National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Trichloroethylene
• TRICHLOROETHENE (9CI)

Human Toxicity Excerpts

• IN ACUTE INHALATION EXPOSURES RAPID COMA MAY ENSUE WITH EVENTUAL DEATH FROM HEPATIC OR RENAL FAILURE. AN OCCASIONAL SUDDEN DEATH SUGGESTS VENTRICULAR FIBRILLATION. SEQUELAE, WHICH MAY BE MORE COMMON AFTER INHALATION THAN AFTER INGESTION, INCLUDE LIVER AND KIDNEY LESIONS, REVERSIBLE TRIGEMINAL (OR OTHER NERVE) DEGENERATION AND PSYCHIC DISTURBANCES. [Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. II-112]**PEER REVIEWED**
  
• ... Workers exposed @ concn avg about 10 ppm ... complained of headache, dizziness and sleepiness. ... An epidemiology study on the hepatic tumor incidence in subjects working with trichloroethylene ... failed to show a correlation between liver /cancer/ and occupational exposure. ... Another ... study looked at the mortality of 2117 workers exposed to trichloroethylene ... found no correlation between cancer and occupational exposure. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986., p. 596]**PEER REVIEWED**
  
• Trichloroethylene is only mildly irritating to the skin if allowed to evaporate. From continued use of the material in contact with the skin, defatting can take place. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4196]**PEER REVIEWED**
  
• Fatal hepatic failure has been observed following the use of trichloroethylene as an anesthetic. This effect has occurred in patients with complicating conditions such as malnutrition, toxemias, burns, or those who have received transfusions. [Dafalque RJ; Clin Pharm Ther 2: 665 (1961) as cited in USEPA; Ambient Water Quality Criteria Document: Trichloroethylene p.C-17 (1980) EPA-440/5/80-007]**PEER REVIEWED**
  
• Prolonged occupational exposure to trichloroethylene has been associated with impairment of peripheral nervous system function, persistent neuritis and temporary loss of tactile sense and paralysis of the fingers after direct contact with the solvent. [Bardodej Z, Vyskocil J; AMA Arch Ind Health 13: 581 (1956) as cited in USEPA; Ambient Water Quality Criteria Document: Trichloroethylene p.C-17 (1980) EPA 440/5/80-007]**PEER REVIEWED**
  
• A case of severe liver necrosis following a prolonged (4-1/2 hour) use of trichloroethylene as an anesthetic has been reported. [Herdman KN; Br Med J (3): 689-90 (1945) as cited in Health and Safety Executive Monograph: Trichloroethylene #6 p.14 (1982)]**PEER REVIEWED**
  
• Following chronic and acute overexposure to trichloroethylene during operation of a dry cleaning unit, symptoms included symmetrical bilateral VIIIth cranial nerve deafness as well as cerebral cortical dysrhythmia and alterations in the electroencephalogram. The patient recovered after the exposure stopped. [Tomasini M, Sartorelli E; Med Lav 62: 277-80 (1971) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.5-2 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• Acute overexposure to trichloroethylene resulted in chronic involvement of the bulbar cranial nerves and esophageal and pharyngeal motility impairment. [Lawrence WH, Partyka EK; Ann Int Med 95 (6): 710 (1981) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.5-2 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• Autopsy findings in a 16 yr old boy who died while sniffing plastic cement containing TCE indicated severe heart failure. ... Liver failure is not the usual cause of death among solvent sniffers, but liver biopsies often reveal toxic centrilobular necrosis. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-165]**PEER REVIEWED**
  
• The behavioral effects of exposure to trichloroethylene /indicate that/ laboratory /and work-place/ exposure to 540 or 1080 mg/cu m for 70 min, has no effect on reaction time or short-term memory. [Gamberale F et al; Scand J Work Environ Health 4: 220-4 (1976) as cited in WHO; Environ Health Criteria 50: Trichloroethylene p.83 (1985)]**PEER REVIEWED**
  
• Chromosome analyses of cultured lymphocytes from 28 workers aged 23-67 who had been employed on degreasing unit using trichloroethylene for 1-21 years showed high rates of hypodiploid cells (9 of 28). [Konietzko H et al; Arch Toxicol 40 (3): 201-6 (1978)]**PEER REVIEWED**
  
• Evoked trigeminal potentials were studied in 104 subjects occupationally exposed to trichloroethylene. Subjects had an average exposure time of 8.23 yr and an average daily exposure of 7 hr (exposure levels were not given). Controls were 52 healthy nonexposed subjects. Symptoms suffered by 49 of the exposed subjects included dizziness, headache, asthenia, insommnia, mood perturbation, and sexual problems. Eighteen subjects had trigeminal nerve symptoms. These subjects were significantly older (p< 0.001) than asymptomatic subjects. Forty subjects had a pathological trigeminal somatosensory evoked potential. Of these, 28 had a normal trigeminal examination and 12 an abnormal one. For those with trigeminal symptoms, an abnormal trigeminal somatosensory evoked potential was observed in subjects who had the longest and most intense exposure periods. [Barret L et al; Arch Environ Health 42 (5): 297-302 (1987)]**PEER REVIEWED**
  
• Estimated human lifetime carcinogenic risk: 3.77X10-7 for male and 6.84X10-8 for female /From table, assuming a daily consumption of 1 liter of water containing trichloroethylene in a concn of 1 ug/l/ [National Research Council. Drinking Water & Health. Volume 5. Washington, D.C.: National Academy Press, 1983., p. 84]**PEER REVIEWED**
  
• ... Eye irritation: 160 ppm; supportable during 30 min: 379-372 ppm; full /SRP: CNS depression/: 2,500-6,000 ppm; severe toxic effects: 2,000 ppm= 10,940 mg/cu m, 60 min; symptoms of illness: 800 ppm= 4,376 mg/cu m; unsatisfactory /exposure level/: > 400 ppm= 2,188 mg/cu m [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• ... The estimated fatal oral dose in humans is 3-5 ml/kg. The lowest concn produce unconsciousness in adult humans is 16 mg/l (3,000 ppm); the equivalent oral dose is 40-150 ml. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-165]**PEER REVIEWED**
  
• 77 of 104 trichloroethylene workers showed abnormal electrocardiographic tracings, which may precede permanent heart damage. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 721]**PEER REVIEWED**
  
• Adverse psychological and behavioral abnormalities have been reported in industrial overexposures and include symptoms of headache, fatigue, lightheadedness, depression, insomnia, irritability, and confusion. Cranial and peripheral neuropathies have been associated with industrial and medical use. Selective trigeminal neuralgia has been diagnosed in one study in 20% of trichloroethylene workers by demonstrating electrophysiological abnormalities. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 992]**PEER REVIEWED**
  
• Skin: defatting action /of trichloroethylene/ can cause dermatitis. [U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5., p. ]**PEER REVIEWED**
  
• In anesthetic concn, trichloroethylene causes little or no irritation to the respiratory tract. Trichloroethylene causes increased respiratory rate (tachypnea) but decreased alveolar ventilatory amplitude, which is associated with decreased blood oxygen tension and increased carbon dioxide tension. [Dobkin A, Byles P; Clin Anesth 1: 44-65 (1963) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.5-11 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• ... In almost all cases where a xenobiotic /incl trichloroethylene/ has a terminal carbon with two halides attached, side-chain oxidation mediated by cytochrome p450 will produce a toxic, reactive intermediate. [Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991., p. 121]**PEER REVIEWED**
  
• Eight men inhaled trichloroethylene at concentrations of 0, 100, 300, and 1000 ppm for 2 hr. Each man received the different concentrations in random order. Five tests of visualmotor performance were administered to each volunteer three times during each 2 hr session, and one additional test was administered immediately before and immediately after exposure. At a concentration of 1000 ppm, the compound adversely affected performance in tests of depth perception, steadiness, and manual skill but had no statistically significant effect on performance in three other standard tests. The small increase in errors associated with 100 and 300 ppm were not statistically significant. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 694]**PEER REVIEWED**
  
• Six naive volunteers were exposed to trichloroethylene aerosol and vapor for 8 hr in one day (two 4 hr exposures separated by a 1.5 hr interval); the concentration varied from 90 to 130 ppm. A slight sense of dizziness and transient eye irritation occurred during maximal fractuations in concentration. Although there was no objective disturbance of motor function, coordination, equilibrium, or behavior, there was a statistically significant decrement in performance of standard tests of perception, memory, complex reaction time, and manual dexterity. Similar results were obtained when the study was repeated with six workers who were accustomed to the odor of the compound. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 694]**PEER REVIEWED**
  
• Three volunteers each placed one thumb in trichloroethylene for 30 min. They experienced a burning sensation on the dorsum of their thumbs within 3-18 min, and this burning became moderately severe within 5 min after onset in two persons but remained mild in one. The pain became more intense for several minutes just after the thumbs were removed from the solvent, and tingling persisted for 30 min. Erythema subsided within 2 hr. The compound was measurable in the breath of some volunteers within 10 min after exposure started and in all within 20 min. The mean peak breath concentration was 0.5 ppm. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 694]**PEER REVIEWED**
  
• Vapors of trichloroethylene are only slightly irritating to the respiratory tract. Premedication with atropine or scopolamine hydrobromide is recommended to eliminate possible mucus secretions. The anesthetic typically accelerates respiratory rate. As the tachypnea progresses, respiratory activity becomes more rapid and shallower. Sudden bursts of tachypnea are sometimes associated directly with surgical stimulation. [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 195]**PEER REVIEWED**
  
