast to the smooth muscles of other hairs which are
    innervated by the sympathetic system.

         In chronically poisoned rats (initial injection of 10 to 20 mg
    thallium acetate/kg followed by weekly subcutaneous injections of
    5 mg/kg for 4 to 26 weeks) (Herman & Bensch, 1967), black speckling of
    periorbital hairs occurred occasionally.  In other chronically
    poisoned rats (section 7.3) showing complete depilation, light
    microscopy revealed effects similar to those after acute intoxication,
    i.e. a keratinized epidermis, decrease in the size of sebaceous glands
    and reduction of the number of hair shafts and follicles, the latter
    becoming atrophic or replaced by scars, collagen or fat (Downs et al.,
    1960).

    7.4.2  Eye

         Autoradiography of adult mice demonstrated a relative
    accumulation of thallium in the lens of the eye (André et al., 1960). 
    A biochemical investigation showed that in addition to binding to
    melanin in the hair follicles, thallium also binds strongly to melanin
    in the mouse eye.  This might result in iritis and retrobulbar
    neuritis, which are regularly observed symptoms of thallium
    intoxication (Tjälve et al., 1982).

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

         Thallium affects reproduction in various ways.  Buschke & Peiser
    (1922a) found a total reduction of sexual activity in intoxicated rats
    and mice, which did not develop after administration to young animals
    (Buschke & Peiser, 1922b,c) (section 7.3).  This effect could be
    antagonized by the administration of an ovarial hormone and
    hypophyseal tissue (Buschke, 1929).  Smith & Carson (1977) also
    emphasized that sexual activity is usually lessened in chronically
    poisoned animals.

    7.5.1  Gonadotoxic effects

         Several early, contradictory reports dealt with the question of
    whether or not thallium affects ovarian function or the estrous cycle
    (Smith & Carson, 1977).  Buschke et al. (1927a) and Buschke & Berman
    (1927) described strong inhibition of the estrous cycle in mice.

         More attention has been directed to the effects on the male
    reproductive system.  Cytotoxic and perhaps mutagenic effects (section
    7.6) can affect the offspring.

         In several laboratory species, acute or repeated treatment with
    thallium(I) salts resulted in similar or even higher concentrations of
    thallium being found in the testes compared to other organs (section
    6.2), pointing perhaps to a special susceptibility (Gehring & Hammond,
    1967; Krassowski et al., 1977, 1980; Sabbioni et al., 1980a,b; Talas &

    Wellhöner, 1983; Aoyama, 1989).  However, an effect on offspring has
    not been investigated in detail.  Landauer (1930) demonstrated effects
    on chickens, but only two cocks were included.  A second
    investigation, a dominant lethal test using rats, is discussed in
    section 7.6.

         Several authors have reported histological findings.  In acutely
    poisoned rats the epithelial cells of the seminal vesicle contained
    numerous autophagic vacuoles (Herman & Bensch, 1967), and in acutely
    intoxicated rabbits and dogs spermatogenesis was inhibited (Larson et
    al., 1939; Truhaut, 1960; Zook & Gilmore, 1967).  Chronic poisoning
    caused total atrophy of testes in some rats (Buschke & Peiser,
    1922a,b,c) or considerably disturbed spermatogenesis, which, however,
    returned to normal after termination of thallium administration
    (Buschke, 1929).  A 6-month administration of thallium carbonate in
    the drinking-water of mice (0.001 mg/litre or 0.01 mg/litre) caused a
    decrease in sperm fertility at the high dose level and reduced sperm
    motility at the lower dose level (Wei, 1987).  Increased desquamation
    of spermatogenic epithelium in rats was observed after oral
    administration of 0.001 mg thallium carbonate/kg (Shabalina et al.,
    1980).  In rats treated with 10 mg thallium/litre in their
    drinking-water for 2 months, but not in those treated for only for 1
    month, there was rearrangement of the germinative epithelium,
    premature release of germinal cells into the seminiferous tubules, low
    epididymal sperm motility, the appearance of immature elements in the
    semen and a high susceptibility in the Sertoli cells (Formigli et al.,
    1985, 1986; Grégotti et al., 1985), the latter also reacting very
    sensitively in  in vitro studies (Grégotti et al., 1993).  However,
    thallium treatment did not affect the absolute or relative weight of
    the testes or the plasma levels of testosterone.  The mechanisms
    underlying the findings for thallium may involve its antimitotic
    effect or its effect on energy metabolism (Formigli et al., 1985,
    1986).  The use of thallium-201 (1-10 µCi), which is also utilized for
    diagnosis in medicine, for testicular imaging in mice caused loss of
    testicular weight and reduction in the number of sperm heads.  These
    effects were less severe when thallium-204 (1-10 µCi) was used.  This
    must have been due to the different radioisotopes (probably the
    low-energy Auger electrons of thallium-201), rather than to the
    physicochemical properties of thallium that determine uptake (Rao et
    al., 1983).

    7.5.2  Embryotoxicity and teratogenicity

    7.5.2.1  Chickens

         Injections of thallium (1 or 2 mg per egg) into the yolk sac of
    4-day-old chick embryos strongly affected growth and survival. 
    Injections of thallium sulfate (0.7 mg/egg) into the chorioallantoic
    membrane caused similar effects (Karnofsky et al., 1950; Ridgway &
    Karnofsky, 1952).

         More striking were the effects on the development of bones of the
    embryonic chick: achondroplasia, leg-bone curvature, parrot beak
    deformity and microcephaly (Karnofsky et al., 1950; Karnofsky & Lacon,
    1964).  The achondroplasia did not occur after injections of 0.2 mg
    thallium sulfate/egg into the yolk sac, but with the larger doses
    increasing percentages of the embryos showed shorter bones than
    normal, and the tibia and femora were strikingly curved.  Thallium
    sulfate and nitrate showed a similar ability to produce achondroplasia
    (Karnofsky et al., 1950).

         Achondroplasia was only produced if thallium treatment was
    performed during a critical, sensitive period (Hall, 1977, 1985). 
    This period began on day 5 of incubation and ended after 205 to 207 h
    of incubation, coinciding with a 66% decrease in growth rate of the
    embryos.  During this period thallium bound rapidly to skeletal
    tissues.  Light and electron microscopy showed the primary site of
    action to be the cartilage, maturing hypertrophic chondrocytes being
    most affected (Ford et al., 1968; Hall, 1972; Skrovina et al., 1973). 
    An increase of glucosamine and a decrease of the mucopolysaccharides
    without a simultaneous loss of collagen indicated an interference with
    cartilage metabolism (Ford et al., 1968).  According to Hall (1972),
    thallium treatment caused an "abnormal distribution of the acid
    mucopolysaccharides in otherwise normal cartilage matrix and the
    formation of necrotic areas within the maturing hypertrophic
    chondrocytes".  The reduced secretion of the acid mucopolysaccharide
    into the intercellular matrix did not affect ossification.

    7.5.2.2  Mammals

         In mammals, the results are inconsistent and there seems to be
    great variation between species and strains (Claussen et al., 1981). 
    Intraperitoneal injection in rats on days 8 to 10 (2.5 mg thallium
    sulfate/kg) or on days 12 to 14 (2.5 or 10.0 mg/kg) of gestation had
    no effect on resorption rates but significantly reduced the body
    weight of fetuses examined on day 21 of gestation.  Hydronephrosis and
    non-ossification of vertebral bodies were observed.  The effects on
    fetal body weight and vertebrae were also induced by a low potassium
    diet and were not increased by an additional dose of thallium (Gibson
    & Becker, 1970).  According to Barlow & Sullivan (1982), the increase
    in hydronephrosis may not be related to thallium.  Adverse effects on
    the cartilage of long bones in 6- and 9-day-old rats treated
    intraperitoneally with thallium sulfate were described by Nogami &
    Terashima (1973).  These results might explain the reduced growth of
    the suckling rats of thallium-intoxicated dams (Ehrhardt, 1927). 
    Ossification of rat skulls was also reduced (Buschke et al., 1927b).

         In a preliminary study on mice, oral administration of thallium
    sulfate (0.3, 1 and 8 mg thallium/kg body weight) to 3-6 pregnant SWS
    mice (gestation day 9) caused achondroplasia in 12.5, 14 and 50% of
    the offspring, respectively (Achenbach et al., 1979a,b).  Earlier
    administration of thallium induced miscarriage, while older fetuses
    were only slightly affected.  In other substrains of the SWS mice,
    administration of 10 to 20 mg/kg induced no teratological effects
    (Claussen et al., 1981).  Under similar conditions, but using 29 NMRI
    mice and oral doses of 0.8 and 8 mg thallium/kg body weight, the
    weights of fetuses and placentas were not affected by the treatment
    with thallium sulfate, but a slight, statistically non-significant
    increase in the intra-uterine mortality rate was found in embryos
    examined 18 days after fertilization.  A significantly increased rate
    of double placentas and of effusions of blood in the thigh of the
    fetuses was observed at 8 mg/kg (Török & Schmahl, 1982).  Oral
    administration of 3 or 6 mg thallium chloride or acetate per kg per
    day to NMRI mice (about 30 per group; day 6 to 15 of gestation) had no
    observable effects on skeleton or organs at day 18 of gestation
    (Claussen et al., 1981).  However, post-implantation losses were
    increased after administration of 6 mg thallium chloride/kg, but only
    young embryonic stages were affected.  Administration of 6 mg thallium
    acetate/kg caused a reduction in the weight of embryos.  In a parallel
    study with rats, 6 or 4.5 mg thallium chloride or acetate/kg was
    lethal to the dams (gestation day 6 to 15), while 3 mg/kg induced no
    embryotoxic effects but increased malformations of ribs and vertebrae
    (Claussen et al., 1981).

         Studies of mouse embryos cultured  in vitro showed that low
    levels of thallium (0.2 mg/litre) affected the pre-implantation stage
    (summarized by Formigli et al., 1985).

          In vitro cultivation of mouse limb buds (day 11 of gestation)
    in medium containing 10 mg/litre for a period of 3 days, followed by
    cultivation in normal medium for another 3 days, caused impaired
    development of the hand skeleton (Barrach & Neubert, 1985).  In a
    similar study, the extent of this effect was also increased by
    decreasing the potassium concentrations of the medium, and vice versa
    (Neubert & Bluth, 1985).  The authors suggested that an interference
    of thallium with mammalian embryonic development is possible if its
    concentration in embryonic tissues reaches levels above 2-3 mg/kg.

         When rat embryos (10.5 days after fertilization) were cultured
    for 48 h in media containing thallium sulfate (3, 10, 30 or 100 mg
    thallium/litre), embryotoxic effects were evident at all concen 
    trations.  Increasingly deleterious effects occurred on growth and on
    mesoderm and entoderm at concentrations from 10 to 100 mg/litre. 

    Whereas macroscopically no or only minor abnormalities could be
    detected, histological examination of the embryos revealed that cell
    necroses in the brain developed even at the lowest concentration.  At
    higher concentrations these effects increased, and necrosis was
    complete at 30 mg/litre.  The authors doubted whether a suggested
    embryotoxic concentration of 1 mg/litre can be achieved without severe
    maternal poisoning (Anschütz et al., 1981).

    7.5.2.3  Delayed effects on development of offspring

         Many offspring of chronically poisoned rats showing total
    alopecia died during the first two days after birth.  In the other
    pups, hair development was severely impaired (section 7.4), and these
    pups died within 4 to 5 weeks after birth.  In a second litter all
    offspring showed alopecia, but none of them died so early (Buschke,
    1911).

         In studies by Claussen et al. (1981), oral administration of 6 mg
    thallium chloride/kg to NMRI mice dams (day 6 to 15 of gestation)
    reduced the initial increase in weight of the offspring and slightly
    increased the mortality rate during the first 3 weeks.  In a parallel
    study with rats, oral administration of 3 mg thallium chloride or
    acetate per kg caused similar effects.

         In rats, exposed prenatally by treating the dams with 0.01 g
    thallium sulfate/litre in their drinking-water, gestation and weight
    of offspring were not affected, but hair development was retarded
    during the first 60 days of life.  At an age of 30 or 60 days, the
    hypotensive and hypertensive cardiovascular responses to acetylcholine
    or to isoprenaline and noradrenaline, respectively, were lower than
    the responses of control animals (Matera et al., 1986; Rossi et al.,
    1988).  Comparisons with postnatally exposed pups showed that the
    reactivity of the developing vascular autonomic nervous system was
    also lowered (Rossi et al., 1988).

         Oral doses of 0.1, 0.5 or 1.0 mg thallium/kg body weight
    (thallium sulfate) given to rats on days 6, 7, 8 and 9 of gestation
    impaired the learning ability of their adult offspring in operant
    behaviour tests.  Postnatal administration of thallium (same doses)
    had no such effect (Bornhausen & Hagen, 1984).

    7.6  Mutagenicity and related end-points

         Only two microbiological investigations have been performed;
    these indicated no mutagenic effects (Claussen et al., 1981).  Both
    used the Ames test.  Dehnen, whose unpublished data were described by
    Claussen et al. (1981), investigated the effects of thallium(I)
    acetate and used 3.1 µg-29.2 mg thallium/plate and the  Salmonella
     typhimurium strains TA98, 1535, 1537 and 1538.  Similarly, the use
    of Ames tests with thallium chloride and acetate (doses not given) and

     S. typhimurium strains TA98, 100, 1535, 1537 and 1538, with and
    without metabolic activation, indicated no mutagenic effects (Claussen
    et al., 1981).  According to these authors, no sister-chromatid
    exchange was found in bone marrow cells after oral administration of
    thallium chloride to Chinese hamsters (5 or 10 mg thallium/kg body
    weight; twice after 24 h; 8 animals per dose).

         However, thallium(I) carbonate induced sister-chromatid exchange
    and chromosomal aberrations in one cell line and hypoxanthine-guanine
    phosphoribosyl-transferase gene mutation in another cell line (Zhang,
    1988).  In studies with embryonic fibroblasts of various mouse and rat
    strains, the same thallium(I) compound (0.5 to 46.9 mg/litre) caused a
    significant increase in the single-stranded DNA fraction after
    incubation of rat fibroblasts and cells of one mouse strain (C57Bl/6),
    whereas cells of the CBA mouse strain were resistant to the same
    concentrations.  In a test of survival and mutability of vaccinia
    virus in both mouse cell lines, the CBA cells showed increased
    survival of the virus, suggesting greater efficiency of the repair
    systems (Zasukhina et al., 1980, 1983).

         In a dominant lethal test, white rat males received daily oral
    doses of 5, 50 and 500 ng thallium carbonate/kg body weight over 8
    months.  Thereafter they were mated with untreated females.  On
    gestation day 20, 18 dams were killed.  At the two higher doses there
    was a tendency towards an increase in embryonic mortality, whereas at
    the lowest dose the number of resorptions and post-implantation deaths
    were increased (Zasukhina et al., 1983).  Using these data in a
    T-test, the differences between the means for the total embryonic
    death of treated and untreated mice were statistically significantly
    different (p < 0.05).

         A mutagenic effect on sperm cells of rats was reported after oral
    administration of 0.0001 mg thallium carbonate/kg (Shabalina et al.,
    1980).  However, the report lacked detail concerning the experimental
    set-up and the Task Group considered that it could not be used for
    evaluation of the health effects of thallium.

    7.7  Carcinogenicity

         No standardized carcinogenicity studies have so far been
    performed (ATSDR, 1992).  Owing possibly to their cytotoxic effects,
    thallium salts may have a local antineoplastic effect in mice and rats
    (Hart et al., 1971; Hart & Adamson, 1971; Adamson et al., 1975).

    7.8  Neurotoxicity

    7.8.1  Central nervous system

    7.8.1.1  Histology and ultrastructure

         In the brains of subacutely poisoned rats, Herman & Bensch (1967)
    (section 7.1.2) occasionally found foci of perivascular cuffing, while
    the mesencephalon of two of the four rats contained an extensive
    region of acute necrosis.  In addition, numerous lipofuscin bodies
    were sometimes present in neuron cytoplasm.  This was also found to
    occur following chronic poisoning; electron microscopy showed effects
    on mitochondria (Herman & Bensch, 1967).

         The brain of acutely poisoned guinea-pigs (subcutaneous injection
    of 15 or 18 mg thallium sulfate/kg) showed slight microscopic
    alterations, e.g., swelling of cells and vacuolization in the
    perikaryon (Tackmann & Lehmann, 1971).  In the right parietal cortex
    of rats, microglia cells and alpha astrocytes were affected 24 h after
    an intraperitoneal injection of 40 mg/kg (Reyners et al., 1981).  At
    24 h after intraperitoneal injection of 32 mg/kg into newborn rats,
    the encephalon showed oedema and congestion; even after an additional
    50 days, there was focal destruction of neurons and irregular fibrosis
    of the capillary vessels (Barroso-Moguel et al., 1990).

         Ataxia and tremors are known to be associated with cerebellar
    lesions and both neurological disorders occur in cases of thallium
    intoxication.  Ultrastructural alterations of the cerebellum,
    especially of the mitochondria, were evident in rats after poisoning
    by daily intraperitoneal injections of thallium acetate (5 mg
    thallium/kg for 7 days) (Hasan et al., 1978a).  Effects in other brain
    regions indicate that the effects of thallium on the activity of
    endocrine glands may be mediated via changes in hypothalamic control
    (Hasan et al., 1977b).  Using identical conditions, Hasan et al.
    (1977a) observed an apparent increase in the number of
    oligodendrocytes and suggested a correlation with thallium-induced
    neuronal chromatolysis described by other authors, since the usual
    functions of oligodendrocytes are the formation of myelin and the
    nutrition of neurons.

    7.8.1.2  Electrophysiological and biochemical investigations

         In addition to the direct effects of thallium on the cardio 
    vascular and respiratory apparatus of the dog, cat, rabbit, goat and
    pigeon, indirect effects involving higher vasomotor and respiratory
    centres (but mostly dependent on a decrease in vasomotor reactivity)
    were found following acute poisoning (section 7.1.2) (Rossi et al.,
    1981).

         Extra- and intracellular recording of central neuronal activity
    in hippocampal slice preparations from guinea-pigs and rats showed
    that thallium (20 to 40 mg/litre) seems to have a predominantly
    postsynaptic effect in hippocampal slice preparations, perhaps by
    exerting an unspecific influence on the intracellular metabolic
    mechanisms of the CA1 pyramidal cells (Lohmann et al., 1989).  Daily
    intraperitoneal injections of thallium(I) acetate (4 mg/kg for 7 days)
    indicated that the electrophysiological parameters of noradrenergic
    transmission in rat cerebellum were reduced (Marwaha et al., 1980).

         The association of the corpus striatum with the pathogenesis of
    the abnormal movements that have been reported after thallium
    intoxication is shown by an increased firing rate of the caudate
    neurons of rats, 3 to 4 h after intravenous injection of 10 mg
    thallium sulfate/kg (Hasan et al., 1977c).  After daily
    intraperitoneal injections of 5 mg thallium(I) acetate/kg for 7 days
    (section 7.8.1), the protein content of the corpus striatum was
    significantly increased and the respective breakdown enzymes were
    depleted.  However, the latter did not occur in the cerebrum (Hasan et
    al., 1977b,c).

         Certain motor dysfunctions are known to be associated with a
    decrease in the level of brain dopamine, an aspect supported by the
    data of Hasan et al. (1978b).  Convulsive disorders may also be
    related to a brain deficiency of gamma-aminobutyric acid (GABA)-ergic
    mechanisms.  Data obtained by Hasan et al. (1977d), but not those by
    Nisticò et al. (1984), support this interpretation.  Neurotoxicity
    could also result from changes in the concentrations of amino acids
    and other neurotransmitters (Ali et al., 1990) or an acceleration of
    monoamine catabolism (Osorio-Rico et al., 1994).

         Further important mechanistic aspects were increases found in the
    lipid peroxidation rates and in the activity of the lysosomal enzyme
    ß-galactosidase, especially in the cerebellum, brainstem and cortex,
    after daily intraperitoneal injection of 8 mg thallium(I) acetate/kg
    for 6 days in rats (Brown et al., 1985).  Also a lower dose of 4 mg/kg
    selectively altered patterns of behaviour (section 7.8.1.3).  An
    increased deposition of lipofuscin-like pigment granules in the
    cerebellar neurons and an increase in lipid peroxidation rates in the
    cerebrum and brainstem of rats (which was even exceeded by that in the
    cerebellum) were described in a previous study (Hasan & Ali, 1981).
    This seems to be an important mechanism of toxicity (section 7.9).

    7.8.1.3  Behavioural toxicology

         Intraperitoneal injections of 10 or 20 mg thallium sulfate/kg
    produced only a slight conditioned flavour aversion in rats, perhaps
    due to the delayed onset of symptoms (Nachman & Hartley, 1975; Peele

    et al., 1986).  Oral administration induced a dose-dependent aversion
    to saccharin at all but the lowest dose of 2.5 mg/kg (Peele at al.,
    1986, 1987).  This difference might be explained by irritation of the
    gastrointestinal tract after oral uptake of thallium.

         In a detailed investigation of the effects of daily
    intraperitoneal injections of 4 or 8 mg thallium(I) acetate/kg for 6
    days on several behavioural patterns of rats, changes of behaviour
    were intensified with increased dose.  Some of the changes correlated
    with biochemical effects (section 7.8.1.2) (indicating cellular
    damage) in certain regions of the brain (Brown et al., 1985).

         In pest control campaigns against wild rodents, the dying animals
    left their hiding places and came to the surface, presumably due to
    extreme thirst and breathing disturbances (Larson et al., 1939).

    7.8.2  Peripheral nervous system

         In the final phase of lethal intoxication and  in vitro, a
    parasympathetic stimulation seems to occur.  Because thallium
    diminishes the effects of adrenaline on isolated hearts or intestine,
    even after parasympathetic blockage, it is thought that it may destroy
    adrenaline (Truhaut, 1960).

         In the initial phase of intoxication, sympathetic nerves are
    stimulated (Buschke & Peiser, 1922b).  Investigating the effects of
    0.2 to 204 mg thallium(I) and thallium(III) ions/litre on the ATPases
    of the amine-storing granules from bovine adrenal medulla and splenic
    nerves, a specific inhibition by thallium(III), but not by
    thallium(I), was observed at concentrations which might occur in the
    tissues after intoxication with thallium(I).  The authors suggested
    that thallium(I) is oxidized to thallium(III) in the organism. 
    Because the ATPase of the nerve granula which store noradrenaline was
    nearly ten-fold more sensitive than that of the adrenal medulla, which
    stores mainly adrenaline, this might explain the strongly increased
    elimination of noradrenaline (Burger & Starke, 1969).

    7.8.2.1  Histology and ultrastructure

         In the peripheral and optic nerves of acutely, subacutely and
    chronically poisoned rats (Herman & Bensch, 1967) (section 7.8.1), no
    consistent or even slight changes were revealed by light or electron
    microscopy.  However, partial atrophy of the optic nerve was found by
    Buschke et al. (1928).  In addition, acute poisoning of a dog (Greving
    & Gagel, 1928) and guinea-pigs (subcutaneous injection of 15 or 18 mg
    thallium sulfate/kg) (Tackmann & Lehmann, 1971) caused alterations of
    the axons and myelin sheaths which were evident under the light
    microscope.  In a 36-week study (Manzo et al., 1983) (section 7.3), in

    which rats were given thallium sulfate in their drinking-water (10 mg
    thallium/litre), about 50% of the animals developed Wallerian
    degeneration (myelin debris and vacuolization); lamination of the
    myelin sheath of the sciatic nerve fibres was confined to some large
    and medium-sized fibres.  Degenerative lesions found in the white
    matter of the spinal cord of poisoned rabbits may account for the
    paralysis of the hind legs (Truhaut, 1960).

         In a number of  in vitro studies, thallium affected nerves,
    e.g., cell outgrowth was inhibited (Sharma & Obersteiner, 1981;
    Windebank, 1986) or the myelin sheath disintegrated (Peterson &
    Murray, 1965).

    7.8.2.2  Electrophysiological and biochemical investigations

         Following a subcutaneous injection of 15 mg thallium sulfate/kg
    to guinea-pigs, within days the larger and faster conducting nerve
    fibres degenerated before the slower fibres and became inexcitable
    (Kaeser & Lambert, 1962; Tackmann & Lehmann, 1971). In a subchronic
    study (section 7.3) on rats, which received thallium sulfate via their
    drinking-water (10 mg thallium/litre), the motor and sensory action
    potential amplitudes were unaffected after 40 days of poisoning but
    decreased after 240 days (Manzo et al., 1983).  Then the motor action
    potential latency was increased, and no fibrillation activity was
    observed in the tibialis anterior muscle.

         Neuromuscular transmission in thallium-treated rats and mice has
    been investigated in detail using phrenic nerve-diaphragm preparations
    (Wiegand et al., 1983, 1984a, 1986).  The relationship between
    thallium concentration (z, in mM) and duration of paral  ysis (y, in
    minutes) is approximated by the equation y = 4.6 × e8.4z (Csicsaky &
    Wiegand, 1981).  It has been suggested that thallium interferes
    presynaptically with spontaneous transmitter release by antagonizing
    these calcium-dependent processes, rather than by interfering with the
    presynaptic influx of calcium ions (Wiegand et al., 1983, 1984a,b;
    Wiegand, 1988).  Additional data indicate that thallium, like other
    heavy metals (Cooper et al., 1984), irreversibly blocks phasic
    transmitter release, while spontaneous transmitter release is
    reversibly enhanced (Wiegand et al., 1986; Csicsaky et al., 1988). 
    The sequence of the toxic effects indicate that thallium needs to be
    transported across the cell membrane before it can finally interfere
    with the release mechanisms.  This rather indirect mode of action of
    thallium was also found in the recordings of presynaptic ion currents.

         Perineural recording techniques and the blocking of potassium
    channels excluded the possibility that presynaptic potassium or
    calcium channels were influenced by thallium in acute superfusion
    experiments.  Thus, the mechanisms that cause enhancement of the
    spontaneous release of acetylcholine and the reduction of phasic
    transmitter release at the neuromuscular junction, both of which are
    induced by thallium, remain unknown at present (Wiegand et al., 1990).

    7.9  In vitro test systems: cell lines

         Ultrastructural studies with cultured fetal mouse heart cells
    showed swollen mitochondria with loss of cristae, disintegration of
    the membrane system, and a protective effect of selenium (Liu, 1986)
    (section 7.10.2).

         A cytotoxic effect on ovary cells was observed in  in vitro
    experiments on Chinese hamster ovary cells.  After a 16-h incubation
    with thallium(I) nitrate (40 mg/litre), 50% of the cells did not form
    colonies during the following 7 days (section 7.9) (Hsie et al., 1984;
    Tan et al., 1984).

