The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for THALLIUM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

DECEMBER 1994

Prepared by: Tim Borges and Mary Lou Daugherty, Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

TOXICITY SUMMARY UPDATE

This report is an update of the Toxicity Summary for Thallium (CAS Registry No. 7440-28-0). The original summary for this chemical was submitted in 1991. The update was performed by incorporating any new human health toxicity data published since the original submittal of the report. Pertinent pharmacokinetic, toxicologic, carcinogenic, and epidemiologic data were obtained through on-line searches of the TOXLINE database from 1991 through 1994. In addition, any changes to EPA-approved toxicity values (reference doses, reference concentrations, or cancer slope factors) from the Integrated Risk Information System (IRIS) (current as of December 1994) and/or the Health Effects Assessment Summary Tables, Annual FY-94 and July Supplement No. 1, for this chemical were incorporated in this update.

EXECUTIVE SUMMARY

Thallium, a naturally occurring elemental metal, is commonly found in minerals and as thallium salts. It can also be released into the environment from industrial sources. Atmospheric thallium contaminates surface soils by deposition allowing for the exposure of humans by oral, dermal, or inhalation routes. The most common nonoccupational sources of thallium exposure are contaminated food crops and tobacco. Although normally present in the urine of humans, elevated urine thallium concentrations have been associated with adverse health effects.

The primary targets of thallium toxicity are the nervous, integumentary, and reproductive systems. In humans, acute exposures produce paresthesia, retrobulbar neuritis, ataxia, delirium, tremors, and hallucinations. This implies central, peripheral, and autonomic nervous system involvement (Stokinger, 1981; de Groot and Van Heijst, 1988; Kazantzis, 1986). Human and animal chronic exposures result in alterations of the brain, spinal cord, and peripheral nerves (Stokinger, 1981; Manzo et al., 1983b). In both humans and animals, alopecia is the most common indicator of long-term thallium poisoning (Stokinger, 1981; Manzo et al., 1983b).

An increased incidence of congenital malformations was found in children of parents exposed to thallium through the consumption of home-grown fruits and vegetables. However, a causal relationship between these effects and thallium exposure could not be confirmed (Dolgner et al., 1983). In animal studies, thallium compounds produced testicular effects in male rats and slight fetotoxicity and significant impairment of learning ability in the offspring of treated female rats (Formigli et al., 1986; Roll and Matthiaschk, 1981; Bornhausen and Hagen, 1984).

Reference doses (RfDs) have been calculated for subchronic and chronic oral exposure to several thallium compounds. The values, derived from a single study where thallium treatment increased AST and LDH activities in rats, are based on NOAELs ranging from 0.23 to 0.28 mg/kg/day (EPA, 1986). The subchronic RfDs are 8.00E-04 (thallium sulfate, chloride, and carbonate) or 9.00E-04 mg/kg/day (thallium nitrate and acetate) (EPA, 1994a), and the chronic RfDs are 8.00E-05 (thallium sulfate, chloride, and carbonate) or 9.00E-05 mg/kg/day (thallium nitrate and acetate) (EPA, 1994b-f).

Data suitable for evaluating the carcinogenicity of thallium to humans or animals by ingestion, inhalation, or other routes of exposure were not found. Thallium sulfate, selenite, nitrate, chloride, carbonate, and acetate have been placed in EPA's weight-of evidence Group D, not classifiable as to human carcinogenicity based on inadequate human and animal data (EPA, 1994b-g).

1. INTRODUCTION

Found at concentrations of approximately 0.7 ppm in the earth's crust, thallium (CAS Number 7440-28-0), is a heavy, bluish-white elemental metal that is softer than lead (Budavari et al., 1989). Having an atomic weight of 204, a density of 11.9 g/cm³, and a melting point of 303.5C, thallium exists in two oxidation states, +3 (thallic) and the more common and stable +1 (thallous). Although it can be found in pure metallic form, thallium is more commonly found in minerals such as crookesite, lorandite, and hutchinsonite and as thallous sulfate, sulfite, nitrate, carbonate, and oxide salts or as thallic oxide and thallic chloride (Hui, 1983; Kazantzis, 1986). Before 1972, the major use of thallium in the U.S. was as a rodenticide, a practice since banned because of its extreme toxicity. Currently, thallium is used in photoelectric cells, lamps, electronics, semiconductors, and in organic catalysts. Thallium isotopes are used in imaging procedures for the evaluation of myocardial disease (Hui, 1983; Kazantzis, 1986).