• A retrospective cohort study of 14,457 workers at an aircraft maintenance facility was undertaken to evaluate mortality associated with exposures in their workplace. The purpose was to determine whether working with solvents, particularly trichloroethylene, posed any excess risk of mortality. The study group consisted of all civilian employees who worked for at least one year at Hill Air Force Base, Utah, between 1 January 1952 and 31 December 1956. Work histories were obtained from /official records/ ... and the cohort was followed up for ascertainment of vital state until 31 December 1982. Observed deaths among white people were compared with the expected numbers of deaths, based on the Utah white population, and adjusted for age, sex and calendar period. Significant deficits occurred for mortality from all causes (SMR 92, 95% CI 90-95), all malignant neoplasms (SMR 90, CI 83-97), ischemic heart disease (SMR 93, 95% CI 88-98), nonmalignant respiratory disease (SMR 87, 95% CI 76-98) and accidents (SMR 61, 95% CI 52-70). Mortality was raised for multiple myeloma in white women (SMR 236, 95% CI 87-514), non-Hodgkin's lymphoma in white women (SMR 212, 95% CI 102-390), and cancer of the biliary passages and liver of white men dying after 1980 (SMR 358, 95% CI 116-836). Detailed analysis of 6929 employees occupationally exposed to trichloroethylene, the most widely used solvent at the base during the 1950s and 1960s, did not show any significant or persuasive association between several measures of exposure to trichloroethylene and any excess of cancer. Women employed in departments in which fabric cleaning and parachute repair operations were performed had more deaths than expected from multiple myeloma and non-Hodgkin's lymphoma. The inconsistent mortality patterns by sex, multiple and overlapping exposures, and small numbers made it difficult to ascribe these excesses to any particular substance. ... [Spirtas R et al; Br J Ind Med 48 (8): 515-30 (1991)]**PEER REVIEWED**
  
• Human subjects with high repeated, but non-occupational, exposure may exhibit toxic effects on the liver (e.g., elevated aspartate & alanine aminotransferase), renal insufficiency, & abnormal EEG patterns. [WHO; Environ Health Criteria 50: Trichloroethylene p.82 (1985)]**PEER REVIEWED**
  
• Acute effects on the CNS are characterized by two sequential phases (i.e., excitation & depression), & are usually reversible. ... In the early phase of excitation, euphoria & inebriation are present. The subsequent phase of CNS depression is characterized by various degrees of narcosis culminating in coma. Muscular hypotomy, muscular spasms, reduced tendon reflexes, & loss of coordination may occur. [WHO; Environ Health Criteria 50: Trichloroethylene p.82 (1985)]**PEER REVIEWED**
  
• Childhood leukemia in a community in Massachusetts, USA, where water from two wells was contaminated with trichloroethylene /was studied/. Measurements made in 1979 showed a concentration of 267 ppb (ug/l) trichloroethylene in the well water. Twenty cases of childhood leukemia were diagnosed in the community in 1964-83, and these were associated with a significantly higher estimated cumulative exposure to water from the two contaminated wells than a random sample of children from the community (observed cumulative exposure, 21.1; expected cumulative exposure, 10.6; p= 0.03). [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V63 103 (1995)]**PEER REVIEWED**
  
• A study conducted in New Jersey, USA, during 1979-87 included 75 towns, of which 27 were included in a /previous/ study. Trichloroethylene concentrations were measured during 1984-85, and an average level was assigned to each town. The highest level assigned was 67 ug/l. The water supply of six towns contained > 5 ug/l trichloroethylene (average, 23.4 ug/l). Women in these towns had a significantly higher total incidence of leukemia than the inhabitants of towns were the concentration of trichloroethylene in drinking water was < 0.1 ug/l (relative risk, 1.4; 95% CI, 1.1-1.9); no such effect was seen for men (1.1, 0.84-1.4). The risk among women was particularly elevated for acute lymphocytic leukemia, chronic lymphocytic leukemia in childhood was also significantly increased, in girls but not in boys. Increased risks for non-Hodgkin's lymphoma were apparent in towns in the highest category of trichloroethylene contamination (0.2; 0.94-1.5 for men and 1.4; 1.1-1.7 for women) and was particularly elevated for high-grade lymphomas. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V63 104 1995]**PEER REVIEWED**
  
• Trichloroethylene (Tri) caused modest cytotoxicity in freshly isolated human proximal tubular (hPT) cells, as assessed by significant decreases in lactate dehydrogenase (LDH) activity after 1 hr of exposure to 500 muM Tri. Oxidative metabolism of Tri by cytochrome p450 to form chloral hydrate (CH) was only detectable in kidney microsomes from one patient out of four tested & was not detected in hPT cells. In contrast, GSH conjugation of Tri was detected in cells from every patient tested. The kinetics of Tri metab to its GSH conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) followed biphasic kinetics, with apparent Km & Vmax values of 0.51 & 24.9 mM & 0.10 & 1.0 nmol/min/mg protein, respectively. S-(1,2-dichlorovinyl)-L-cysteine (DCVC), the cysteine conjugate metabolite of Tri that is considered the penultimate nephrotoxic species, caused both time- & concn-dependent increases in LDH release in freshly isolated hPT cells. Preincubation of hPT cells with 0.1 mM aminooxyacetic acid did not protect hPT cells from DCVC-induced cellular injury, suggesting that another enzyme besides the cysteine conjugate beta-lyase may be important in DCVC bioactivation. ... These data indicate that the pathway involved in the cytotoxicity & metab of Tri in hPT cells is the GSH conjugation pathway & that the cytochrome p450-dependent pathway has little direct role in renal Tri metabolism in humans. [Cummings; Lash LH; Toxicological Sciences 53 (2): 458-466 (2000)]**PEER REVIEWED**
  
• Trichloroethylene (TCE) is both acutely toxic & carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung & is markedly less toxic following acute exposure. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell & is characterized by vacuolation & incr in cell replication. Chloral, a metabolite of TCE that accumulates in Clara cells and has been shown to be the cause of the toxicity, also causes aneuploidy in some test systems. Cytotoxicity, increased cell division, & aneuploidy are known risk factors in the development of cancer & provide a plausible mode of action for TCE as a mouse lung carcinogen. All acute & chronic effects of TCE on the mouse lung are believed to be a direct consequence of high cytochrome P450 activity & impaired metab of chloral in Clara cells. Comparisons between species suggest that the ability of the human lung to metabolize TCE is approx 600-fold < that in the mouse. In addtn, the human lung differs markedly from the mouse lung in the number & morphology of its Clara cells. Thus, the large quantitative differences between the metabolic capacity of the mouse lung & the human lung, together with the species differences in the number & morphology of lung Clara cells, suggest that the risks to humans are minimal & that other tumor sites should take precedent over the lung when assessing the potential risks to humans exposed to TCE. [Green T; Environ Health Perspect 108 (2): 261-264 (2000)]**PEER REVIEWED**
  
• An ecological epidemiological study was conducted with data obtained from an environmental dose-reconstruction study & the Arizona Birth Information Tapes. Before 1981, a portion of the city of Tucson water-distribution system was contaminated with trichloroethylene (i.e., <5 ug/l of water to 107 ug/l of water). Target & comparison populations were selected with a Geographic Information System. Logistical-regression analysis revealed an association between maternal exposure to trichloroethylene via drinking water & very-low-birth-weight babies (i.e., < 1,501 grams) (odds ratio = 3.3; 95% confidence interval = 0.5, 20.6; & Wald chi-square p value = 0.2). No association was found between maternal exposure to trichloroethylene via drinking water & low birth weight or full-term low-birth-weight infants (gestational period > 35 wk & <46 wk). [Rodenbeck SE et al; Arch Environ Health 55 (3): 188-194 (2000)]**PEER REVIEWED**
  
• ... Changes in EKG waves have been observed among persons with exposure to trichloroethylene. [International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998., p. 7.22]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• MUTAGENICITY: MUTATION RESEARCH 86: 355 (1981). MOUSE IN VIVO SOMATIC MUTATION ASSAY (SPOT TEST) - COAT COLOR MUTANTS: POSITIVE. [GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871), p. ]**PEER REVIEWED**
  
• ... REPORTED SYMPTOMS OF CHRONIC INTOXICATION IN DOGS IN 3-8 WEEKS AFTER INHALATION OF 500 TO 750 PPM FOR 4-8 HOURS DAILY, 5-6 DAYS PER WEEK. THE SYMPTOMS CONSISTED OF LETHARGY, ANOREXIA, NAUSEA, VOMITING AND LOSS OF WEIGHT. LIVER DYSFUNCTION WAS ALSO SHOWN IN THESE DOGS. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979), p. 263]**PEER REVIEWED**
  
• ... REPEATED EXPOSURE TO 3000 PPM (27 EXPOSURES DURING 36 DAYS) ... CAUSED DISTURBANCES OF EQUILIBRIUM AND COORDINATION ... AFTER ... 1ST WEEK SALIVATION, RESTLESSNESS AND HYPEREXCITABILITY, THEY RECOVERED ... ONLY HISTOLOGICAL ABNORMALITY ... FAT VACUOLES IN ... LIVER OF FEMALE RATS. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 197]**PEER REVIEWED**
  
• WHEN SOYA-BEAN MEAL IS EXTRACTED WITH TRICHLOROETHYLENE IT WAS TOXIC TO CATTLE ... THE SYNDROME IN CATTLE IS KNOWN VARIOUSLY AS STOCKMAN DISEASE, DUREN DISEASE AND BARBANT DISEASE. [Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975., p. 262]**PEER REVIEWED**
  