         Using three mammalian cell lines (human diploid embryonic
    fibroblasts, HeLa cells and mouse fibroblasts) to test 11 heavy
    metals, thallium was found to belong to the group of metals with a
    strong inhibitory (on proliferation) or lethal effect.  After
    treatment for 7 days, the minimal inhibitory concentrations of
    thallium(I) and thallium(III) for all three cell lines were 4 mg/litre
    and 2 mg/litre, respectively, while the 50% inhibitory concen 
    trations were 10-15 mg/litre and 5-15 mg/litre, respectively.  Half of
    the cells were killed by 20-40 mg/litre (Fischer, 1981).

    7.10  Factors modifying toxicity

    7.10.1  Enhancement of elimination

         Various substances have been evaluated for their ability to
    enhance faecal or renal elimination of thallium (e.g., Lund, 1956b). 
    In rats, potent diuretic agents such as furosemide and ethacrynic acid
    increased renal elimination of thallium, but did not further increase
    the elimination induced by feeding a potassium-rich diet (Lameijer &
    van Zwieten, 1977a,b).  A sodium-rich diet did not promote the renal
    elimination of thallium (Lameijer & van Zwieten, 1979).  In rats, oral
    application of activated charcoal increased faecal elimination by
    about 80% but did not affect urinary elimination (e.g., Lund, 1956b). 
    In contrast, potassium chloride and cystine only increased renal
    elimination by 47% and 60%, respectively.  Meyer & Tal (1957) reported
    that some compounds containing sulfur and labile methyl groups seem to
    reduce the toxicity of thallium in rats.

         Dithizone (diphenylthiocarbazone), which forms a firm complex
    with thallium, increased faecal elimination by 33% and urinary
    elimination by 75% in rats (Lund, 1956b).  After treatment with
    diethyldithiocarbamate "dithiocarb", the resulting lipophilic
    thallium(I) chelate readily passed the blood-brain barrier and was

    rapidly decomposed in the brain (Kamerbeek et al., 1971a).  However,
    it did not protect animals from death after administration of lethal
    doses of thallium (Danilewicz et al., 1980).  The benefit of other
    agents, such as the diuretic 2,3-dimercapto-succinic acid (Liang et
    al., 1980) or other compounds with mercapto groups (Oehme, 1972), has
    still to be proven in the treatment of thallotoxicosis.

         Comparing different antidotal treatments in rats, Lehmann &
    Favari (1985) found an increase in thallium elimination to 99% by
    dithizone, 93% by activated charcoal, 64% by the diuretic agent
    furosemide, 82% by Prussian Blue, and 92% by combining Prussian Blue
    and furosemide, whereas the untreated controls had only eliminated 53%
    of the administered dose (2 mg) within 8 days.  After treatment with
    Prussian Blue and D-penicillamine in combination, the dangerous
    redistribution of D-penicillamine did not occur and elimination of
    thallium was better than after administration of Prussian Blue alone
    (Rios & Monroy-Noyola, 1992).  The efficiency of Prussian Blue could
    be increased by synthesizing batches with a smaller crystal size (Rios
    et al., 1991; Kravzov et al., 1993).  New compounds, such as rhyolith,
     N-acetylcysteine and dimercaprol, were no more, or even less,
    effective (Dvorák, 1973; Henderson et al., 1985).

    7.10.2  Selenium

         Selenium not only protected isolated fetal hearts against damage
    by thallium (section 7.9), but also decreased its lethal effect in
    young rats; however, thallium-induced hair-loss was not prevented
    (Ewan, 1978; Ostádalová & Babicky, 1987).  Thallium inhibited
    pulmonary elimination of volatile selenium compounds, increased the
    retention of selenium in kidneys and liver, and did not protect
    against chronic selenosis (Levander & Argrett, 1969).  Thallium did
    not affect the distribution of selenium in the body of mice; in
     in vitro systems it seemed to interact with selenite in glutathione
    solution and in erythrocytes (Naganuma et al., 1983).

    7.11  Mechanisms of toxicity - mode of action

         Although several (perhaps interconnected) mechanisms have often
    been postulated, the exact mechanism of thallium toxicity is still
    unknown (Cavanagh et al., 1974; Prick, 1979; Sabbioni & Manzo, 1980;
    Nessler & Briese, 1985; Chandler & Scott, 1986; Cavanagh, 1988).

         Conflicting results have been obtained with respect to the
    effects of thallium on sodium/potassium ATPase activity  in vitro
    (stimulation) (Ivashchenko & Balmukhanov, 1974) and  in vivo
    (inhibition) (Mourelle et al., 1988).  The irreversible inhibition of
    the unidirectional transport of sodium may be due to an inhibition of
    transport energy (Skulskii & Lapin, 1983).  The affinity of the
    thallium ion for the sodium/potassium ATPase is 9-10 times greater
    than that of the potassium ion (Britten & Blank, 1968; Inturrisi,

    1969).  Since the thallium permeability of biological membranes is
    usually 10 to 100 times greater than that of potassium and since a
    similar activation of membrane sodium/potassium ATPase in human
    erythrocytes and rat liver cells is caused by thallium concentrations
    that are ten times lower than those of potassium and higher
    concentrations of ouabain are needed to inhibit thallium-activated
    ATPase, a high selectivity of thallium(I) ions for potassium transport
    pathways exists (Skulskii et al., 1973, 1975; Gutknecht, 1983; Favari
    & Mourelle, 1985; Zeiske & van Driessche, 1986).  However,  in vitro
    studies must take into account the fact that concentrations of only
    0.01 g thallium/litre are likely to occur in cells after lethal
    poisoning with 10 mg/kg body weight, assuming uniform distribution and
    no elimination (Burger & Starke, 1969).

         Owing to the similarity in ionic radii of potassium and thallium,
    and since the affinity of the thallium ion for sodium/potassium ATPase
    is greater than that of the potassium ion, thallium accumulates within
    the cell at the expense of potassium.  The strong interaction of
    thallium with sites normally occupied by potassium may block cycles
    that depend on recurrent potassium translocation (Sabbioni & Manzo,
    1980).

         Once inside the cell, various mechanisms are evident, e.g.,
    effects on other enzymes (Sabbioni & Manzo, 1980), the inhibition of
    protein synthesis (Hultin & Näslund, 1974), the antimitotic effect of
    thallium compounds (section 7.9) (Sabbioni & Manzo, 1980), especially
    in the testes (sections 7.5 and 8.5.1), and/or the involvement of
    riboflavin vitamin B12, which is coenzyme to a number of enzymes
    (Emsley, 1978; Nessler & Briese, 1985).  Any effect on riboflavin or
    on enzymes containing sulfhydryl groups (see below) should result in a
    disturbance of pyruvate metabolism (summarized by Nessler & Briese,
    1985).  Experimental animals suffering from riboflavin deficiency show
    symptoms similar to those of thallium intoxication (Schoental &
    Cavanagh, 1977).

         Another postulated mechanism considers the general capacity of
    thallium to react with thiol groups, thus interfering with a variety
    of processes (Zeiske & van Driessche, 1986).  Although the toxic
    effect of thallium is reduced by diets high in cystine, methionine and
    betaine (Oehme, 1972), interference with the metabolism of
    sulfur-containing amino acids does not seem to be directly involved in
    toxicity (Garcia Bugarin et al., 1989) and strong reactions with
    thiols were observed for thallium(III) but not for thallium(I)
    compounds (Douglas et al., 1990).  An additional aspect of the
    reaction of thallium with sulfhydryl groups is the induction of free
    radical formation (section 7.8).  This is indicated by increased lipid
    peroxidation rates in the brain.  Processes leading to lipid
    peroxidation finally damage cell membranes by subsequent reactions of

    free radicals with sulfhydryl enzymes (section 7.11).  Lipid
    peroxidation results in a deficiency of glutathione and leads to the
    accumulation of lipid peroxides in the brain, liver and kidney and,
    presumably, finally to lipofuscin granules (Herman & Bensch, 1967;
    Aoyama et al., 1988).  The possibility that this mechanism is
    responsible for the neurotoxic effects of thallium was supported by
    the simultaneous administration of thallium and acetyl-homocysteine
    thiolactone, which prevented reduction in the level of sulfhydryl
    radicals in the cerebellum and significantly increased glutathione
    levels (Hasan & Haider, 1989).  This hypothesis is further supported
    by the protective effect of 1) silymarin against thallium hepato 
    toxicity (Mourelle et al., 1988), 2) selenium, demonstrated with the
    thallium-induced ultrastructural changes found in isolated fetal mouse
    heart cell (sections 7.9 and 7.10.2.) (Liu, 1986), and 3) selenium and
    vitamin E against membrane damage by uncontrolled lipid peroxidation
     in vivo (Hasan & Ali, 1981).

         The mode of action of thallium seems to be mainly based on a
    disturbance in the function of the mitochondria (Barckow & Jenss,
    1976), although they are affected by high concentrations of almost all
    heavy metals (Byczkowski & Sorenson, 1984).  The thallium(I) cation
    may either enter isolated rat liver mitochondria passively, i.e. in an
    energy-independent manner (Barrera & Gómez-Puyou, 1975), or penetrate
    the mitochondrial membrane electrophoreti  cally (Skulskii et al.,
    1978).  The entry of thallium into the intramitochondrial space and
    the interaction of cytosolic thallium with mitochondria membranes may
    explain the deleterious effects (Skulskii et al., 1984).  In isolated
    mitochondria, thallium(I) acetate caused an uncoupling of oxidative
    phosphorylation and swelling of the isolated mitochondria (Melnick et
    al., 1976).  Using ascite tumour cells  in vitro, Ivashchenko et al.
    (1973) found a strong, thallium-induced increase in oxygen consumption
    and lactic acid production, which were inhibited by ouabain and sodium
    fluoride.  However, whereas oxygen consumption and anaerobic
    glycolysis of tissues were affected  in vitro, tissues from rats with
    chronic or acute (first day) poisoning did not differ from those of
    controls (Thyresson, 1950).

         Comparing the effects of monovalent and trivalent thallium on
    isolated rat liver mitochondria, only thallium(III) nitrate uncoupled
    oxidation from phosphorylation (Hollunger, 1960).  This effect could
    not be reversed by adding edetic acid or dimercaprol (sections 7.10.1
    and 8.6).

    8.  EFFECTS ON HUMANS

         The toxicology of thallium is summarized in Fig. 1.

    8.1  General population exposure

         Thallium concentration in early-morning urine samples of nine
    non-exposed subjects ranged from 0.13 to 1.69 µg/litre (Weinig & Zink,
    1967).  Smith & Carson (1977) gave a range of 0.6 to 2.0 µg/litre with
    a mean urinary thallium concentration of 1.3 µg/litre.

         The initial use of thallium in medicine, mainly as a depilatory
    drug, caused many cases of intoxication.  The observation of side
    effects led to more detailed toxicological studies after 1918, and its
    medical use was abandoned after 1945 (Emsley, 1978; Briese & Nessler,
    1985a).  Since thallium is tasteless, odourless, without colour and
    highly toxic, and used to be easily obtainable, it was often used for
    suicide, homicide and attempts at illegal abortion (Kemper & Bertram,
    1984; Manzo & Sabbioni, 1988).  Also large numbers of accidental
    intoxications have occurred, e.g., in Berlin, Germany there were 110
    cases of accidental ingestion and 39 attempted suicides by children
    involving corn poisoned with thallium sulfate from 1967 to 1976; three
    of the children died (von Mühlendahl et al., 1978).  Munch (1934b)
    summarized thallium intoxications prior to 1934.  He found reports on
    8006 children who had been treated with thallium as a depilatory
    agent.  Intoxication occurred in 447 cases and 8 children died.  In
    connection with its use as a rodenticide or insecticide, 21 poisonings
    and 5 deaths occurred.

         Recently, intoxications occurred after ingestion of a Chinese
    herbal medication/nutritional supplement containing 30 g thallium per
    litre, but other samples contained no thallium (Schaumburg et al.,
    1992).

    8.1.1  Acute toxicity

         Cases of acute intoxication by thallium salts in humans, which
    always cause severe symptoms, have been reported for single or
    multiple oral doses of the order of 100 mg or more for adults, i.e.
    1.5 to 2 mg/kg body weight (Table 25).

         Symptoms of acute thallium toxicity vary with age, dose and route
    of administration (Venugopal & Luckey, 1978).  According to Sharma et
    al. (1986), one-tenth (2-10 mg/person) of the lethal thallium dose for
    adults causes death in children. However, reports of the therapeutic
    use of thallium in which children tolerated larger doses than adults
    indicate the contrary (Ormerod, 1928; Sessions & Goren, 1947; Prick,
    1979).  Of 75 children who had accidentally ingested thallium sulfate,

    FIGURE 1

    only two showed symptoms of thallium intoxication: a 2-year-old child
    who had ingested 3.5 mg thallium/kg and eliminated 130 µg
    thallium/litre in the urine showed no reflex movements of the legs in
    the second week, while another child with 3.9 mg thallium/litre in its
    urine and 40 µg/litre in its blood showed no neurological symptoms
    apart from a massive alopecia in the second week.  In one of two
    lethal cases, the urine contained 10.3 mg/litre, and the death of both
    children occurred within 2 days (von Mühlendahl et al., 1978).  The
    influence of age is unclear, but this may be due to the reporting of
    doses either as total dose or as mg/kg body weight.  Therapeutic uses
    of thallium in the 1930s (8 mg/kg) resulted in peripheral neuritis in
    about 10% of the patients (Cavanagh, 1979).

        Table 25.  Acute toxicity of thallium
                                                                                         

    Toxicitya     Dose                    Adult/children    Reference
                                                                                         

    TT            > 1.5 mg/kg             not specified     Schoer (1984)

    MLD           10-12 mg/kg             adult             Kazantzis (1994)
                  2-10 mg/kg              children

    MLD           14-18 mg/kg             not specified     Sessions & Goren (1947)

    Lethality     20-100 mg per person    adult             Sharma et al. (1986)
                  2-10 mg per person      children
                                                                                         

    a   MLD = minimal lethal dose; TT = toxicity threshold
    
         In adults lethal doses vary between 6 and 40 mg/kg (500 to
    3000 mg/person), with an average dose of 10-15 mg/kg body weight
    (Schoer, 1984).  Without therapy the average dose usually results in
    death within 10-12 days (Kemper, 1979), but, summarizing 150 mostly
    suicidal cases of thallium intoxication, most of the patients who had
    ingested about 600 mg and had no gastric lavage within the initial 2 h
    died within 8-10 h (Potes-Gutierrez & Del Real, 1966). After
    accidental ingestion of 10-fold overdoses of thallium acetate
    (80 mg/kg), given as a depilatory in ringworm disease (Tinea), four
    children died after 1-2 days (Lynch et al., 1930).  Sessions & Goren
    (1947) had previously suggested 14 to 18 mg thallium/kg body weight to
    be the minimal fatal dose.

         The triad of gastroenteritis, polyneuropathy and alopecia is
    regarded as the classic syndrome of thallium poisoning (Gastel, 1978),
    but in some cases gastroenteritis and alopecia are not observed. 
    Other symptoms also develop in varying sequence.  Both lethal and
    sublethal doses give rise to most of the symptoms, but these same
    symptoms vary in intensity and time, probably in a dose-dependent way. 
    The following general trends have been summarized from numerous
    reviews and case reports, e.g., Muller (1961), Moeschlin (1965, 1986),
    Potes-Gutierrez & Del Real (1966), Venugopal & Luckey (1978), Gastel
    (1978), Möllhoff et al. (1979), Sabbioni & Manzo (1980), Davis et al.
    (1981), Saddique & Peterson (1983), Kemper & Bertram (1984), Le Quesne
    (1984), Schoer (1984), Ohnesorge (1985), Nessler & Briese (1985),
    Chandler & Scott (1986), Arnold (1986), Hayes & Laws (1991) and ATSDR
    (1992).

         People who died within 8-10 h showed increasing tachycardia,
    progressive hypotension, early hyporeflexia and peripheral cyanosis. 
    The ingestion of lower lethal doses causes gastrointestinal
    haemorrhages (blood in faeces), gastroenteritis, metallic taste,
    salivation, nausea and vomiting.  Neurological disorders become
    apparent within 2-5 days irrespective of the route of administration. 
    Within 5-7 days hallucination, lethargy, delirium, convulsions, a
    tingling pain in the extremities and muscular weakness are followed by
    coma.  The cause of death is respiratory failure or cardiac arrest.

         The sequence of symptoms in less severe intoxications is outlined
    in Fig. 2.  Similar clinical symptoms develop after ingestion of
    lethal doses, which are promptly treated by enhancing elimination
    (Graben et al., 1978).  Within hours after ingestion, thallium often
    induces nausea or vomiting, which may also appear in the next 2 days. 
    Other initial symptoms, e.g., diarrhoea, abdominal pain and a dull
    feeling in body extremities, occasionally occur.  Constipation is
    common and may be difficult to treat, thus interfering with antidotal
    treatment with Prussian Blue (section 8.1).  Starting at day 4, a dark
    region, resembling melanin pigment, may appear in the hair roots (this
    could be of diagnostic value).

         Following this latent period, in the early phase lasting about 1
    week, some of the typical thallium disorders slowly develop
    (culminating in the third or fourth week).  Firstly, retrosternal and
    abdominal colic-like pains, as well as pain and tenderness in the
    legs, often become prominent.  Excessive thirst, sleeplessness,
    restlessness, hysteriform behaviour and electro-encephalographic
    abnormalities indicate involvement of the central nervous system.  A
    characteristic symptom of sensory neuropathy is the extreme
    sensitivity of the lower extremities.  The neurological syndrome can
    also include optic neuritis, numbness of fingers and toes with loss of
    sensation to pin-prick and touch, and the "burning feet syndrome".  As
    an additional sign of a mixed sensory-motor neuropathy, ankle reflexes

    are lost early, while other reflexes may be maintained for a time or
    even increased.  During this phase, thallium intoxication can mimic a
    systemic lupus erythematosus or a pseudobulbar paralysis
    (Guillain-Barré syndrome or Landry's ascending paralysis) (Gastel,
    1978; Alarcón-Segovia et al., 1989; Cavanagh, 1991).  The renal
    function is generally not affected in the early course of poisoning;
    only a slight albuminuria with formed elements in the urine may be
    found.  Urinary elimination of porphyrins and porphyrin precursors may
    be greatly increased during this early phase (Merguet et al., 1969;
    Paulson et al., 1972; Bank et al., 1972; Graben et al., 1978).

         During the second week hypertension and tachycardia are
    frequently observed symptoms (Romero Romero et al., 1989).  Sometimes
    peroneal paralysis and atrophy of other muscles may develop.  After a
    short phase of perspiration, the skin becomes dry and scaly (probably
    due to an effect on the sweat and sebaceous glands) and sometimes
    necrotic.  Damage to hair papillae seems to be responsible for loss of
    head hair.  This frequently begins during the second week.  Complete
    depilation occurs within about one month and regrowth begins some time
    later, often without any pigment.

         About 3 to 4 weeks after poisoning, dystrophy of the nails is
    shown by the appearance of white lunular stripes (Mees's stripes),
    which are also observed in cases of arsenic poisoning (Buschke &
    Langer, 1927; Greving & Gagel, 1928).

         After 4 to 5 weeks, survival of the patient is likely, but
    recovery requires months.  Sometimes neurological and mental
    disturbances, as well as electro-encephalographic abnormalities and,
    rarely, forms of paranoia, persist.  Occasionally, cataract (opacity
    of the eye lens) has been described.  In children a high percentage of
    the neurological disorders were still present after 4 years.  Double
    optic atrophy in one patient after 3 months was reported (Munch,
    1934).

    8.1.2  Effects of long-term exposure: chronic toxicity

         Studies of long-term exposure to thallium resulting in chronic
    poisoning have been summarized by Buschke & Langer (1927), Moeschlin
    (1965), Gefel et al. (1970), Schoer (1984) and Goldblatt (1989)
    without any information about doses.  The symptoms show strong
    variation and are in general milder than in cases of acute
    intoxication.  Depending on the level of exposure, a relatively long
    latent period (several weeks) may be followed by just a few symptoms. 
    Peripheral sensorial disturbances, mental aberrations, loss of weight
    and sleeplessness seem to be the most common (Valentin et al., 1971;
    Sabbioni & Manzo, 1980; Nessler, 1985b).  In more severe cases,
    disturbances of vision, pain without marked polyneuritis, and loss of 

    FIGURE 2

    hair were reported.  Later, severe polyneuritis may develop, with an
    inability to walk, amaurosis (blindness) and pronounced cachexia. 
    Cardiac disorders include hypertension, irregular pulse and
    angina-like pain.  Renal dysfunction is indicated by albuminuria and
    haematuria.  Other symptoms are gastric anacidity, lack of appetite,
    loss of weight, endocrine disorders, psychoses and encephalitis.

         Complete rehabilitation takes months and can be interrupted by
    relapses, probably caused by remobilization of thallium from tissue
    depots.

         Epidemiological studies carried out in the contaminated area of
    Lengerich, Germany, comprising about 1200 people, revealed positive
    correlations between the concentration of thallium found in urine or
    hair samples and polyneuritic symptoms such as paraesthesias and pain
    in muscles and joints, as well as psychasthenic symptoms such as
    headache, sleep disorders and fatigue.  No correlation was found with
    respect to gastrointestinal troubles or skin disorders.  Surprisingly,
    a negative correlation with hair loss was found.  Only one of 51
    people with > 20 µg thallium/litre urine showed lunular stripes in
    the nails (LIS, 1980; Brockhaus et al., 1980, 1981b; Dolgner &
    Wiegand, 1982; Schoer, 1984).  Strong individual variation in
    sensitivity prevents an estimation of the thallium concentration in
    the urine at which no effects occur (Dolgner & Wiegand, 1982).

    8.2  Occupational exposure

         There have been numerous reports of factory workers with thallium
    poisoning, but no fatal cases have occurred.  Peripheral sensorial
    disturbances, mental changes, loss of weight, and sleeplessness are
    the symptoms which seem to prevail (Munch, 1934b; Muller, 1961;
    Malcolm, 1979; Saddique & Peterson, 1983; Triebig & Büttner, 1983;
    Schoer, 1984; Nessler, 1985b; Junghans & Nessler, 1985; Ohnesorge,
    1985; Kazantzis, 1986).  In Germany, the United Kingdom and some other
    countries, thallium poisoning represents an occupational disease
    entitling the victim to compensation.  In Germany, such compensation
    was granted in three cases between 1970 and 1985 (Ewers, 1988).

         Increased thallium concentrations in the urine of workers have
    often been found.  For example, the urine of workers in a company
    producing alloy anode plates for use in magnesium sea water batteries
    contained up to 236 µg thallium/litre, but no differences in medical
    records of exposed and unexposed workers could be demonstrated
    (Marcus, 1985).  In his review of thallium, Ohnesorge (1985)
    summarized several reports of industrial poisoning.  Exposure over
    several months or years resulted in typical thallium symptoms, e.g.,
    leg pains, tiredness, alopecia and psychological disorders, but also

    (in one case) blindness.  Permanent blindness was also reported in
    another review by McDonald (1941).  Exposure to more than 0.01 mg
    thallium/m3 for 16 to 17 years caused disorders of the vascular
    system, as well as neurological symptoms (Ohnesorge, 1985).  From the
    triad of gastroenteritis, polyneuropathy and alopecia, only disorders
    of the gastrointestinal tract were not reported.

         Glomme (1983) emphasized that objective symptoms of polyneuritis
    may not be demonstrable for some time.  In addition to the changes in
    the superficially provoked tendon reflexes, a pronounced weakness and
    a fall-off in the speed of pupillary reflexes can occur.

         In a further study on cement plant workers, 36, selected at
    random, were subjected to thallium analyses of blood, urine and hair,
    together with a neurological examination and electrophysiological
    investigation including sensory and motor nerve conductive velocities,
    evoked potentials and electro-encephalography (Ludolph et al., 1986). 
    One half of the workers examined suffered from concurrent disorders,
    including diabetes mellitus.  Although multiple symptoms and signs of
    neurological disorders were detected, no correlation was found between
    the electrophysiological findings and thallium levels in blood, urine
    and hair.  Urinary thallium levels were above 5 µg/litre in five of
    the examined workers.  Blood thallium levels above 2 µg/litre were
    found in 16 workers and hair thallium levels above 20 µg/kg in four
    workers.  The investigators concluded that more thorough
    epidemiological techniques would be required to reveal a possible
    causal relationship between chronic low-dose thallium exposure and
    neurological deficits.

    8.3  Subpopulations at special risk

         There are no subpopulations at special risk of thallium
    intoxication except workers in the respective industries and
    populations living in thallium-contaminated areas.  There are no good
    data to suggest that infants or pregnant women are more sensitive to
    the effects of thallium than the general population.  The available
    data, however, are inadequate to fully assess these subpopulations. 
    Because thallium is eliminated in both urine and faeces, any
    subpopulations with diminished excretory capabilities (e.g., renal
    insufficiency) may be at increased risk of thallium poisoning.  It has
    been recommended that workers be excluded from working with thallium
    if they suffer from renal or hepatic disease, anaemia, blood
    dyscrasias, hypertension, alcoholism, chronic infections or endocrine
    gland dysfunction.  It has also been recommended that workers
    potentially exposed to thallium should be encouraged to eat
    potassium-rich food, as thallium and potassium ions can mimic each
    other  in vivo.  Accordingly, potassium-deficient individuals may
    also be at increased risk from thallium toxicity.

    8.4  Target organs in intoxicated humans: pathomorphology and
         pathophysiology

         Effects on the different organs have been summarized by Prick
    (1979), Sabbioni & Manzo (1980) and ATSDR (1992).  In nearly all
    affected organs direct cytotoxic effects, as well as indirect effects,
    caused by damage to the nervous system, have been found (Prick, 1979).

    8.4.1  Gastrointestinal tract and renal system

         In a fatal case of thallium poisoning, in which the woman died
    after at least 14 days, there was gross dilatation of the stomach and
    a thin "blue line" was evident at the margin of the gingiva of the
    lower incisors, but no alterations of the intestinal wall were
    apparent (Curry et al., 1969). Other patients who died 1 to 16 days
    after oral poisoning showed hyperaemia, congestion of the gut,
    punctate haemorrhages in the mucosa of the stomach and upper
    intestinal tract, and swelling of the mucosal cells (Lynch et al.,
    1930; Munch et al., 1933; Heath et al., 1983).  As a result of
    depilatory treatment in children, gastric hypoacidity was reported
    (Buschke, 1929), an effect also observed after a suicide attempt
    (Greving & Gagel, 1928).

         In several cases of oral poisoning, usually fatal, the liver was
    usually found to be congested, greyish yellow or yellow in colour, had
    microscopic fatty infiltrations of the hepatocytes and a tendency to
    central necrosis (Lynch et al., 1930; Munch et al., 1933; Curry et
    al., 1969).