Human exposure to thallium occurs by oral, dermal, or inhalation routes. Thallium is released into the atmosphere from industrial operations such as coal-fired power plants, smelting operations, and cement factories. Following release, thallium can either be inhaled or settle from the atmosphere and contaminate surface water or soil. Because plants take up thallium, the primary nonoccupational sources of thallium exposure are through the consumption of fruits and vegetables grown in contaminated soil and the use of tobacco products (ATSDR, 1991). Although thallium is normally detected in the urine of humans (<2.0 µg/L), it is not considered an essential element, and no known metabolic functions have been described (Hui, 1983; Goyer, 1986; Tietz, 1986).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Information regarding the absorption of thallium following inhalation exposure was not found. Thallium uptake into the circulatory system is rapid following oral exposure. Lie et al. (1960) reported that thallium was detected in all major tissues and organs of rats treated with a single gavage or intratracheal dose of ²⁰⁴thallium nitrate. The time-related decrease of the total tissue burden of thallium, expressed as the percent of administered dose, followed a single exponential function that could be extrapolated to 100%. The authors concluded that thallium was completely absorbed from the gastrointestinal tract and lungs. Manzo et al. (1983a) reported that rats given oral doses between 2 µg and 2 mg absorbed 50% of the thallium within 1 hour and 90% within 3 hours with no evidence that the absorption mechanisms became saturated.

Information on human oral thallium absorption is limited. In a study conducted by Barclay et al. (1953), a middle-aged woman with terminal cancer was given a single oral dose of ²⁰⁴thallium nitrate. Seventy-two hours after treatment, <0.5% of the administered thallium had been recovered in the feces while 11% was recovered in the urine. These data imply that extensive absorption of thallium occurred. Systemic toxicity following the use of depilatory creams suggests thallium is absorbed through human skin (Prick et al., 1955).

2.2. DISTRIBUTION

Following absorption, thallium uptake into the circulatory system is rapid. Thallium is quickly distributed from the blood to the tissues with an apparent blood half-life of <5 minutes (Talas and Wellhoener, 1983; Talas et al., 1983). In the tissue, thallium translocates from the extracellular fluid to the intracellular space where it is exchanged for and disrupts potassium homeostasis. Studies in rats and humans show that except for the kidney, the concentration of thallium per gram among various tissues is relatively constant (Barclay et al., 1953; Lie et al., 1960; Sabbioni et al., 1980). The higher concentrations of thallium found in the kidney (>5.5 times that found in other tissues) result from renal filtration and intracellular thallium accumulation. Thallium can cross blood-brain and placental barriers (Heyroth 1947; Lie et al., 1960; Rios et al., 1989).

2.3. METABOLISM

Little information on the metabolism of thallium was found. Sabbioni et al. (1980) reported that the retention of radioactivity in rats after oral administration of radiolabelled thallous or thallic sulfate was similar. The authors suggested that the different oxidation states of thallium were transformed in vivo to a single valence. In support of this hypothesis, the authors noted the similar LD₅₀s of various thallous and thallic salts. At present, however, the in vivo valence of thallium is unknown.

