The Risk Assessment Information System

Toxicity Summary for TRICHLOROETHENE

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.

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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 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

MARCH 1993

Prepared by: Rosmarie A. Faust, Ph.D, Chemical Hazard Evaluation Group, Biomedical Environmental Information Analysis Section, Health and Safety Research Division, ^*, 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.

EXECUTIVE SUMMARY

Trichloroethene (TCE) is an industrial solvent used primarily in metal degreasing and cleaning operations. TCE can be absorbed through the lungs, mucous membranes, gastrointestinal tract, and the skin. TCE is extensively metabolized in humans to trichloroacetic acid and trichloroethanol, as well as to several minor metabolites, with most of the absorbed dose excreted in urine (ATSDR, 1989; U.S. EPA, 1985).

Human and animal data indicate that exposure to TCE can result in toxic effects on a number of organs and systems, including the liver, kidney, blood, skin, immune system, reproductive system, nervous system, and cardiovascular system. In humans, acute inhalation exposure to TCE causes central nervous system symptoms such as headache, dizziness, nausea, and unconsciousness (U.S. EPA, 1985). Among the reported effects from occupational exposure studies are fatigue, light-headedness, sleepiness, vision distortion, abnormal reflexes, tremors, ataxia, nystagmus, increased respiration, as well as neurobehavioral or psychological changes. Cardiovascular effects include tachycardia, extrasystoles, EKG abnormalities, and precordial pain (Landrigan et al., 1987; Grandjean et al., 1955; Milby, 1968). The use of TCE as an anesthetic has been associated with cardiac arrhythmias (U.S. EPA, 1985).

Cases of severe liver and kidney damage, including necrosis, have been reported in humans following acute exposure to TCE (Defalque, 1961), but these effects generally are not associated with long-term occupational exposures. In animals, TCE has produced liver enlargement with hepatic biochemical and/or histological changes (Nomiyama et al., 1986; Kjellstrand et al., 1981, 1983; Stott et al., 1982; Tucker et al., 1982) and kidney enlargement, renal tubular alterations and/or toxic nephropathy (NTP, 1982, 1986a, 1988). Also observed in animals were hematological effects (Tucker et al., 1982; Mazza and Brancaccio, 1967) and immunosuppression (Sanders et al., 1982). Inhalation studies with rats indicate that TCE is a developmental toxicant causing skeletal ossification anomalies and other effects consistent with delayed maturation (Healy et al., 1982; Dorfmueller et al., 1979). TCE may cause dermatitis and dermographism (U.S. EPA, 1985).

Reference Doses (RfDs) and Reference Concentrations (RfCs) for subchronic and chronic oral and inhalation exposure to TCE are presently under review by EPA (U.S. EPA, 1992a).

Epidemiologic studies have been inadequate to determine if a correlation exists between exposure to TCE and increased cancer risk. Chronic oral exposure to TCE increased the incidences of hepatocellular carcinomas in mice and renal adenocarcinomas and leukemia in rats (NTP, 1988; Maltoni et al., 1986; NTP, 1986a, 1982; NCI, 1976). Chronic inhalation exposure induced lung and liver tumors in mice and testicular Leydig cell tumors in rats (Maltoni et al., 1986, 1988; Fukuda et al., 1983; Bell et al., 1978). Although U.S. EPA's Science Advisory Board recommended a weight-of-evidence classification of C-B2 continuum (C = possible human carcinogen; B2 = probable human carcinogen), the agency has not adopted a current position on the weight-of-evidence classification (U.S. EPA, 1992b). In an earlier evaluation, TCE was assigned to weight-of-evidence Group B2, probable human carcinogen, based on tumorigenic responses in rats and mice for both oral and inhalation exposure and on inadequate data in humans (U.S. EPA, 1987, 1990). Carcinogen slope factors are 1.1E-2 (mg/kg/day)^-1 and 6.0E-3 (mg/kg/day)^-1 for oral and inhalation exposure, respectively. The corresponding unit risks are 3.2E-7 (µg/L)^-1 and 1.7E-6 (µg/m³)^-1, respectively (U.S. EPA, 1992b).