         At least 6 weeks after intoxication, renal biopsy of a patient
    with 13.8 mg thallium/litre in his urine showed diffuse proliferative
    glomerulonephritis with granular immunofluorescence for IgG, IgM and
    C3 (Alarcón-Segovia et al., 1989).  In the postmortem examinations by
    Lynch et al. (1930), Munch et al. (1933) and Curry et al. (1969),
    sections of kidney were dull red or congested and showed marked
    hyperaemia, cloudy swelling of tubules and degenerative changes of
    glomeruli.  Weinig & Schmidt (1966) also reported kidney damage (but
    perhaps from a previous attempt at poisoning) in a woman and her son
    who died after taking thallium.  This kidney damage may have been
    responsible for the relatively low thallium concentrations in the
    son's kidney in comparison to concentrations in other tissues (section
    6.2.2).

    8.4.2  Cardiovascular system

         Accidental poisoning of three children, who died within two days,
    caused fatty degenerations in the victims' hearts.  These were more
    marked and more dispersed in the youngest child, who survived longest
    (Lynch et al., 1930).  In some cases of postmortem-diagnosed thallium
    poisoning, resulting in death within 4-14 days, fresh haemorrhagic
    myocardial lesions were found (Heath et al., 1983; Andersen, 1984),

    while in another case only a few focal haemorrhages were present
    (Curry et al., 1969).  Haematological changes, e.g., anaemia,
    leucocytosis, eosinophilia, thrombocytopenia (at least partly
    resulting from a toxic effect on bone marrow) and lymphopenia, have
    been summarized by Saddique & Peterson (1983) and Luckit et al.
    (1990).

         In five patients suffering from severe and protracted thallium
    poisoning, cardiovascular changes were recorded (Machtey & Bandmann,
    1961; Franke et al., 1979). The patients' blood pressure showed marked
    fluctuations, even in the course of one day, but systolic and
    diastolic hypertension occurred only on a temporary basis.  The
    authors believed that these changes and also the observed tachycardia
    and electro-cardiographic changes were caused by direct effects of
    thallium on the autonomic nervous system.  Tachycardia can appear
    about a week after intoxication and last for 5 weeks (Franke et al.,
    1979).  Involvement of the autonomic nervous system is also indicated
    by changes in renal function and by the urinary concentrations of
    various metabolites (brenzcatecholamines, vanillin-mandelic acid,
    ß-aminolaevulinic acid, porphobilinogen, coproporphyrin and total
    porphyrins) during hypertension and tachycardia resulting from
    thallium poisoning (Bock et al., 1968).  Concentrations of
    brenzcatechinamines and porphobilinogen were greatly increased, and
    hypertension and tachycardia could be influenced by administration of
    alpha- and ß-receptor blockers.  In addition, increased elimination of
    brenzcatecholamines, which presumably originate not only from the
    adrenal medulla but also from the sympathetic nervous system,
    indicates a strong stimulation of the adrenergic system (Bock et al.,
    1968).

    8.4.3  Skin and hair

         Five young men suffering from thallium poisoning showed
    follicular plugging of the skin on the nose and cheeks and in the
    nasolabial folds by keratinous material, crusted eczematous lesions
    and acneiform eruptions on the face, dry scaling on palms and soles,
    and alopecia, not only of the scalp but sometimes also of the
    eyelashes, lateral eyebrows, arms and legs.  Histological examination
    of skin biopsies from both scalp and cheek showed disintegrating
    hairshafts, gross follicular plugging and eosinophilic keratohyaline
    granules in the adjacent granular layer of the epidermis.  Sebaceous
    glands were sometimes necrotic.  Biopsies of the pustular lesions on
    the face showed folliculitis and necrosis of the follicles, while in
    those from the feet marked hyperkeratosis and hypergranulosis were
    evident (Heyl & Barlow, 1989).  Effects on the follicles are also
    reported by Hausman & Wilson (1964) and Bonnet & Pedace (1979), but in
    a woman who died at least 14 days after intoxication no hyperkeratosis
    in any part of the skin was found (Curry et al., 1969).

         As is the case in experimental animals (section 7.4.1), the
    reason for the different sensitivities of different types of hair
    (lanugo, pubic and axillary hair is much less or is later affected
    than hair of the head) in humans is unclear (Buschke & Peiser, 1926;
    Buschke, 1929; Cavanagh, 1988).  Cavanagh et al. (1974) emphasized a
    direct effect on the keratinocytes, and Cavanagh (1988) finally
    suggested that the difference is due to the fact that hair follicle
    cells are only affected when they are mitotically active.

         The depilatory effect generally does not result in permanent hair
    loss.  Since the new hairs which grow following thallium-induced
    alopecia are stronger than those lost and also develop in regions
    which had been hairless prior to the thallium poisoning, Buschke
    successfully used thallium in therapy of alopecia induced by hair
    disease (Buschke & Curth, 1928).

         Soon after poisoning, hair papilla are seen to contain black
    regions and the growing end is tapered (e.g., Hausman & Wilson, 1964;
    Curry et al., 1969; Saddique & Peterson, 1983).  In some reviews this
    phenomenon is interpreted as black pigmentation.  However, Ludwig
    (1961) had already shown that these regions do not contain deposits of
    pigments or thallium but small amounts of air which had entered the
    shaft.  Later investigations demonstrated that the gaseous inclusions
    result from a trophic disorder in keratin formation (Kijewski, 1984;
    Metter & Vock, 1984).  In both investigations, scanning electron
    microscopy demonstrated a loosening of the elements of the fibre layer
    of the hairs.

    8.4.4  Nervous system

         Neurological disorders showing strong variability are one of the
    three major symptoms of thallium poisoning (Möllhoff et al., 1979;
    Prick, 1979; Sabbioni & Manzo, 1980; Le Quesne, 1984; Manzo &
    Sabbioni, 1988).  In contrast to the other disorders, neurological
    deficits usually persist.  Ataxia, mild spastic paraparesis and
    impairment of intellectual powers developed after treatment of scalp
    ringworm with thallium and persisted for 36 years, and it is possible
    that increasing problems with mobility after 33 years were also due to
    the treatment (Barnes et al., 1984).

    8.4.4.1  Central nervous system

         Like some other heavy metal intoxications, those caused by
    thallium are usually associated with subacute and chronic (but rarely
    with acute) encephalopathy (Rosenstock & Cullen, 1986). In one patient
    who died 9 days after ingesting 5-10 g thallium nitrate, no
    abnormalities were evident in histological or ultrastructural
    examinations of the central nervous system (Davis et al., 1981).  The
    brain of another patient, who died within 4 days of intoxication and
    had an extreme postmortem concentration of 36 mg/litre in his blood,
    was moderately swollen (Andersen, 1984).

         Seven people who died 11 to 16 days after accidental ingestion of
    thallium had localized oedema and various grades of chromatolysis in
    their neurons, especially those of the pyramidal tract, the third
    nucleus, the substantia nigra and the pyramidal cells of the globus
    pallidus.  Blood vessels were distended with blood (Munch et al.,
    1933).

         In a fatal case of thallium poisoning, the brain of the dead
    person was slightly swollen and oedematous about 4 weeks after the
    ingestion of around 33 mg thallium sulfate/kg body weight.  Petechial
    haemorrhages were found in the white matter, particularly in the
    parietal regions and subthalamic areas.  The brain stem and cerebellum
    showed a normal appearance.  Axonal swelling and fragmentation in the
    cortico-spinal tracts could be traced through the mid-brain, pons and
    medulla into the spinal cords.  Chromatolysis of brain stem nuclei was
    only marked in facial and hypoglossal nuclei and nerve fibre
    degeneration only in the spinal tract of the 5th nerve (Kennedy &
    Cavanagh, 1976).

         In a suicidal case, general degeneration of ganglion cells,
    damage to axons and disintegration of myelin sheaths were observed in
    the brain of the person, who died 21 days after intoxication.  Fatty
    degeneration of ganglion cells, acute swelling of oligodendroglia, a
    spongy appearance of the basal ganglia and a particular concentration
    of lesions in the calcarine cortex were prominent (Karkos, 1971).  In
    another fatal case, autopsy showed degeneration of ganglion cells in
    the brain and spinal cord (Gefel et al., 1970).

         Detrimental effects on intellectual functions were assumed not
    only in a patient suffering from ringworm treatment (section 8.4.4)
    (Barnes et al., 1984), but also in a student of chemistry who
    eliminated 60 mg thallium/litre in his urine after poisoning in the
    laboratory (Thompson et al., 1988).  The data obtained from
    intelligence tests on the student, performed 7 and 13 months after the
    near fatal intoxication, were compared with those of his non-identical
    twin brother who was of a similar educational background.  Although
    the brothers are not totally comparable, the tests indicated severe
    deterioration particularly in memory and performance abilities and, 13
    months later, there was only little general improvement.

    8.4.4.2  Peripheral nervous system

         Histological and ultrastructural examination of postmortem
    samples can produce inconsistent results, presumably because of the
    different periods of time between intoxication and sampling and
    because of differences in dose size.  In general, clinical symptoms
    and signs can be correlated to neuropathological findings (Cavanagh,
    1979).

         Damage to the autonomic nervous system accounts for many of the
    effects on various organs, e.g., fever, tachycardia, labile blood
    pressure, orthostatic hypotension, urinary retention, constipation and
    cardiac arrhythmias (Gastel, 1978; Prick, 1979).  Thallium
    intoxication causes symmetric, mixed peripheral neuropathy (Rosenstock
    & Cullen, 1986).  Distal nerves are more strongly affected than more
    proximal nerves, and earlier but lesser degrees of change occur in
    nerves with shorter axons, e.g., the cranial nerves (Cavanagh et al.,
    1974; Cavanagh, 1979, 1988).

    a)  Histology and ultrastructure

         Neuropathological findings vary.  Little evidence of neuronal
    degeneration in the sciatic nerve or spinal cord were found in a
    person who died about 14 days after intoxication (Cavanagh et al.,
    1974).  In a fatal case of poisoning, in which the patient died just 9
    days after intoxication (section 8.4.4.1), a sural nerve biopsy was
    obtained 2 days before death.  In addition, postmortem samples of
    peripheral and cranial nerves and sections from various parts of the
    central nervous system were taken. Ultrastructural examination of the
    sural nerve showed that the myelin sheaths had often disintegrated
    into a series of ovoids along the course of the axon (Davis et al.,
    1981).  Similar findings have also been reported from other sural
    nerve biopsies, taken, for example, 3 days in one case and at least 5
    to 6 weeks after thallium poisoning, from patients who survived (Bank
    et al., 1972; Paulson et al., 1972; Alarcón-Segovia et al., 1989;
    Dumitru & Kalantri, 1990).  Degenerated myelin sheaths contained
    myelin figures and electron-dense granules, whereas axons usually had
    a normal appearance and rarely contained densely packed neurofilaments
    (Bank et al., 1972).  Munch et al. (1933) and Davis et al. (1981)
    found axon degeneration in peripheral nerves, even in axons with
    ultrastructurally normal myelin sheaths; axons were swollen and
    contained vacuoles and distended mitochondria.  Non-myelinated axons
    on the other hand showed only slight or no abnormalities.  Beadings of
    axons were not only present in distal portions of peripheral nerves,
    but also in some cranial nerves, whereas the other cranial nerves and
    the proximal portions of peripheral nerves were histologically normal.

         In another postmortem examination of a patient who died about 4
    weeks after intoxication (section 8.4.4.1) (Kennedy & Cavanagh, 1976),
    the nerve fibres of several peripheral nerves were severely reduced,
    long fibres in particular being more severely affected.  Changes in
    neurons of the spinal cord were evident in all regions but most
    strikingly in the lumbosacral region, where many neurons clearly
    showed the classical chromatolytic changes which indicate attempted
    regeneration.  Dorsal column changes in the spinal tracts could
    clearly be correlated in time with the peripheral nerve symptoms, and

    the slight changes in the lateral cortico-spinal tracts could be
    traced to the recent necrotic lesions in the diencephalon (Kennedy &
    Cavanagh, 1976).  Demyelination of the dorsal columns in sections of
    cervical spinal cord was also observed during the postmortem
    examination of a women who died at least 14 days after intoxication
    (Curry et al., 1969).

         The severe damage to the vagus, denervation of the carotid sinus,
    and lesions of the sympathetic ganglia found in postmortem
    examinations indicate the involvement of the autonomic nervous system
    (Gastel, 1978).

    b)  Electrophysiological investigations

         In a case of thallium poisoning in which the patient survived, a
    sural nerve biopsy was obtained and nerve conduction and serial
    electromyographic studies were carried out, beginning 10 days after
    onset of the symptoms and ending 24 months later (Dumitru & Kalantri,
    1990).  Initially, the plantar nerves of the foot showed profound
    axonal loss, from which there was no recovery, as shown by conduction
    studies over the next 2 years.  During the initial 4 months, sural and
    peroneal nerves also underwent axonal loss but recovered within 2
    years.  In other cases of thallium intoxication, nerve conduction
    studies gave normal results or revealed retarded latencies of nerves
    of the upper (more than the lower) extremities, as well as temporal
    dispersion indicating demyelination (Alarcón-Segovia et al., 1989).

         Sensory fibres of the nervus medianus were examined in a patient
    with acute thallium poisoning in order to assess the effects on the
    conduction velocities of faster and slower nerve fibres.  Two months
    after the onset of symptoms the patient showed evidence of distal
    sensorimotor neuropathy, but only the conduction velocities of faster
    fibres were below the normal lower limit.  Nine months later, symptoms
    had almost disappeared and conduction velocities of both slower and
    faster fibres were within the normal range (Yokoyama et al., 1990). 
    Only a slight electrophysiological correlation with the symptoms of a
    persistent polyneuropathy were reported from an examination carried
    out 3 years after a case of intoxication (Feudell, 1982).

    c)  Visual disorders

         Retrobulbar neuritis and resulting visual impairment can develop
    or persist months after termination of treatment with
    thallium-containing depilatories, and even optic atrophy may occur
    (e.g., Buschke & Langer, 1927; Lillie & Parker, 1932; Mahoney, 1933;
    Bank et al., 1972; Bahiga et al., 1978; Tabandeh et al., 1978;
    Schmidbauer & Klingler, 1979).  An ascendent (retinal) atrophy of the
    optic nerve may result from the toxic effects of thallium on the

    retina (Hennekes, 1983).  Nerve fibres in oculomotor muscles can also
    show degenerative changes (Cavanagh et al., 1974).  In patients with
    optic neuritis some reduction in visual acuity always persists
    (Goldblatt, 1989).  About 10 months after thallium intoxication, a
    keratoconjunctivitis sicca was found to have developed
    (Alarcón-Segovia et al., 1989).

    8.4.5  Other organs

         Effects on the lung and endocrine glands were found in six
    postmortem examinations (death occurred 11 or 15/16 days after
    ingestion of thallium).  Light microscopy showed the alveoli distended
    with serum, marked hyperaemia and a few areas with bronchopneumonia
    (Munch et al., 1933).  In another fatal case the pleurae were free
    from haemorrhages and adhesions (Curry et al., 1969).  Of the
    endocrine glands only the adrenals were affected.  They showed marked
    hyperaemia, small haemorrhages in the medulla, areas of necrosis and
    nuclear disintegration (Munch et al., 1933).  In other lethal cases
    the adrenals were enlarged but without haemorrhages (Curry et al.,
    1969), or were haemorrhagic (Gefel et al., 1970), or the concentration
    of lipoids was reduced (Buschke, 1929).

         A biopsy, taken 50 days after intoxication, showed marked areas
    of atrophy of muscle tissue (Franke et al., 1979).  Muscle fibrosis
    was reported by Gefel et al. (1970) in a fatal case of thallium
    poisoning.

    8.5  Special effects

    8.5.1  Reproduction and developmental effects

         Few data are available with respect to the effects of thallium on
    human reproduction (Schardein & Keller, 1989).  Female cycles are
    arrested, and libido and potency of males decrease (Buschke & Langer,
    1927; Greving & Gagel, 1928).  Effects on sperm are known to occur in
    cases of chronic intoxication (Cottier, 1980). It should be noted that
    minor amounts of thallium accumulate in the testis after diagnostic
    scintigraphy, but possible effects have not been investigated.

         There are no reports of any teratogenic effects in humans and an
    extrapolation of animal data to humans is somewhat problematical (Kolb
    Meyers, 1983; Mottet, 1985).

         Reviews of more than 20 cases of thallium intoxication during
    pregnancy by Petersohn (1960), Moeschlin (1965), Stevens & Barbier
    (1976), Graben et al. (1980) and Barlow & Sullivan (1982) can be
    summarized as follows: all attempts at illegal abortion were in vain;
    the prolonged use of a depilatory cream seems to have been the cause

    of 1 neonatal death.  Two attempts at illegal abortion with thallium
    in the first trimester of pregnancy did not affect the development of
    the fetuses, although rather low birth weights were recorded.  In four
    additional cases of intoxication during this period of pregnancy, the
    outcome was not reported.

         Intoxication occurring after the first trimester can induce in
    the newborn baby some symptoms of acute intoxication seen in adults,
    e.g., rash and alopecia.  Two babies born after the intoxication of
    their mothers in the 5th and 6th months of pregnancy showed reduced
    weight or no effects, respectively.  Also no effects were found in a
    case of intoxication (0.35 g thallium) in the 7th month of pregnancy
    or in an additional six cases.  However, in two cases during this
    period (0.15 g thallium in one case), premature births occurred,
    showing alopecia areata and low weight of one baby.  Alopecia areata
    and lunular stripes in the nails were observed in two newborn babies. 
    Low birth weight was common.

         Petersohn (1960) reported an attempt at illegal abortion by
    ingesting 0.5 g thallium 8 weeks before term.  However, the fetus
    developed normally.  The child had well-developed hair and apart from
    being relatively underweight showed no signs of thallium poisoning,
    whereas the mother developed alopecia and polyneuritis (Erbslöh,
    1960).  A suicide attempt with about 1.2 g thallium 2 days before
    birth caused the death of a newborn girl after 5 days; fresh blood in
    the faeces was observed from the 3rd day onwards.

         In the population living around the cement plant in Lengerich,
    Germany, 300 women gave birth in the years 1978 and 1979.  Eleven
    children exhibited congenital malformations or abnormalities, five
    showing major malformations (e.g., cleft lip and palate, clubfoot, hip
    dislocation and ventricular septum defect).  The rate of malformation
    was higher than expected, but the authors suggested that the real
    frequency of malformation in unaffected populations is underestimated. 
    It was difficult to correlate the effects with the intensity of
    exposure, since the degree of exposure to which the mothers were
    subjected during pregnancy could not be ascertained (Dolgner et al.,
    1983).  It should be noted that the fathers were not included in the
    investigations.  Embryotoxic effects were not considered in the
    investigation at Lengerich (Claussen et al., 1981).

    8.5.2  Carcinogenicity

         The carcinogenicity of thallium has not been adequately evaluated
    in humans.  A study by Marcus (1985) on occupationally exposed workers
    showed that the incidence of benign neoplasms (not further
    characterized) was not significantly increased in the workers.

    However, only 86 thallium-exposed and 79 controls were included in
    this study and the length of observation time was not stated.  The
    study was also limited by the availability of medical records.  Other
    reports involving human exposure to thallium did not include an
    investigation of carcinogenicity.

    8.5.3  Immunotoxicological effects

         Reduced resistance against secondary infections has been reported
    only by Moeschlin (1965), but actual data on the possible
    immunological effects of thallium are not available.

    8.6  Factors modifying toxicity: enhancement of elimination

         In studies on laboratory mammals (section 7.10.1) and in tests
    with patients, enhancement of elimination was attempted (Stevens et
    al., 1974).  This might be achieved, provided that the thallium is not
    fixed intracellularly (Barckow & Jenss, 1976).  Sodium salts were
    previously used as an antidote for human thallotoxicosis (Munch,
    1934a), but intravenous injection of sodium thiosulfate (Sessions &
    Goren, 1947) often increased the severity of symptoms (Munch, 1934a). 
    Although increased urinary elimination of thallium theoretically
    should reduce its fatal effects, treatment with potassium salts caused
    a worsening of the symptoms of thallotoxicosis in humans (Papp et al.,
    1969).  This was presumably due to a mobilization of intracellular
    thallium, an increase in plasma levels, and redistribution (Bank et
    al., 1972; Gastel, 1978).

         Dithizone has also been used to treat cases of human poisoning
    (summarized by Bendl, 1969 and Papp et al., 1969), in spite of its
    goitrogenic and perhaps diabetogenic effects in experimental animals. 
    Clinical therapy with dithizone is often more effective than treatment
    with potassium chloride and charcoal (Paulson et al., 1972). 
    Respiratory distress, confusion and diplopia have been cited as
    examples of negative side effects by Barckow & Jenss (1976) and were
    also reported by Saddique & Peterson (1983), but they were not
    attributed to the dithizone treatment by Paulson et al. (1972). 
    Dithizone presumably mobilizes thallium from the compartments with
    maximal concentrations, thus increasing the toxic load of the nervous
    system (Cavanagh et al., 1974; Ghezzi & Bozza Marrubini, 1979).

         Other agents, D-penicillamine and the chelating
    diethyldithio-carbamate ("dithiocarb"), have also been used as
    antidotes (Sunderman, 1967; Montoya Cabrera et al., 1979).  Dithiocarb
    caused a three-fold increase in urinary elimination during therapy of
    a woman (Sunderman, 1967).  D-penicillamine was used to treat a
    patient who initially had 1200 µg thallium/litre in her urine, as well

    as two other people with thallium poisoning.  The authors emphasized
    that no adverse effects occurred (Alarcón-Segovia et al., 1989).  In a
    detailed comparative survey by Cavanagh et al. (1974), it was stated
    that for neither of these two antidotes (nor for several other
    antidotes) was formal proof of benefit available.  Negative effects of
    dithiocarb therapy, such as deterioration of cerebral function, have
    been observed in patients (Kamerbeek et al., 1971a).

         Haemoperfusion does not affect the course of thallium
    intoxication, according to Heath et al. (1983). Successful treatment
    by haemodialysis was reported by Barckow & Jenss (1976) and Piazolo et
    al. (1971).  Elimination of thallium by haemoperfusion or
    haemofiltration should be restricted to intoxications with high doses
    of thallium during the previous 24 h (Briese & Nessler, 1985b).

         A very effective oral antidote in experimental animals and humans
    is Prussian Blue, potassium ferric hexacyanoferrate(II), an inorganic
    pigment which is not absorbed by the gut (Heydlauf, 1969; Dvorák,
    1970; Kamerbeek et al., 1971b; Günther, 1971; Barbier, 1974; Ghezzi &
    Bozza Marrubini, 1979; Lehmann & Favari, 1984, 1985).  Potassium ions
    in the molecule are exchanged for thallium ions.  Thus, absorption in
    the intestine is prevented and the thallium-loaded molecule is
    eliminated with the faeces (Forth & Henning, 1979). This therapy
    results in faecal elimination greatly exceeding urinary elimination
    (Stevens et al., 1974).  Prussian Blue is now the main therapeutic
    agent (Forth & Henning, 1979; Lehmann & Favari, 1984; Kazantzis, 1986;
    Pai, 1987; Chandler et al., 1990), the colloidally soluble form being
    preferable (de Groot & van Heijst, 1988).

         Prussian Blue therapy and forced diuresis with furosemide and
    mannitol (10 g of the soluble form dissolved in 100 ml 1.5% mannitol
    as a laxative, twice daily orally or intraduodenally, until urinary
    thallium elimination is < 0.6 mg/24 h), perhaps supplemented by
    haemodialysis, is currently considered the optimal therapy for
    thallium intoxication (Barckow & Jenss, 1976; Forth & Henning, 1979;
    Briese & Nessler, 1985b; Chandler & Scott, 1986; Wainwright et al.,
    1988; IPCS, 1992; Aderjan et al., 1994).  If Prussian Blue is not
    available, activated charcoal can be used (IPCS, 1992).  The effects
    on target organs, for instance neurotoxic effects, must be treated
    symptomatically (Forth & Henning, 1979; Kemper, 1979; Briese &
    Nessler, 1985b).  In laboratory experiments on rats the hepatotoxicity
    of thallium was prevented by treatment with silymarin, which has been
    shown to have a hepatoprotective effect in man against several toxic
    substances (Mourelle et al., 1988).

    8.7  Protective measures against excessive occupational exposure

         The high toxic potency of thallium has been considered in its TLV
    or MAK value (threshold limit value or maximum concentration at the
    workplace) of 0.1 mg/m3 (Schaller et al., 1980; MT, 1983; Marcus,
    1985; DFG, 1990).  This value is the limit for a 40-h working week in
    the USA, France, Germany, United Kingdom and other western countries,
    and has been reduced in the former-USSR to 0.01 mg/m3 air (Sabbioni
    & Manzo, 1980; Nessler, 1985b).  The MAK value is the mean value
    during the normal 8-h working day, and, during this period, only once
    may a ten-fold higher concentration occur for a period of 30 min (DFG,
    1990).  According to the West German General Administration Regulation
    on Air Pollution Control, thallium concentration in dust fall-out
    should not exceed 0.01 mg/m2 per day (Ohnesorge, 1985; Ewers, 1988).

         On the basis of several reports of recommendations for the
    protection of employees in industrial plants using thallium, e.g., by
    Hill & Murphy (1959), Malcolm (1979), Glomme (1983), Nessler (1985b)
    and a very detailed one by Sessions & Goren (1947), the following
    protective measures are advisable.

    a)  General recommendations

        i)    Access to rooms in which thallium is used should be restricted
              to a limited number of employees.

        ii)   Employees should repeatedly be informed about risk and
              industrial hygiene, in a similar way to employees working with
              radioisotopes.  They should be instructed to report any unusual
              health symptoms.

        iii)  Employees should be encouraged to eat potassium-rich food.

    b)  Medical control

        i)    By means of a preplacement examination, people suffering from
              renal, hepatic or neurological diseases, anaemia, blood
              dyscrasias, hypertension, alcoholism, chronic infections of
              endocrine gland dysfunction should be excluded from working with
              thallium.

        ii)   Urinary thallium should be periodically determined as a means of
              showing the effects of education programmes and improving
              industrial hygiene.  The intervals will depend on the degree of
              exposure.

        iii)  Periodic examinations should pay particular attention to the
              early toxic effects of thallium, e.g., renal function,
              gastrointestinal disturbances, the presence of paraesthesia and
              alopecia.

    c)  Engineering control

        i)    Dust scattering should be avoided and handling of thallium
              should be conducted under exhaust ventilation.

        ii)   Floors and tables should be wet-mopped.

        iii)  Dust samplers should be installed for environmental monitoring
              to permit the evaluation of possible sources of contamination.

    d)  Personal protective equipment and hygienic measures

        i)    Employees should be required to use protective work clothes
              including gloves.

        ii)   When indicated, personal exposure monitoring should be
              performed.

        iii)  Complete sets of personal work clothes should be kept in
              accommodation separate from that employed for street clothes.
              Before changing clothes, gloves should be thoroughly washed and
              then hands, using separate towels.

        iv)   Depending on the level of exposure, work clothing should be
              washed periodically.

        v)    Clothes should be changed before eating, drinking and smoking,
              all of which should be prohibited at the workplace.

        vi)   Washing and shower facilities should be provided and their use
              enforced.

        vii)  Individual respirators should be worn in all operations
              producing dust or fumes.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Since the majority of results have been obtained in laboratory
    experiments, field observations on plants (mainly near the cement
    plant in Lengerich) have not been considered under a special
    subheading but have been included in sections 4.1.2.2, 9.3.1.2 and
    9.3.1.6, and those on vertebrates have been included in sections 9.3.2
    and 9.3.3.