2.4. EXCRETION

The primary routes of thallium excretion for animals and humans are the urine and feces, but the predominant route is species-dependent. Limited studies in humans suggest that thallium is excreted in the urine with little fecal excretion (Barclay et al., 1953). In rats and rabbits, however, fecal excretion exceeds urinary excretion (Lie et al., 1960; Rauws, 1974; Talas and Wellhoener, 1983). The secretion of thallium occurs against a concentration gradient all along the gastrointestinal tract of these species (Schaefer and Forth, 1980; Gregus and Klaassen, 1986). Extensive entero and enteral thallium cycling occurs in humans and animals, which is a process broken by Prussian blue or by ferric hexacyanoferrate (Rauws, 1974, Tabandeh et al., 1994). Thallium deposition into hair and nails of both humans and animals is considered an important route of elimination. Other routes of thallium elimination include tears, saliva, and milk (Prick et al., 1955; Richelmi et al., 1980). The biological half-life of thallium in humans has been estimated to be between 2.2 and 22 days (Talas et al., 1983; Barclay et al., 1953).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Following acute exposure, clinical signs of thallium toxicity develop slowly. The first signs include hemorrhage into the gastrointestinal tract and symptoms of gastroenteritis such as nausea, vomiting, abdominal pain, and diarrhea or constipation. These typically occur within 14 hours of exposure (Stokinger, 1981; de Groot and Van Heijst, 1988). The symptoms are followed within 5 days by alopecia and effects characteristic of central, peripheral, and autonomic nervous system involvement. These include paresthesia, particularly of the lower extremities, retrobulbar neuritis, ataxia, delirium, tremors, hallucinations, and tachycardia (Stokinger, 1981; de Groot and Van Heijst, 1988; Kazantzis, 1986;Tabandeh et al., 1994). In severe toxicity, hypertension, cardiomyopathy accompanied by electrocardiographic changes, testicular toxicity, hypokalemia, leukocytosis, and thromocytopenia have been reported. Death from respiratory failure is preceded by convulsions and coma. The minimum lethal dose (LD_LO) of soluble thallium salts for an adult has been estimated to be 0.2-1.4 g (3-20 mg thallium/kg).

3.1.1.2 Animal

Animal studies in various species have shown that the acute toxicity of various soluble and insoluble, organic and inorganic thallium salts (malonate, acetate, sulfate, nitrate, carbonate, and oxide) are independent of the anion, the valence (thallous or thallic), and animal species (rat, mouse, guinea pig, rabbits, and hamster) (Stokinger, 1981; Aoyama, 1989). The acute oral LD₅₀s of various thallium salts, expressed as mg thallium/kg body weight, range between 15-50 mg/kg (Stokinger, 1981, EPA, 1988). Death results from respiratory failure (Munch, 1928).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

The most common sign of long-term human toxicity to thallium is alopecia. With the exception of the axillary and facial hair, it begins approximately 10 days after ingestion and progresses to complete hair loss in one month (Stokinger, 1981).

3.1.2.2. Animal

In a 90-day study, male and female Sprague-Dawley rats were treated by gavage with 0, 0.01, 0.05, or 0.25 mg/kg/day of an aqueous solution of thallium sulfate (EPA, 1986). The animals were evaluated for treatment-related changes in body and organ weight, food consumption, hematology and clinical chemistry results, neurologic and ophthalmologic effects, and histopathology. Adverse clinical effects included dose-related increases in the incidence of alopecia, lacrimation, and exophthalmos. Serum chemistry results showed a moderate dose-related increase in sodium concentration and serum aspartate transaminase (AST) and lactate dehydrogenase (LDH) activities with a decrease in blood sugar concentration. The NOAEL for this study was 0.25 mg/kg/day of thallium sulfate.

In another subchronic study, rats were fed diets containing 0, 5, 15, 30, or 50 ppm of thallium acetate for 15 weeks (Downs et al., 1960). By week 12, all rats in the 30 and 50 ppm groups had died and by week 15, 4/10 rats in the 15-ppm group, 2/10 rats in the 5-ppm group, and 4/10 control rats had died. The growth rate was depressed in male rats given 30 ppm. Treated rats that survived until the end of the study had alopecia and a slight increase in kidney weight (dose not specified). There were no histopathological findings. Thallium oxide was also tested, and it produced effects similar to those of thallium acetate (Downs et al., 1960).

Deshimaru et al. (1977) treated rats with approximately 5.7 mg/kg/day of thallium (I) acetate for 6 months and observed alopecia and ultrastructural degenerative changes in muscle tissue. Although degenerative changes were also observed in the cerebrum, thalamus, and hypothalamus, there were no signs of neurologic effects. In a Russian study, however, behavioral changes and altered blood protein profiles were observed in rabbits dosed orally for 5-6 months with 0.25 mg/kg/day of thallium (I) sulfate and with 0.25 mg/kg/day of thallium (I) carbonate (Tikhova, 1964). The behavioral changes consisted of aggressiveness, retardation, and rear limb paralysis. The results of the study were reported in abstract form, and no further details were available.