1. INTRODUCTION

Trichloroethene (trichlorothylene; TCE; CAS No. 79-01-6) is a colorless, highly volatile liquid that is miscible with water and a number of organic solvents (U.S. EPA, 1985). It has a molecular weight of 131.4, a boiling point of 87C, and a density of 1.4642 at 20/4C (Weast, 1989). TCE is a man-made chemical and is not known to occur naturally. It is mainly used as a solvent in industrial degreasing and cleaning of metals, but is also used as a solvent for waxes, fats, resins, and oils, and in numerous other applications. Prior to 1977, TCE had been used as an anesthetic, grain fumigant, disinfectant, and extractant of spice oleoresins in food and of caffeine in the production of decaffeinated coffee. Workers in the vapor degreasing industry appear to be exposed to the highest atmospheric levels of TCE. TCE has been detected in both surface and ground waters; however, most (80-95%) TCE used is released to the atmosphere by evaporative losses (ATSDR, 1989).

The evaluation of the toxicity of TCE is complicated by the presence or absence of stabilizers. Industrial grade TCE usually contains stabilizers such as triethylamine, triethanolamine, epichlorohydrin, or stearates, chemicals that can be toxic by themselves. In the absence of stabilizers, TCE readily decomposes to dichloroacetylene, phosgene, carbon monoxide, and hydrogen chloride. These decomposition products are also toxic (O'Donoghue, 1985).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Trichloroethene can be absorbed through the lungs, digestive tract, skin, and mucous membranes. The primary route of human exposure to the chemical is through pulmonary uptake, which is rapid but requires about 8 hours to reach tissue equilibrium. The total dose absorbed is directly proportional to the concentration in inspired air, and for a given concentration, body burden increases with duration and frequency of exposure, and with exercise (U.S. EPA, 1985). After ingestion, 90-95% of a dose of 40-60 mg/kg was recovered in expired air and in urine of rats, suggesting almost complete absorption of the compound (Daniel, 1963). Tsuruta (1978) estimated skin absorption by in vivo and in vitro techniques and reported rates of 7.82 to 12.1 µg/min/cm² in mice.

2.2. DISTRIBUTION

Following uptake into the body, TCE is rapidly distributed from blood to all tissues, particularly adipose tissue, and appears in sweat and saliva (U.S. EPA, 1985). TCE readily passes through the placenta and was detected in the blood of babies at birth after the mothers had received TCE anesthesia (Laham, 1970).

2.3. METABOLISM

The principal site of TCE metabolism is the liver, although metabolism may also occur in the lungs, kidneys, spleen, and small intestine (ATSDR, 1989). The initial biotransformation may involve the formation of two intermediates, TCE epoxide and chloral. In man and animals, TCE is extensively metabolized to trichloroacetic acid, trichloroethanol, and trichloroethanol glucuronide. Several minor metabolites have also been identified, including oxalic acid, dichloroacetic acid, N-(hydroxyacetyl)-aminoethanol, and carbon dioxide. Reactive intermediate metabolites, such as the epoxide, covalently bind to cellular macromolecules, principally protein and to a much smaller extent, DNA. It is estimated that humans metabolize between 40 and 75% of the retained dose (U.S. EPA, 1985). At relatively low TCE concentrations, saturation of TCE metabolism has not been demonstrated in humans. However, both oral and inhalation studies have provided evidence for saturation of TCE metabolism in rats (ATSDR, 1989). There are quantitative differences in the rates of metabolism in different species. For example, mice metabolize TCE at a greater rate than rats and as a result produce more tissue-binding metabolites in the liver and kidney when compared to rats (Stott et al., 1982).