         The toxicity of thallium has been considered to be comparable
    with that of mercury and lead, which are its neighbours in the
    Periodic Table (Emsley, 1978).

    9.1  Microorganisms

         Buschke & Jacobsohn (1922) observed a sterilizing effect of
    metallic thallium on various bacteria placed on agar plates.  The
    antibiotic effect of thallium was also recognized during postmortem
    examination of thallium-poisoned humans, which were less decomposed
    than other corpses (Muller, 1961).

         The most important effect of thallium on microorganisms seems to
    be the complete or partial inhibition of nitrate formation by
     Nitrobacter agilis, observed at concentrations of 0.8 to 16 mg
    thallium/litre (Tandon & Mishra, 1969).  However, nitrification in
    soils was only reduced at high thallium concentrations, which also
    affected plants considerably (McCool, 1933).  Direct effects on soil
    microflora were demonstrated by Drucker et al. (1979).  The numbers of
    total aerobic bacteria and the distribution of other microorganisms
    were affected at concentrations as low as 1 and 10 mg/kg soil, whereas
    soil respiration was only reduced at 100 mg/kg soil.  Thallium was
    less toxic than silver, mercury, chromium, cadmium, copper, nickel and
    zinc (in descending order of toxicity) but more toxic than other
    elements, e.g., arsenic and lead (Drucker et al., 1979).  However, the
    properties of the soil and the form of thallium used in this study
    were not reported.

         The only known positive effect of thallium on organisms has been
    described by Richards (1932), who obtained a higher yield of yeast in
    the presence of 0.1, 1 or 10 mg thallium/litre culture medium.  Higher
    concentrations inhibited the growth of  Saccharomyces cerevisiae.
    This positive effect of thallium needs to be verified, since it could
    have been caused by contamination of the thallium, which would not
    have been detected by the analytical methods available at that time. 
    Using the same microorganism, Norris et al. (1976) found a growth
    inhibition of 50% after the addition of 153 mg/litre to liquid culture
    (which contained 31.3 g potassium/litre) or 10.2 mg/litre to agar
    medium.  The same inhibitory effect with  Escherichia coli was obtained
    after the addition of 184.0 mg/litre liquid culture or 10.2 mg/litre

    agar and with  Bacillus megaterium after adding 3.1 or 5.1 mg/litre,
    respectively.  The concentrations of thallium (added to the agar
    medium), which prevented colony formation, i.e. 15.3, 20.4 and
    40.8 mg/litre for  B. megaterium, S. cerevisiae and  E. coli,
    respectively, also show interspecies differences.  Constant thallium
    concentrations of about 30% of those concentrations which inhibited
    growth rates by 50%, but with lower concentrations of potassium in the
    liquid medium, caused a decrease in the growth rates of  B. megaterium
    and  S. cerevisiae (Norris et al., 1976).

         Potassium/thallium antagonism has been observed using
     Thiobacillus ferrooxidans.  Iron oxidation by growing cultures in a
    potassium-free medium, but with 0.204 to 204.39 mg thallium (as
    sulfate) per litre, was normal at 20.4 mg thallium/litre but inhibited
    by 204.39 mg/litre.  However, this inhibitory concentration did not
    affect iron oxidation in the normal medium containing about 180 mg
    potassium/litre (Tuovinen & Kelly, 1974).

         In inhibitory tests with  Azotobacter chroococcum and
     A. vinelandii on agar plates, 20 mg thallium sulfate produced very
    strong inhibition, comparable to that of gold or chromate, and
    stronger than that of zinc or copper (den Dooren de Jong & Roman,
    1971).  The two latter heavy metals were found to be also less
    inhibitory in tests using the bacterium  Klebsiella pneumoniae
    (Sikka et al., 1987).  However, in a previous study this bacterium was
    much more sensitive to sulfates of zinc, copper and cadmium than to
    that of thallium (Wilson & Dean, 1977).  The different toxicity
    mechanisms were also shown by strains resistant to these heavy metals. 
    Thallium-resistant strains showed the opposite reaction and were more
    sensitive to gentamycin and chloramphenicol than the wild strain.  In
    liquid medium, up to 0.2 mg thallium/litre reduced the doubling time
    (correlated to the concentration) but induced no lag, whereas higher
    concentrations also induced a lag of initial development.  On agar
    plates, concentrations of up to 0.3 g/litre were not toxic, but with
    0.4 g/litre bacterial colonies developed only rarely. A reduction in
    the potassium concentrations increased the toxicity of thallium in
    both media.  A synergistic effect, and not a purely additive effect,
    with zinc and cadmium occurred only at concentrations above
    0.1 g/litre (Wilson & Dean, 1977).

         The enhanced isolation of mycoplasms in the presence of
    considerable numbers of other bacteria from the human urogenital tract
    (Tully et al., 1983) might be caused by a species-specific differences
    in the sensitivity to thallium, which had been added to the culture
    medium in addition to penicillin.  Such a selective cultivation of
    bacteria through the addition of different concentrations of thallium
    to the agar can be used as a taxonomic criterion and should be
    considered when using clinical material (Kunze 1972a,b).

         Different toxicities of thallium(I), thallium(III) and
    organothallium compounds were shown in a study on bacteria and fungi
    by Srivastava et al. (1973).  At low concentrations (1 and
    5 mg/litre), the growth of  Colletotrichum falcatum, the causative
    fungus of a sugarcane disease, was affected more by thallium(III)
    chloride than by thallium(I) chloride.  However, at higher
    concentrations the effect of the thallium(III) compound did not
    increase, and the fungus was affected more by the monovalent thallium. 
    With both compounds the inhibition did not exceed 20% compared to
    controls, even after the addition of 80 mg/kg.  The organothallium
    chlorides (diphenyl derivatives) were considerably more toxic than the
    thallium chlorides, causing a reduction of mycelial growth of 50%,
    even at concentrations of 13 or 16 mg/kg.  This inhibition was
    obtained with < 1 mg/kg for most ditolyl derivatives (Srivastava et
    al., 1973).

         Five fungal species of the genus Aspergillus were similarly
    sensitive to thallium nitrate.  Their sensitivity to cadmium and
    mercury nitrate was similar, but they were less sensitive to the
    nitrates of nine other metals (Filimonova et al., 1973).

         Anaerobic bacteria are more sensitive to thallium(I) than to
    organothallium compounds (Huber et al., 1978).  In several cases the
    inhibition of bacterial growth was greater at lower concentrations of
    the organothallium compounds.

    9.2  Aquatic organisms

         Little is known about the toxicology of thallium in aquatic
    systems.  Wachs (1988) classified thallium, together with lead and
    zinc, into the toxic class II.  Because of a lack of complex
    formation, its toxicity is not affected by water hardness, copper,
    etc. (Zitko et al., 1975).  Acute and chronic toxicities to freshwater
    aquatic life are reported to occur at 1400 and 40 µg/litre,
    respectively.  One species of fish is even affected at 20 µg/litre
    after 2600 h of exposure.  Marine aquatic life seems to be affected at
    2130 µg/litre, and as in the case of freshwater organisms, it is clear
    that more sensitive species than those tested might exist (US EPA,
    1980).

    9.2.1  Plants

         Results from studies on algae and higher aquatic plants are given
    in Table 26.  Photosynthesis is affected, as shown by the reduced
    oxygen evolution of the algal endosymbiont of the ciliate  Paramecium
     bursaria (Di Gaudio & Hirshfield, 1976).  In comparison to other
    heavy metals, higher concentrations of thallium were needed to reduce
    the light-induced oxygen evolution of the freshwater alga
     Chlamydomonas reinhardii (Overnell, 1975); about 2 mg thallium/litre
    buffer caused a reduction of about 50%.  Thallium strongly affects

    NADP reduction or the dark stage reactions of photosynthesis. 
    However, it seems to inhibit photosystem I only slightly, and this
    could not be confirmed in a very detailed later investigation with the
    green alga  Chlorella saccharophila, which also showed a reduced
    oxygen evolution (Wystrcil et al., 1987).  Measurements of the
    variable fluorescence indicated a primary action of thallium on
    electron transfer in photosystem II.  At low concentrations of
    thallium (2 mg/litre), disturbances of the thylakoid membranes could
    explain the altered variable fluorescence.  A change in the colour of
    the algal suspension to a greyish green and the alterations of the
    fluorescence intensity indicated effects on the pigments (Wystrcil et
    al., 1987). This has also been found for the alga  Chlamydomonas
     reinhardtii.  ß-Carotin showed the greatest sensitivity, followed by
    chlorophyll a and then chlorophyll b (Maier-Reiter et al., 1987).  In
    addition to an increase in the degradation rate of the pigments, the
    biosynthesis rate was reduced (section 9.3.1.2).

         In a comparison of the toxicity of seven heavy metals for the
    marine diatom Ditylum brightwellii, thallium (thallium(I) chloride)
    possessed the lowest toxicity, which was not affected by the chelating
    agent EDTA (Canterford & Canterford, 1980).  Within 5 days a 50%
    growth reduction was obtained with 330 to 350 µg total thallium/litre,
    corresponding to 0.15-0.17 mg free thallium per litre.  To obtain
    total inhibition, concentrations of about 2.2 times higher were needed
    (Table 26), but the cells showed an abnormal appearance, i.e.
    pseudo-resting spore-like cells and shrinkage of protoplast and
    concentration of chromophores, within about 3 days (Canterford &
    Canterford, 1980; Canterford, 1980).

         Species-specific sensitivities, but also different effects of the
    monovalent and the trivalent forms of thallium, were evident in two
    marine algae,  Phaeodactylum tricornutum and  Dunaliella tertiolecta
    (Table 26) (Puddu et al., 1985, 1988).  Complex formation with EDTA
    reduced the toxicity of the thallium(III) compound.  Using different
    strains of three acidophilic algae, the type and level of inhibition
    of growth after culture in a medium containing thallium sulfate was
    very similar in the strains of  Cyanidium caldarium and  Cyanidioschyzon
    merolae, whereas strains of  Galdieria sulphuraria showed different
    effects (Albertano & Pinto, 1986).

         Generally, freshwater algae are affected at concentrations as low
    as 100 µg/litre (US EPA, 1980).  In the submerged macrophyte  Elodea
     canadensis, 1.4 and 2.8 mg thallium/litre water (as thallium(I)
    sulfate) reduced the photosynthetic oxygen evolution during 24 h by
    50% and 90%, respectively (Brown & Rattigan, 1979).  In parallel
    experiments, the free-floating  Lemna minor was much more sensitive
    (Table 26).  The uptake and accumulation of thallium (thallium(I)
    acetate) and its effects on growth parameters of  L. minor (frond area,


        Table 26.  Toxicity of thalliuma to aquatic plants
                                                                                                                                                

    Species                   Parameter           Exposure time            Concentration of thalliumb            Reference
                                                                     LOELc          EC50d            TECe
                                                                                                                                                

    Algae

    Chlamydomonas             oxygen              0.25 h                            2                            Overnell (1975)
    reinhardii                evolution

    C. reinhardii             concentration       22 h               > 0.2          20                           Maier-Reiter et al. (1987)
                              of pigments

    Ditylum brightwellii      growth              5 days                            0.34             0.73        Canterford & Canterford (1980)

    Dunaliella tertiolecta    growth              -                  0.08                                        Puddu et al. (1988)
                                                                     0.18g

    D. tertiolecta            growth              -                  0.18g                                       Puddu et al. (1985)

    Elodea canadensis         damage              28 days                           2.0                          Brown & Rattigan (1979)

    E. canadensis             oxygen evolution    24 h                              1.4                          Brown & Rattigan (1979)

    Phaeodactylum             growth              -                  0.14                                        Puddu et al. (1988)
    tricornutum                                                      0.22g

    P. tricornutum            growth              -                  0.24g                                       Puddu et al. (1985)
                                                                                                                                                

    Table 26 (contd).
                                                                                                                                                

    Species                   Parameter           Exposure time            Concentration of thalliumb            Reference
                                                                     LOELc          EC50d            TECe
                                                                                                                                                

    Selenastrum               concentration       96 h                              0.11                         US EPA (1978)
    capricornutum             of pigments

    S. capricornutum          growth              96 h                              0.10                         US EPA (1978)

    Higher Plants

    Lemna minor               growth (weight)     10 days            0.014          0.04                         Kwan & Smith (1988)
                                                                     281.5h         510.0h

    L. minor                  growth              10 days            0.016          0.047                        Kwan & Smith (1988)
                              (frond number)                         293.8h         550.1h

    L. minor                  growth              10 days            0.008          0.033                        Kwan & Smith (1988)
                              (frond area)                           195.8h         443.7h

    L. minor                  damage              28 days            0.008                                       Brown & Rattigan (1979)
                                                                                                                                                

    a   Thallium(I), unless otherwise stated
    b   mg thallium/litre nutrition solution, unless otherwise stated
    c   LOEL = low-observed-effect level
    d   EC50 = concentration at which the life parameters were reduced by 50%
    e   TEC = concentration at which life parameters were totally inhibited
    f   - = no data given
    g   Thallium(III)
    h   mg thallium/kg dry weight of plant
        fresh weight, frond number) were determined by Kwan & Smith (1988). 
    High concentrations of 1 and 2 mg/litre water induced chlorosis by the
    eighth day, and 2 days later the fronds were completely devoid of any
    colour.  Comparing the number of fronds at different concentrations of
    thallium during a period of 10 days, a stimulatory effect was evident
    after exposure to 2 µg/litre and 10 µg/litre at the end of the period.
    However, smaller fronds were produced and, therefore, the surface area
    covered by  Lemna also decreased at the lowest thallium concentrations.
    At 20 µg/litre or more, all growth parameters were reduced. 
    Subsequent culture in thallium-free water resulted in good recovery
    from the previous thallium exposure, provided that the concentration
    had not exceeded 20 µg/litre.  The bioconcentration factor (based on
    plant weight) was 88 000 at the lowest exposure (2 µg/litre) and 6000
    at an exposure of 153 µg/litre.

         Using 40 µg/litre growth medium, the thallium concentrations in
     L. minor did not further increase after 140 h, and over 80% of the
    thallium remained in the plant (Smith & Kwan, 1989). In plant
    homogenates, thallium showed little association with proteins, and the
    reactions of the thallium in the soluble fraction were comparable to
    those of the free metal ion.  Like potassium, thallium accumulates in
    the cell vacuole.  When various concentrations of thallium were added
    to the medium (0.02 to 0.2 mg/litre), about 0.04 mg/litre caused a 50%
    reduction of growth after a period of 10 days (Smith & Kwan, 1989). 
    Since concentrations of 0.05 to 0.09 mg/litre were found in rivers
    contaminated by mining (Zitko et al., 1975), significant effects on
    macrophytes in such rivers would be expected, given the long exposure
    period.

    9.2.2  Animals

         Toxicity data on aquatic animals are summarized in Table 27.  In
    an immobilization test on  Daphnia magna, it was shown that the
    toxicity of thallium(I) nitrate was higher than that of nickel or
    cadmium but lower than that of copper, silver or mercury (Bringmann &
    Kühn, 1982).  In general, arthropods were affected at lower
    concentrations than fish.  The 96-h LC50 values were much lower for
    the daphnids (water fleas)  Daphnia magna and  Mysidopsis bahia
    (2.2 mg/litre) than for the freshwater fish  Lepomis macrochirus
    (bluegill) (120 mg/litre), although 50% of fathead minnows  (Pimephales
     promelas) were killed by 0.86 mg/litre (LeBlanc, 1984).

         Comparing vertebrate with invertebrate marine species, about 10%
    of the concentration needed to kill 50% of sheepshead minnows or
    tidewater silversides was sufficient to kill 50% of marine shrimps (US
    EPA, 1980).  Acute values were 3- to 32-fold higher than chronic
    values (US EPA, 1980).

         Considerable differences between species were also evident in a
    study by Nehring (1962/63).  This study also showed that in perch
     (Perca fluviatilis) lethal thallium effects depend on the length of
    exposure.  The fish were killed by 200 or 500 mg/litre within 10 h,
    while concentrations of 100, 90-50, 40 and 20 mg/litre caused death
    within 2, 2.5-3.5, 7.5 and 14 days, respectively.  At 15 mg/litre, the
    perch survived at least 17 days.  Trout  (Salmo gairdneri) and roach
     (Rutilus rutilus) were more sensitive and died within 8 and 14 days,
    respectively, at 4 mg/litre.  In these species no effects were
    observed within 17 days at concentrations of 2 mg/litre.

         Juvenile Atlantic salmon  (Salmo salar) are exceptionally
    sensitive to thallium contamination (Zitko et al., 1975).  The 18-day
    LC50 is 0.1 mg/litre.  The mortality of fish exposed to 0.03 mg/litre
    was reported to be equal to that of the controls.  The authors
    suggested that 0.02 mg/litre be regarded as a no-observed-effect level
    (NOEL), and that 0.04 mg/litre be regarded as a low-observed-effect
    level (LOEL).  Mixtures with copper or zinc did not alter thallium
    toxicity.

         Behavioural alterations in perch were reported by Nehring
    (1962/63), even at low concentrations.  Initially, following exposure
    to thallium, food consumption increased, but after one or two days
    neuronal damage occurred.  This was indicated by uncoordinated
    movement, paralysis of gills and disturbance of balance.  Similar
    effects on movement and respiration in fish had already been observed
    by Swain & Bateman (1909/10).

         Larvae of fathead minnows  (Pimephales promelas) were much more
    sensitive than the embryos to thallium sulfate (LeBlanc & Dean, 1984). 
    No effect on the rate of hatching was observed at concentrations up to
    200 µg/litre, but at 720 µg/litre no hatching occurred.  At
    350 µg/litre no larvae survived. Growth was affected at 120 µg/litre.

         In a study by Birge (1978), rainbow trout  (Salmo gairdneri) eggs
    were exposed to thallium from fertilization to 4 days after hatching
    (total of 28 days). The exposure water was renewed every 12 h.  An
    LC50 of 0.17 mg/litre and an LC1 of 0.0084 mg/litre were reported.
    Goldfish  (Carassius auratus) eggs were also exposed to thallium from
    fertilization to 4 days after hatching (total of 7 days).  The
    exposure water was renewed every 12 h.  An LC50 of 7.00 and an LC1
    of 0.0525 mg/litre were reported (Birge, 1978).


        Table 27.  Toxicity of thalliuma to aquatic animals
                                                                                                                                                

    Species                    Stage       Parameter     Exposure time          Concentration of thallium          Reference
                                                                              LOELb       EC50c       TECd
                                                                                                                                                

    Invertebrates

    Daphnids                   -e          survival        48 h                           2.2                      LeBlanc (1984)

    Daphnia magna              juvenile    mobility        24 h               > 0.003     0.11        0.95         Bringmann & Kühn (1982)

    Daphnia sp.                adult       survival        72 h               2-4                                  Nehring (1962/63)

    Gammarus sp.               adult       survival        72 h               4                                    Nehring (1962/63)

    Mysid shrimp                           survival        96 h               2.1                                  US EPA (1978)
    (Mysidopsis bahia)

    Vertebrates

    Atlantic salmon            juvenile    survival        47 h                           10                       Zitko et al. (1975)
    (Salmo salar)                                          112 h                          1
                                                           435 h                          0.1
                                                           2600 h             0.03

    Sheepshead minnow          adult       survival        96 h                           20.9                     US EPA (1978)
    (Cyprinodon variegatus)

    Bluegill                   adult       survival        96 h                           132                      US EPA (1980)
    (Lepomis macrochirus)

                               adult       survival        96 h                           120                      LeBlanc (1984)
                                                                                                                                                

    Table 27 (contd).
                                                                                                                                                

    Species                    Stage       Parameter     Exposure time          Concentration of thallium          Reference
                                                                              LOELb       EC50c       TECd
                                                                                                                                                

    Perch                      adult       survival        72 h               60                                   Nehring (1962/63)
    (Perca fluviatilis)

    Fathead minnow             embryo      hatch           > 0.2                                      < 0.72       LeBlanc & Dean (1984)
    (Pimephales promelas)      larva       survival        30 day             < 0.04                  < 0.35
                               larva       growth          30 day             > 0.04                  > 0.2

                               adult       survival        96 h                           0.86                     LeBlanc (1984)

                               adult       survival        96 h               0.08                                 US EPA (1980)

                               adult       survival        96 h                           1.8                      US EPA (1980)

    Roach                      adult       survival        72 h               40-60                                Nehring (1962/63)
    (Rutilus rutilus)

    Rainbow trout              adult       survival        72 h               10-15                                Nehring (1962/63)
    (Salmo gairdneri)

    Tidewater silverside                   survival        96 h                           24                       Dawson et al. (1975/77)
    (Mendia berrylina)

    Toad                       adult       survival        -                                            16.7g        Swain & Bateman (1909/10)
                                                                                                                                                

    a   mg thallium/litre water
    b   LOEL = low-observed-effect level
    c   EC50 = concentration at which the life parameters were reduced by 50%
    d   TEC = concentration at which life parameters were totally inhibited
    e   - = data not given
    f   12 days in experiments with other species
    g   mg/kg injected into a lymph sinus
             Amphibia are also affected by thallium.  Development of frog
    spawn was unaffected by concentrations of 40.8 and 200 mg/litre, but a
    concentration of 0.4 mg/litre killed all tadpoles on hatching (Dilling
    & Healey, 1926).  This indicates that the absorption of thallium by
    the eggs was minimal.  Injections of lethal concentrations of thallium
    acetate (> 0.005 g) into the lymph sinus of adult toads (Table 27)
    caused loss of control of the hindlimbs and death by asphyxia (Swain &
    Bateman, 1909/10).  In a study on the narrow-mouth toad  (Gastrophryne
     carolinensis), eggs were exposed to thallium from fertilization to 4
    days post-hatch (total 7 days).  The exposure water was changed every
    12 h.  An LC50 of 0.11 and an LC1 of 0.0024 mg/litre were reported
    (Birge, 1978).

    9.3  Terrestrial organisms

    9.3.1  Plants

         Early investigations into the toxicity of thallium to plants were
    summarized by Scharrer (1955).  The most obvious effects are decreased
    productivity, inhibition of photosynthesis and direct cytotoxicity. 
    Toxicity data are listed in Table 28.

    9.3.1.1  Plant photosynthesis

         In a study by Bazzaz et al. (1974), the net photosynthesis of
    excised tops of sunflowers  (Helianthus annuus) decreased both with
    time and with the concentration of thallium in the nutrient solution
    (2 to 200 mg/litre).  At the highest concentration, photosynthesis was
    inhibited by about 70% after 1 day, and the plants began to wilt.  At
    the lower concentrations, these visible symptoms appeared 4 days
    later.  There was a strong log-linear relationship between
    photosynthesis and the thallium content of the plants.  Stomatal
    opening was reduced by 30 and 90%, respectively, at concentrations of
    0.2 and 2 mg thallium/litre, but increased concentrations only caused
    a slight additional effect (Bazzaz et al., 1974).  In a direct
    comparison Carlson et al. (1975) observed that the effects of thallium
    sulfate on photosynthesis and transpiration in sunflowers were similar
    to those in maize  (Zea mays) at low thallium concentrations (up to
    2 mg thallium/litre solution).  Higher concentrations, up to
    10 mg/litre, induced further inhibition in maize but not in
    sunflowers.  Using the data of Carlson et al. (1975), there was a good
    linear correlation for maize between the occurrence of stomatal
    opening (y) and thallium content of the solution (x):

              y = 66.4 - 0.4 x; regression coefficient = 0.93

    This was greater than the correlation calculated using the data for
    sunflowers:

              y = 45.1 - 0.4 x; regression coefficient = 0.66.