3.1.3. Chronic Toxicity

3.1.3.1. Human

People living near a cement plant in Germany and exposed to thallium by the consumption of fruits and vegetables grown in private gardens were examined for health effects (Brockhaus et al., 1981). Without specific tests for toxicity, the subjects were evaluated for a correlation between thallium exposure (as measured by urine and hair concentrations) and the prevalence of certain symptoms. No positive exposure-response relationship was found for dermal or gastrointestinal effects, and a negative correlation was found for hair loss. However, a clear exposure-response relationship was found for sleep disorders, tiredness, weakness, nervousness, headache, other psychic alterations, and neurological and muscular symptoms.

3.1.3.2 Animal

Female Sprague-Dawley rats were given thallium sulfate in drinking water for 36 weeks (Manzo et al., 1983b) at a concentration equivalent to 10 mg/L of thallium or approximately 1.4 mg/kg/day. By the end of treatment, rat mortality in the treated group was 21%. Alterations in motor and sensory action potentials, histopathological changes in the sciatic myelin sheath, and axonal destruction were indicators of peripheral nerve degeneration. At the end of the study, some animals were almost hairless while others showed no evidence of hair loss.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Dolgner et al. (1983) examined the possibility that thallium-induced developmental toxicity had occurred in children living near a cement plant that emitted dust containing thallium until 1979. The main route of exposure was through the consumption of home-grown vegetables and fruit. The results were compared to an unexposed control population that consisted of patients in hospitals located 25 to 50 km from the plant. Urine thallium concentrations were elevated in most of the exposed population (0.1-76.5 µg/L) when compared with the control population (average = 0.3 µg/L), suggesting significant exposure. Children born between January 1978 and August 1979 (n=297) were examined for developmental defects. The number of congenital malformations (5) was greater than expected (0.8) with an observed/expected ratio of 6.25. However, based on the arguments that no specific pattern of congenital malformations was found and that several cases had been reported in the literature of thallium intoxication during pregnancy in which no congenital abnormalities were observed, the investigators concluded that a causal relationship between thallium exposure and congenital malformations is unlikely to exist.

3.1.4.2. Animal

Roll and Matthiaschk (1981) studied thallium developmental toxicity in Wistar rats and NMRI mice. The animals were given thallium chloride or thallium acetate by gavage on gestational days 6-15. Mice treated with 6 mg/kg/day of thallium chloride had a slight increase in postimplantation fetal loss and a slight decrease in birth weight. Rats given 3 mg/kg/day of thallium acetate had a slight increase in postimplantation loss. Skeletal and soft tissue malformations were not seen.

Bornhausen and Hagen (1984) investigated the effect of prenatal thallium exposure of Wistar rats on the learning ability of adult female offspring. Pregnant rats were treated by gavage on gestational days 6-9 with doses of 0, 0.1, 0.5, or 2.0 mg/kg and the offspring were tested at approximately 3 months of age. All doses produced significant impairment of learning ability in the offspring. No histopathologic lesions in the brain, liver, or kidney were found.

Male Wistar rats received drinking water containing 10 ppm thallium sulfate (approximately 0.7 mg thallium/kg/day) for 60 days (Formigli et al., 1986). At the end of treatment, high concentrations of thallium were found in the testes. On microscopic examination, the testicular effects included disarrangement of the tubular epithelium, cytoplasmic vacuolation with distention of the smooth endoplasmic reticulum of the Sertoli cells, decreased testicular ß-glucuronidase activity, and reduced sperm motility.