2.4. EXCRETION

TCE is eliminated by two major processes, liver metabolism with subsequent elimination of metabolites and pulmonary excretion of the parent compound. In humans, most of retained TCE is excreted as urinary metabolites (58%); 5% or more may be excreted in the feces; and about 11% is eliminated through the lungs (ATSDR, 1989). In contrast, when TCE was given by gavage to rats, 10-20% of the dose was excreted in the urine as trichloroacetic acid and trichloroethanol, 0-0.5% as TCE in the feces, and 72-85% as TCE in the expired air (Daniel, 1963).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Fatalities have been reported following accidental or intentional ingestion of TCE. The lethal oral dose for adults is approximately 7 g/kg (WHO, 1985). Accidental ingestion of TCE has resulted in inebriety, vomiting, diarrhea, collapse and coma, followed by either death or recovery with transient neurological sequelae (amnesia, headache, numbness, weakness of extremities, psychosis or hemiparesis). At autopsy, pulmonary edema and liver and kidney necrosis were observed (Defalque, 1961). Hepatorenal failure was reported in one fatal case of accidental ingestion of TCE (Kleinfield and Tabershaw, 1954). There are indications that the hepatotoxic effects of TCE are enhanced by concomitant exposure to ethanol or isopropyl alcohol (IARC, 1979). Case studies suggest that ingestion of 350-500 mL of TCE can produce cardiac arrhythmias (Dhuner et al., 1957).

3.1.1.2. Animal

Oral LD₅₀s for TCE are 2402 and 2443 mg/kg for male and female mice, respectively, 4920 mg/kg for rats, and 5680 mg/kg for dogs (ATSDR, 1989).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic oral toxicity of TCE in humans was unavailable.

3.1.2.2. Animal

Male mice given 250-2400 mg/kg TCE by gavage, 5 days/week for 3 weeks exhibited a dose-related hepatocellular hypertrophy (Stott et al., 1982). Significantly increased liver weights were seen in male CD-1 mice given daily gavage doses of 240 mg/kg/day, but not 24 mg/kg/day, for 14 days (Tucker et al., 1982). The same investigators administered TCE in drinking water to CD-1 mice for 6 months at concentrations of 18-660 mg/kg/day (males) and 18-793 mg/kg/day (females). Treatment-related effects included increased relative liver weights and increased urinary ketone and protein concentrations at 393 mg/kg/day (males) and increased liver and kidney weights at the highest doses in both sexes. Also observed at the highest doses were decreased erythrocyte and leukocyte counts and increased fibrinogen levels in males after 4 and 6 months and shortened prothrombin time in females after 6 months (Tucker et al., 1982).

Sanders et al. (1982) evaluated the immune status of male and female CD-1 mice following exposure to TCE in drinking water at doses of 18-666 mg/kg/day (males) and 18-793 mg/kg/day (females) for 4 or 6 months. The TCE-induced immunotoxic effects observed were more pronounced in females and included depressed cell-mediated response to sheep erythrocytes at 18 mg/kg after 4 months and at 739 mg/kg/day after 6 months; depressed antibody-forming cell response at 437 mg/kg/day after 4 months but not after 6 months; and inhibited bone marrow stem cell colonization after 4 and 6 months.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic oral toxicity of TCE in humans was unavailable.

3.1.3.2. Animal

Renal effects characterized as cytomegaly were observed in F344 rats treated by gavage with 500 or 1000 mg/kg/day TCE, 5 days/week for 103 weeks and in B6C3F₁ mice similarly treated with 1000 mg/kg/day (NTP, 1982; 1986a). Also observed in rats were signs of central nervous system (CNS) toxicity, including ataxia, lethargy, convulsions, and hind limb paralysis. These effects were described as sporadic and transient. Cytomegaly of renal tubular cells and toxic nephropathy was seen in ACI, August, Marshall, and Osborne-Mendel rats treated by gavage with 500 or 1000 mg/kg/day for 103-104 weeks (NTP, 1988).

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental and reproductive toxicity of TCE in humans following oral exposure was unavailable.

3.1.4.2. Animal

Rats exposed to TCE by gavage in corn oil at doses of 0, 10, 100, or 1000 mg/kg/day for 2 weeks prior to and throughout mating to day 21 of gestation exhibited increased maternal mortality, decreased maternal weight gain, and decreased neonatal survival in the high-dose group (Manson et al., 1984).

Two-generation fertility studies (NTP, 1985, 1986b) exposed male and female F344 rats and CD-1 mice to diets containing 75, 150, or 300 mg/kg/day TCE. In rats, the two higher doses caused a reduction in the number of live pups/litter and the highest dose caused increased testis and epididymis weights (combined) in the F₀ generation. Mice exposed to the highest dose exhibited increased neonatal mortality, increased testis and epididymis weights (combined) in F₁ mice, and reduced sperm motility in F₀ and F₁ mice.