• CATS AND GUINEA PIGS EXPOSED TO 1000 PPM DAILY FOR 1 1/2 HR ... FROM 10 DAYS TO 10 MONTHS ... IN THOSE WHICH SURVIVED SEVERAL MONTHS, CIRRHOSIS AND BILIARY HYPERPLASIA ... LATTER PROGRESSING IN SOME ANIMALS TO PROLIFERATIVE 'BILIARY ADENOMATOSIS'. [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 198]**PEER REVIEWED**
  
• GASTRIC INTUBATION OF 2.4 OR 1.2 G/KG BODY WT TRICHLOROETHYLENE 5 TIMES WEEKLY IN MALE B6C3F1 MICE (AGE NOT SPECIFIED) & OF 1.8 OR 0.9 G/KG BODY WT IN FEMALES INDUCED HEPATOCELLULAR CARCINOMAS IN 30/98 MICE GIVEN LOW DOSE & IN 41/95 (43.2%) MICE GIVEN HIGHER DOSE. HEPATOCELLULAR CARCINOMAS ... IN 1/40 (2.5%) CONTROL MICE. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V11 268 (1976)]**PEER REVIEWED**
  
• FEMALE RATS EXPOSED TO VAPORS OF 200 TO 1800 PPM FOR 2 WK SHOWED NO EFFECTS INDICATIVE OF TREATMENT-RELATED MATERNAL TOXICITY, EMBRYOTOXICITY, ... TERATOGENICITY OR BEHAVIORAL DEFECTS. ... /SRP: EVIDENCE OF DEVELOPMENTAL DELAY WAS SEEN/. [DORFMUELLER MA ET AL; TOXICOLOGY 14 (2): 153-66 (1979)]**PEER REVIEWED**
  
• PURE TRICHLOROETHYLENE STABILIZED BY AMINE BASE, ADMIN BY INHALATION @ 0, 100 & 500 PPM FOR 6 HR/DAY, 5 DAY/WK FOR 18 MO TO /NMRI/ MICE, RATS & SYRIAN HAMSTERS. ONLY FEMALE MICE SHOWED INCR IN MALIGNANT LYMPHOMAS. [HENSCHLER D ET AL; ARCH TOXICOL 43 (4): 237-48 (1980)]**PEER REVIEWED**
  
• EXPOSURE OF MALE MICE TO TRICHLOROETHYLENE VAPORS DURING 24 HR @ LEVELS OF 50, 202 & 450 PPM DID NOT REVEAL MUTAGENIC EFFECTS IN DOMINANT LETHAL ASSAY. [SLACIK-ERBEN R ET AL; ARCH TOXICOL 45 (1): 37-44 (1980)]**PEER REVIEWED**
  
• TRICHLOROETHYLENE WAS AMONG HALOGENATED HYDROCARBONS TESTED FOR CARCINOGENICITY BY CHRONIC ADMIN BY 1 OR MORE ROUTES IN HA:ICR SWISS MICE. TCE INACTIVE BY CRITERIA USED. [VAN DUUREN BL ET AL; J NATL CANCER INST 63 (6): 1433-40 (1979)]**PEER REVIEWED**
  
• ... 50 MALE & 50 FEMALE B6C3F1 HYBRID MICE, 5 WK OLD, WERE ADMIN 99% PURE TRICHLOROETHYLENE, CONTAINING 0.19% 1,2-EPOXYBUTANE & 0.09% EPICHLOROHYDRIN IN CORN OIL BY GAVAGE ON 5 DAYS A WK FOR 78 WK. HIGH DOSE MALES RECEIVED 2000-2400 MG/KG BODY WT/DAY, & FEMALE 1400-1800 MG/KG BODY WT/DAY; LOW DOSE MALE & FEMALES RECEIVED 1000-1200 MG/KG BODY WT/DAY & 700-900 MG/KG BODY WT. ALL SURVIVING ANIMALS WERE OBSERVED UNTIL ... 95 WK OF AGE. ... HEPATOCELLULAR CARCINOMA OCCURRED IN 1/20 CONTROL MALES AND 0/20 CONTROL FEMALES, IN 26/50 LOW DOSE MALES & 4/50 LOW DOSE FEMALES, & IN 31/48 HIGH DOSE MALES, 11/47 HIGH DOSE FEMALES. METASTASES OF THE LIVER CELL TUMORS TO THE LUNG WAS FOUND IN 7/98 TREATED MALES & IN 1 CONTROL MALE. LUNG TUMORS OCCURRED IN TREATED ANIMALS OF BOTH SEXES ... ONLY ONE LUNG ADENOMA IN FEMALE. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V20 555 (1979)]**PEER REVIEWED**
  
• A single 1000 mg/kg body wt dose ... in corn oil was admin by gavage to 50 mice of each sex, and doses of 1000 and 500 mg/kg body wt were given in the same manner to 50 rats of each sex 5 days/wk for 2 yr. For each group of test animals there were corresponding groups of controls composed of 50 animals of each sex. The trichloroethylene was stabilized with an amine antioxidant (diisopropylamine) and contained no detectable traces of 1,2-epoxybutane or epichlorohydrin. ... The results observed in the mice support the previous NCI (1976) findings that trichloroethylene significantly incr the incidence of hepatocellular carcinomas in B6C3F1 mice of both sexes. [National Research Council. Drinking Water & Health. Volume 5. Washington, D.C.: National Academy Press, 1983., p. 82]**PEER REVIEWED**
  
• IN VIVO AND IN VITRO METHODOLOGIES THAT HAVE EMPLOYED THE YEAST SCHIZOSACCHAROMYCES POMBE AS GENETIC INDICATOR HAVE BEEN UTILIZED TO INVESTIGATE THE MUTAGENICITY OF TWO TRICHLOROETHYLENE (TCE) SAMPLES OF PURE AND TECHNICAL GRADE. BOTH TCE SAMPLES GAVE NEGATIVE RESULTS FOR IN VIVO AND IN VITRO ASSAYS, WHEREAS THE 2 CONTAMINANTS WERE FOUND MUTAGENIC ONLY IN VITRO. [ROSSI AM ET AL; TERATOGENESIS CARCINOG MUTAGEN 3 (1): 75 (1983)]**PEER REVIEWED**
  
• No liver lesions or hepatomas were found in NLC mice which had received oral doses of 0.1 ml of a 40% solution of trichloroethylene in oil twice weekly for an unspecified period. [Fishbein L; Potential Indust Carcins & Mutagens p.147 (1977) USEPA 560/ 5-77-005]**PEER REVIEWED**
  
• Trichloroethylene (3.3 mM) in the presence of a metabolic activating microsomal system induced reverse mutations in Escherichia coli strain K12. It has also been shown to induce frame-shift as well as base substitution mutations in Saccharomyces cerevisiae strain XV185-14C in the presence of mouse liver homogenate. [Fishbein L; Potential Indust Carcins & Mutagens p.147 (1977) USEPA 560/ 5-77-005]**PEER REVIEWED**
  
• In rabbits, blood levels of greater than 30 mg/l (following continuous iv infusion of 1-5 mg/kg/min, trichloroethylene) induced positional nystagmus /SRP: rapid movement of the eyeball when the head is held in various positions/. [Tham R et al; Acta Pharmacol Toxicol 44: 336-42 (1979) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.5-6 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• ACS purity trichloroethylene induced both point mutation and gene conversion at the ilv and trp loci of the D7 strains of Saccharomyces cerevisiae in the presence of a mouse liver 10,000 g supernatant metabolizing system. A dose response was observed in both instances over the range of 10-40 mM. [Bronzetti G et al; J Envir Pathol Toxicol 1: 411-18 (1978) as cited in Health and Safety Executive Monograph: Trichloroethylene #6 p.8 (1982)]**PEER REVIEWED**
  
• Application of 0.1 ml of trichloroethylene directly applied to the eye of a rabbit produced a mild-moderate conjunctivitis with some epithelial abrasions being noted on examination with fluorescein. Microscopic examination on day 7 indicated epithelial keratosis in the process of healing. The eye returned to normal in two weeks. [Duprat P et al; Eur J Toxicol 3: 171-77 (1976) as cited in Health and Safety Executive Monograph: Trichloroethylene #6 p.6 (1982)]**PEER REVIEWED**
  
• Concentration of 1 mM trichloroethylene induced transformation of rat embryo cells (Fischer rat embryo cell system F1706) in vitro which appeared as a progressively growing foci of cells lacking contact inhibition and by the growth of macroscopic foci when inoculated in semi-solid agar. The transformed cells grew as undifferentiated fibrosarcomas at the site of inoculation in 100% of newborn Fischer rats between 27 and 68 days post-inoculation. [Price PJ et al; In Vitro 14: 290 (1978) as cited in USEPA; Ambient Water Quality Criteria Document: Trichloroethylene p.C-23 (1980) EPA-440/5/80-007]**PEER REVIEWED**
  
• Chronic administration /by gavage/ of 2400 mg/kg per day of trichloroethylene to male B6C3F1 mice, induced localized cell necrosis, enhanced DNA synthesis, and centrilobular hepatocellular swelling. Prolonged exposure (3 weeks), the primary response was dose-related centrilobular hepatocellular swelling and the occurrence of mineralized (calcified) cells. [Stott WT et al; Toxicol Appl Pharm 62: 137-51 (1982) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.4-35 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• Trichloroethylene was non-mutagenic in the Ames Salmonella assay when tested with TA100 in a 10 liter desicator. Exposure levels were as high as 20% in air (v/v) for up to 16 hr. The assay was performed in the presence and absence of a phenobarbital-induced liver S9 fraction from male mice. Chloral hydrate, a metabolite of trichloroethylene, was found to be mutagenic in strain TA100 in the Salmonella standard plate incorporation assay in doses ranging from 0.5 to 10.0 mg/plate. The mutagenic activity was enhanced in the presence of rat liver S9 mix. [National Research Council. Drinking Water & Health. Volume 5. Washington, D.C.: National Academy Press, 1983., p. 81]**PEER REVIEWED**
  