        Table 28.  Toxicity of thalliuma to terrestrial plantsb
                                                                                                                                                

    Species                    Parameter            Exposure time             Concentration of thalliumc            Reference
                                                                          LOELd          EC50e        TECf
                                                                                                                                                

    Brassica napus             shoot growth         10 days               > 20h,n                                   Makridis & Amberger (1989b)

    B. napus                   shoot growth         18 days               800i,n                                    Makridis & Amberger (1989b)
                                                                          < 2h,n

    B. napus                   shoot growth         28 days               > 2669                                    Allus et al. (1987)
                                                                          > 10.0h

    B. napus                   root growth          28 days               > 760                                     Allus et al. (1987)
                                                                          > 10.0h

    Cucumis sativus            growth               10 days               < 10h                                     Puerner & Siegel (1972)

    Garden lettuce             growth               7 days                > 100                                     Schweiger & Hoffmann (1983)
                                                                          10h

    Garden lettuce             growth               summer                30                                        Hoffmann et al. (1982)
                                                                          < 10k                       > 500k

    Green kale                 growth               7 days                > 500                                     Schweiger & Hoffmann (1983)
                                                                          10h

    Helianthus annuusg         photosynthesis       4-5 days                             63                         Bazzaz et al. (1974)
    (sunflower)

    H. annuus                  photosynthesis       4-9 days                             82                         Carlson et al. (1975)
                                                                                                                                                

    Table 28 (contd).
                                                                                                                                                

    Species                    Parameter            Exposure time             Concentration of thalliumc            Reference
                                                                          LOELd          EC50e        TECf
                                                                                                                                                

    H. annuus                  growth               7 days                > 100                                     Schweiger & Hoffmann (1983)
                                                                          10h

    H. annuusg                 stomata opening      8 h                   < 0.2h         approx.                    Bazzaz et al. (1974)
                                                                                         0.8h

    Hordeum vulgare            shoot growth                               20                                        Davis et al. (1978)
                                                                          0.5h

    H. vulgare                 shoot growth         28 days               > 21                                      Allus et al. (1987)
                                                                          < 0.2h

    H. vulgare                 root growth          28 days                              < 86                       Allus et al. (1987)
                                                                                         < 0.2h

    Kohlrabi                   growth               summer                > 600                                     Hoffmann et al. (1982)
    (young)                                                               500k

    Lolium perenne             shoot growth         21 days               0.71                        251.2         Al-Attar et al. (1988)

    L. perenne                 root growth          21 days               2.1                         1990          Al-Attar et al. (1988)

    Nicotiana tabacump         survival             24 h                                 0.02h                      Siegel (1977)

    N. tabacum                 germination          24 h                                 0.02h                      Siegel (1977)

    Phaseolus vulgaris         growth               33 days                              < 0.55h                    Kaplan et al. (1990)
                                                                                                                                                

    Table 28 (contd).
                                                                                                                                                

    Species                    Parameter            Exposure time             Concentration of thalliumc            Reference
                                                                          LOELd          EC50e        TECf
                                                                                                                                                

    P. vulgaris                shoot growth         10 days               130i,n                                    Makridis & Amberger (1989b)
                                                                          < 1h,n

    Pisum sativum              stem growth          28 days               5-10                                      Pötsch & Austenfeld (1985)
                                                                          210-360h
                                                                          5-10n                                     Pieper & Austenfeld (1985)
                                                                          115-123h,n

    Pisum sativum              leaf growth          28 days               1-5                                       Pötsch & Austenfeld (1985)
                                                                          30-75h
                                                                          > 10n                                     Pieper & Austenfeld (1985)
                                                                          30-43h,n

    P. sativum                 root growth          28 days               > 10                                      Pötsch & Austenfeld (1985)
                                                                          > 180h
                                                                          > 10n                                     Pieper & Austenfeld (1985)
                                                                          > 80h,n

    Radishl                    growth               summer                35                                        Hoffmann et al. (1982)
                                                                          < 500k

    Radishm                    growth               summer                < 300
                                                                          > 500k

    Rape                       growth               summer                > 500                                     Hoffmann et al. (1982)
                                                                          200k                        500k

    Spinach                    concentration        14 days                              < 150                      Maier-Reiter et al. (1987)
                               of pigments                                               > 0.2h
                                                                                                                                                

    Table 28 (contd).
                                                                                                                                                

    Species                    Parameter            Exposure time             Concentration of thalliumc            Reference
                                                                          LOELd          EC50e        TECf
                                                                                                                                                

    Spinach                    growth               9 days                280i                                      Schweiger & Hoffmann (1983)
                                                                          2h,i

    Vicia faba                 stem growth          28 days               > 10                                      Pötsch & Austenfeld (1985)
                                                                          > 222h
                                                                          5-10n                                     Pieper & Austenfeld (1985)
                                                                          36-76h,n

    V. faba                    leaf growth          28 days               > 10                                      Pötsch & Austenfeld (1985)
                                                                          > 8h
                                                                          5-10n                                     Pieper & Austenfeld (1985)
                                                                          5-7h,n

    V. faba                    root growth          28 days               > 10                                      Pötsch & Austenfeld (1985)
                                                                          > 1320h
                                                                          > 10n                                     Pieper & Austenfeld (1985)
                                                                          > 575h,n

    Zea mays                   growth               7 days                > 100                                     Schweiger & Hoffmann (1983)
    (corn)                                                                10h

    Z. mays                    root growth          28 days               1h                                        Logan et al. (1984)

    Z. mays                    shoot growth         28 days               1h                                        Logan et al. (1984)

    Z. mays                    root growth          28 days               1h,n                                      Logan et al. (1984)

    Z. mays                    shoot growth         28 days               1h,n                                      Logan et al. (1984)
                                                                                                                                                

    Table 28 (contd).
                                                                                                                                                

    Species                    Parameter            Exposure time             Concentration of thalliumc            Reference
                                                                          LOELd          EC50e        TECf
                                                                                                                                                

    Z. mays                    photosynthesis       4-9 days                             82                         Carlson et al. (1975)

    Z. mayso                   stomata opening      8 h                                  2h                         Carlson et al. (1975)
                                                                                                                                                


    a   Thallium(I), unless otherwise stated
    b   Whole plants, unless otherwise stated
    c   mg thallium/kg dry weight of plant tissue, unless otherwise stated
    d   LOEL = low-observed-effect level
    e   EC50 = concentration at which the life parameters were reduced by 50%
    f   TEC = concentration at which life parameters were totally inhibited
    g   Tops
    h   mg thallium/litre nutrition solution
    i   Concentration at which the life parameters were reduced by 10%
    k   mg thallium/kg soil
    l   Root
    m   Leaf
    n   Thallium(III)
    o   Epiderm
    p   Protoplast
    q   Seed
             The effects of thallium on the photosynthesis of spinach
    chloroplasts have been investigated by Wystrcil et al. (1987).  Some
    alterations of variable fluorescence indicated a primary action of
    thallium on electron transfer in photosystem II, which was also
    evident in green algae (section 9.2.1).  In photosystem I, superoxide
    dismutase might also be affected by thallium (Wystrcil et al., 1987).

    9.3.1.2  Cytotoxic effects

         Chlorosis, followed by marginal necrosis of the leaves, is the
    most prominent sign of thallium toxicity in plants.  Different courses
    of thallium poisoning in various plant species were reported by McCool
    (1933) and later by Spencer (1937) in tobacco, by Carlson et al.
    (1975) in corn and sunflowers, by Davis et al. (1978) in barley, by
    Makridis & Amberger (1989b) in bushbeans and rape, and by Kaplan et
    al. (1990) in beans.  Similar observations on the leaves of trees in
    the vicinity of the cement plant in Lengerich, Germany were reported
    by LIS (1980).

         The course and location of chlorosis seemingly depend on thallium
    concentrations in the substrate and presumably correspond to the
    distribution of thallium in the plant (Schweiger & Hoffmann, 1983).

         In isolated protoplasts of  Nicotiana tabacum, a cytotoxic
    effect was also observed; 10% and 50% had lysed after a 24-h
    incubation in 4 (± 0.4) and 20 (± 2) µg thallium/litre, respectively,
    irrespective of the age of the protoplasts (Siegel, 1977).  These
    values are nearly identical to the percentages of seed in which
    germination was inhibited (Siegel, 1977).

         Chlorosis indicates a reduced concentration of pigments (section
    9.2.1).  In spinach, it is firstly the concentration of ß-carotene
    which is reduced, then that of chlorophyll  a and finally that of
    chlorophyll  b.  The concentrations of ß-carotene and chlorophyll  a
    were about half the normal value after 2 weeks of incubation in a
    hydroculture medium containing thallium nitrate (0.2 mg
    thallium/litre) (Maier-Reiter et al., 1987).

    9.3.1.3  Growth of plants

         Adverse effects of thallium on the growth of plants have been
    reported for various test systems (Table 28).  In a comparison of the
    effects of three heavy metals on the growth of cabbage seedlings,
    cadmium and thallium were found to be less toxic than silver (Allus et
    al., 1988).

         Initial mycelial growth of three fungal species was inhibited on
    agar plates containing 0.25 or 0.50 mg thallium/litre (Seeger & Gross,
    1981).

         In tobacco plants, concentrations as low as 5 mg thallium(I) per
    litre inhibited terminal growth and caused a temporary outgrowth of
    axillary buds all resembling natural frenching, i.e. a reticulate
    interveinal chlorosis.  In hydrocultures the root system was strongly
    affected after 12 days at 0.067 mg thallium/litre.  Thallium(I)
    nitrate and sulfate were similarly toxic.  The toxic effects of lower
    concentrations were reduced by the addition of aluminium sulfate,
    nitrogen and potassium iodide.  In other species of  Nicotiana, only
    terminal growth, chlorophyll formation or roots were affected, and the
    level of sensitivity to thallium corresponded to the level of
    susceptibility to frenching in the field (Spencer, 1937).

         After being watered for 15 days with 20 or 200 mg thallium per
    litre, the growth of cucumber seedlings was unaffected, but growth was
    reduced by 2000 mg thallium/litre.  Toxicity was increased by limiting
    the uptake of potassium.  The higher sensitivity of the epicotyls
    compared to the hypocotyls indicated that cell multiplication
    processes are more sensitive than those entailing cell enlargement and
    differentiation, a phenomenon known from many other stress factors and
    toxic substances (Siegel & Siegel, 1976).  In corn, production of top
    and root biomass was severely reduced to between 50 and 60% of the
    controls (Carlson et al., 1975).

         From the differential reduction in weight in parts of the bean
    plant, it has been shown to be possible to rank them according to
    their increasing sensitivity to thallium(I): roots >> upper leaves
    > lower leaves = upper stems > lower stems.  Results from hydroponic
    cultures were similar to those from field studies (Kaplan et al.,
    1990).  In another variety of bean, the weights of leaves and stems,
    but not those of roots, were affected by exposure to thallium(III) (up
    to 2 mg/kg).  However, thallium(I) had no effect (Pötsch & Austenfeld,
    1985; Pieper & Austenfeld, 1985).

         Garden lettuce and radish growing in soils treated with TlNO3
    exhibited considerably reduced growth at concentrations in dry plant
    tissue of 30-35 mg thallium/kg (Hoffmann et al., 1982).  Growth of
    perennial rye grass  (Lolium perenne) was adversely affected when
    concentrations of thallium exceeded about 0.7 mg/kg dry weight in
    shoots and 2.0 mg/kg dry weight in roots (Al-Attar et al., 1988).

    9.3.1.4  Different sensitivities to thallium(I) and thallium(III)

         Only small differences were observed between the toxic effects of
    thallium(I) and thallium(III) on the dry weight of roots and shoots of
    maize.  Growth was slightly more reduced after application of
    thallium(I) (Logan et al., 1984).  Similarly, in two detailed studies
    of the effects of thallium(I) and thallium(III) nitrate (0.2, 1, 2 mg
    thallium/litre nutrient solution) on the dry weight of pea plants,
    growth was found to be affected more after exposure to thallium(I).

    However, completely opposite results were obtained for field beans
    (Pötsch & Austenfeld, 1985; Pieper & Austenfeld, 1985).  Following
    complexation of thallium(III) and thallium(I) nitrate with EDTA,
    plants reacted differently to the two compounds.  In bean stems and
    roots, but not in leaves, concentrations of thallium were increased by
    thallium(III) EDTA compared to those resulting from thallium(III) on
    its own, while thallium(I) EDTA resulted in similar or lower thallium
    concentrations than thallium(I) on its own in all three plant organs. 
    In the stems and leaves of peas, thallium(III) EDTA resulted in lower
    thallium concentrations than thallium(III) on its own, while in the
    roots thallium levels were the same for both salts.  Consistently
    higher thallium concentrations were found in leaves, stems and roots
    of peas after exposure to thallium(I) EDTA, compared to thallium(I) on
    its own (Pötsch & Austenfeld, 1985; Pieper & Austenfeld, 1985).

    9.3.1.5  Concentration of trace elements

         The effects of thallium on plants could be caused mainly by an
    imbalance of essential cellular monovalent cations or by a disturbed
    uptake of trace elements (Yopp et al., 1974; Schweiger & Hoffmann,
    1983).  As can be concluded from the data summarized in Table 29,
    thallium seems to have no uniform effect on the trace element content;
    the differences between the two investigations using beans are
    striking.  In most studies the concentration of magnesium was found to
    be reduced.

         Exposure to thallium(III) chloride reduced the concentrations of
    potassium and trace elements such as copper, zinc and iron in bush
    beans by up to 20%; calcium, magnesium and manganese were only
    slightly affected (Makridis & Amberger, 1989b).  Rape was less
    sensitive; uptake was decreased for potassium and copper, but
    increased for zinc (and for calcium, magnesium, manganese and iron by
    the reduced growth).

         Complex effects on trace elements were found in studies with
    Pisum sativum and Vicia faba in which thallium(I) and thallium(III)
    nitrate and their respective EDTA complexes were used (Table 29)
    (Pötsch & Austenfeld, 1985; Pieper & Austenfeld, 1985).

    9.3.1.6  Sensitivity of plants

         Differing sensitivities among plant species, strains and
    individuals have been reported for a number of air-borne contaminants
    (Guderian, 1977).  Species differences were also evident in many
    investigations of thallium, including the detailed studies carried out
    at Lengerich, Germany (LIS, 1980).  There the residues of pyrite
    roasting had been used for six years before effects were obvious


        Table 29.  Thallium-induced changes in uptakea or concentrations of trace elements in plants
                                                                                                                                                

                                         Part of                           Trace elements                         Reference
                                         plant
                                                       B      Ca     Cu     Fe     Mg     Mn     Mo     Zn
                                                                                                                                                

    Thallium(I)

    Compound              TlNO3          shoot         -      -      d      -      -      i      -      d      Schweiger & Hoffmann (1983)
    Concentrationb        10
    Exposure time         7 days
    Species               sunflower

    Compound              Tl2SO4         root          u      u      i      u      d      i      u      i      Kaplan et al. (1990)
    Concentration         1              leaf          ic     d      u      u      d      u      ic     ic
    Exposure time         33 days
    Species               bean

    Compound              TlNO3          root          -      -      u      u      -      d      -      d      Pötsch & Austenfeld (1985)
    Concentration         0.2-2          stem          -      -      u      u      -      d      -      u
    Exposure time         28 days        leaf          -      -      u      u      -      u      -      u

    Compound              +EDTA          root          -      -      u      u      -      d      -      u
    Species               bean           stem          -      -      u      u      -      u      -      u
                                         leaf          -      -      u      u      -      u      -      u

    Compound              TlNO3          root          -      -      d      u      -      d      -      d      Pötsch & Austenfeld (1985)
    Concentration         0.2-2          stem          -      -      u      i      -      d      -      u
    Exposure time         28 days        leaf          -      -      u      u      -      u      -      u
                                                                                                                                                

    Table 29 (cont'd).
                                                                                                                                                

                                         Part of                           Trace elements                         Reference
                                         plant
                                                       B      Ca     Cu     Fe     Mg     Mn     Mo     Zn
                                                                                                                                                

    Compound              +EDTA          root          -      -      u      u      -      d      -      u
    Species               pea            stem          -      -      u      i      -      i      -      u
                                         leaf          -      -      i      i      -      u      -      i

    Thallium(III)

    Compound              Tl(NO3)3       root          -      -      u      u      -      d      -      d      Pieper & Austenfeld (1985)
    Concentration         0.2-2          stem          -      -      u      u      -      d      -      i
    Exposure time         28 days        leaf          -      -      u      u      -      d      -      u

    Compound              +EDTA          root          -      -      u      u      -      d      -      u
    Species               pea            stem          -      -      u      i      -      i      -      u
                                         leaf          -      -      i      i      -      i      -      i

    Compound              Tl(NO3)3       root          -      -      u      u      -      d      -      d      Pieper & Austenfeld (1985)
    Concentration         0.2-2          stem          -      -      u      u      -      d      -      u
    Exposure time         28 days        leaf          -      -      u      u      -      d      -      d

    Compound              +EDTA          root          -      -      u      u      -      d      -      u
    Species               bean           stem          -      -      u      u      -      u      -      u
                                         leaf          -      -      u      u      -      u      -      u

    Compound              TlCl3                        -      i      d      d      u      i      -      d      Makridis & Amberger (1989b)
    Concentration         10-20
    Exposure time         10 days
    Species               bean
                                                                                                                                                

    Table 29 (cont'd).
                                                                                                                                                

                                         Part of                           Trace elements                         Reference
                                         plant
                                                       B      Ca     Cu     Fe     Mg     Mn     Mo     Zn
                                                                                                                                                

    Compound              TlCl3                        -      id     d      id     id     id     -      i      Makridis & Amberger (1989b)
    Concentration         10-20
    Exposure time         10 days
    Species               rape
                                                                                                                                                

    a    d = decrease; u = unchanged; i = increase; - = not determined
    b    mg/litre solution
    c    Only upper not lower leaves
    d    Increase by reduced growth
        (Gubernator et al., 1979).  Coniferous trees were not affected, oaks
    only slightly, and summer lime trees far more than winter ones.  Sweet
    cherry trees were more sensitive to thallium than sour cherry trees. 
    The leaves of pear trees still appeared healthy when apple and plum
    trees had already lost theirs.  Very sensitive vegetables included
    beans, cucumber and potatoes.  The sensitivity of fodder plants varied
    too; the yield of maize was strongly reduced, but not that of rape or
    turnip.  There seems to be a tendency for plants with a "hard" leaf
    surface to be less affected than those with a soft, hairy surface
    (LIS, 1980).

         Mechanisms of resistance to thallium seem to vary.  Comparing the
    growth data of beans (section 9.3.1.3) and peas, the higher tolerance
    of beans to thallium(I) and thallium(III) (section 9.3.1.4)
    corresponds to a higher concentration of thallium in the roots than in
    the stems, which in turn contained more thallium than the leaves
    (Pötsch & Austenfeld, 1985; Pieper & Austenfeld, 1985).  The more
    sensitive peas possessed high thallium concentrations in the stems,
    followed by those in the roots and leaves.  Just the opposite
    distribution is evident when barley and rape are compared: a higher
    concentration in roots than shoots in the susceptible barley and the
    opposite in the tolerant rape (Allus et al., 1987).

         Green rape possesses a much higher resistance than beans after
    application with thallium(III) chloride.  Roots were more sensitive
    than shoots and became brown.  Using a 2 µg/litre nutrition solution,
    the growth of bush beans was increasingly reduced after 3 days.  The
    first signs of reduced growth of rape were observed after 8 days
    incubation in a solution of 5 mg/litre; other symptoms could only be
    recognized after the thallium concentration was increased to
    10 mg/litre.  Then growth of the roots decreased and they became brown
    (Makridis & Amberger 1989b).  Thus, two mechanisms seem to enable
    survival at high thallium concentrations: beans (and perhaps barley,
    but not peas) reduce the amount of thallium which is transported to
    the leaves, whereas the leaves of rape are only affected at very high
    concentrations of thallium.  Tolerance to relatively high
    concentrations of thallium may be a result of complexation in plant
    tissue, a phenomenon observed with other heavy metals (Cataldo &
    Wildung, 1978).

         In addition, selective pressure can increase tolerance.  The
    morphology of plants in the Alsar region of Yugoslavia, with a
    naturally high soil thallium concentration, is not affected (Zyka,
    1972), whereas such concentrations cause severe damage at other
    locations (Schoer, 1984).  In the Alsar region, zonation of plant
    species with respect to soil thallium concentration can be observed
    (Zyka, 1972), indicating the levels which are toxic to the various
    species.

    9.3.2  Wild animals

         The effects of thallium on invertebrates have rarely been
    investigated.  After ant workers ingested about 0.2 mg thallium
    chloride or thallium acetate per insect over a period of 2 months, all
    survived (Jeantet et al., 1977).  Field baits containing thallium
    sulfate or acetate have been used against the fire ant and Pharaoh's
    ant and destroyed about 90% of the colonies.  These studies and the
    toxic effects on crickets have been summarized by Negherbon (1959).

         Corn poisoned with thallium sulfate has been used on a large
    scale to control rodents.  Such pest control carried out in the field
    can affect various seed-eating animals and their predators (Munch et
    al., 1974).  An oral LC50 of 35 mg/kg fresh weight in starlings
     (Sturnus vulgaris) was reported by Schafer (1972).  This LC50 was
    calculated following a single dose of thallium sulfate administered
    via gavage, with a 7-day observation period.  Thallium-poisoned baits
    have also been used to control predatory birds.  It was presumed that
    9 out of 37 bald and golden eagles, which were collected sick or dead
    in the USA, died from thallium poisoning in 1971-1972.  Their kidneys
    contained high concentrations of thallium (14 to 63 mg/kg) (Cromartie
    et al., 1975).  In experimentally poisoned eagles, which died from a
    single oral dose of 120 mg thallium/kg body weight, the kidneys
    contained 39 and 104 mg/kg (Bean & Hudson, 1976).  Linsdale (1931)
    reported the toxic effects of excessive use of thallium in California
    for "ground squirrel control" on 58 species of game birds, song birds
    and other wild animals.  In 1972 all use of thallium in pesticides was
    banned in the USA (Smith & Carson, 1977); in a study on birds carried
    out between 1977 and 1981 no elevated thallium levels could be
    detected (Wiemeyer et al., 1986).

         In Denmark, partridges, pheasants, red foxes, badgers and martens
    were found to be killed by direct ingestion of thallium-containing
    rodenticides or poisoned prey (summarized by Munch et al., 1974;
    Clausen & Karlog, 1974).  Patho-anatomical findings from 1963 to 1971
    indicated that 55 out of 299 red foxes and 5 out of 17 badgers
    examined had suffered from poisoning.  Determinations of thallium
    concentrations in the kidney, liver and intestines demonstrated that
    27 foxes and 1 badger had presumably been killed by thallium (Table
    15).  In most of the foxes not suspected of thallium poisoning,
    thallium concentrations were < 0.1 mg/kg.  Several of the poisoned
    foxes showed abnormal behaviour, but only one fox showed clear
    hair-loss.  A typical sign in poisoned foxes was an empty stomach
    (Munch et al., 1974). This was not observed in poisoned martens and
    badgers.  In addition, there were no skin lesions.  Before death, many
    of the martens showed uncoordinated movements and loss of balance. 
    The thallium concentrations in the inner organs of martens and badgers
    ranged up to 92 mg/kg wet weight (Table 15) (Clausen & Karlog, 1974).

    9.3.3  Household pets and farm animals

         Accidental poisoning of pet animals (dogs and cats), ducks and
    pigeons has been reported repeatedly (Zook & Gilmore, 1967).  The
    first detailed investigations considering toxic effects in dogs and
    cats were performed to evaluate the risk of rodent poisoning campaigns
    with thallium sulfate.  Such cases used to be numerous, but in recent
    years only occasional poisonings have occurred, due to the reduced use
    of thallium as a rodenticide.  For example, in Baden-Württemberg,
    Germany, only 6 dogs, 4 cats and some ducks and pigeons were found to
    have been poisoned by thallium from 1977 to 1989, and then no case
    occurred up to 1992 (F. Baum, 1993, Institute of Animal Hygiene,
    Freiburg, Germany; personal communication to the IPCS).

         Symptoms of chronic intoxications in pets and farm animals are
    similar to those of acute intoxications and can usually best be
    observed in dogs.  In ruminants uncharacteristic symptoms develop
    (Hapke, 1984).

         In some areas with naturally very high thallium levels, e.g., in
    Yugoslavia and Israel, natural poisoning of farm animals after
    consumption of vegetation has occurred (summarized by Gough et al.,
    1979).

         Table 30 summarizes early investigations by Ward (1931) and Shaw
    (1932) on the toxicity of thallium sulfate to farm animals (quails,
    geese, ducks and cattle), carried out in order to assess the risks of
    its use as a rodenticide.  In ducks an intraperitoneal injection of up
    to 10 mg thallium/kg did not affect the birds, 15-25 mg/kg caused loss
    of feathers on the back and 35-100 mg/kg was lethal within 24-63 h
    (Ward, 1931).  After feeding barley contaminated with 35, 50, or 75 mg
    thallium/kg, ducks survived, or died in 12 days, or overnight,
    respectively.  Those ducks which died showed a mucous clogging of the
    nasal passages (resulting in a marked gasping for breath), profuse and
    green-coloured diarrhoea, loss of accommodation, wobbly gait and
    extreme exhaustion.  Death was due to respiratory failure and occurred
    within 2 h after the beginning of intermittent asphyxial spasms.
    Dissection of the dead ducks demonstrated that the intestinal tract
    was plugged with a thick yellowish mucous.  In addition, irritations
    and ulcerations were present in the small intestine, and the livers
    were enlarged and degenerated (Ward, 1931).

         The same author investigated the effect on cattle (Ward, 1936). 
    Using thallium(I) sulfate, one cow received 50 mg thallium/kg body
    weight and 3 heifers 35, 25 and 15 mg/kg, the latter two additional
    doses of 20 and 35 mg/kg at 69 and 31 days after the first
    administration.  Two of the animals defaecated small quantities of
    bloody faeces, all showed muscular twitching of flank and drooling of
    a stringy mucous from nose and mouth.  The cow died 5 days after


        Table 30. Acute toxicity of thallium(I) sulfate for farm animals
                                                                                                                            

    Species        Route of             Period of            Toxicitya        Dose (mg thallium/kg       Reference
                   administration       observation                           body weight)
                                                                                                                            

    Quail          oral                 7 days               LC100            approx. 12                 Shaw (1932)

    Goose          oral                 14 days              LC100            approx. 15                 Shaw (1932)
                   oral                 2-3 days             LC100            approx. 30-45              Shaw (1932)

    Duck           oral                 14-21 days           LC100            approx. 30                 Shaw (1932)
                   oral                 > 15 days            LOEL             approx. 50                 Ward (1931)
                   intraperitoneal      > 15 days            LOEL             approx. 25                 Ward (1931)

    Cow            oral                 14 days              LOEL             approx. 25                 Ward (1936)
                                                                                                                            

    a   LC100 = concentration at which all animals were killed; LOEL = low-observed-effect level
        administration, and the two heifers with the highest doses lived 11
    and 14 days.  The last animal was killed 3 days after the last
    administration.  Pathological changes were evident in the lymphatic
    vessels (congested and oedematous), the liver (pale or congested) and
    kidney (congested) and the walls of the digestive tract (haemorrhages,
    ulcerations).  Other organs appeared normal, and no significant
    depilatory effect occurred.  Recently Frerking et al. (1990) reported
    thallium poisoning in cattle caused by the use of contaminated silage. 
    Symptoms were muscular twitching, colic, nervous behaviour, extreme
    thirst, drooling from nose and mouth, loss of hair at the tail and,
    later, erosion of nasal epithelium.  The authors estimated that over a
    period of 6 weeks the cows had ingested 0.75 mg thallium/kg body
    weight daily (a total of 17 g thallium).

         Anthropogenic contamination, especially from cement plants in
    Germany, led to detailed studies of the effect of
    thallium-contaminated fodder on the development of farm animals. 
    Continuous supplementation of maize-soybean fodder with 2, 4, 15 or
    40 mg thallium(I) nitrate/kg in a 42-day broiler test and a
    280(322)-day laying hen test caused obvious effects only at the
    highest concentration (Ueberschär et al., 1986).  In comparison to
    control animals provided with uncontaminated feed, the body weight of
    the treated broilers and hens was reduced by about 14 and 32%,
    respectively; in the latter, laying rate (18%), feed efficiency (10%)
    and eggshell thickness (2%) were also reduced.  In broilers fed with
    the two higher concentrations of thallium, gizzard erosion occurred.