3.1.5. Reference Dose

The development of a Reference Dose for TCE is under review by EPA (U.S. EPA, 1992a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Acute inhalation exposure to TCE causes central nervous system symptoms, such as headache, dizziness, nausea, and in some cases unconsciousness. Lower levels may affect visual and motor performance (U.S. EPA, 1985). Case reports reviewed by Grant (1974) indicate that acute exposure to TCE may produce paralysis of the trigeminal nerve or extraocular muscle as well as vision disturbances. It was suggested that the observed visual effects were produced by decomposition products such as dichloroacetylene rather than by TCE. Although permanent central nervous system damage has been reported after exposure to TCE, respiratory and cardiac failure are the likely causes of death following acute inhalation exposure. The use of TCE as an anesthetic has been associated with cardiac arrhythmias, bradycardia, atrial and ventricular premature contractions, and ventricular extrasystole (U.S. EPA, 1985). In controlled studies of human exposure, impairment of psychophysiological function was seen in volunteers exposed to 110 ppm for two 4-hour periods. Exposure to 200 ppm for 7 hours over 5 days produced fatigue and sleepiness (IARC, 1979).

Cases of severe liver damage, including necrosis, resulting from acute occupational exposure to lethal concentrations of TCE have been reported. A few case reports described renal dysfunction and failure resulting from occupational or intentional exposure (U.S. EPA, 1985).

3.2.1.2. Animal

Reported LC₅₀ values for TCE range from 7,480 to 49,000 ppm for mice and from 12,500 to 26,300 ppm for rats (ATSDR, 1989). Rats exposed to 250-4,000 ppm TCE for up to 4 hours exhibited decreased avoidance responses (Kishi et al., 1986). Sensitization of the heart to epinephrine-induced arrhythmia was observed in dogs exposed to 5,000-10,000 ppm for 10 min and in rabbits exposed to 6,000 ppm for 1 hour (U.S. EPA, 1985). Chakrabarti and Tuchweber (1988) reported that rats exposed to 1,000 or 2,000 ppm TCE for 6 hours exhibited significantly increased urinary levels of gamma-glutamyltranspeptidase activity, and glucose and protein concentrations, which are biochemical changes indicative of renal injury.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Landrigan et al. (1987) reported that seven of nine TCE-exposed workers involved in a metal degreasing operation experienced fatigue, light-headedness, sleepiness, shortness of breath, dyspnea on exertion, palpitations, nausea, and headache. Similar symptoms were not reported in non-exposed controls. The mean duration of employment of exposed workers was 4.4 years. Breathing zone levels of TCE for the five workers who were exposed to the highest TCE concentrations ranged from 117 to 357 mg/m³ and averaged 89 mg/m³. Short-term peak exposures ranged from 413 to 2000 mg/m³.

Grandjean et al. (1955) evaluated the effects of TCE in 50 workers who had been occupationally exposed for an average of 3.75 years. Signs of severe neurological disturbances (vision distortion, abnormal reflexes, slow tremors, ataxia, or nystagmus) occurred in 28% of the exposed workers. Symptoms of autonomic nervous system involvement (excessive respiration, circulatory symptoms, tremors, gastrointestinal upset, palpitations, tachycardia, extrasystoles, precordial pain, and pronounced modification of dermographism) occurred in 36% of the workers. Slight to moderate psychic disturbances (short-term memory loss, slow understanding, emotional instability, and fewer word associations) occurred in 34% of the workers.

In a case study reported by Milby (1968), vomiting and abdominal cramps, as well as an erratic heart beat, an abnormal EKG, sleepiness, weakness, and loss of appetite occurred in a worker who had been exposed to TCE for 1 month. Breathing zone measurements after the incident ranged from 260 to 280 ppm TCE. James (1963) reported fatty degeneration of the liver in a worker who had become addicted to TCE over a 9-year period.