• Sperm exam from mice exposed to 0.3% for 4 hr daily for 5 days revealed incr abnormalities after 28 days. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 572]**PEER REVIEWED**
  
• Rats exposed to 37,000, 42,000, and 56,000 mg/cu m of trichloroethylene vapor for two hours exhibited elevated activities of serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and isocitrate dehydrogenase. Hepatotoxicity (indicated by the increased levels of these hepatic enzymes in the serum) was greatly enhanced by pretreatment with 3-methylcholanthrene. [Carlson GP; Res Comm Chem Pathol Pharmacol 7: 637 (1974) as cited in USEPA; Ambient Water Quality Document: Trichloroethylene p.C-19 (1980) EPA-440/5/80-007]**PEER REVIEWED**
  
• Trichloroethylene was neither embryotoxic nor teratogenic in Sprague-Dawley rats and Swiss Webster mice inhaling trichloroethylene. These results have been confirmed in two other studies in female rats exposed in one case to 500 ppm and in other to 1800 ppm. Trichloroethylene was found to be weakly mutagenic in Escherichia coli in the presence of a metabolizing system ... or in extensive studies in Drosophila. Positive effects in some studies may be due to epoxy stabilizers sometimes present in trichloroethylene. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986., p. 596]**PEER REVIEWED**
  
• Female Sprague-Dawley rats were given trichloroethylene (TCE) in distilled drinking water at concentrations of 312, 625, and 1250 mg/l. Dams received TCE from 14 days prior to breeding, throughout gestation, and until the pups were weaned at 21 days of age. Control dams received untreated distilled water. Male offspring of experimental and control dams were used to study exploratory behavior either 28, 60, or 90 days of age. Wheel-running, feeding, and drinking behavior tests in rat pups were conducted for 24 hr/day from 55-60 days of age. At 28 days of age, no difference in exploratory activity was seen among treatment groups. At 60 and 90 days of age, rat pups exposed to /SRP: even the lowest concentrations/ of TCE exibited increased levels of exploration. Rats exposed to 1250 mg/l TCE were more active on the wheel than controls or those exposed to 625 mg/l TCE. No significant differences were detected among treatment groups for the levels or timing of feeding or drinking activities. [Taylor DH et al; Sci Total Environ 47: 415-20 (1985)]**PEER REVIEWED**
  
• Trichloroethylene was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Trichloroethylene was tested doses at doses of 0.01, 0.033, 0.10, 0.333, and 1.0 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Trichloroethylene was negative in these tests and the highest ineffective dose tested in any S typhimurium strain was 1.0 mg/plate. Slight clearing of the background bacterial lawn occurred in all cultures at the high dose. [Mortelmans K et al; Environ Mutagen 8: 1-119 (1986)]**PEER REVIEWED**
  
• Affected fathead minnows, 31 days old, in toxicant concentrations ranging from 8.43-77.3 mg/l, lost schooling behavior, swam in a corkscrew/spiral pattern near the surface, were hyperactive & hemorrhaging. Equilibrium loss was not observed prior to death. No effect data were recorded. Individual lengths & weights were not recorded; however, the measured mean weight was 0.109 g. Spike recovery data were not available, but the mean recovery was likely >90%. [Geiger D.L., Poirier S.H., Brooke L.T., Call D.J., (eds). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. II. Superior, Wisconsin: University of Wisconsin-Superior, 1985., p. 33]**PEER REVIEWED**
  
• Trichloroethylene /0.5 ml/ (purity 99.5%) applied to the shaved non-abraded skin of rabbits for 24 hours under an occlusive dressing, produced severe skin irritation. [Duprat P et al; Eur J Toxicol 9(3): 171-7 (1976) as cited in WHO; Environ Health Criteria 50: Trichloroethylene p.50 (1985)]**PEER REVIEWED**
  
• Trichloroethylene (1.0 ml) /purity not specified/ was applied, occluded in a skin depot, to the clipped skin of a guinea pig. Histological examinations performed at 15 minutes, 1, 4, and 16 hour /indicated/ degenerative changes (pyknotic nuclei) were observed in the epidermis after 15 minutes, and were progressive (pyknosis, karyolysis, junctional separation of the epidermis) up to the end of the study. [Kronevi T et al; Int J Tiss React 111(1): 21-30 (1981) as cited in WHO; Environ Health Criteria 50: Trichloroethylene p.50 (1985)]**PEER REVIEWED**
  
• Groups of 49-50 female ICR mice 4 weeks of age ... exposed by inhalation to trichloroethylene (purity = 99.8%, with 0.128% carbon tetrachloride, 0.019% benzene, 0.019% epichlorohydrin, and 0.01% 1,1,2-trichlorethane) at 0.270, 810, or 2430 mg/cu m 7 hr/day for 5 days/wk, for 104 weeks. The surviving animals were /sacrificed/ 107 weeks after the start of the study. Mortality was similar in control and treated groups. Lung adenomas were found in 5, 2, 5, and 4 mice in the control, low-dose, mid-dose and high-dose groups, respectively. Adenocarcinomas occurred in 1/49, 3/50, 8/50, and 7/46 mice in the control, low-dose, mid-dose and high-dose groups, respectively; increased incidences in the mid- and high-dose groups were statistically significant compared with controls. [Fukuda K et al; Ind Health 21: 243-5 (1983) as cited in WHO; Environ Health Criteria 50: Trichloroethylene p.65 (1985)]**PEER REVIEWED**
  
• A pure sample of trichloroethylene, stabilized with thymol /concentration not specified/ did not induce forward mutations at the HGPRT locus of a Chinese hamster V-79 cell line treated in vitro, with or without S9 mix metabolic activation. [Loprieno N, Abbondandolo A; Comparative Mutagenic Evaluation of Some Industrial Compounds. Proc Symp Short-Term Test Syst Defect Carcinogenesis pp. 333-56 (1980) as cited in WHO; Environ Health Criteria 50: Trichloroethylene p.71 (1985)]**PEER REVIEWED**
  
• Gelatinsorbitol microcapsules containing 44.1% trichloroethylene (TCE) were prepared and mixed in NIH-07 rodent meal diet and provided at microcapsule concentrations of 0 (untreated control group), 1.25, 2.5, 5.0, or 10% (equivalent to 0, 0.55, 1.10, 2.21, or 4.41% TCE in the diet, respectively) to groups of 10 male F344 rats for 14 days. An additional control group received diets containing 5% empty capsules. For comparisions, TCE dissolved in corn oil was administered by gavage to different groups of 10 male rats for 14 consecutive days at dose levels adjusted to correspond to those in the feed study. Treatment-related deaths occurred only in the highest dose group of the gavage study. Body weight gain and feed consumption were reduced in high-dose groups of both the feed and gavage studies. ... Dose-related increases in organ (liver and kidney) weight/body weight ratios, individual cell necrosis in the liver, and hepatic microsomal NADPH cytochrome-c reductase and peroxisomal palmitoyl-CoA oxidase and catalase activities were found in both the dosed-feed and gavage groups. Induction of cytochrome p450 occurred only in the dosed-feed study. [Melnick RL et al; Fundam Appl Toxicol 8 (4): 432-42 (1987)]**PEER REVIEWED**
  
• ... MAJOR CONSIDERATION MUST BE GIVEN TO CUMULATIVE EFFECTS OF THIS COMPOUND. ... IN LONG-TERM FEEDING STUDIES CARRIED OUT BY THE NATIONAL CANCER INSTITUTE (1976b), ... MICE (BOTH SEXES, AT BOTH LOW AND HIGH DOSE LEVELS) EXPERIENCED A HIGHLY SIGNIFICANT INCREASE IN HEPATOCELLULAR CARCINOMAS. ... MIKISKOVA AND MIKISKA (1966) DEMONSTRATED THAT TRICHLOROETHANOL HAD A PRONOUNCED DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 475]**PEER REVIEWED**
  
• When fed in drinking water to mice for 4 to 6 months at concentrations of 0, 0.1, 1.0, and 2.5, and 5.0 mg/ml of water, "There was a decreased body weight gain at the highest dose, which could be attributed to a decrease in fluid consumption. The most significant effects attributable to TCE were an increase in liver weight in both sexes accompanied by increased nonprotein sulfhydryl levels in the males, and an increase in kidney weight in both sexes accompanied by increases in protein and ketones in the urine. ... The 6 months average daily doses were 0, 144, 217, 393, and 660 mg/kg body weight for the male mice. Female mice averaged 0, 18, 193, 437, and 793 mg/kg/day. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4197]**PEER REVIEWED**
  
• ... Several species of animals /were exposed/ 7 hr/day, 5 days/week for approximately 6 months. At 3000 ppm by volume in air, rats and rabbits both showed an increase in liver and kidney weight. At 400 ppm rats showed an increase in liver and kidney weights and the male rats also showed significantly less growth. Guinea pigs had increased liver weights and the growth of the exposed males was less than the controls. Rabbits showed a slight increase in liver weight. An exposed monkey showed no response at 400 ppm. At 200 ppm, the only effect was depressed growth in guinea pigs. Rats, rabbits, and monkeys showed no response. At a concentration of 100 ppm, none of the species showed any significant response. The maximum concentrations tolerated without adverse effect for the 6 month period were as follows: monkeys, 400 ppm; rats and rabbits, 200 ppm; and guinea pigs, 100 ppm. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4197]**PEER REVIEWED**
  