         In a detailed feeding study with fattening pigs with respect to
    performance, health and meat residues, low concentrations of thallium
    (daily intake of 0.05 and 0.1 mg thallium/kg body weight) were without
    any effects on weight gain, carcass quality, health, or haematological
    and biochemical parameters (Konermann et al., 1982).  Daily
    administration of 0.3 or 1.0 mg/kg body weight in drinking-water was
    toxic to sheep, and the animals had to be killed after 4 and 6 weeks,
    respectively (Hapke et al., 1980).  Administration of daily doses of
    0.03 and 0.1 mg thallium/kg body weight to sheep (for 11 weeks in
    drinking-water) and 0.025 mg/kg body weight to steers (for 6 months in
    fodder) caused no deaths (Hapke et al., 1980).  However, in both
    species daily uptake of 0.1 mg/kg body weight affected the animals
    after several weeks or months; fodder should therefore contain less
    than 0.5 mg/kg dry weight.  Protein-rich food reduced the toxic action
    of thallium (Hapke, 1984).

    10.  EVALUATION

     10.1  Evaluation of human health risks

    10.1.1  Exposure levels

         Since thallium is a naturally occurring element, humans are
    exposed to low levels in drinking-water, food and ambient air. 
    Drinking-water concentrations are often below the level of detection
    (0.3 µg/litre) and rarely contribute more than 1 µg/litre.  The total
    intake of thallium from drinking-water has been estimated to be
    < 1 µg/day for the vast majority of humans.  In uncontaminated areas,
    the dietary contribution of thallium has been estimated to be less
    than 5 µg/day, with most of this coming from vegetables.  Increased
    dietary intakes have been reported for individuals living in areas
    with thallium-contaminated soils; vegetables in these areas have been
    found to contain thallium concentrations 1-2 orders of magnitude
    higher than those grown in uncontaminated areas.  However, the actual
    dietary intakes for individuals consuming contaminated vegetables have
    not been determined.  In areas where there are no point sources of
    thallium, ambient air concentrations are very low (< 1 ng/m3),
    typically contributing less than 0.005 µg/day to the total intake. 
    Concentrations of thallium in workplace air can be several orders of
    magnitude higher than those in ambient air, resulting in a
    significantly increased total thallium intake.  At the level of the
    threshold limit values (TLVs) in some countries (0.1 mg/m3), the
    thallium intake from inhalation alone would be of the order of
    1000 µg/day (assuming inhalation of 10 m3 during a workshift).  This
    intake from inhalation alone (which may be even higher in some
    workplaces) is about 500-fold higher than the total intake from
    non-occupationally exposed humans living in non-contaminated areas.

         There are only limited data about the actual thallium content of
    workplace air.  The most recent (1980s) concentrations of thallium
    observed were < 22 µg thallium/m3 (in the production of a special
    thallium alloy and in a thallium smelter).  Average urinary
    concentrations were determined to be in the range of 0.3-8 µg/litre
    for cement workers and 0.3-10.5 µg/litre for foundry workers.

    10.1.2  Kinetics

         Thallium is rapidly and well absorbed through the
    gastro-intestinal and respiratory tracts and is also taken up through
    the skin. It is rapidly distributed to all organs and passes the
    placenta, as indicated by the rapid fetal uptake, and the blood-brain
    barrier.  Because of its rapid accumulation in cells, concentrations
    of thallium in whole blood do not reflect the levels in tissues.  In
    acute poisoning of experimental animals or humans, initially high
    concentrations of thallium appear in the kidney, low concentrations in
    fat tissue and brain, and intermediate concentrations in the other
    organs; later the thallium concentration of the brain also increases.

         Elimination of thallium may occur through the gastrointestinal
    tract (mainly by mechanisms independent of biliary excretion), kidney,
    hair, skin, sweat and breast milk.  Intestinal reabsorption (mainly
    from the colon) may occur with a consequent decrease in total body
    clearance.  In rats, the main routes of thallium elimination are
    gastrointestinal (about 2/3) and renal (about 1/3), while in rabbits
    the contribution of the two routes is about equal.  Thallium is also
    secreted in saliva.

         As with many other substances, the excretion of thallium in
    humans differs from that in laboratory animals since the rate of
    excretion is generally much lower in humans (rate constant =
    0.023-0.069 day-1) than in animals (average rate constant = 0.18
    day-1).  Another major difference between humans and animals is the
    relative contribution of the different routes of excretion.  In
    humans, renal excretion seems to be much more important than in
    animals, although its relative contribution to the total body
    clearance has not been definitively established, due principally to
    the lack of sufficient human data.  Moreover, exposure levels,
    duration of exposure, impairment of excretory organ function,
    potassium intake and concomitant treatment of acute poisoning may
    widely influence the results.

         In a case report in which radioactive thallium (2.3 mg) was
    therapeutically administered, urinary excretion of thallium within
    72 h after dosing was 11% of the administered concentration, whereas
    the gastrointestinal elimination was 0.5% during the same time period. 
    According to this study, renal excretion of thallium is about 73%,
    whereas that through the gastrointestinal tract is about 3.7% of the
    daily excreted amount.  Elimination through hair has been estimated to
    be 19.5% and that through skin and sweat 3.7%.

         On the basis of the total daily excretion value, the daily intake
    of thallium has been estimated to be about 11 µg and 0.9 µg in
    chronically exposed and unexposed population, respectively; based on
    the total amount of thallium in the body, a daily intake of about
    2.3 µg may be calculated in unexposed populations.

         The biological half-life of thallium in laboratory animals
    generally ranges from 3 to 8 days.  In humans it is about 10 days but
    values of up to 30 days have been reported.

         No data on the biotransformation of thallium are available.

    10.1.3  Toxic effects

         Thallium salts are mainly tasteless, odourless, colourless and
    highly toxic.  They were easily obtainable as rodenticides in the past
    and are still available in some developing countries.  Acute thallium
    poisoning has resulted from accidental ingestion of thallium sulfate
    and its use for suicide, homicide and attempts at illegal abortion. 
    Cases of homicide involving multiple low doses can induce chronic
    intoxication.  Chronic thallium intoxication has been observed in
    occupationally exposed workers, and symptoms suggestive of thallium
    poisoning have been seen in population groups in contaminated areas.

         Clinical manifestations of acute thallium poisoning may occur
    within hours or several days after exposure.  Symptoms are often
    diffuse and initially may include anorexia, metallic taste, nausea,
    vomiting, retrosternal and abdominal pain, pain in the limbs, and
    paraesthesia.  Gastrointestinal haemorrhage occasionally occurs; later
    on constipation is a common symptom.  After the second day of thallium
    poisoning, effects on the central and peripheral nervous systems,
    skin, kidneys, eyes, cardiovascular and respiratory systems
    progressively develop.  Extreme sensitivity and pain in the legs,
    later followed by the "burning feet" syndrome and paraesthesia, are
    common manifestations.  Insomnia, depression, hallucination, lethargy,
    delirium, convulsions and coma may be followed by death, usually
    between 10 and 12 days. Where survival extends beyond a week or so,
    both motor and sensory neuropathy with cranial nerve involvement and
    retrobulbar neuritis may develop.  Common circulatory disorders, such
    as hypertension, tachycardia and ischaemic cardiac changes, may also
    occur.  Frequently loss of head hair and sometimes also body hair
    occurs after the second week of thallium poisoning.  Dystrophy of the
    nails is manifested by the occurrence of lunular stripes (Mee's lines)
    3 to 4 weeks after intoxication.  Recovery requires months and
    occasionally some of the neurological and mental disturbances are
    permanent.  Permanent blindness may follow retrobulbar neuritis and
    optic nerve atrophy.

         Clinical features are generally milder in cases of chronic
    poisoning than in acute thallium intoxication.  Occurrence of chronic
    thallium poisoning usually begins with neurological symptoms such as
    tiredness, fatigue, headache and insomnia.  In some cases the first
    clinical findings include alopecia and constipation.  The triad of
    gastroenteritis, polyneuropathy and alopecia is regarded as the
    classical syndrome of thallium poisoning, but in some cases
    gastroenteritis and alopecia have not been reported.

         Postmortem examinations following thallium poisoning reveal
    damage in various organs.  Haemorrhage in the mucosa of the intestine,
    lungs and heart, kidney damage, fatty infiltration of the liver and
    heart, and degeneration of neurons, including ganglion cells and
    axons, with disintegration of myelin sheaths have all been observed.

         Limited data are available on the effects of thallium on human
    reproduction.  Libido and male potency have been found to be adversely
    affected in poisoning cases.  There is no adequate evidence for a
    genotoxic effect of thallium, and there have been no reports of any
    carcinogenic or immunological effects.

         Following low-level environmental exposure to thallium, a
    dose-response relationship has been shown between thallium excretion
    in urine and the prevalence of tiredness, weakness, sleep disorders,
    nervousness, headache, muscle and joint pain and paraesthesia.  Based
    on replies to a questionnaire, a similar dose-response relationship
    was seen when thallium in hair was taken as an indicator of exposure
    and uptake.

    10.1.4  Dose-response relationship (animals)

         No lifetime studies of thallium administration have been
    conducted on laboratory animals.  In addition, no studies by the route
    of inhalation are available.  Three studies of intermediate duration
    by the oral route are described in this report.  A no-observed-effect
    level could not be determined from any study.  The lowest doses were
    used in a 90-day gavage study (0, 0.01, 0.05 or 0.25 mg/kg body weight
    per day).  Small but statistically significant changes in some
    clinical chemistry parameters were seen at the lowest dose level, as
    was alopecia.  From animal studies, it therefore appears that an
    intake of 0.01 mg/kg per day may be associated with adverse effects. 
    No doses lower than this have been tested.

         On the basis of LC50 values in animals and known lethal doses
    in humans, it appears that humans may be more sensitive than
    laboratory rodents to the toxic effects of thallium.  Because of the
    availability of human data and the apparently greater sensitivity of
    humans, a quantitative evaluation of animal data for use in a risk
    assessment has not been conducted here.

    10.1.5  Dose-response relationship (humans)

         Cases of acute thallium poisoning (with symptoms and signs listed
    in the section 10.1.3) have occurred as a result of ingestion of doses
    of thallium (in the form of soluble salts) as low as 1.5 mg/kg body
    weight.  Higher doses give rise to more severe symptoms.  Doses that
    have given rise to lethal poisoning are in the order of 10 mg/kg.

         Concerning risks related to long-term exposure to lower doses of
    thallium, the Task Group considered that an evaluation, although
    uncertain, could best be performed on the basis of observed
    relationships between urinary excretion of thallium and the occurrence
    of symptoms.  The urinary excretion value can be taken as an indicator
    of the daily total absorbed dose from inhalation and dietary intake.

         A population-based study on unexposed healthy subjects living in
    northern Italy was performed with the aim of determining trace element
    concentrations, including thallium, in blood, serum or plasma, and
    urine, in which the collection, handling and analysis of the samples
    was carried out under rigorous standardized protocols.  The 496
    subjects in this study, drawn from both urban and rural areas were
    screened for normality by means of a questionnaire and clinical and
    biochemical examination (with the exclusion of those with a history of
    occupational exposure, heavy smokers, and those in a diseased state). 
    The mean urinary thallium concentration was 0.42 ± 0.09 µg/litre
    (range 0.07-0.7 µg/litre).  Other carefully controlled studies in
    population samples showed similar urinary concentrations, e.g., 0.4 ±
    0.2 µg/litre and 0.3 ± 0.2 µg/litre in rural and urban population
    samples, respectively, and 0.3 ± 0.14 µg/litre in a sample of 149
    subjects.  This gives credence to a mean value of 0.3-0.4 µg/litre for
    urinary thallium concentration in an unexposed population.  In all
    three studies, involving a total of 686 subjects, the range of urinary
    thallium concentrations was 0.06-1.2 µg/litre.  As thallium has a
    short biological half-life, measured in days, and if a steady state
    can be assumed to exist in such population-based samples, the above
    urinary excretion value can be taken as an indicator of total dose in
    terms of absorption following inhalation and total daily dietary
    intake.

         By contrast, in a population sample living in the vicinity
    of thallium emission into the atmosphere, the mean urinary 
    thallium concentration was 5.2 µg/litre ± 8.3 µg/litre (range
    0.1-76.5 µg/litre).  Although a questionnaire on health effects was
    compiled on each subject, no objective tests were performed.  From the
    replies to the questionnaire a clear dose-response relationship was
    found between thallium concentration in urine and the prevalence of
    tiredness, weakness, sleep disorder, headache, nervousness,
    paraesthesia, muscle and joint pain.  A similar dose-response
    relationship was found when thallium in hair was taken as an indicator
    of exposure.  In a limited study on cement plant workers with thallium
    exposure, where five workers showed urinary thallium levels above
    5 µg/litre, but where the time interval between cessation of exposure
    and urine collection was not stated, paraesthesia was reported in five
    workers and distal muscle weakness in three.  However, these symptoms
    could not be related to thallium exposure.

         From the above limited studies it is suggested that an
    approximately 15-fold increase in urinary excretion of thallium above
    the mean non-exposed level of 0.3 to 0.4 µg/litre may be related to
    subjective symptoms which could possibly be considered as early
    adverse health effects.

         It is known from clinical practice that there is an increased
    urinary concentration of thallium in acute poisoning cases.  In 14
    cases of thallium poisoning with recovery after therapy, the urinary
    thallium concentrations ranged from 500 to 20 400 µg/litre.  In seven
    of these cases concentrations were below 2700 µg/litre.  It should be
    recognized that these values are not entirely comparable to those in
    long-term exposure since they do not represent steady-state
    conditions.

         In summary, the Task Group considered that exposures causing
    urinary thallium concentrations below 5 µg/litre are unlikely to cause
    adverse health effects.  In the range of 5-500 µg/litre the magnitude
    of risk and severity of adverse effects are uncertain, while exposures
    giving values over 500 µg/litre have been associated with clinical
    poisoning.

    10.2  Evaluation of the effects of thallium on the environment

         Thallium is an element which occurs naturally in the earth's
    crust, primarily in the monovalent form.  In marine water and some
    localized strongly oxidizing freshwater and soil, thallium may be
    present primarily in the oxidized trivalent form.  The major
    anthropogenic sources of thallium released to the environment are
    smelting of metallic ores, mining, special cement production, and the
    combustion of fossil fuels, principally coal.  Relatively little
    thallium is released into the environment because of the production
    and use of thallium compounds.  Thallium levels reported in air are
    generally < 1 ng/m3 although mean values up 15 ng/m3 have been
    reported in industrial and urban air.  Thallium may be released
    directly to the environment following its use as a rodenticide,
    although such use has been restricted or banned in many countries.

         Thallium tends to persist in soil, although it may be leached to
    water under acidic conditions.  Monovalent thallium is relatively
    stable in solution whereas trivalent thallium may be removed from the
    water column by precipitation as the oxide or hydroxide.  Although
    thallium can bioconcentrate, it is unlikely to biomagnify in aquatic
    or terrestrial food webs.  Thallium concentrations in water tend to be
    low, a maximum concentration of 2.4 mg/litre having been reported for
    industrial waste water.  Thallium concentrations in surface water from
    industrial regions have been reported to range from 1 to 100 µg/litre,
    while surface water in uncontaminated areas normally contains lower
    levels.  Concentrations of thallium in seawater range from < 0.01 to
    0.02 µg/litre.

         Most studies of effects on aquatic organisms have used soluble
    monovalent thallium compounds.  Acute toxic effects have been reported
    in freshwater algae exposed to thallium at 100 µg/litre.  Reduced
    growth of aquatic macrophytes was reported following a 28-day
    exposure to 8 µg/litre.  The 48-h LC50 reported for  Daphnia was
    2200 µg/litre, while a 24-h LC50 of 110 µg/litre has also been
    reported.  The 96-h LC50 values for freshwater fish range from 860
    to 132 000 µg/litre.  An LC50 of 40 µg/litre has been reported for
    freshwater fish exposed to thallium for approximately 40 days.  The
    96-h LC50 values for marine species are 2100 µg/litre for
    invertebrates and 20.9-24 mg/litre for fish.  The available aquatic
    toxicity data suggest that thallium can harm aquatic organisms. 
    However toxic effects are likely to be limited to sites adjacent to
    point sources such as some metal mining and smelting operations and
    cement plants.

         Thallium concentrations in uncontaminated soil typically range
    from about 0.1 to 1.0 mg/kg dry weight, although higher levels can
    occur near natural sources such as thallium-enriched shales and some
    metallic ore deposits.  Levels are generally somewhat elevated near
    anthropogenic sources such as cement plants using thallium-containing
    pyrite (up to 21 mg/kg dry weight) and base metal smelters (up to
    2.1 mg/kg dry weight) that release large quantities of thallium to the
    atmosphere.

         Very few data have been identified concerning the effects on
    terrestrial organisms of thallium in soil.  The results of one study
    suggest that microbial community structure is disturbed at
    concentrations in the range of 1 to 10 mg/kg dry weight.  However, the
    properties of the soil and the form of thallium used in this study
    were not identified.

         Plants growing in uncontaminated soil normally contain 0.01 to
    0.3 mg thallium/kg dry weight, while those growing near cement plants
    using thallium-enriched pyrite have been reported to contain much
    larger amounts (100 to 1000 mg/kg dry weight).  Reduced growth has
    been reported in sensitive plant species at concentrations of about
    1 mg thallium/kg of dry plant tissue following exposure to monovalent
    thallium.  Toxic effects on terrestrial plants are therefore possible
    near some cement plants using thallium-enriched pyrite.

         The use of thallium as a rodenticide has resulted in poisoning of
    non-target organisms including foxes, badgers, martens, partridges,
    pheasants and eagles.  Poisoning of domestic animals, such as dogs,
    cats, ducks and pigeons, has also been widely reported.  The number of
    wildlife poisoning incidents has declined as a result of the reduced

    use of thallium as a rodenticide.  In countries with naturally high
    thallium levels, such as former-Yugoslavia and Israel, some farm
    animals have been poisoned following ingestion of vegetation with a
    high thallium content.  Symptoms of thallium poisoning have been
    reported in cows that were calculated to have consumed 0.75 mg
    thallium/kg body weight per day for a 6-week period.

    11.  CONCLUSIONS AND RECOMMENDATIONS

         The currently limited industrial uses of thallium are unlikely to
    pose a threat to the general environment.  At industrial facilities
    such as metal mining and smelting operations and cement plants using
    pyrite, which can release significant amounts of thallium, the
    concentration of thallium in industrial raw materials as well as stack
    gases and waste water should be monitored and, if necessary,
    controlled.  Waste materials containing water-soluble thallium
    compounds should be sealed and marked to avoid leaching and pollution
    by dust.

         In the general population, environmental exposure to thallium
    does not pose a health threat.  The total intake has been estimated to
    be less than 5 µg/day, with the vast majority coming from foodstuffs;
    drinking-water and air generally contribute very small amounts of
    thallium.

         Due to its toxicity to both humans and non-target environmental
    species, the use of thallium as a rodenticide has been prohibited in
    many countries.  Where thallium is still available for such use,
    however, the potential for accidental poisoning or for its use in
    homicide or suicide remains a significant concern.  It is recommended
    that the use of thallium as a rodenticide be prohibited worldwide,
    particularly as less hazardous methods of rodent control are
    available.

         Atmospheric emissions from industrial sources (e.g., cement
    plants using thallium-containing pyrite) have resulted in increased
    concentrations of thallium in biological samples (e.g., urine and
    hair) from the population living in the vicinity.  A relationship was
    found between thallium concentrations in urine and hair and the
    prevalence of symptoms possibly indicating early health effects of
    thallium.  The limited available data are not sufficient for
    determining an acceptable limit for emissions.  Steps should be taken,
    however, to limit emissions to the greatest extent possible.  Where
    thallium may be released into the environment, monitoring of both
    atmospheric emissions and resulting dust deposition rates should be
    performed.  Where environmental monitoring reveals thallium levels
    significantly above background, it is recommended that biomonitoring
    of the population living in the vicinity of the point source be
    carried out.  If biomonitoring reveals excessive exposure to thallium,
    emissions from the point source should be re-evaluated and an effort
    made to reduce them.

         Since current occupational exposures to thallium may be of
    concern to health, it is recommended that measures be taken to reduce
    occupational exposure (as described in section 8.7 of this monograph). 
    Furthermore, revision of threshold limit values for thallium warrants
    consideration.

         All thallium analyses should be accompanied by a quality
    assurance programme.  This requires certified reference materials of
    one matrix and of a similar concentration range to the sample to be
    analysed and participation in an inter-laboratory comparison
    programme.  There is a need to make such reference materials
    available.

         Since thallium is rapidly and well absorbed and its excretion is
    mainly renal, concentrations of thallium in urine may be considered a
    relatively reliable indicator of exposure.  Exposure to thallium
    causing urinary concentrations below 5 µg/litre is unlikely to cause
    adverse human health effects.  For thallium exposure giving rise to
    urinary concentrations in the range 5-500 µg/litre, the magnitude of
    risk and the severity of adverse effects on human health are
    uncertain, while exposure giving rise to 500 µg/litre or more has been
    associated with clinical poisoning.  The estimated daily oral intake
    corresponding to a urinary thallium concentration of 5 µg/litre is
    approximately 10 µg thallium in the form of a soluble compound.

         In view of the considerable uncertainties in the evaluation, the
    Task Group concluded that it was not possible to recommend a
    health-based exposure limit.  Until better information on the
    dose-response relationship becomes available, it seems prudent to keep
    exposures at levels that lead to urinary concentrations of less than
    5 µg/litre.
    12.  FURTHER RESEARCH

    a)   Follow-up epidemiological studies of populations exposed
         chronically to high levels of thallium (e.g., in the vicinity of
         cement plants and natural sources of high concentrations of
         thallium) should be performed to determine whether there is an
         increased risk of pathological effects, e.g., cancer, effects on
         reproduction (especially sperm cells) and congenital
         malformations.  Such follow-up studies are also required in order
         to assess objectively the largely subjective symptom complex
         experienced by certain populations in thallium-contaminated
         areas.

    b)   Toxicokinetics of thallium, with particular respect to
         distribution and excretion, should be studied in people with
         low-level environmental exposure (in both uncontaminated and
         contaminated areas) and in those exposed occupationally. 
         Adequate information from acutely poisoned patients should also
         be compiled to determine toxicokinetics and the relationship with
         the clinical findings.  In addition, an attempt should be made to
         correlate clinical findings with thallium concentrations in
         biological samples.  Patients should be followed for several
         years to ascertain the long-term consequences of acute
         poisonings.

    c)   Early indicators of an effect of thallium on glomerular or
         tubular kidney function, on liver function, on haem biosynthesis
         and on nerve conduction velocity should be sought in asymptomatic
         population samples and in occupationally exposed workers where
         there is evidence of excessive thallium exposure.

    d)   Early indicators of an effect of thallium absorption should be
         sought.  The effects of thallium on the haem biosynthetic pathway
         suggest that estimation of porphyrins in blood and/or urine may
         be a useful approach to detecting specific early effect of
         thallium cellular toxicity.  Similarly observations on the
         endoplasmic reticulum structure with respect to protein synthesis
         and polysome function suggest a need for further studies on liver
         function.

    e)   Chronic bioassays in laboratory animals are needed to assess the
         carcinogenic activity of thallium at low doses.

    f)   Lifetime studies in laboratory animals should be conducted using
         several low doses by the routes of both inhalation and ingestion
         to help determine a dose-response relationship and a
         no-observed-effect level.

    g)   Multi-generation studies of thallium in laboratory animals are
         needed to ascertain the reproductive and teratogenic effects of
         thallium.

    h)   Sample collection, analysis and data presentation should be
         carried out according to a protocol which ensures adequate
         validation of biological monitoring procedures.

    i)   The concentrations of thallium in environmental compartments
         adjacent to point sources should be determined using current
         analytical techniques.  The bioavailability of thallium from
         various matrices should also be determined.

    j)   Total dietary studies should be conducted in areas with high
         thallium concentrations (either natural or from industrial
         sources) to determine the oral intake in populations living in
         these regions.

    k)   Thallium concentrations in soil and vegetables from regions with
         extensive acid rain should be determined.

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    RESUME

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

      Le thallium élémentaire est un métal mou et malléable de couleur
    blanc bleuâtre.  Exposé à l'air humide ou à l'eau, le thallium est,
    selon le cas, rapidement oxydé en surface ou transformé en hydroxyde. 
    Le thallium possède deux importants degrés d'oxydation, le thallium(I)
    et le thallium(III).  Les composés du thallium monovalent (thalleux)
    se comportent comme des dérivés de métaux alcalins, par exemple du
    potassium, alors que les composés du thallium trivalent (dérivés
    thalliques) sont moins basiques et rappellent les sels d'aluminium. 
    Contrairement aux dérivés minéraux dans lesquels l'ion thallium(I) est
    plus stable en solution aqueuse que l'ion thallium(III), ce dernier
    est plus stable dans les dérivés organiques.

         Le dosage du thallium dans des échantillons provenant de
    l'environnement est assez difficile étant donné que la concentration
    est de l'ordre du µg/kg tout au plus.  En général, la limite de dosage
    dans les minéraux, les sols et les poussières est d'environ 20 µg/kg -
    approximativement 0,1 µg/litre pour les solutions aqueuses - et dans
    les produits biologiques, de quelques µg/kg, lorsqu'on ne procède pas
    à une concentration préalable du thallium.

         La spectrométrie d'absorption atomique avec four à tube de
    graphite (GF-AAS) est une méthode d'analyse qui convient bien aux
    applications exigeant une sensibilité élevée avec des prises d'essai
    réduites où la concentration en thallium est de l'ordre de quelques
    µg/kg.  Pour obtenir une bonne précision et une bonne exactitude à des
    teneurs de l'ordre du µg/kg, on peut utiliser la spectrométrie de
    masse avec dilution isotopique (IDMS) et la spectrométrie de masse en
    plasma à couplage inductif (ICP-MS), avec également possibilité de
    dilution isotopique.

    2.  Sources d'exposition humaine et environnementale

         La présence de thallium dans l'environnement résulte à la fois de
    processus naturels et de l'activité humaine.  Ce métal est omniprésent
    dans la nature et on le rencontre en particulier dans les minerais
    sulfurés de divers métaux lourds, quoiqu'en principe à faibles
    concentrations.  Il n'y a guère d'endroits où la concentration en
    thallium d'origine naturelle soit très élevée.   Le thallium n'est
    produit industriellement qu'en petites quantités (la consommation
    industrielle mondiale a été de 10 à 15 tonnes en 1991).  Le thallium
    et ses dérivés ont des applications industrielles très diverses.  Ils
    entrent dans la composition de crèmes épilatoires, de rodenticides et

    d'insecticides, mais ces utilisations sont désormais strictement
    limitées.  On utilise principalement le thallium et ses dérivés dans
    les industries électriques et électroniques ainsi que pour la
    fabrication de verres spéciaux. La scintigraphie en général et le
    diagnostic du mélanome en particulier constituent des applications
    importantes du radio-thallium en médecine et l'on a également recours
    aux dérivés d'arylthallium(III) en biochimie.