3.2.2.2. Animal

Nomiyama et al. (1986) found significant hepatic dysfunction in male Sprague-Dawley rats continuously exposed to 50, 200, or 800 ppm TCE for 12 weeks. Liver weight, total protein, albumin/globulin ratio, plasma glutamic pyruvate transaminase activity, triglyceride, cholesterol ester ratio, and cholinesterase were affected. Renal dysfunction as indicated by glycosuria and alterations in plasma creatine, urine nitrogen, uric acid, and creatine clearance, as well as concentration-related changes in hematocrit, and erythrocyte, reticulocyte, and erythroblast counts were also seen.

Rats exposed to 55 ppm TCE for 14 weeks exhibited enlarged livers but no other adverse hepatic effects (Kimmerle and Eben, 1973). Increased relative liver weight was the only hepatic effect reported in male and female rats, mice, and gerbils exposed to concentrations up to 150 ppm TCE for 30 days, but the effect was more pronounced in mice than in rats or gerbils (Kjellstrand et al., 1981). Histological alterations of the liver characterized by cellular atrophy were associated with liver enlargement in a study with mice exposed to 37 ppm TCE for 30 days (Kjellstrand et al., 1983).

Haglid et al. (1981) reported that continuous exposure to 60 ppm TCE for 3 months resulted in biochemical and histopathological changes in the brain of Mongolian gerbils. These changes are indicative of astroglial hypertrophy and/or proliferation. Behavioral changes (reduced activity) were seen in rats exposed for 12 weeks to TCE at concentrations ranging from 100 to 1000 ppm (Silverman and Williams, 1975).

Exposure to 2790 ppm TCE, 4 hours/day, 6 days/week for 45 days caused myelotoxic anemia in rabbits (Mazza and Brancaccio, 1967). A concentration-related decrease in delta-aminolevulinate dehydratase activity (an enzyme involved in heme regulation) was seen in rats continuously exposed to 50, 400, or 800 ppm for 10 days (Fujita et al., 1984).

3.2.3. Chronic Toxicity

3.2.3.1. Human

Bardodej and Vyskocil (1956) evaluated 75 individuals in dry cleaning and metal degreasing workshops who had been exposed to 5-632 ppm TCE for 1-25 years. Prenarcotic symptoms of chronic exposure included headache, sleepiness, a drunken feeling, nausea, and tinnitus. Other symptoms were intolerance to heat and sunlight, hot flashes, perspiration, exaggerated heart beat, respiratory difficulties, reddening of the skin after mechanical or heat insults, intolerance to alcohol, and dermographism. Cardiovascular effects included vasomotor changes, bradycardia, supraventricular extrasystole, and conduction velocity disturbances. In addition, numerous subjective CNS effects were reported. There was no evidence of liver or kidney damage.

3.2.3.2. Animal

Male Sprague-Dawley rats were exposed to 100, 300, or 600 ppm TCE, 7 hours/day, 5 days/week for 108 weeks. Renal cytokaryomegaly occurred at 300 and 600 ppm, but not at 100 ppm (Maltoni et al., 1988, 1986).

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Two studies suggest that medical personnel exposed to various solvents, including TCE, are susceptible to reproductive effects. A survey of operating room personnel in the U.S. showed that women exposed to anesthetic waste gases (containing TCE) were subject to increased risks of spontaneous abortions and congenital abnormalities in their children. Increased risks of congenital abnormalities were also present among non-exposed wives of male operating room personnel (Cohen et al., 1974). Another survey involving 7949 physicians in the United Kingdom revealed a significantly higher frequency of spontaneous abortions in women anesthesiologists compared with non-anesthesiologists. The frequency of minor abnormalities in children of exposed fathers was 3.09% compared with 2.35% for nonexposed fathers (Knill-Jones et al., 1975).

3.2.4.2. Animal

Dorfmueller et al. (1979) exposed female rats to 1800 ppm TCE for two weeks prior to mating and for 20 days during gestation and found no evidence of maternal toxicity, embryotoxicity, severe teratogenicity, or behavioral deficits in the offspring. Offspring of rats exposed during pregnancy alone showed significant increases of skeletal and soft tissue abnormalities. Reduced body weights were seen in offspring of rats with pregestational exposure alone.