• ... Rats, guinea pigs, dogs, rabbits, and monkeys /were exposed/ 24 hr/day for 90 days to 35 ppm with no effect except slight growth depression. Repeated 8 hr daily exposures to 700 ppm for 90 days were also without effect. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4197]**PEER REVIEWED**
  
• Pregnant /rats and mice and their offsprings/ were exposed for 7 hr to 300 ppm on days 6 to 15 of pregnancy with no evidence of adverse effect on the dams, on reproduction, or on the offspring by any of the usual criteria of a teratogenic study. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4198]**PEER REVIEWED**
  
• In a teratology reproduction study, the NTP fed microencapsulated trichloroethylene to rats and mice at doses as high as 300 mg/kg/day to rats and 750 mg/kg/day to mice with little effect. Sperm motility was reduced 45% in F0, males and 18% in F1, male mice. There is no ready explanation for less response in the F1-generation male mice. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4198]**PEER REVIEWED**
  
• When fed to B6D2F1 mice by gavage on days 1 to 5, 6 to 10, or 10 to 15 (day 1, vaginal plug) trichloroethylene in corn oil cause no reproductive, maternal, or foal effects. Daily dosages were 0, 1/10, or 1/100 of the oral LD50 (2402 mg/kg used as LD50 value). Weanlings were kept for 21 days or 42 days. Trichloroethylene also had no effect on in vitro fertilization. [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994., p. 4198]**PEER REVIEWED**
  
• Apart from two reports in which trichloroethylene weakly induced mutation in Salmonella typhimurium TA1535, purified trichloroethylene did not induce gene mutation in various strains of Salmonella in the absence of metabolic activation; however, trichloroethylene containing directly mutagenic epoxide stabilizers did. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V63 131 (1995)]**PEER REVIEWED**
  
• Previous epidemiological studies with humans & laboratory studies with chickens & rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the cardiac defects in humans & laboratory animals produced by TCE are diverse, a majority of them involves valvular & septal structures. Progenitors of the valves & septa are formed by an epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular (AV) canal & outflow tract areas of the heart. Based on these studies, we hypothesized that TCE might cause cardiac valve & septa defects by specifically perturbing epithelial-mesenchymal cell transformation. We tested this hypothesis using an in vitro chick-AV canal culture model. This study shows that TCE affected several elements of epithelial-mesenchymal cell transformation. In particular, TCE blocked the endothelial cell-cell separation process that is associated with endothelial activation. Moreover, TCE inhibited mesenchymal cell formation throughout the concn range tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of the fully formed mesenchymal cells. Finally, the expression of 3 proteins (selected as molecular markers of epithelial-mesenchymal cell transformation) was analyzed in untreated & TCE-treated cultures. TCE inhibited the expression of the transcription factor Mox-1 & extracellular matrix (ECM) protein fibrillin 2. In contrast, TCE had no effect on the expression of alpha-smooth muscle actin. These data suggest that TCE may cause cardiac valvular & septal malformations by inhibiting endothelial separation & early events of mesenchymal cell formation in the heart. [Boyer AS et al; Toxicological Sciences 53 (1): 109-117 (2000)]**PEER REVIEWED**
  
• Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concns & durations. The goal of this project was to describe the relationship between the concn & duration of exposure to inhaled trichloroethylene (TCE), a representative volatile organic chemical, tissue dose as predicted by a physiologically based pharmacokinetic model, & neurotoxicity. Three measures of neurotoxicity were studied: hearing loss, signal detection behavior, & visual function. The null hypothesis was that exposure scenarios having an equivalent product of concn & duration would produce equal toxic effects, according to the classic linear form of Haber's Rule ... . All experiments used adult male, Long-Evans rats. Acute & repeated exposure to TCE increased hearing thresholds, & acute exposure to TCE impaired signal detection behavior & visual function. Examination of all three measures of neurotoxicity showed that if Haber's Rule were used to predict outcomes across exposure durations, the risk would be overestimated when extrapolating from shorter to longer duration exposures, & underestimated when extrapolating from longer to shorter duration exposures. For the acute effects of TCE on behavior & visual function, the estimated concn of TCE in blood at the time of testing correlated well with outcomes, whereas cumulative exposure, measured as the area under the blood TCE concn curve, did not. ... Models incorporating dosimetry can account for differing exposure scenarios & will therefore improve risk assessments over models considering only parameters of external exposure. [Boyes WK et al; Environ Health Perspect 108 (2): 317-322 (2000)]**PEER REVIEWED**
  
• Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute chloral hydrate (CH), dichloroacetate (DCA), & trichloroacetate (TCA). CH & TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concns of TCA in blood required to induce liver cancer approach the mM range. Concns of DCA in blood associated with carcinogenesis are in the sub-muM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA &/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPARalpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPARalpha that are observed in rodents. This may be attributed to lower levels of expressed PPARalpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, & suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA & TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis. [Bull RJ; Environmental Health Perspectives 108 (2): 241-259 (2000)]**PEER REVIEWED**
  
• The possibility that the acute neurotoxic effects of organic solvents change with repeated exposure will affect risk assessment of these pollutants. ... Rats inhaling trichloroethylene (TCE) showed a progressive attenuation of impairment of signal detection behavior across several wk of intermittent exposure, suggesting the development of tolerance. Here, we explored the development of tolerance to TCE during 2 wk of daily exposures, & the degree to which learned behavioral modifications ("behavioral tolerance") could account for the effect. Adult Long-Evans rats were trained to perform a visual signal detection task (SDT) in which a press on one lever yielded food if a visual stimulus (a "signal") had occurred on that trial, & a press on a second lever produced food if no signal had been presented. In two experiments, with 2000 & 2400 ppm of TCE res pectively, trained rats were divided into two groups (n = 8/group) with equivalent accuracy & then exposed to TCE in two-phase studies. In Phase 1, one group of rats received daily SDT tests paired with 70-min TCE exposures, followed by 70-min exposures to clean air after testing. The other group received daily SDT tests in clean air, followed by 70-min exposures to TCE (unpaired exposure & testing). All rats thus received the same number & daily sequence of exposures to TCE that differed only in the pairing with SDT testing. Both concns of TCE disrupted performance of the paired groups & this disruption abated over the 9 days of exposure. In Phase 2, the pairing of exposure & test conditions were reversed for the two groups. The groups that were shifted from unpaired to paired exposures (Unpaired-Paired groups) showed qualitatively similar patterns of deficit & recovery as did the rats whose tests were initially paired with TCE (Paired-Unpaired groups), indicating that task-specific learning was involved in the development of tolerance. Quantitative differences in the magnitude & duration of the effects of TCE in the two groups indicated that other factors, not specific to the SDT, also contributed to the development tolerance to TCE. [Bushnell PJ et al; Neurotoxicology and Teratology 22 (2): 221-229 (2000)]**PEER REVIEWED**
  
• Exposure of rats to trichloroethylene induces a sustained excretion of large amounts of formic acid in urine. Both of the major metabolites, trichloroethanol & trichloroacetic acid, were found to induce this response, but not the minor metabolite S-(1, 2-dichlorovinyl) cysteine. Other polychlorinated solvents, including carbon tetrachloride & chloroform, also increased urinary formate excretion. Addition of folic acid either to diet or drinking water modulated the response indicating that these rats were folate deficient. Two markers of vitamin B(12) deficiency, methylmalonic acid & 5-methyltetrahydrofolate, were also markedly incr in urine & plasma respectively. The incr in 5-methyltetrahydrofolate is consistent with a folate deficiency caused by an inhibition of the vitamin B(12) dependent methionine salvage pathway. Since both vitamin B(12) & chemicals containing polychlorinated carbon atoms readily form free radicals, it is suggested that trichloroacetic acid & trichloroethanol interact with vitamin B(12) through a free radical mechanism inducing a B(12) deficiency &, as a consequence, a folate deficiency. As a result of the folate deficiency, excess formic acid, which is normally utilised through this pathway, is excreted in urine. [Dow JL; Green T; Toxicology 146 (2-3): 123-136 (2000)]**PEER REVIEWED**
  
• ... There is increasing evidence relating exposure to trichloroethylene /(1,1,2-trichloroethene)/ with autoimmunity. To investigate potential mechanisms, we treated the autoimmune-prone MRL + / + mice with trichloroethylene in the drinking water at 0, 2.5 or 5.0 mg/ml ... . As early as 4 wk of treatment. Western blot analysis showed a dose-dependent incr in the level of trichloroethylene-modified proteins, indicating that a reactive metabolite of trichloroethylene was formed. Significant increases in antinuclear antibodies (ANA) & total serum immunoglobulins were found following 4-8 wk of trichloroethylene treatment, indicating that trichloroethylene was accelerating an autoimmune response. Investigation into possible mechanisms of this autoimmune response revealed that trichloroethylene tre atment dramatically increased the expression of the activation marker CD44 on splenic CD4+ T cells at 4 wk. In addtn, splenic T cells from mice treated for 4 wk with trichloroethylene secreted more IFN-gamma & less IL-4 than control T cells, consistent of a T-helper type 1 (Th1) type immune or inflammatory response. A specific immune response directed against dichloroacetylated proteins was found at 22 wk of trichloroethylene treatment. ... The results suggest that trichloroethylene treatment accelerated an autoimmune response characteristic of MRL + / + mice in association with nonspecific activation of Th1 cells. In addtn, long-term treatment with trichloroethylene led to the initiation of a trichloroethylene-specific immune response. [Griffin JM et al; Iimmunopharmacology 46 (2): 123-137 (2000)]**PEER REVIEWED**
  