3.1.5 Reference Dose

3.1.5.1 Subchronic

ORAL RfD_S: 0.0008 mg/kg/day (thallium sulfate)

0.0009 mg/kg/day (thallium nitrate)

0.0008 mg/kg/day (thallium chloride)

0.0008 mg/kg/day (thallium carbonate)

0.0009 mg/kg/day (thallium acetate)

UNCERTAINTY FACTOR: 300

PRINCIPAL STUDY: EPA, 1986; derivation reported in EPA, 1994a

3.1.5.2 Chronic

ORAL RfD_C: 0.00008 mg/kg/day (thallium sulfate)

0.00009 mg/kg/day (thallium nitrate)

0.00008 mg/kg/day (thallium chloride)

0.00008 mg/kg/day (thallium carbonate)

0.00009 mg/kg/day (thallium acetate)

UNCERTAINTY FACTOR: 3000

NOAEL: 0.25 mg/kg/day (thallium sulfate)

0.26 mg/kg/day (thallium nitrate)

0.23 mg/kg/day (thallium chloride)

0.23 mg/kg/day (thallium carbonate)

0.26 mg/kg/day (thallium acetate)

CONFIDENCE:

Study: Low

Data Base: Low

RfD: Low

VERIFICATION DATA: 4/21/88 (for all compounds)

PRINCIPAL STUDY: EPA, 1986; derivation reported in EPA, 1994b-f

COMMENTS: All RfD_C calculations are based on data from one study in which thallium sulfate was tested in rats (EPA, 1986). The NOAEL of 0.25 mg/kg/day for thallium sulfate was converted to the corresponding NOAEL for each of the thallium compounds based on molecular weights. The confidence in the study, data base, and RfD is "low." There were uncertainties in the results, and supporting studies showed adverse health effects at doses slightly higher than the NOAEL. The uncertainty factor of 3000 includes factors of 10 to extrapolate from subchronic to chronic data, 10 for intraspecies extrapolation, 10 to account for interspecies variability, and a factor of 3 to account for lack of chronic toxicity and reproductive data.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

Information on the acute inhalation toxicity of thallium to humans and animals was not available.

3.2.2 Subchronic Toxicity

The results of a 12-month inhalation study with thallium (III) oxide in rats was reported by the EPA (1979). The rats were exposed to 0.5-2.0 mg/m³, 7 hours/day, 5 days/week for 12 months (concentrations were adjusted periodically) and interim sacrifices done at 6, 9, and 12 months. Clinical signs of toxicity included alopecia, deteriorating health, and mortality. At interim sacrifices, pale or dark livers, a granular appearance of the kidneys, and white or grey spots in the lungs were found. The tissues were not examined microscopically.

3.2.3 Chronic Toxicity

3.2.3.1 Human

One-hundred-twenty-eight male cement workers exposed to thallium for 1 to 42 years (mean=19.5 years) in three different manufacturing plants were evaluated based on medical history and physical examination (Schaller et al., 1980). Urinary thallium levels were slightly elevated in some cases (<0.3-6.3 µg/g of creatinine, exposed group; 1.1 µg/g of creatinine, upper normal limit), but the workers showed no clinical evidence of thallium poisoning.

A health survey in the Soviet Union was done on 51 workers exposed to thallium for 16 to 17 years that at times exceeded the maximum allowable concentration of 0.01 mg Tl/m³ set for thallium iodide and thallium bromide. Some men showed a functional nervous syndrome that consisted of asthenia and neurosis or asthenia and autonomic dysfunction, as well as vascular disorders (Stokinger, 1981). Increased concentrations of thallium were found in the urine.

Workers exposed to thallium during cement production were evaluated for neurological effects (Ludolph et al., 1986). The average duration of employment for the 36 workers was 22.9 years. Although no control group was used for comparison, the investigators reported a "high incidence of impairment of the central and peripheral nervous system, accompanied by a high level of concurrent disease." Stokinger (1981) has reported that edema of the pial and arachnoidal membranes and alterations in the ganglion cells of the ventral and dorsal horns of the spinal cord are characteristic of chronic thallium sulfate poisoning.

3.2.3.2 Animal

Information on the chronic inhalation toxicity of thallium to animals was not available.

3.2.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive inhalation toxicity of thallium to humans and animals was not available.

3.2.5 Reference Concentration

Subchronic and chronic inhalation reference concentrations for thallium and thallium salts have not been derived.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1 Human

An intravenous injection of thallium resulted in a significant dose-dependent decrease in mean arterial pressure and heart rate. The maximum fall in blood pressure occurred 3-5 minutes post-injection (Lameijer and van Zwieten, 1976).