Wistar rats exposed to 100 ppm TCE for 4 hours daily on days 8-21 of gestation exhibited increased resorptions, reduced fetal weight gains, and increased frequency of bipartite or absent skeletal ossification centers (Healy et al., 1982). However, Sprague-Dawley rats and Swiss Webster mice exposed to 300 ppm TCE on days 5-15 of gestation exhibited no significant maternal, embryonal, or fetal toxicity and no evidence of teratogenicity (Schwetz et al., 1975).

Sperm abnormalities were reported in mice exposed to 2000 ppm anesthetic-grade TCE vapor, 4 hours/day for 5 days (Land et al., 1979) or to 500 ppm TCE, 7 hours/day for 5 days (Beliles et al., 1980).

3.2.5. Reference Concentration

The development of a Reference Concentration is under review by EPA (U.S. EPA, 1992a).

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Acute dermal exposure to TCE has been associated with reddening and dermatographic skin burns. The vapor may cause general dermatitis (U.S. EPA, 1985). Hypersensitivity to TCE, resulting in severe dermatological abnormalities, such as Steven-Johnson syndrome (erythema multiformis major), was reported in one study (Phoon et al., 1984). A skin condition termed "degreasers' flush" has been reported in workers who had consumed alcohol before or after exposure to TCE (Stewart et al., 1974). Direct contact of TCE vapor or liquid with the eye causes superficial damage to the cornea, but complete recovery occurs within a few days (Grant, 1974).

3.3.1.2. Animal

The dermal LD₅₀ for TCE in rabbits is > 20 mL/kg (Smyth et al., 1969).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of TCE by other routes of exposure in humans or animals was unavailable.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of TCE by other routes of exposure in humans or animals was unavailable.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of TCE by other routes of exposure in humans or animals was unavailable.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Liver: Mice developed increased liver weight and hepatocellular hypertrophy following oral exposure to TCE.

2. Kidney: Rats and mice developed increased kidney weights, cytomegaly of renal tubular cells, and toxic nephropathy following oral exposure to TCE.

3.4.1.2. Other Target Organ(s)

1. Central nervous system: Chronic oral exposure of rats caused transient CNS effects including ataxia, lethargy, convulsions, and hind limb paralysis.

2. Reproduction: Increased neonatal mortality, increased testis and epididymis weights, and reduced sperm motility was seen in a two-generation fertility study with rats.

3. Hematopoietic system: Rats exposed to TCE in drinking water exhibited decreased erythrocyte and leukocyte counts, increased fibrinogen levels, and shortened prothrombin time.

4. Immune system: Mice exposed to TCE in drinking water exhibited immunotoxic effects characterized by delayed hypersensitivity, suppressed antibody forming cell response, and decreased bone marrow stem cell colonization.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Nervous system: CNS symptoms in workers exposed to TCE by inhalation included headache, sleepiness, vision distortion, nausea, abnormal reflexes, tremors, ataxia, nystagmus, and increased respiration. TCE exposure may also cause psychic disturbances such as short-term memory loss and fewer word associations. Subchronic exposure of gerbils induced biochemical and histopathological changes in the brain.

2. Liver: Following inhalation exposure to TCE, rodents developed enlarged livers and biochemical changes indicative of liver damage. Liver damage in humans is primarily associated with acute exposure to TCE. The hepatotoxic effects of TCE are enhanced by concomitant exposure to alcohol.

3. Kidney: Rats developed renal cytokaryomegaly following chronic inhalation exposure to TCE.

4. Cardiovascular system: Occupational exposure to TCE has been associated with vasomotor changes, tachycardia, bradycardia, extrasystoles, conduction disturbances, and precordial pain. TCE sensitizes the heart to cardiac arrhythmias.

5. Hematopoietic system: Inhalation of TCE induced myelotoxic anemia in rabbits and produced dose-related changes in several hematological indices in rats.

6. Reproduction: Inhalation studies with rodents indicate that TCE may cause increased resorptions, reduced fetal body weight, and ossification anomalies. Exposure to high concentrations produced sperm abnormalities in mice.

3.4.2.2. Other Target Organ(s)

Skin: Reddening of the skin following mechanical or heat insults and dermographism was seen in workers exposed to TCE by inhalation.