         Du thallium peut être libéré dans l'environnement par des
    fonderies (dépôts de déchets ou émissions dans l'atmosphère), des
    centrales thermiques à charbon, des briqueteries et des cimenteries
    (dans ce cas, exclusivement des émissions dans l'atmosphère).  On
    estime que l'industrie mobilise ainsi chaque année dans le monde de
    2000 à 5000 tonnes de thallium.  Les émissions de thallium dues aux
    différentes opérations industrielles varient largement d'un type
    d'industrie à l'autre.

         Les émissions des centrales thermiques à charbon peuvent avoir
    une teneur en thallium de 700 µg/m3 d'air et celles des cimenteries
    des teneurs allant jusqu'à 2500 µg/m3.  Cette dernière valeur peut
    être ramenée à < 25 µg/m3 en ayant recours à d'autres matières
    premières et en changeant de procédé.  Le thallium se volatilise lors
    de la combustion du charbon et des matières premières utilisées pour
    la production de ciment puis il se recondense à la surface des
    particules de cendre dans les parties de l'installation où la
    température est plus basse.  Ces particules peuvent contenir jusqu'à
    50 mg de thallium/kg de cendres volantes et sont souvent de petite
    taille, de sorte que seulement 50% d'entre elles sont retenues par les
    filtres.  De même, environ un tiers des particules émises par les
    centrales thermiques sont de faible granulométrie et peuvent par
    conséquent se déposer dans les voies respiratoires inférieures.

         Les effluents provenant de bassins d'évacuation de terrils et
    contenant dans un cas jusqu'à 1620 et dans un autre jusqu'à
    36 µg/litre de thallium ont provoqué, dans les cours d'eau adjacents,
    l'apparition de concentrations de thallium respectivement égales à 88
    et 1 µg/litre.  Dans les collections d'eau de pluie situées aux
    alentours d'une cimenterie, on a constaté la présence de
    concentrations de thallium allant jusqu'à 37 µg/litre.  On a trouvé
    dans le sol aux alentours de terrils de mines, des concentrations
    atteignant 60 mg/kg.  Au voisinage de la base de fours à métaux, et
    près de briqueteries et de cimenteries, on a trouvé des concentrations
    respectivement égales à 2, 0,6 et 27 mg/kg de terre.

         Dans les zones contaminées, la concentration de thallium dans la
    plupart des légumes, des fruits et des viandes est inférieure à
    1 mg/kg de poids frais.  Les teneurs sont plus élevées dans les choux
    (crucifères) avec des concentrations allant jusqu'à 45 mg/kg dans les
    choux frisés.  Il y a corrélation entre la concentration du thallium
    dans les tissus des animaux d'élevage et la concentration de ce métal
    dans le fourrage.  Au voisinage de certaines cimenteries, on a signalé
    des teneurs plus élevées en thallium dans le fourrage (par exemple
    jusqu'à 1000 mg/kg dans le colza) ainsi que dans la viande de boeuf et
    de lapin (jusqu'à 1,5 et 5,8 mg/kg, respectivement).

    3.  Transport, distribution et transformation dans l'environnement

         A proximité de sources ponctuelles telles que les centrales
    thermiques à charbon, certaines cimenteries et fonderies de métaux, la
    principale source de thallium atmosphérique est constituée par les
    cendres volantes.  Une étude a montré que près de la totalité du
    thallium présent dans les poussières en suspension d'une cimenterie
    s'y trouvait sous la forme de chlorure de thallium(I) soluble.

         La destinée du thallium qui parvient jusqu'au sol (par exemple
    sous forme de dépôt de cendres volantes) dépend en grande partie de la
    nature de ce sol.  C'est en particulier les sols à forte teneur en
    argile, en matières organiques et en oxydes de fer et manganèse qui
    retiennent le plus de thallium.  L'accroissement de la teneur en
    thallium par incorporation dans des complexes stables ne se produit
    que dans les couches supérieures.  La fixation du thallium par les
    végétaux est d'autant plus importante que le pH est plus bas.  Dans
    certains sols fortement acides, d'importantes quantités de thallium
    peuvent parvenir par lessivage jusqu'aux eaux de surface et aux eaux
    souterraines.

         On peut s'attendre à ce que la majeure partie du thallium présent
    à l'état dissous dans les eaux douces se trouve sous sa forme
    monovalente.  Toutefois, dans les eaux où la teneur en oxygène est
    forte et dans la plupart des eaux de mer, il peut y avoir prédominance
    du thallium(III).  Le thallium peut disparaître de l'eau par diverses
    réactions d'échange, de complexation ou de précipitation.

         Le thallium peut également subir une bioconcentration, mais il
    est peu probable que sa concentration s'accroisse le long de la chaîne
    alimentaire aquatique ou terrestre.

    4.  Concentrations dans l'environnement et exposition humaine

         Dans les secteurs qui ne sont pas contaminés, les concentrations
    de thallium dans l'air sont généralement inférieures à 1 ng/m3; dans
    l'eau elles sont inférieures à 1 µg/litre et dans les sédiments
    aquatiques, inférieures à 1 mg/kg.  Dans l'écorce terrestre, la
    concentration moyenne varie de 0,1 à 1,7 mg/kg, mais on peut trouver
    des concentrations beaucoup plus élevées, par exemple jusqu'à

    1000 mg/kg dans le charbon et les rares minerais de thallium que l'on
    rencontre contiennent jusqu'à 60% de cet élément.  Les produits
    alimentaires d'origine végétale ou animale en contiennent généralement
    moins de 1 mg/kg de poids sec et l'apport d'origine alimentaire moyen
    chez l'homme se révèle inférieur à 5 µg/jour.  On estime que l'apport
    de thallium par la voie respiratoire est inférieur à 0,005 µg de
    thallium par jour.

         On ne possède que des données limitées sur la concentration
    effective de thallium dans l'air des lieux de travail.  Les valeurs
    les plus récemment observées (dans les années 80) étaient inférieures
    à 22 µg de thallium par m3 (il s'agissait d'un four à thallium
    installé dans un atelier produisant un alliage spécial à base de
    thallium).  Chez des ouvriers d'une cimenterie, on a trouvé des
    concentrations urinaires moyennes allant de 0,3 à 8 µg/litre et chez
    des ouvriers d'une fonderie, des valeurs de 0,3 à 10,5 µg/litre.

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

         La thallium est rapidement et bien absorbé au niveau des voies
    digestives et respiratoires et il pénètre également à travers la peau. 
    Il se répartit rapidement dans l'ensemble des organes et traverse la
    barrière placentaire (comme le montre sa fixation rapide dans les
    tissus foetaux) ainsi que la barrière hématoencéphalique.  Comme il
    s'accumule rapidement dans les cellules, la concentration du thallium
    dans le sang total ne reflète pas sa concentration tissulaire.  Dans
    les cas d'intoxication aiguë chez l'homme et l'animal d'expérience on
    constate, au début, de fortes concentrations de thallium au niveau du
    rein et de faibles concentrations dans les tissus adipeux et le
    cerveau, les concentrations dans les autres organes se situant entre
    les deux;  ultérieurement la concentration de thallium dans le cerveau
    augmente également.

         L'élimination du thallium peut s'effectuer par la voie digestive
    (essentiellement par des mécanismes indépendants de l'excrétion
    biliaire), par les reins, les cheveux, la peau, la sueur et le lait
    maternel.  Il peut y avoir réabsorption intestinale, principalement au
    niveau du côlon avec pour conséquences une diminution de la clairance
    totale.  Chez le rat les principales voies d'élimination sont la voie
    digestive (environ les deux tiers) et la voie rénale (environ un
    tiers);  chez le lapin, ces deux voies sont d'une importance
    sensiblement égale.  Le thallium peut également être excrété par la
    salive.

         Comme dans le cas de nombreuses autres substances, l'excrétion du
    thallium n'est pas identique chez l'homme et chez l'animal de
    laboratoire, la vitesse d'excrétion étant généralement beaucoup plus
    faible chez l'homme (constante de vitesse = 0,023-0,069 jour-1) que
    chez l'animal d'expérience (constante de vitesse moyenne = 0,18
    jour-1).  Une autre différence importante que l'on observe entre
    l'homme et l'animal concerne l'importance relative des diverses voies
    d'excrétion.  Chez l'homme, il semble que l'excrétion rénale soit
    beaucoup plus importante que chez l'animal, encore que sa contribution
    à la clairance totale n'ait pas encore été définitivement établie,
    principalement du fait de l'insuffisance des données.  En outre, le
    niveau d'exposition, sa durée, les insuffisances au niveau des organes
    excréteurs, ainsi que le traitement anti-poison qui est administré,
    sont autant de facteurs qui peuvent influer considérablement sur les
    résultats.

         Une étude a montré que la quantité totale de thallium excrétée
    quotidiennement était de 73% environ par la voie rénale et seulement
    de 3,7% environ par la voie digestive.  On a estimé à 19,5% la
    proportion excrétée dans le système pileux et par la voie percutanée
    et à 3,7% la proportion excrétée dans la sueur.

         Chez l'animal de laboratoire, la demi-vie biologique du thallium
    oscille généralement entre trois et huit jours.  Chez l'homme elle est
    d'environ 10 jours, mais on a fait état de valeurs allant jusqu'à 30
    jours.

         On ne dispose d'aucune donnée sur la biotransformation du
    thallium.

    6.  Effets sur les mammifères de laboratoire et les systèmes d'épreuve
        in vitro

         La toxicité des sels de thallium(I) ne varie pas de manière
    spectaculaire d'une espèce à l'autre.  Généralement, l'ingestion d'une
    dose de 20 à 60 mg de thallium par kg de poids corporel est mortelle
    en l'espace d'une semaine.  Les cobayes sont légèrement plus sensibles
    que les autres animaux de laboratoire.  L'oxyde de thallium(III),
    insoluble dans l'eau, présente une toxicité aiguë par voie orale ou
    parentérale un peu plus faible que les sels de thallium(I).  la
    comparaison des données de toxicité aiguë montre que le thallium
    présente une biodisponibilité élevée par toutes les voies
    d'exposition.  La plupart des organes sont affectés mais on constate
    quelques variations intra- et interspécifiques pour ce qui concerne
    les signes d'intoxication et l'ordre dans lequel ils se manifestent.

         Les symptômes d'une intoxication aiguë par le thallium se
    manifestent en général dans l'ordre suivant: on constate tout d'abord
    une anorexie, des vomissements et une dépression, puis apparaissent
    une diarrhée et des manifestations cutanées (inflammation au niveau
    des divers orifices, furoncles, chute de cheveux), après quoi
    apparaissent une dyspnée et des troubles nerveux.  Enfin la mort
    survient par insuffisance respiratoire.

         les symptômes d'une intoxication chronique sont analogues.  La
    chute des cheveux est de règle.

         L'examen histologique révèle des lésions cellulaires et en
    particulier une nécrose.  Cette nécrose a été observée au niveau des
    reins, du foie, de l'intestin, du myocarde et du système nerveux.  On
    a observé dans nombreuses cellules, un gonflement des mitochondries
    avec disparition des crêtes, une dilatation du réticulum endoplasmique
    agranulaire, une augmentation du nombre de vacuoles autophagiques et
    de granules de lipofuscine, enfin, une disparition des
    microvillosités.  Les altérations fonctionnelles qu'entraîne le
    thallium peuvent s'expliquer par la destruction physique de la
    membrane des organites subcellulaires.  Au niveau du coeur, les effets
    arythmogènes se limitent au noeud sinusal.

         L'intoxication par le thallium provoque des anomalies sélectives
    au niveau de certains comportements, qui sont corrélées aux effets
    biochimiques (ce qui indique des lésions cellulaires) observés dans
    certaines régions de l'encéphale.  Un certain nombre d'effets
    neurologiques semblent être dus à l'action directe du thallium, par
    exemple l'ataxie et les tremblements qui seraient dus à des lésions
    cérébelleuses ou à des modifications de l'activité endocrine provoquée
    par des lésions au niveau de l'hypothalamus. Le système nerveux
    autonome, et principalement les fibres adrénergiques, peuvent être
    activés par le thallium.  Dans les nerfs périphériques, il semble que
    l'action du thallium s'exerce au niveau présynaptique, avec libération
    spontanée du neurotransmetteur, par antagonisme avec ce processus qui
    dépend du calcium.

         On ne sait toujours pas exactement par quel mécanisme s'exerce la
    toxicité du thallium.  On pense qu'il en existe plusieurs, liés les
    uns aux autres.  Un aspect important de l'intoxication par le thallium
    consiste dans une augmentation sensible de la peroxydation des lipides
    et de l'activité d'un enzyme lysosomique, la ß-galactosidase.  Il en
    résulte un déficit en glutathion qui entraîne l'accumulation de
    lipides peroxydés dans l'encéphale et vraisemblablement la formation
    de granules de lipofuscine.  Il semble que le mode d'action du
    thallium consiste principalement dans une perturbation de la fonction
    des mitochondries.

         Une intoxication chronique par le thallium entraîne chez l'animal
    une réduction de l'activité sexuelle et les effets gonadotoxiques du
    thallium sont manifestes chez le mâle au niveau des organes
    reproducteurs.  Chez des rats qui avaient reçu pendant 16 jours 10 mg
    de thallium par litre d'eau de boisson, on a constaté qu'au niveau des
    testicules, c'étaient les cellules de Sertoli qui étaient les plus
    sensibles et la desquamation de l'épithélium spermatogène a entraîné
    la présence de spermatozoïdes immatures dans le sperme.  Ce phénomène
    pourrait expliquer le moindre taux de survie des embryons et la durée
    de vie réduite de la progéniture après intoxication à doses sublétales
    du père.

         Après injection de thallium dans des oeufs de poule on a constaté
    chez les embryons, la présence d'effets tératogènes, une inhibition de
    la croissance et des anomalies dans le développement osseux; toutefois
    ces effets sont controversés chez les mammifères, même à des doses
    toxiques pour la mère.  On a mis en évidence le passage
    transplacentaire du thallium mais les nombreuses souches de souris et
    de rats n'ont pour ainsi dire pas présenté d'effets tératogènes.

         Deux épreuves de mutagénicité microbiologique effectuées sur
     Salmonella typhimurium ont donné des résultats négatifs et les
    résultats de la recherche  in vivo d'échanges entre chromatides
    soeurs demeurent controversés.  Toutefois, selon certaines études, on
    aurait observé des aberrations chromosomiques et une augmentation
    sensible des brèches dans l'ADN monocaténaire.

         On manque d'études à long terme sur la cancérogénicité du
    thallium.

    7.  Effets sur l'homme

         Etant donné que les sels de thallium sont inodores, incolores et
    sans saveur, leur forte toxicité et la facilité avec laquelle on
    pouvait s'en procurer naguère - et encore maintenant dans certains
    pays en développement - ont fait qu'on les a souvent utilisés à des
    fins de suicide, d'homicide, de tentatives d'avortement illicites avec
    pour résultat, dans ce cas particulier, des intoxications aiguës. 
    D'ailleurs on considère que les intoxications par la thallium sont une
    des causes les plus fréquentes, à l'échelle mondiale, des
    empoisonnements volontaires ou accidentels chez l'homme.  Ce que l'on
    sait des intoxications chroniques par le thallium se limite aux
    intoxications professionnelles, aux groupes de population vivant dans
    des zones contaminées et aux cas d'homicide par absorption de
    nombreuses petites doses.

         Les symptômes de l'intoxication aiguë par le thallium dépendent
    de l'âge, de la voie d'administration et de la dose.  Les doses qui se
    sont révélées mortelles varient entre 6 et 40 mg/kg, les valeurs
    moyennes se situant entre 10 et 15 mg/kg. Si un traitement n'est pas
    institué, cette dose moyenne entraîne généralement la mort en l'espace
    de 10 à 12 jours, mais on a également connaissance de cas où la mort
    est survenue en l'espace de 8 à 10 heures.

         La triade gastro-entérite, polynévrite et alopécie est considérée
    comme le symptôme classique de l'intoxication par le thallium, mais il
    est arrivé qu'on n'observe ni gastroentérite ni alopécie.  Il y a
    également d'autres symptômes qui varient dans leur séquence, leur
    ampleur et leur intensité.

         Les symptômes de l'intoxication par le thallium sont souvent
    diffus et commencent par de l'anorexie, des nausées, des vomissements,
    une saveur métallique, de la salivation, des douleurs rétro-sternales
    et abdominales et quelquefois des hémorragies gastro-intestinales
    (selles sanglantes).  On observe ensuite fréquemment une constipation
    qui peut être rebelle au traitement et gêner par conséquent l'action
    de l'antidote.   Au bout de 2 à 5 jours, les troubles caractéristiques
    de l'intoxication par le thallium apparaissent peu à peu, quelle soit
    la voie d'exposition.  Les effets sur le système nerveux central et
    périphérique sont variables mais ce que l'on constate de manière
    caractéristique et systématique chez les intoxiqués par le thallium,
    c'est une hypersensibilité des jambes, à laquelle font suite le
    syndrome des "pieds brûlants" et une paresthésie.  L'atteinte du
    système nerveux central (SNC) se traduit par des symptômes tels
    qu'hallucinations, léthargie, délire, convulsions et coma.  Les
    symptômes circulatoires couramment rencontrés sont une hypertension,
    une tachycardie et dans les cas graves, une défaillance cardiaque.  Au
    bout de la deuxième semaine, les cheveux commencent à tomber et
    quelquefois même les poils du corps.  La dystrophie unguéale se
    manifeste par l'apparition de lunules blanches (lignes de Mee) 3 à 4
    semaines après l'intoxication.  Les zones noires que l'on trouve dans
    la papille pileuse ne sont pas dues à des dépôts de pigment ou de
    thallium mais à la présence de petites quantités d'air qui pénètrent
    dans la tige du poil.

         Dans les cas mortels, la mort peut survenir quelques heures à
    plusieurs semaines après l'intoxication, mais la plupart du temps le
    décès intervient dans les 10 à 12 jours.  La cause du décès est
    principalement due à une insuffisance rénale, neurologique et
    cardiaque.

         En cas d'intoxication sublétale, la guérison peut souvent prendre
    des mois. Des séquelles peuvent subsister: problèmes neurologiques et
    troubles mentaux, anomalies électroencéphalographiques et cécité.  En
    outre, il semble que les fonctions intellectuelles des survivants
    soient affectées.

         En cas d'intoxication chronique, les symptômes sont analogues
    mais généralement moins prononcés qu'en cas d'intoxication aiguë.  La
    cécité peut quelquefois être permanente.  La guérison complète prend
    des mois et il peut y avoir des rechutes.

         A l'occasion d'un incident dans une cimenterie de Lengerich en
    Allemagne où il y avait eu émission de thallium et que l'on a bien
    étudiée, on a constaté que la concentration du thallium dans le
    système pileux et les urines des personnes exposées n'était pas
    corrélée avec certaines caractéristiques généralement associées à
    l'intoxication chronique, mais seulement avec des symptômes
    neurologiques subjectifs.

         L'examen de biopsies et de pièces d'autopsie après intoxication
    par le thallium révèle des lésions au niveau de divers organes.  Par
    exemple, après l'ingestion de doses mortelles, on constate des
    hémorragies de la muqueuse intestinale, des poumons, des glandes
    endocrines et du coeur, des infiltrations graisseuses au niveau du
    foie et du myocarde, ainsi que des altérations dégénératives des
    glomérules et des tubules rénaux.  Dans l'encéphale, on peut observer
    une dégénérescence graisseuse des cellules glanglionnaires, des
    lésions au niveau des axones et la désagrégation des gaines de
    myéline.

         L'action directe du thallium sur le système nerveux autonome peut
    produire des variations dans la tension artérielle.  L'intoxication
    par le thallium provoque une névrite symétrique périphérique.  Les
    nerfs distaux sont davantage touchés que les nerfs proximaux et les
    lésions, bien que plus précoces, sont moins prononcées dans le cas des
    nerfs dont l'axone est court, par exemple les nerfs crâniens.  Les
    axones sont enflés et ils présentent des vacuoles et des mitochondries
    distendues.  Dans les cas d'intoxication mortelle, on a observé de
    graves lésions du nerf vague, l'énervation du sinus carotidien et des
    lésions au niveau des ganglions sympathiques.  Dans les cas
    d'intoxication sublétale, les nerfs atteints peuvent subir une
    dégénérescence de l'axone qui peut être définitive ou s'améliorer
    partiellement dans les 2 ans.

         Une névrite optique rétrobulbaire entraînant des troubles visuels
    peut s'installer et persister pendant des mois après un traitement par
    une crème dépilatoire à base de thallium; il peut même y avoir une
    atrophie du nerf optique.

         On n'a guère de données concernant les effets du thallium sur la
    reproduction humaine.  Il peut y avoir des effets indésirables sur le
    cycle menstruel, la libido et la puissance sexuelle masculine.  On
    sait en outre qu'une intoxication chronique peut produire des effets
    sur les spermatozoïdes.  Comme chez l'animal, il y a passage

    transplacentaire; on l'a observé dans un cas d'avortement provoqué par
    le thallium. Toutefois, on connaît environ 20 cas d'intoxication par
    le thallium en cours de grossesse où, à part le fait que les
    nouveaux-nés avaient un poids de naissance relativement faible et
    présentaient une alopécie, leur développement foetal ne paraissait pas
    avoir souffert.

         On ne sait rien des effets cancérogènes et on ne possède aucune
    donnée sur les effets immunologiques du thallium.  On ne possède pas
    non plus d'éléments suffisants en faveur d'effets génotoxiques
    éventuels.

         Le traitement des intoxications par le thallium associe la
    diurèse provoquée, l'administration de charbon actif et la prévention
    de la réabsorption par le côlon au moyen d'administration de bleu de
    Prusse (hexacyanoferrate(II) de potassium et de fer(II)).

    8.  Relation dose-réponse chez l'homme

         Dans les populations non exposées, la concentration urinaire
    moyenne du thallium est de 0,3 à 0,4 µg/litre.  Etant donné que le
    thallium a une courte demi-vie biologique, exprimée en jours, si l'on
    suppose réunies les conditions d'un état stationnaire, la
    concentration urinaire peut être considérée comme un indicateur de la
    dose totale après absorption de thallium par inhalation ou ingestion.

         On a constaté, dans un échantillon d'une population vivant à
    proximité d'une source d'émission de thallium dans l'atmosphère, une
    concentration urinaire moyenne de 5,2 µg/litre.  L'existence d'une
    relation dose-réponse nette a été observée entre la concentration
    urinaire de thallium et la prévalence des effets suivants: fatigue,
    faiblesse, troubles du sommeil, migraines, nervosité, paresthésie,
    douleurs musculaires et articulaires.  On a également fait état d'une
    relation dose-réponse analogue en utilisant la teneur des cheveux en
    thallium comme indicateur de l'exposition.

         Le Groupe de travail a estimé qu'une exposition entraînant une
    concentration urinaire de thallium inférieure à 5 µg/litre n'est
    probablement pas susceptible de causer des effets nocifs.  Dans
    l'intervalle 5-500 µg/litre, l'ampleur du risque et la gravité des
    effets nocifs restent incertaines, mais une exposition entraînant une
    concentration urinaire supérieure à 500 µg/litre correspond à une
    intoxication avec des manifestations cliniques.

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

         Le thallium est nocif pour tous les organismes mais il existe des
    différences évidentes entre les espèces, voire entre les souches d'une
    même espèce.  La toxicité peut être différente selon qu'il s'agit de
    dérivés minéraux du thallium(I) ou du thallium(III) ou encore de
    composés organothalliens.

         L'effet le plus important du thallium sur les microorganismes
    semble consister dans l'inhibition de la nitrification par les
    bactéries terricoles.  Les résultats d'une étude consacrée à ce
    phénomène tendent à indiquer que la structure de la communauté
    biologique est perturbée lorsque la concentration de thallium dans le
    sol se situe dans les limites de 1 à 10 mg/kg de poids sec;  toutefois
    on n'a pas pu déterminer sous quelle forme le thallium avait été
    utilisé dans cette expérience.

         Le thallium est fixé par toutes les parties de la plante, mais
    principalement par les racines.  Une fois qu'il a pénétré dans la
    cellule, il se concentre de manière inégale dans le cytosol,
    probablement en étant lié à un peptide.  La concentration de thallium
    que l'on rencontre dans les végétaux dépend des propriétés du sol
    (plus spécialement du pH et de la teneur en argile et en matières
    organiques), ainsi que du stade de développement et de la partie du
    végétal.  Il s'accumule dans les zones contenant de la chlorophylle
    mais il existe des végétaux résistants au thallium où cette
    accumulation est moindre.  La présence de thallium réduit la
    production d'oxygène, probablement par action directe sur les
    transferts d'électrons au niveau du photosystème II.  La présence de
    chlorose traduit son effet nocif sur les pigments.  En outre, il
    semble que la toxicité du thallium soit associée à une moindre
    fixation des oligo-éléments.  Il y a également une action nocive sur
    la croissance, les racines étant plus sensibles que les feuilles ou
    les tiges.  On a observé ces effets à des concentrations ne dépassant
    pas un 1 mg de thallium par kg de tissu végétal sec, après exposition
    à des dérivés du thallium(I).

         Dans la plupart des études consacrées aux effets du thallium sur
    les organismes aquatiques, on a utilisé des dérivés solubles du
    thallium(I).  La concentration de thallium la plus faible pour
    laquelle on a observé des effets sur les espèces aquatiques est de
    8 µg/litre, concentration qui a provoqué une réduction de la
    croissance de certains végétaux aquatiques.  En ce qui concerne les
    invertébrés, les effets nocifs se font souvent sentir à des
    concentrations plus faibles que chez les poissons (les valeurs de la
    CL50 à 96 heures sont de 2,2 mg de thallium par litre pour les
    daphnies et de 120 mg/litre pour une espèce de poisson d'eau douce). 
    La valeur la plus faible de la CL50 a été observée après une
    exposition d'environ 40 jours;  elle était dans le cas de poissons, de
    40 µg/litre.

         Les nombreux cas d'intoxication par le thallium observés dans la
    faune sauvage sont dus à son utilisation à grande échelle comme
    rodenticide.  Chez les animaux granivores et chez les prédateurs,
    c'est au niveau du système nerveux central ou des voies digestives que
    se produisent les effets les plus graves.  On a également observés de
    tels effets chez des animaux de ferme.  En outre, le thallium provoque
    la chute des plumes dorsales chez les canards, une salivation au
    niveau du nez et de la bouche chez les bovins, et une réduction de la
    croissance chez les poulets, les poules pondeuses, les moutons et les
    taureaux.