3.3.1.2 Animal

Single intraperitoneal doses of 33-132 mg/kg/day of thallium (as thallium chloride) to animals (species not given) induced ultrastructural and biochemical changes in the liver consistent with injury to the membranes of subcellular hepatocyte organelles (Woods and Fowler, 1986). Subcutaneous injections of 7.8-15.5 mg/kg of thallium as thallium acetate were associated with degenerative changes in mitochondria and increased glycogen deposition in the liver (Herman and Bensch, 1967).

3.3.2 Subchronic Toxicity

Information on the subchronic toxicity of thallium to humans and animals by routes other than ingestion and inhalation was not available.

3.3.3 Chronic Toxicity

Information on the chronic toxicity of thallium to humans and animals by routes other than ingestion and inhalation was not available.

3.3.4 Developmental Toxicity

3.3.4.1 Human

Information on the developmental toxicity of thallium to humans by routes other than ingestion and inhalation was not available.

3.3.4.2 Animal

Sprague-Dawley rats were injected intraperitoneally with 2.5 mg/kg thallium sulfate on gestational days 8-10 or 12-14 (Gibson and Becker, 1970). Fetal body weights were significantly reduced and the incidence of hydronephrosis was increased in all treatment groups. Although the absence of vertebral bodies was also observed, fetal resorption was not increased. The investigators concluded that the failure of thallium sulfate to produce severe teratogenic effects in rats when compared with chickens is the result of placental restriction of thallium transfer.

Thallium compounds injected into developing chicken eggs were associated with embryolethality and the development of achondroplastic dwarfs (Karnofsky et al., 1950; Landauer, 1960; Ford et al., 1968; Hall 1972; Skrovina et al., 1973). The chondrogenic cells of the long bones of both chicken and mammalian embryos are sensitive to thallium (Hall, 1985; Neubert and Bluth, 1985). Neubert and Bluth (1985) concluded that thallium concentrations >10-15 µM (2.0-3.1 µg/mL) in the tissues of mammalian embryos may adversely affect fetal development but that these levels are not expected to occur in environmentally exposed humans.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1 Primary target(s)

1. Nervous system: Treatment of rats with thallium acetate for 6 months resulted in ultrastructural degenerative changes in the cerebrum, thalamus, and hypothalamus; rabbits treated for 6 months with thallium sulfate and thallium carbonate had behavioral changes characterized by aggressiveness, retardation, and rear limb paralysis. Chronic effects found in humans include edema of the pial and arachnoidal membranes; alterations in the ganglion cells of the ventral and dorsal horns of the spinal cord; sleep disorders; tiredness; weakness; nervousness; headache; optic neuropathy; blepharoptosis, lens opacities; ophthalmoplegia; and other psychic, neurological, and muscular symptoms. Animals treated for 36 weeks had alterations in peripheral nerves as evidenced by changes in the sciatic myelin sheath and axonal destruction.

2. Skin: In both humans and animals, alopecia is the most common symptom of long-term poisoning with thallium. In severe poisoning, a maculopapular skin rash and white striation of the nail bed (Mee's lines) will likely develop.

3.4.1.2 Other targets

Reproductive system: In one study, children living near a cement plant whose parents were exposed to thallium through the consumption of home-grown vegetables and fruit had an increased incidence of congenital malformations when compared with a control population. However, a causal relationship between these effects and thallium could not be verified. In animal experiments conducted by parenteral routes of exposure, thallium compounds produced signs of fetotoxicity and impairment of the learning ability of offspring of treated animals. Testicular effects were found in treated male rats.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target(s)

1. Nervous system: One occupational health survey revealed functional nervous effects consisting of asthenia and neurosis or asthenia and autonomic dysfunction in exposed populations. Another study showed a "high incidence of impairment of the central and peripheral nervous system ...." Chronic effects found in humans include edema of the pial and arachnoidal membranes, alterations in the ganglion cells of the ventral and dorsal horns of the spinal cord.

2. Skin: Alopecia has been reported in experimental animals exposed by inhalation to thallium.

4. CARCINOGENICITY

The EPA evaluated two studies on chronic health effects of workers exposed to thallium. They examined the medical records (Marcus, 1985) and medical histories and performed physical examinations (Schaller et al., 1980) of the workers. They reported that the studies were inadequate for the assessment of carcinogenicity. Data on the carcinogenicity of thallium to animals were not available.