• The mechanism of trichloroethylene-induced liver peroxisome proliferation & the sex difference in response was investigated using wild-type Sv/129 & peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice. Trichloroethylene treatment (0.75 g/kg for 2 wk by gavage) resulted in liver peroxisome proliferation in wild-type mice, but not in PPARalpha-null mice, suggesting that trichloroethylene-induced peroxisome proliferation is primarily mediated by PPARalpha. No remarkable sex difference was observed in induction of peroxisome proliferation, as measured morphologically, but a markedly higher induction of several enzymes & PPARalpha protein & mRNA was found in males. On the other hand, trichloroethylene induced liver cytochrome P450 2E1, the principal enzyme responsible for metabolizing trichloroethylene to chloral hydrate, only in males, which resulted in similar expression levels in both sexes after the treatment. Trichloroethylene influenced neither the level of catalase, an enzyme involved in the reduction of oxidative stress, nor aldehyde dehydrogenase, the main enzyme catalyzing the conversion to trichloroacetic acid. These results suggest that trichloroethylene treatment causes a male-specific PPARalpha-dependent increase in cellular oxidative stress. [Nakajima T et al; CCarcinogenesis 21 (4): 677-682 (2000)]**PEER REVIEWED**
  
• Trichloroethylene (TCE), dichloroacetic acid (DCA), & trichloroacetic acid (TCA) are environmental contaminants that are carcinogenic in mouse liver. 5-Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcription of mRNA, including the protooncogenes, c-jun & c-myc. ... TCE decreased methylation of the c-jun & c-myc genes & increased the level of their mRNAs. Decreased methylation of the protooncogenes could be a result of a deficiency in S-adenosylmethionine (SAM), so that methionine, by increasing the level of SAM, would prevent hypomethylation of the genes. For 5 days, female B6C3F1 mice were admin, daily by oral gavage, either 1000 mg/kg bw of TCE or 500 mg/kg DCA or TCA. At 30 min after each dose of carcinogen, the mice received, by ip injection, 0, 30, 100, or 450 mg/kg methionine. Mice were euthanized at 100 min after the last dose of DCA, TCA, or TCE. Decreased methylation in the promoter regions of the c-jun & c-myc genes & increased levels of their mRNA & proteins were found in livers of mice exposed to TCE, DCA, & TCA. Methionine prevented both the decreased methylation & the increased levels of the mRNA & proteins of the two protooncogenes. The prevention by methionine of DCA- TCA-, & TCE-induced DNA hypomethylation supports the hypothesis that these carcinogenes act by depleting the availability of SAM. Hence, methionine would prevent DNA hypomethylation by maintaining the level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, or TCE must be sufficient to decrease the level of SAM in order for these carcinogens to be active. [Tao L et al; Toxicological Sciences 54 (2): 399-407 (2000)]**PEER REVIEWED**
  

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Human Toxicity Values

• Estimated fatal oral dose 3 to 5 mg/kg [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 990]**PEER REVIEWED**
  

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Non-Human Toxicity Values

• LC50 Rat inhalation 26,000 ppm/1 hr. [Vernot EH; Toxicol Appl Pharmacol 42 (2): 417-24 (1977)]**PEER REVIEWED**
  
• LC50 Rat inhalation 12,000 ppm/4 hr. [Siegel J; Toxicol Appl Pharmacol 18 (1): 168-74 (1971)]**PEER REVIEWED**
  
• LC50 Mouse inhalation 8450 ppm/4 hr. [Friberg L; Acta Pharmacol Toxicol 9 (4): 303-12 (1953)]**PEER REVIEWED**
  
• LD50 Rabbit percutaneous 29 g/kg. [Smyth HF; Am Ind Hyg Assoc J 23 (2): 95-107 (1962)]**PEER REVIEWED**
  
• LD10 Female CD-1 Mouse gavage 1161 mg/kg; male CD-1 mouse gavage 1347 mg/kg. [Tucker AN et al; Toxicol Appl Pharmacol 62 (3): 351-7 (1982)]**PEER REVIEWED**
  
• LD50 Female CD-1 Mouse gavage 2443 mg/kg; male CD-1 mouse gavage 2402 mg/kg [Tucker AN et al; Toxicol Appl Pharmacol 62 (3): 351-7 (1982)]**PEER REVIEWED**
  
• LD90 Female CD-1 Mouse gavage 2443 mg/kg; male CD-1 mouse gavage 4253 mg/kg. [Tucker AN et al; Toxicol Appl Pharmacol 62 (3): 351-7 (1982)]**PEER REVIEWED**
  
• LD100 Female CD-1 Mouse gavage 5500 mg/kg; male CD-1 mouse gavage 6000 mg/kg. [Tucker AN et al; Toxicol Appl Pharmacol 62(3): 351-357 (1982)]**PEER REVIEWED**
  
• LD50 Mouse inhalation 49,000 ppm/30 min [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• Rat inhalation 100 ppm/8 hr, no effect. [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• Rabbit inhalation 1,200 ppm/473 hr, no effect. [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• Rabbit, ape, rat, guinea pig inhalation 730 ppm/8 hr/day, 6 weeks, no effects. [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• LD50 Mouse inhalation 5,500 ppm/10 hr [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 1135]**PEER REVIEWED**
  
• LD50 Dog oral 5680 mg/kg [WHO; Environmental Health Criteria 50; Trichloroethylene p.55 (1985)]**PEER REVIEWED**
  
• LD50 Dog ip 2,800 mg/kg [WHO; Environmental Health Criteria 50; Trichloroethylene p.55 (1985)]**PEER REVIEWED**
  
• LD50 Rabbit dermal 20 ml/kg [WHO; Environmental Health Criteria 50; Trichloroethylene p.55 (1985)]**PEER REVIEWED**
  
• LD50 Rat oral 4920 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 690]**PEER REVIEWED**
  
• LD50 Mouse (female) oral 2443 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 690]**PEER REVIEWED**
  
• LD50 Mice (male) oral 2402 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 690]**PEER REVIEWED**
  
• LD50 Mouse ip 3222 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 690]**PEER REVIEWED**
  
• LD50 Dog ip 2783 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 690]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• ... It can penetrate intact human skin. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-165]**PEER REVIEWED**
  
• PLACENTAL TRANSMISSION DATA: TIME TO APPEAR IN FETUS--2 MIN; TIME TO FETAL/MATERNAL CONCN EQUILIBRIUM--6 MIN; FETAL/MATERNAL CONCENTRATION RATIO--1.0 /FROM TABLE/ [LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971., p. 100]**PEER REVIEWED**
  
• ... A DAILY EXPOSURE LEVEL OF APPROXIMATELY 100 PPM, ONLY ONE-THIRD OF THE RETAINED TRICHLOROETHYLENE (CALCULATED) IS EXCRETED AS METABOLITES IN THE URINE DURING THE WORK DAY. [Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980., p. 475]**PEER REVIEWED**
  
• BINDING OF TCE TO LIVER MICROSOMAL PROTEINS OF MALE B6C3 HYBRID MICE WAS 46% HIGHER THAN /BINDING OF/ (14)C-TCE TO MICROSOMAL PROTEINS FROM MALE OSBORNE-MENDEL RATS. [BANERJEE S ET AL; CANCER RES 38 (3): 776-80 (1978)]**PEER REVIEWED**
  
• 10 VOLUNTEER STUDENTS WERE EXPOSED TO 250-380 PPM OF TRICHLOROETHYLENE FOR 160 MIN. RETENTION AMOUNTED TO 36%. 16% OF THE RETAINED AMT WAS ELIMINATED THROUGH RESPIRATION AFTER EXPOSURE. TRICHLOROACETIC ACID EXCRETION IN FEMALES WAS 2-3 TIMES MORE THAN THAT IN MALES FOR THE 1ST 24 HR AFTER EXPOSURE. TWICE AS MUCH TRICHLOROETHANOL WAS EXCRETED IN MALES THAN IN FEMALES FOR THE 1ST 12 HR. THESE FINDINGS SUGGEST A SEX DIFFERENCE IN HUMAN METABOLISM OF TRICHLOROETHYLENE. [NOMIYAMA K, NOMIYAMA H; INT ARCH ARBEITSMED 28 (1): 37-48 (1971)]**PEER REVIEWED**
  