    RESUMEN

    1.  Identidad, propiedades físicas y químicas, y métodos analíticos

         El talio elemental es un metal blando y maleable de color blanco
    azulado.  Cuando se expone al aire húmedo o al agua, se produce
    respectivamente una oxidación rápida de su superficie o la formación
    del hidróxido correspondiente.  Tiene dos estados de oxidación
    importantes: talio(I) y talio(III).  Los componentes monovalentes
    (talosos) se comportan de manera análoga a los metales alcalinos, como
    por ejemplo el potasio, mientras que los compuestos trivalentes
    (tálicos) son menos básicos, parecidos al aluminio.  A diferencia de
    los compuestos inorgánicos en los que el ion talio(I) es más estable
    en soluciones acuosas que el ion talio(III), este último es más
    estable en compuestos orgánicos.

         La determinación del talio en muestras del medio ambiente es algo
    difícil, porque sus concentraciones son del orden de µg/kg o
    inferiores.  En general, cuando no se aplica una concentración
    previamente establecida de talio, los límites de la determinación en
    minerales, suelos y polvo son de unos 20 µg/kg, en soluciones acuosas
    de 0,1 µg/litro y en materiales biológicos de unos pocos µg/kg.

         La espectrometría de absorción atómica en horno de grafito es un
    método analítico idóneo para aplicaciones en las que se necesita una
    alta sensibilidad debido a las pequeñas cantidades de muestra con un
    contenido de talio de unos pocos µg/kg.  La espectrometría de masas
    con dilución isotópica y la espectrometría de plasmamasa con
    acoplamiento inductivo, posiblemente combinada con la dilución
    isotópica, son métodos excelentes de determinación, con buena
    precisión y exactitud, del orden de µg/kg.

    2.  Fuentes de exposición humana y ambiental

         El talio está presente en el medio ambiente como consecuencia de
    procesos naturales y procedente de fuentes debidas a actividades
    humanas.  Está muy extendido en la naturaleza y se encuentra sobre
    todo en las menas de sulfuro de diversos metales pesados, aunque suele
    estar en concentraciones bajas.  Sólo hay unas pocas zonas con
    concentraciones naturales de talio muy elevadas.

         La producción industrial es muy pequeña (el consumo industrial en
    todo el mundo en 1991 fue de 10-15 toneladas/año).  El talio y sus
    compuestos tienen una amplia variedad de aplicaciones industriales. 
    Ahora se ha limitado rigurosamente su uso como depilatorio humano y
    como rodenticida e insecticida.  Sus principales aplicaciones están en
    las industrias eléctrica y electrónica y en la producción de vidrios
    especiales.  Otro campo importante de aplicación es el uso de
    radioisótopos en medicina para la escintigrafía, así como el
    diagnóstico de melanomas y el uso de compuestos de ariltalio(III) en
    bioquímica.

         Las pérdidas en el medio ambiente proceden sobre todo de la
    fundición de minerales (depósitos de materiales de desecho y emisiones
    a la atmósfera), las centrales eléctricas alimentadas por carbón, las
    fábricas de ladrillos y de cemento (todas ellas con emisiones a la
    atmósfera).  Se calcula que los procesos industriales movilizan en
    todo el mundo de 2000 a 5000 toneladas/año.  Las emisiones de talio
    debidas a procesos industriales varían mucho en función del tipo de
    industria.

         Las emisiones de las centrales eléctricas alimentadas por carbón
    pueden contener una concentración de talio de 700 µg/m3 de aire de
    salida y las de las fábricas de cemento hasta 2500 µg/m3.  Esta
    última cifra se puede reducir hasta < 25 µg/m3 mediante el uso de
    otras materias primas y cambiando el proceso de producción.  El talio
    se volatiliza durante la combustión del carbón o la materia prima
    utilizada en la fabricación de cemento y se vuelve a condensar sobre
    la superficie de las partículas de ceniza en las partes más frías del
    sistema. Estas partículas contienen hasta 50 mg de talio/kg de
    polvillo de ceniza y son con frecuencia de pequeño tamaño, de manera
    que los filtros de las fábricas de cemento retienen sólo un 50%. 
    Alrededor de un tercio de las partículas que emiten las centrales
    eléctricas son también de un tamaño tan pequeño que se pueden
    depositar en las vías respiratorias inferiores.

         Los efluentes procedentes de los depósitos de decantación de
    residuos mineros, con un contenido de hasta 1620 y 36 µg/litro,
    produjeron en los ríos de vertido niveles elevados de 88 y 1 µg/litro,
    respectivamente.  En los estanques de agua de lluvia cercanos a una
    fábrica de cemento se encontraron hasta 37 µg/litro.  En el suelo se
    han detectado concentraciones máximas de 60 mg/kg en zonas próximas a
    materiales de desecho de minas; en las cercanías de fundiciones de
    metales no preciosos y de fábricas de ladrillos y de cemento se
    detectaron concentraciones de 2, 0,6 y 27 mg/kg, respectivamente.   En
    las zonas contaminadas, la mayoría de las hortalizas, frutas y carne
    contienen menos de 1 mg de talio/kg de peso fresco.  Las
    concentraciones son superiores en las coles (Brassicaceae), habiéndose
    notificado niveles de hasta 45 mg/kg en la col rizada verde.  Las
    concentraciones de talio en los tejidos de los animales de granja se
    corresponden con las concentraciones en el forraje.  En las cercanías
    de algunas fábricas de cemento, se han descrito niveles superiores en
    el forraje (por ejemplo, hasta 1000 mg/kg en la colza) y en la carne
    de vacuno y de conejo (hasta 1,5 y 5,8 mg/kg, respectivamente).

    3.  Transporte, distribución y transformación en el medio ambiente

         Cerca de fuentes localizadas, como centrales eléctricas de
    carbón, algunas fábricas de cemento y operaciones de fundición de
    metales, la fuente principal de talio en el aire es la emisión de
    polvillo de ceniza.  Los resultados de un estudio indican que casi
    todo el talio del polvo flotante procedente de una fábrica de cemento
    estaba presente como cloruro de talio(I) soluble.

         El destino final del talio que se incorpora al suelo (debido, por
    ejemplo, al depósito del polvillo de ceniza) depende fundamentalmente
    del tipo de suelo.  La retención es máxima en suelos que contienen
    grandes cantidades de arcilla, materia orgánica y óxidos de
    hierro/manganeso.  La incorporación de talio a complejos estables sólo
    produce concentraciones más elevadas en las capas superiores del
    suelo.  La absorción del talio por la vegetación va aumentando a
    medida que el pH del suelo disminuye.  En algunos suelos fuertemente
    ácidos se puede producir lixiviación de cantidades importantes de
    talio al terreno y las aguas superficiales próximos.

         La mayor parte del talio disuelto en agua dulce suele ser
    monovalente.  Sin embargo, en agua dulce muy oxidada y en la mayor
    parte del agua marina puede predominar la forma trivalente.  El talio
    se puede eliminar de la columna de agua y acumularse en el sedimento
    mediante diversas reacciones de intercambio, formación de complejos o
    precipitación.

         Aunque puede darse una bioconcentración del talio, la
    bioamplificación del elemento en las redes alimentarias acuática o
    terrestre es improbable.

    4.  Niveles medioambientales y exposición humana

         En zonas no contaminadas por talio, las concentraciones en el
    aire suelen ser < 1 ng/m3, en el agua < 1 µg/litro y en los
    sedimentos del agua < 1 mg/kg.  Las concentraciones medias en la
    corteza terrestre oscilan entre 0,1 y 1,7 mg/kg, pero es posible
    encontrar niveles muy elevados, por ejemplo hasta de 1000 mg/kg en el
    carbón, y los minerales de talio que raramente se encuentran contienen
    hasta un 60% del elemento.  Los alimentos de origen vegetal y animal
    suelen contener < 1 mg/kg de peso seco y la ingestión media humana de
    talio con los alimentos parece ser inferior a 5 µg/día.  Se estima que
    la absorción a través del sistema respiratorio es < 0,005 µg de
    talio/día.

         Se dispone sólo de datos limitados sobre el contenido real de
    talio en el aire de los lugares de trabajo.  Las concentraciones
    observadas más recientemente (decenio de 1980) fueron < 22 µg de
    talio/m3 (en la producción de una aleación especial de talio y en
    una fundición de talio).  El promedio de la concentración determinada
    en orina fue del orden de 0,3-8 µg/litro en los trabajadores del
    cemento y de 0,3-10,5 µg/litro en los de funderías.

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

         El talio se absorbe con rapidez y facilidad a través de los
    tractos gastrointestinal y respiratorio, así como por vía cutánea.  Se
    distribuye en poco tiempo por todos los órganos y atraviesa la
    placenta (como se demuestra por la rápida absorción fetal) y la

    barrera hematoencefálica.  Debido a su acumulación rápida en las
    células, las concentraciones de talio en la sangre no se corresponden
    con su nivel en los tejidos.  En casos de intoxicación aguda de
    animales experimentales o de personas, se producen al principio
    concentraciones de talio elevadas en el riñón, bajas en el tejido
    adiposo y en el cerebro e intermedias en los demás órganos; luego
    aumentan también sus niveles en el cerebro.

         La eliminación del talio se puede producir a través del tracto
    gastrointestinal (básicamente mediante mecanismos independientes de la
    excreción biliar), el riñón, el pelo, la piel, el sudor y la leche
    materna.  Se puede producir  una reabsorción intestinal (sobre todo
    desde el colon), con la consiguiente disminución en la eliminación
    total del organismo.  En la rata, las principales vías de eliminación
    del talio son la gastrointestinal (unos dos tercios) y la renal
    (alrededor de un tercio), siendo semejante la contribución de ambas
    vías en el caso de los conejos.  El talio se elimina también por la
    saliva.

         Al igual que con otras muchas sustancias, la excreción de talio
    en el ser humano difiere de la observada en los animales de
    laboratorio; en aquél la velocidad de excreción es mucho más baja
    (constante de velocidad = 0,023-0,069 día-1) que en éstos (la
    constante de velocidad media = 0,18 día-1).  Otra diferencia
    importante entre el hombre y los animales es la contribución relativa
    de las distintas vías de excreción.  La excreción renal parece ser
    mucho más importante en el ser humano que en los animales, aunque no
    se ha determinado completamente su contribución relativa a la
    eliminación total del organismo, debido fundamentalmente a la falta de
    suficientes datos respecto al hombre.  Además, los niveles de
    exposición, su duración, la alteración de la función de los órganos de
    excreción, la absorción de potasio y el tratamiento correspondiente de
    la intoxicación aguda pueden influir considerablemente en los
    resultados.

         En un estudio sobre la excreción renal de talio se notificó un
    resultado de alrededor del 73%, mientras que a través del tracto
    gastrointestinal fue de sólo el 3,7% de la cantidad diaria excretada. 
    La excreción estimada a través del pelo y la piel y del sudor fue del
    19,5% y el 3,7%, respectivamente.

         La semivida biológica del talio en animales de laboratorio oscila
    generalmente entre 3 y 8 días; en el ser humano es de unos 10 días,
    aunque se ha informado de valores superiores a los 30 días.

         No se dispone de datos sobre su biotransformación.

    6.  Efectos en mamíferos de laboratorio y en sistemas de ensayo
        in vitro

         No hay diferencias específicas sorprendentes por especies en
    cuanto a la toxicidad de las sales de talio(I).  Normalmente, una
    ingestión oral de 20 a 60 mg de talio/kg de peso corporal es letal en
    un plazo de una semana.  Los cobayos son ligeramente más sensibles que
    otros animales de experimentación.  El óxido tálico(III) insoluble en
    agua muestra una toxicidad aguda algo más baja por vía oral o
    parenteral que las sales de talio(I).  Al comparar los datos de
    toxicidad aguda se aprecia una elevada biodisponibilidad a partir de
    todas las vías de exposición.  Afecta a la mayor parte de los órganos,
    pero los signos de intoxicación y la sucesión de los mismos indican
    una cierta variabilidad intraespecífica e interespecífica.

         Los síntomas de la intoxicación aguda se suceden en general de la
    manera siguiente:  en primer lugar anorexia, vómitos y depresión, más
    tarde diarrea, cambios cutáneos (inflamación en los orificios
    corporales, furúnculos cutáneos, pérdida de pelo) y luego disnea y
    trastornos nerviosos.  Por último, la insuficiencia respiratoria que
    provoca la muerte.

         Los síntomas de la intoxicación crónica son semejantes a los de
    la intoxicación aguda.  Se produce regularmente pérdida de pelo.

         En el examen histológico se puede observar necrosis u otros daños
    celulares.  Se han detectado cambios necróticos en los riñones, el
    hígado, el intestino, el corazón y el sistema nervioso.  En numerosas
    células se ha observado hinchazón de las mitocondrias y pérdida de
    crestas, dilataciones del retículo endoplasmático liso, aumento del
    número de vacuolas autofágicas y de gránulos de lipofucsina y pérdida
    de microvellosidades.  Las alteraciones de procesos funcionales
    debidas al talio pueden estar provocadas por la rotura física de las
    membranas de los orgánulos subcelulares.  En el corazón, los efectos
    arritmogénicos se limitan al nódulo sinoatrial.

         La intoxicación por talio provoca la alteración selectiva de
    determinados elementos de la conducta relacionados con efectos
    bioquímicos (lo que indica un daño celular) en ciertas regiones
    cerebrales.  Algunos efectos neurológicos parecen deberse a la acción
    directa, por ejemplo la ataxia y el temblor a causa de trastornos del
    cerebelo o alteraciones de la actividad endocrina debidos a cambios en
    el hipotálamo.  El talio puede activar el sistema nervioso autónomo,
    fundamentalmente el adrenérgico.  En los nervios periféricos parece
    interferir a nivel presináptico en la liberación espontánea del
    transmisor, ejerciendo un efecto antagónico en estos procesos
    dependientes del calcio.

         No se conoce todavía el mecanismo exacto de la toxicidad del
    talio.  Se han propuesto varios mecanismos, que tal vez están
    relacionados entre sí.  Un aspecto importante de la intoxicación por
    talio es el aumento significativo de la peroxidación de lípidos y de
    la actividad de una enzima lisosómica, la ß-galactosidasa.  El
    resultado es una deficiencia de glutatión que provoca la acumulación
    de peróxidos de lípidos en el cerebro y, al parecer, por último, la
    formación de gránulos de lipofucsina.  Parece que el mecanismo de
    acción del talio radica fundamentalmente en una alteración de la
    función mitocondrial.

         Los animales con intoxicación crónica suelen presentar una
    actividad sexual reducida, y en el sistema reproductor del macho son
    evidentes los efectos gonadotóxicos del talio.  En los testículos de
    ratas que recibieron 10 mg de talio/litro de agua de beber durante 16
    días, las células de Sertoli fueron las más sensibles y la descamación
    del epitelio espermatogénico provocó la aparición de espermatozoides
    inmaduros en el semen.  Esto podría explicar el menor índice de
    supervivencia de los embriones o la reducción del periodo de vida de
    la descendencia tras una intoxicación subletal por talio de los
    padres.

         Tras la inyección de talio en huevos, se observaron en los
    embriones de pollo efectos teratogénicos, inhibición del crecimiento y
    trastornos del desarrollo óseo, pero en los mamíferos estos efectos
    son discutibles, incluso a dosis tóxicas para la madre.  Aunque se ha
    demostrado que atraviesa la placenta, muchas estirpes de ratones y
    ratas no muestran efectos teratogénicos en absoluto, o sólo
    ligeramente.

         Dos pruebas de mutagenicidad microbiológica en  Salmonella
     typhimurium dieron resultados negativos, y las pruebas  in vivo sobre
    intercambio de cromátides hermanas fueron controvertidas.  Sin
    embargo, en estudios aislados se han observado aberraciones
    cromosómicas o un aumento significativo de la fragmentación del ADN de
    cadena sencilla.

         No se dispone de estudios de larga duración sobre la
    carcinogenicidad del talio.

    7.  Efectos en el ser humano

         Debido a que las sales de talio son insípidas, inodoras,
    incoloras, muy tóxicas, fáciles de obtener en el pasado e incluso
    ahora en algunos países en desarrollo, este elemento se ha utilizado a
    menudo con fines suicidas, homicidas y de aborto ilegal, provocando
    intoxicación aguda.  Es más, se considera que la intoxicación por

    talio es una de las causas más frecuentes, a escala mundial, de
    intoxicación humana voluntaria o accidental.  Los conocimientos sobre
    la intoxicación crónica se limitan a la exposición profesional, a
    grupos de población que viven en zonas contaminadas y a casos de
    homicidio con dosis bajas múltiples.

         Los síntomas de toxicidad aguda del talio dependen de la edad, la
    vía de administración y la dosis.  Las dosis que han resultado letales
    varían entre 6 y 40 mg/kg, con un promedio de 10 a 15 mg/kg.  Sin
    tratamiento, esta dosis media suele producir la muerte en un plazo de
    10 a 12 días, pero también se han descrito casos de defunción en 8-10
    horas.

         Se considera que la gastroenteritis, la polineuropatía y la
    alopecia son los tres síntomas clásicos de la intoxicación por talio,
    pero en algunos casos no se observó gastroenteritis ni alopecia. 
    También se producen otros signos y síntomas, con un orden de
    aparición, amplitud e intensidad variables.

         Los síntomas de la intoxicación son a menudo imprecisos y
    consisten al  principio en anorexia, náuseas, vómitos, sabor metálico,
    salivación, dolor retrosternal y abdominal y a veces hemorragia
    gastrointestinal (sangre en heces).  Luego se suele observar
    estreñimiento, que puede ser resistente al tratamiento, interfiriendo
    así con el antídoto administrado.

         Después de un periodo de dos a cinco días aparecen lentamente
    algunos de los trastornos asociados normalmente al talio, con
    independencia de la vía de exposición.  Aunque los efectos en el
    sistema nervioso central y periférico varían, un rasgo constante y
    característico de la intoxicación por talio en  el hombre es la
    sensibilidad extrema de las piernas, a la que sigue el «síndrome de
    los pies urentes» y la parestesia.  Su acción sobre el sistema
    nervioso central (SNC) se refleja en síntomas tales como
    alucinaciones, letargia, delirio, convulsiones y coma.  Los síntomas
    circulatorios normales son hipertensión, taquicardia y, en los casos
    graves, insuficiencia cardiaca.  Después de la segunda semana de la
    intoxicación se suele producir pérdida del pelo y, a veces, del vello;
    la distrofia de las uñas se detecta por la aparición de rayas
    semicirculares blancas (líneas de Mee) tres o cuatro semanas después
    de la intoxicación.  Las regiones negras que se observan en las
    papilas pilosas no se producen por la deposición de pigmentos o de
    talio, sino que se deben a pequeñas cantidades de aire que entran en
    el tallo piloso.


         En los casos letales, la muerte sobreviene en un plazo que oscila
    entre unas horas y varias semanas, pero normalmente se produce a los
    10 ó 12 días.  Las causas del fallecimiento son generalmente
    insuficiencia renal, del SNC y cardiaca.

         En intoxicaciones subletales, la recuperación requiere con
    frecuencia meses.  A veces persisten los trastornos neurológicos y
    mentales, así como las anomalías electroencefalográficas y la ceguera. 
    Por otra parte, parece ser que los supervivientes sufren un deterioro
    de las funciones intelectuales.

         En casos de intoxicación crónica los síntomas son semejantes,
    pero en general más leves que en la intoxicación aguda.  A veces se
    produce ceguera permanente.  La recuperación completa requiere meses y
    se puede interrumpir por recaídas.

         En un caso bien investigado de emisión de talio alrededor de una
    fábrica de cemento de Lengerich, Alemania, las concentraciones de
    talio en el pelo y la orina de las personas expuestas no se
    correspondían con algunas características típicas que suelen estar
    relacionadas con la intoxicación crónica por talio, sino sólo con
    síntomas neurológicos subjetivos.

         La autopsias y biopsias realizadas tras las intoxicaciones por
    talio ponen de manifiesto daños en diversos órganos.  Por ejemplo,
    tras la ingestión de dosis letales se producen hemorragias en la
    mucosa intestinal, los pulmones, las glándulas endocrinas y el
    corazón, infiltraciones grasas en el hígado y el tejido cardiaco, así
    como cambios degenerativos en los glomérulos y los túbulos renales. 
    En el cerebro se puede observar degeneración grasa de las células
    ganglionares, lesiones axonales y desintegración de las vainas de
    mielina.

         Las variaciones de la presión sanguínea pueden deberse a los
    efectos directos del talio en el sistema nervioso autónomo.  La
    intoxicación por talio produce neuropatía periférica mixta simétrica. 
    Los nervios distales sufren más daños que los proximales, y los
    nervios de axón corto, por ejemplo los craneales, se ven afectados
    antes, aunque en menor grado.  Los axones se hinchan y contienen
    vacuolas y mitocondrias dilatadas.  En los casos de intoxicación
    letal, se han observado daños graves del nervio vago, desnervación del
    seno carotídeo y lesiones de los ganglios simpáticos.  En la
    intoxicación subletal, los nervios afectados pueden sufrir
    degeneración axonal, con recuperación nula o sólo parcial en un plazo
    de dos años.

         A veces se produce una neuritis retrobulbar con los consiguientes
    trastornos visuales, que puede persistir durante meses, después de un
    tratamiento con productos depilatorios con talio; este trastorno puede
    desembocar incluso en la atrofia óptica.   Los datos sobre los efectos
    del talio en la reproducción humana son limitados.  Puede afectar
    negativamente al ciclo menstrual, la libido y la potencia masculina. 

    Se sabe que la intoxicación crónica tiene efectos sobre el esperma. 
    Al igual que en los estudios con animales, se ha observado que
    atraviesa la placenta; esto se ha puesto de manifiesto tras un aborto
    inducido por el talio.  Sin embargo, en unos 20 casos de intoxicación
    por talio durante el embarazo no se vio afectado el desarrollo fetal,
    salvo el peso relativamente bajo y la alopecia de los recién nacidos.

         No se dispone de informes sobre efectos carcinógenos o datos
    sobre efectos inmunológicos debidos al talio.  No hay pruebas
    suficientes de efectos genotóxicos.

         El tratamiento de la intoxicación por talio combina la diuresis
    forzada, el uso de carbón vegetal activado y la prevención de la
    reabsorción en el colon mediante la administración de azul de Prusia,
    hexacianoferrato(II) férrico potásico.

    8.  Relación dosis-respuesta en el ser humano

         La concentración media de talio en orina en la población no
    expuesta es de 0,3 a 0,4 µg/litro.  Habida cuenta de que el talio
    tiene una semivida biológica breve, establecida en días, y suponiendo
    unas condiciones estables, se puede tomar esta concentración urinaria
    como indicador de la dosis total tras la inhalación y la ingestión con
    los alimentos.

         La concentración media en la orina en una muestra de población
    que vive cerca de una fuente de emisión de talio fue de 5,2 µg/litro. 
    Se encontró una relación dosis-respuesta clara entre las
    concentraciones en la orina de talio y el predominio de cansancio,
    debilidad, trastornos del sueño, dolor de cabeza, nerviosismo,
    parestesia y dolor muscular y de las articulaciones.  Se informó
    asimismo de una relación dosis-respuesta semejante cuando se utilizó
    el talio en el pelo como indicador de la exposición.

         El Grupo Especial de Trabajo consideró que las exposiciones que
    producen concentraciones de talio en la orina inferiores a 5 µg/litro
    probablemente no son perjudiciales para la salud.  En el margen de 5 a
    500 µg/litro, la magnitud del riesgo y la gravedad de los efectos
    adversos son inciertas, mientras que la exposición que da lugar a más
    de 500 µg/litro está asociada a una intoxicación clínica.

    9.  Efectos en otros organismos en el laboratorio y en el medio
        ambiente

         El talio afecta a todos los organismos, pero hay diferencias
    específicas de especies e incluso de variedades.  Los diferentes
    compuestos inorgánicos de talio(I) y talio(III), así como sus
    compuestos orgánicos, pueden tener distinta toxicidad.

         El efecto más importante del talio en los microorganismos parece
    ser la inhibición de la nitrificación por las bacterias del suelo. 
    Los resultados de un estudio parecen indicar que la estructura de la
    flora microbiana se altera a concentraciones en el suelo comprendidas
    entre 1 y 10 mg/kg de peso seco, pero no se precisó la forma de talio
    utilizada en este experimento.

         Absorben talio todas las partes de las plantas, pero sobre todo
    las raíces.  Una vez que ha penetrado en las células, se concentra de
    forma desigual en el citosol, probablemente unido a un péptido.  Las
    concentraciones de talio que se observan en las plantas dependen de
    las propiedades del suelo (en particular el pH y el contenido de
    arcilla y materia orgánica), así como de la fase de desarrollo y de la
    parte de la planta.  Se acumula en las zonas que contienen clorofila,
    pero lo hace en menor grado en las plantas resistentes al talio.
    Reduce la producción de oxígeno, posiblemente por acción directa sobre
    la transferencia de electrones en el fotosistema II.  Su interferencia
    con los pigmentos se pone de manifiesto por la aparición de clorosis. 
    Por otra parte, en el mecanismo de la toxicidad parece intervenir una
    alteración de la absorción de oligoelementos.  Afecta también al
    crecimiento, siendo más sensibles las raíces que las hojas o los
    tallos.  Estos efectos se han descrito tras la exposición a formas
    monovalentes de talio con niveles de sólo 1 mg/kg de tejido vegetal
    seco.

         En la mayoría de los estudios de los efectos en los organismos
    acuáticos se han utilizado compuestos solubles de talio monovalente. 
    La concentración más baja notificada capaz de afectar a las especies
    acuáticas es de 8 µg/litro, con una reducción del crecimiento de las
    plantas.  Los invertebrados se suelen ver afectados a concentraciones
    más bajas que los peces (los valores de la CL50 en 96 horas son de
    2,2 mg de talio/litro para los dáfnidos y de 120 mg/litro para un pez
    de agua dulce).  El valor más bajo de la CL50, notificado tras la
    exposición durante unos 40 días, fue de 40 µg/litro para los peces.

         Muchos casos de intoxicación por talio de la flora y fauna
    silvestres se han debido a su aplicación en gran escala como
    rodenticida.  En animales que se alimentan de semillas y en
    depredadores afecta gravemente sobre todo al SNC y al aparato
    gastrointestinal.  Estos mismos efectos se pueden observar en los
    animales de granja.  A esto hay que añadir que el talio provoca una
    pérdida de plumas dorsales en los patos, salivación de la nariz y la
    boca del ganado vacuno y reducción del crecimiento de los pollos de
    asar, las gallinas ponedoras, las ovejas y los novillos.
    


    See Also:
       Toxicological Abbreviations
       Thallium (ICSC)
       Thallium (PIM 525)