4.1. ORAL EXPOSURES

EPA has classified thallic oxide (EPA, 1994h) and thallium (I) nitrate, acetate, carbonate, chloride, selenite, and sulfate (EPA, 1994b-g) as weight-of-evidence Group D, not classifiable as to human carcinogenicity.

4.2. CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated for thallium.

5. REFERENCES

Aoyama, H. 1989. Distribution and excretion of thallium after oral and intraperitoneal administration of thallous malonate and thallous sulfate in hamsters. Bull. Environ. Contam. Toxicol. 42: 456-463.

ATSDR (Agency for Toxic Substances and Disease Registry). 1991. Draft Toxicological Profile for Thallium. Prepared by Clement Assoc., Inc. under contract 205-88-0608. U.S. Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA, p. 1-91.

Barclay, R.K., W.C. Peacock and D.A. Karnsorsky. 1953. Distribution and excretion of radioactive thallium in the chick embryo, rat and man. J. Pharmacol. Exp. Ther. 107: 178-187.

Bornhausen, M. and U. Hagen. 1984. Operant behavior performance changes in rats after prenatal and postnatal exposure to heavy metals. IRCS Med. Sci. 12: 805-806.

Brockhaus, A., R. Dolgner, U. Ewers, U. Dramer, H. Soddemann, H. Wiegland. 1981. Intake and health effects of thallium among a population living in the vicinity of a cement plant emitting thallium containing dust. Int. Arch. Occup. Environ. Health 48: 375-389.

Budavari, S., M.J. O'Neil, A. Smith and P. Heckelman, Eds. 1989. Merck Index, 11th ed. Merck and Co., Inc. Rahway, N.J. p. 1458.

de Groot, G. and A.N.P. Van Heijst. 1988. Toxicokinetic aspects of thallium poisoning. Methods of treatment by toxin elimination. Sci. Total Environ. 71: 411-418.

Deshimaru, j., T. Miyakawa, S. Sumiyoshi, F. Yasuoka and K. Kawano. 1977. Electron microscopic study of experimental thallotoxicosis. Folia Psych. Neurol. Jpn. 31: 269-275.

Dolgner, R., A. Brockhaus, U. Ewers, H. Wiegand, F. Majewski and H. Soddemann. 1983. Repeated surveillance of exposure to thallium in a population living in the vicinity of a cement plant emitting dust containing thallium. Int. Arch. Occup. Environ. Health 52: 79-94.

Downs, W.L., J.K. Scott, L.T. Steadman and E.A. Maynard. 1960. Acute and subacute toxicity studies of thallium compounds. Am. Ind. Hyg. Assoc. 21: 399-406.

Ford, J.K., E.J. Eyring and C.E. Anderson. 1968. Thallium chondrodystrophy in chick embryos. J. Bone Joint Surg. 50A: 687-700.

Formigli, E., R. Scelsi, P. Poggi, et al. 1986. Thallium induced testicular toxicity in the rat. Environ. Res. 40: 531.

Gibson J.E. and B.A. Becker. 1970. Placental transfer, embryotoxicity and teratogenicity of thallium sulfate in normal and potassium-deficient rats. Toxicol. Appl. Pharmacol. 16: 120-132.

Goyer, R.A. 1986. Toxic effects of metals. In: Toxicology, The Basic Science of Poisons, 3rd ed., C.D. Klaassen, M.O. Amdur and J. Doull, eds., Macmillian Publishing Co., New York, p. 626.

Gregus, Z. and C.D. Klaassen. 1986. Disposition of metals in rats: A comparative study of fecal, urinary and biliary excretion and tissue distribution of eighteen metals. Toxicol Appl. Pharmacol. 85: 24-38.

Hall, B.K. 1972. Thallium induced achondroplasia in the embryonic chick. Devel. Biol. 28: 47-60.

Hall, B.K. 1985. Critical periods during development as assessed by thallium-induced inhibition of growth of embryonic chick tibiae in vitro. Teratology 31: 353-361.

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