3.4.3. Other Routes of Exposure

Skin: Dermal exposure to TCE may cause general dermatitis and hypersensitivity. "Degreasers' flush" may occur in conjunction with alcohol consumption.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Mortality statistics for 1969-1979 in Woburn, Massachusetts revealed a significantly elevated rate of childhood leukemia. Two of the eight municipal wells serving the community were known to be contaminated with TCE and several other chlorinated organic compounds, but the causes of leukemia were not identified in these studies (Kotelchuck and Parker, 1979; Parker and Rosen, 1981).

4.1.2. Animal

Maltoni et al. (1986) treated male and female Sprague-Dawley rats by gavage with TCE (99.9% pure) in olive oil at doses of 50 or 250 mg/kg/day, 4-5 days/week for 52 weeks. There was a dose-related increase in the incidence of leukemia in males, but no increased tumor incidence in females.

Significantly increased incidences of hepatocellular carcinomas occurred in B6C3F₁ mice that were administered time-weighted-average doses of 1170 or 1340 mg/kg/day (males) or 870 or 1740 mg/kg/day (females) by gavage, 5 days/week for 78 weeks. No compound-related carcinogenic effects were found in Osborne-Mendel rats similarly treated with 550 or 1100 mg/kg/day, but this finding was inconclusive because of poor survival. The TCE used in the study was 99% pure but contained stabilizers, including epichlorohydrin, a known carcinogen (NCI, 1976).

Studies by NTP (1982, 1986a) showed significantly increased incidences of hepatocellular carcinomas in male and female B6C3F₁ mice treated by gavage with epichlorohydrin-free TCE at a dose of 1000 mg/kg/day, 5 days/week for 103 weeks. F344 rats treated with 1000 mg/kg/day by the same regimen exhibited renal adenomas and adenocarcinomas; this effect was not seen at 500 mg/kg/day or in females at either dose level. Due to poor survival, the results in rats were considered inadequate. A third NTP study (NTP, 1988) exposed groups of male and female ACI, August, Marshall, and Osborne-Mendel rats by gavage to epichlorohydrin-free TCE in corn oil at doses of 0, 500, or 1000 mg/kg, 5 days/week for 103 weeks. There were significantly increased incidences of renal tubular cell neoplasms in low dose male Osborne-Mendel rats and interstitial cell neoplasms of the testis in high-dose Marshall rats. This study also was considered inadequate for assessment of carcinogenic activity because of toxic nephrosis and low survival.

Henschler et al. (1984) compared the carcinogenicity of TCE stabilized with epichlorohydrin (0.8%) or 1,2-epoxybutane (0.8%) to that of industrial-grade TCE in male and female ICR/Ha Swiss mice. TCE was administered daily by gavage (2.4 g/kg, females; 1.8 g/kg, males) for 18 months, with and without the addition of the epoxides. Animals exposed to epichlorohydrin- or 1,2-epoxybutane-stabilized TCE exhibited an increased incidence of papillomas and carcinomas of the forestomach. This effect was not observed without stabilizers.

4.2. INHALATION EXPOSURES

4.2.1. Human

Epidemiologic studies conducted by Axelson et al. (1978), Malek et al. (1979), and Tola et al. (1980) reported no significant excess cancer risks associated with occupational exposure to TCE, but the studies do not permit definite conclusions because of various study limitations such as inadequate latency periods, small sample size, lack of analysis by tumor site, and multiple chemical exposure (ATSDR, 1989; U.S. EPA, 1985). An update of one of the studies (Axelson, 1986) found a slight increase of bladder cancer and lymphomas in an expanded cohort study; however, details of TCE exposure were not given. A retrospective cohort mortality study of dry-cleaning and/or laundry workers (Blair et al., 1979) found significant increases in the incidence of cancer at several sites (lung/bronchi/trachea, cervix, and skin) among a group of 330 deceased workers. This cancer increase was possibly due to dry-cleaning chemicals (carbon tetrachloride, tetrachloroethylene, and TCE) but could not be related to TCE alone. Paddle (1983) examined tumor registry records in Great Britain and found no association between liver cancer and TCE exposure in workers employed in one TCE production facility.

4.2.2. Animal

Bell et al. (1978) reported no carcinogenic effects in Charles River rats exposed to technical grade TCE at concentrations of 0, 100, 300, or 600 ppm, 6 hours/day, 5 days/week for 24 months. Hepatocellular carcinomas were seen in B6C3F₁ mice similarly exposed to TCE, with a greater incidence of tumors occurring in males than in females. The TCE employed contained 0.148% epichlorohydrin and several other additives.

Wistar rats, NMR mice, and Syrian hamsters were exposed to purified TCE at 0, 100, or 500 ppm, 6 hours/day, 5 days/week for 18 months (Henschler et al., 1980). The only statistically significant effect was an increased incidence of malignant lymphomas in female mice. U.S. EPA (1987) suggested that lymphoma susceptibility may have been enhanced by virus and immunosuppression.

Fukuda et al. (1983) exposed female ICR mice and Sprague-Dawley rats to reagent-grade TCE (containing 0.019% epichlorohydrin) at concentrations of 0, 50, 150, or 450 ppm, 7 hours/day, 5 days/week for 104 weeks. Although there were a number of tumors at several sites in rats and mice, only lung adenocarcinomas were significantly increased in mice at the two highest concentrations compared with controls.

Maltoni et al. (1986, 1988) exposed male and female Sprague-Dawley rats, Swiss mice, and B6C3F₁ mice to 100, 300, or 600 ppm epoxide-free TCE, 7 hours/day, 5 days/week for 104 weeks (rats) or 78 weeks (mice). Statistically significant increased incidences of tumors included testicular Leydig cell tumors in rats at 100 ppm, lung adenomas in male Swiss mice at 300 ppm, hepatomas in male Swiss mice at 600 ppm, and lung adenomas in female B6C3F₁ mice at 600 ppm.

4.3. OTHER ROUTES OF EXPOSURE

4.3.1. Human

Information on the carcinogenicity of TCE in humans by other routes of exposure was unavailable.

4.3.2. Animal

Three weekly topical applications of 1 mg TCE for 581 days did not induce skin tumors in female Swiss ICR/ha mice. Negative results were also reported in a tumor initiation assay in which mice received a single dermal application of 1 mg TCE, followed by 3 weekly applications of a phorbol ester for 581 days (Van Duuren et al., 1979).

4.4. EPA WEIGHT-OF-EVIDENCE

Classification: C-B2 continuum (C = possible human carcinogen; B2 = probable human carcinogen) (U.S. EPA, 1992b).

Comment: This classification is a recent recommendation by EPA's Science Advisory Board. However, EPA has not adopted a current position on the weight-of-evidence classification (U.S. EPA, 1992b). An earlier evaluation (U.S. EPA, 1990) classified TCE as a weight-of-evidence B2 chemical, based on tumor responses in rats and mice exposed to TCE by the oral and inhalation routes of exposure. The available epidemiological data were inadequate to refute or demonstrate a human carcinogenic potential (U.S. EPA, 1987).

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

SLOPE FACTOR: 1.1E-2 (mg/kg/day)^-1 (U.S. EPA, 1992b)

UNIT RISK: 3.2E-7 (µg/L)^-1 (U.S. EPA, 1992b)

PRINCIPAL STUDIES: NCI (1976); NTP (1983); U.S. EPA (1985, 1987, 1988)

COMMENT: The slope factor and unit risk values were provided in U.S. EPA (1985). However, the carcinogenicity files for TCE have been withdrawn from IRIS pending resolution of the weight-of-evidence classification.

4.5.2. Inhalation

SLOPE FACTOR: 6.0E-3 (mg/kg/day)^-1 (U.S. EPA, 1992b)

UNIT RISK: 1.7E-6 (µg/m³)^-1 (U.S. EPA, 1992b)

PRINCIPAL STUDIES: Maltoni et al. (1986); Fukuda et al. (1983); U.S. EPA (1988)

COMMENT: The slope factor and unit risk values were provided in U.S. EPA (1987). However, the carcinogenicity files for TCE have been withdrawn from IRIS pending resolution of the weight-of-evidence classification.

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