• The blood concn of trichloroethylene during inhalation and elimination /in humans/ closely parallels alveolar gas concn. Trichloroethylene most rapidly attains equilibrium by passive diffusion into the vessel rich group of tissues (VRG) (brain, heart, kidneys, liver, endocrine and digestive systems), more slowly with lean mass (MG) (muscle and skin) and lastly with adipose tissue (FG). As determined from elimination kinetics following exposure, trichloroethylene distributes from blood into these 3 major compartments at approx rate constants of VRG: 17 hr(-1) (half-life, 2.4 min), MG: 1.7 hr(-1) (t/2, 25 min) and FG: 0.2 hr(-1) (half-life, 3.5 hr). While MG is 50% of the body vol versus 20% for FG, saturation and desaturation proceeds more rapidly from the MG compartment than the FG compartment because of the considerably greater solubility of trichloroethylene in lipids. Thus, variations in trichloroethylene uptake between individuals is influenced first by lean body mass and second by adipose tissue mass. [USEPA; Health Assessment Document: Trichloroethylene (Draft) p.4-5 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• Careful balance studies using GC methodology show, that after single or repeated daily exposures to trichloroethylene concentrations between 50 and 380 ppm, an average of 11% of /absorbed/ trichloroethylene is eliminated unchanged by the lung (half-life= 5 hr), 2% of the dose is eliminated as trichloroethanol by the lung (half-life 10 to 12 hr) and 58% is eliminated as urinary metabolites. The remaining 30% of the dose has been postulated to be metabolized by additional pathways or routes of elimination of one or more unknown metabolites. [USEPA; Health Assessment Document: Trichloroethylene (Draft) p.4-22 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• The ratio between trichloroethylene exposure and urinary trichloroacetic acid excretion appears to decrease with age. [Grandjean E et al; Br J Ind Med 12: 131 (1955) as cited in USEPA; Ambient Water Quality Criteria Document: Trichloroethylene p.C-10 (1980) EPA 440/5/80-007]**PEER REVIEWED**
  
• Pure trichloroethylene is absorbed through mouse abdominal skin at a rate of 55 nmol/sq cm/min. [Tsuruta H; Ind Health 16: 145-8 (1978) as cited in Health and Safety Executive Monograph: Trichloroethylene #6 p.3 (1982)]**PEER REVIEWED**
  
• When (14)C-trichloroethylene was administered by im injection at a dose of 50 mg/kg, the radioactivity excreted in the urine and feces ranged from 40-60% of the dose in chimpanzees, 11-28% in baboons, and 7-40% in rhesus monkeys. [Muller WF et al; Chemosphere 11: 215-8 (1982) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.4-23 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• When 18 mg/kg of trichloroethylene in 5 ml of water or corn oil was intragastrically administered to fasting rats (400 g), the peak blood concn (5.6 minutes for aqueous solution) averaged 15 times higher for water than for corn oil solution (14.7 vs <1.0 ug/ml). The peak blood concn was reached faster for water than for oil solution, which exhibited a second delayed peak 80 minutes post-absorption. [Withey JR et al; J Appl Toxicol 3 (5): 249-53 (1983) as cited in USEPA; Health Assessment Document: Trichloroethylene (Draft) p.4-2 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• In humans, the blood/air partition coefficient ranges from 9 to 15. Daily body uptake has been estimated to be approximately 6 mg/kg body weight, for an exposure of 4 hr at 378 mg/cu m and /is not influenced/ by the quantity of adipose tissue. [Monster AC et al; Int Arch Occup Environ Health 42: 283-92 (1979) as cited in WHO; Environ Health Criteria: Trichloroethylene p.42 (1985)]**PEER REVIEWED**
  
• Trichloroethylene retention varies according to physical activity. Under laboratory conditions, human volunteers at rest exposed to concentrations of 540 or 1080 mg/cu m for 30 minutes, 50% of the quantity inhaled was retained. The percentage retained decreased from 50% to 25% when activity rose from rest to a 150 watt workload, but, because of increased ventilation, the absolute amount absorbed still increased. [Astrand I, Ovrum P; Scand J Work Environ Health 2: 199-211 (1976) as cited in WHO; Environ Health Criteria: Trichloroethylene p.42 (1985)]**PEER REVIEWED**
  
• Trichlororethylene is expired from the lungs for 2 days after exposure, & traces may be present on the 3rd day. About 8% of the retained material is excreted as metabolites in the feces, but most is excreted in the urine. /It was/ found that an average of 73% of the trichloroethylene retained by men & women after inhalation could be recovered in the urine as follows: monochloroacetic acid, 4%; trichloroacetic acid, 19%; & trichloroethanol, 50%. In humans, excretion of the metabolites of trichloroethylene is fastest for monochloroacetic acid, intermediate for trichloroethanol, & slowest for trichloroacetic acid. Following the use of trichloroethylene as an anesthetic, trichloroacetic acid may be detected in the urine for 5-12 days. Following accidental ingestion of trichloroethylene, trichloroacetic acid was found in the serum & urine for 27 days. [Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991., p. 155]**PEER REVIEWED**
  
• Trichloroethylene & its metabolites appear to cross the placenta readily in many species. In mice, inhalation of trichloroethylene resulted in accumulation of its metabolite, trichloroacetic acid, in amniotic fluid. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V63 121 (1995)]**PEER REVIEWED**
  
• A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) & its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), & dichloroacetic acid (DCA), in the mouse, rat, & human for both oral & inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, & kidney. Cancer dose metrics provided in the model include the area under the concn curve (AUC) for TCA & DCA in the plasma, the peak concn & AUC for chloral in the tracheobronchial region of the lung, & the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Addtl dose metrics provided for noncancer risk assessment include the peak concns & AUCs for TCE & TCOH in the blood, as well as the total metab of TCE divided by the body weight. Sensitivity & uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, & TCOH concns in rodents & humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung & kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung & kidney should be used with caution. [Clewell HJ 3rd et al; Environ Health Perspect 108 (2): 283-305 (2000)]**PEER REVIEWED**
  
• Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals & humans for over 30 yr. Compartmental & physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, & metab of TCE & the production, distribution, metab, & elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral & inhalation routes of exposure & is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE & its metabolites have focused on the major metabolic pathway for metab of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental & PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principal metabolite responsible for TCE-induced live r cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. EPA for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood & plasma measurements of TCA are reported in mice & humans. To reduce confusion about disparately measured & model-predicted levels of TCA in plasma & whole blood, model-predicted outcomes are compared for first-generation (plasma) & second-generation (whole blood) PBPK models published by Fisher & colleagues. Qualitatively, animals & humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE & its metabolites are important tools for providing dosimetry comparisons between experimental animals & humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE. [Fisher JW; Environmental Health Perspectives 108 (2): 265-273 (2000)]**PEER REVIEWED**
  
• Trichloroethylene (TCE) ... is oxidized by high-affinity, low-capacity cytochrome P450 isozymes & subsequently converted to metabolites, some of which are carcinogenic in mice & rats. Although the initial oxidation step is known to be rate-limiting & saturable, the oral dosage-range over which saturation materializes is unclear. One objective of this study was to characterize the dose-dependency of GI absorption of TCE & its kinetics over a wide range of oral bolus doses. A related objective was to investigate cause(s) of the apparent saturation kinetics observed. ... /TCE was/ given in doses of 2 to 1200 mg/kg bw via the stomach tube. ... The rate of GI absorption of TCE diminished as the dosage increased. Pharmacokinetic analysis indicated that TCE was eliminated by capacity-limited hepatic metab, with incursion into nonlinear kinetics with bolus doses :8 to 16 mg/kg. Effects of p-nitrophenol, a competitive metabolic inhibitor, were manifest at a high, but not at a low TCE dose. Gavage bolus doses as high as 1200 mg/kg did not cause rapid elevation of serum enzyme levels, typical of the solvation of hepatocellular membranes observed after portal vein admin of TCE ... . No evidence of cytochrome P4502E1 (CYP2E1) destruction was seen with oral doses up to 1000 mg/kg. Instead, CYP2E1 activity was induced as early as 1 h postdosing. Induction was maximal at 12 hr, then returned toward controls during the next 12 h. Pretreatment with cycloheximide did not reduce CYP2E1 activity in rats given 432 or 1000 mg TCE/kg, suggesting that binding of TCE to CYP2E1 may stabilize the isozyme. Metabolic saturation, in concert with relatively slow GI absorption, are responsible for the prolonged elevation of blood TCE levels in rats given high TCE doses, while suicidal inactivation of CYP2E1 & hepatocellular injury apparently play little role. [Lee KM et al; Toxicology and Applied Pharmacology 164 (1): 55-64 (2000)]**PEER REVIEWED**
  
• ... To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored ... using an ion trap mass spectrometer (MS/MS) to track the uptake & elimination of TCE from dermal exposures in rats & humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers & chamber air TCE concn was quantified for 3-5 h post-dosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, & exhaled breath was analyzed using the MS/MS. The total TCE absorbed & the dermal permeability coefficient (KP) were estimated for each individual by optimization of the PBPK model to the exhaled breath data & the changing media &/or dermal patch concns. Rat skin was significantly more permeable than human skin. Estimates for KP in a water matrix were 0.31 : 0.01 cm/h & 0.015 : 0.003 cm/hr in rats & humans, respectively. KP estimates were more than three times higher from water than soil matrices in both species. KP values calculated using the standard Fick's Law equation were strongly affected by exposure length & volatilization of TCE. In comparison, KP values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration. [Poet TS et al; Toxicological Sciences 56 (1): 61-72 (2000)]**PEER REVIEWED**
  
• In lifetime bioassays, trichloroethylene (TCE, CAS No. 79-01-6) causes liver tumors in mice following gavage, liver & lung tumors in mice following inhalation, & kidney tumors in rats following gavage or inhalation. Recently developed pharmacokinetic models provide estimates of internal, target-organ doses of the TCE metabolites thought responsible for these tumor responses. Dose-response analyses following recently proposed methods for carcinogen risk assessment from the U.S. EPA are conducted on the animal tumor data using the pharmacokinetic dosimeters to derive a series of alternative projections of the potential carcinogenic potency of TCE in humans exposed to low environmental concns. Although mechanistic considerations suggest action of possibly nonlinear processes, dose-response shapes in the observable range of tumor incidence evince little sign of such patterns. Results depend on which of several alternative pharmacokinetic analyses are used to define target-organ doses. Human potency projections under the U.S. EPA linear method based on mouse liver tumors & internal dosimetry equal or somewhat exceed calculations based on admin dose, & projections based on mouse liver tumors exceed those from mouse lung or rat kidney tumors. Estimates of the carcinogenic potency of the two primary oxidative metabolites of TCE--trichloroacetic acid & dichloroacetic acid, which are mouse liver carcinogens in their own right--are also made, but it is not clear whether the carcinogenic potency of TCE can be quantitatively ascribed to metabolic generation of these metabolites. [Rhomberg LR; Environ Health Perspect 108 (2): 343-358 (2000)]**PEER REVIEWED**
  
• Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may occur at real-world, low-dose exposure levels. The present study was undertaken to investigate the pharmacokinetic impact of low-dose coexposures to toluene & trichloroethylene in vivo in male F344 rats using a real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling. Rats were exposed to compounds alone or as a binary mixture, at low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breath from the exposed animals was monitored for the parent cmpds & a PBPK model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during single exposures, thus indicating that no metabolic interaction occurred with the se low doses. In contract, at higher doses the binary PBPK model simulating independent metab was found to under predict the exhaled breath concn, suggesting an inhibition of metab. Therefore the binary mixture PBPK model was used to compare the measured exhaled breath levels from high- & low-dose exposures with the predicted levels under various metabolic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic interaction description yielded a Ki value closest to the Km of the inhibitor solvent, indicating that competitive inhibition is the most plausible type of metabolic interaction between these two solvents. [Thrall KD; Poet TS; J of Toxicology and Environmental Health Part A 59 (8): 653-670 (2000)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• RATS EXCRETE 5-7 TIMES MORE TRICHLOROETHANOL THAN TRICHLOROACETIC ACID AFTER EXPOSURE TO TRICHLOROETHYLENE. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 777]**PEER REVIEWED**
  
• EXCRETION OF METABOLITES HAS BEEN STATED TO AMT TO 56% OF TRICHLOROETHYLENE INHALED-7-27% TRICHLOROACETIC ACID, 22.2-22.5% TRICHLOROETHANOL, FREE OR CONJUGATED, 22.5-45.5% UROCHLORALIC ACID AND SMALL AMT ... OF MONOCHLOROACETIC ACID AND CHLOROFORM. ... [Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965., p. 194]**PEER REVIEWED**
  
• METAB OF TCE PROCEEDED THROUGH FORMATION OF A COMPLEX WITH OXYGENATED CYTOCHROME P450 WHICH, BY REARRANGEMENT, CAN LEAD TO: (A) SUICIDAL HEME DESTRUCTION; (B) FORMATION OF CHLORAL, WHICH COULD BE REDUCED TO TRICHLOROETHANOL AND CONJUGATED TO FORM A GLUCURONIDE OR OXIDIZED TO TRICHLOROACETIC ACID; (C) FORMATION OF TCE OXIDE, WHICH DECOMP TO CO AND GLYOXYLIC ACID; AND (D) METABOLITES WHICH BIND IRREVERSIBLY TO PROTEIN, DNA, AND RNA. [MILLER RE, GUENGERICH FP; CANCER RES 43 (3): 1145-52 (1983)]**PEER REVIEWED**
  
• Hepatic microsomes from rats fed for 3 weeks on an isocaloric diet deficient in carbohydrate (sucrose) had an increased capacity (2-1/2-fold) to metabolize trichloroethylene. [Nakajima T et al; Biochem Pharmacol 31: 1005-11 (1982) as cited in USPEA; Health Assessment Document: Trichloroethylene (Draft) p.4-39 (1983) EPA-600/8-82-006B]**PEER REVIEWED**
  
• IN VITRO ADDITION OF TCE TO INCUBATION MIXTURE DECR METAB OF ETHYLMORPHINE & HEXOBARBITAL BY HEPATIC MICROSOMES IN RATS. INHIBITION OF HEXOBARBITAL METAB WAS COMPETITIVE. REPEATED ADMIN TO RATS DECR MICROSOMAL CYTOCHROME P450; INCR LIVER/BODY WT RATIO, MICROSOMAL PROTEINS, NADPH-CYTOCHROME C REDUCTASE ACTIVITY, ANILINE HYDROXYLASE ACTIVITY. [PESSAYRE D ET AL; TOXICOL APPL PHARMACOL 49 (2): 355-64 (1979)]**PEER REVIEWED**
  
• The metabolism of TCE in rats involves oxidation by the liver /SRP: post-mitochondrial supernatant/ mixed function oxidase system to an epoxide intermediate, which binds covalantly to proteins and causes centrilobular damage in the liver. ... [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-165]**PEER REVIEWED**
  
• Rats and mice metabolize trichloroethylene in a qualitatively similar fashion; however, the greater rate of metabolism in mice resulted in (a) a 4-fold greater burden of metabolized trichloroethylene per kilogram of body weight (600 ppm/hr and 2000 mg/kg oral dose) and (b) 4- and 7-fold higher blood concentrations of trichloroethanol and trichloroacetic acid in mice versus rats (1000 mg/kg oral dose), respectively. Humans metabolize trichloroethylene to trichloroethanol and trichloroacetic acid, but more slowly than either mice or rats, which is thought to have important implications with respect to the greater sensitivity of the mouse to toxic effects of trichloroethylene. Trichloroethylene is metabolized by the cytochrome p450 mixed-function oxidase system to chloral (trichloroacetaldehyde), which is subsequently oxidized to trichloroacetic acid or reduced to trichloroethanol (free and conjugated). [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 691]**PEER REVIEWED**
  
• Trichloroethylene is converted to trichloroethanol, free and conjugated with glucuronic acid. The initial conversion of the solvent is to chloral hydrate. Trichloroacetic and the monochloroacetic acid and trichloroethanol are found in the urine. Urinary metabolites can be used for assessment of exposure. [Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 721]**PEER REVIEWED**
  
• The toxicity & metab of trichloroethylene (TRI) were studied in renal proximal tubular (PT) & distal tubular (DT) cells from male Fischer 344 rats. TRI was slightly toxic to both PT and DT cells, & inhibition of cytochrome P450 (P450; substrate, reduced-flavoprotein:oxygen oxidoreductase (RH-hydroxylating or -epoxidizing); EC 1.14.14.1) increased TRI toxicity only in DT cells. In untreated cells, glutathione (GSH) conjugation of TRI to form S-(1,2-dichlorovinyl)glutathione (DCVG) was detected only in PT cells. Inhibition of P450 transiently increased DCVG formation in PT cells & resulted in detection of DCVG formation in DT cells. Formation of DCVG in PT cells was described by a two-component model (apparent Vmax values of 0.65 & 0.47 nmol/min per mg protein & Km values of 2.91 & 0.46 mM). Cytosol isolated from rat renal cortical, PT, & DT cells expressed high levels of GSH S-transferase (GST; RX:glutathione R-transferase; EC 2.5.1.18) alpha (GSTalpha) but not GSTpi. Low levels of GSTmu were detected in cortical & DT cells. Purified rat GSTalpha2-2 exhibited markedly higher affinity for TRI than did GSTalpha1-1 or GSTalpha1-2, but each isoform exhibited similar Vmax values. Triethyltinbromide (TETB) (9 muM) inhibited DCVG formation by purified GSTalpha1-1 & GSTalpha2-2, but not GSTalpha1-2. Bromosulfophthalein (BSP) (4 muM) only inhibited DCVG formation by GSTalpha2-2. TETB & BSP inhibited approximately 90% of DCVG formation in PT cytosol but had no effect in DT cytosol. This suggests that GSTalpha1-1 is the primary isoform in rat renal PT cells responsible for GSH conjugation of TRI. These data ... describe the metab of TRI by individual GST isoforms & suggest that DCVG feedback inhibits TRI metab by GSTs. [Cummings BS et al; Biochemical Pharmacology 59 (5): 531-543 (2000)]**PEER REVIEWED**
  
• A major focus in the study of metab & disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metab & to identify those metabolites that are causally associated with toxic responses. ... Sex- & species-dependent differences in biotransformation pathways ... can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics & pharmacodynamics of TCE in humans. Sex-, species-, & strain-dependent differences in absorption & distribution of TCE may play some role in explaining differences in metab & susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, & strain-dependent differences in activities of the various enzymes that can metabolize TCE & its subsequent metabolites. An addtl factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metab by two major pathways, cytochrome P450 (P450)-dependent oxidation & conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver & lungs, include chloral hydrate, trichloroacetate, & dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metab of the cysteine conjugate of TCE by the cysteine conjugate beta-lyase generates a reactive metabolite that is nephrotoxic & may be nephrocarcinogenic. Although the P450 pathway is a higher activity & higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. [Lash LH et al; Environmental Health Perspectives 108 (2): 177-200 (2000)]**PEER REVIEWED**
  
• Metabolites of toluene (hippuric acid) & trichloroethylene (total trichloro cmpds) have been estimated in labotratory rats after microsomal induction by phenobarbital. Phenobarbital pretreatment accelerated the removal of total trichloro cmpds, however, excretion of hippuric acid was moderately diminished. Results on cytochrome P450 suggest that microsomal induction by phenobarbital was higher in trichloroethylene treated rats than toluene treated rats. It is concluded that in addition to distinct substrate specificity of CYP450 isozymes several other factors like Vmax/Km & QH determine the metab of organic solvents. [RANA S VS; GUPTA S; JOURNAL OF ENVIRONMENTAL BIOLOGY 21 (2): 105-109 (2000)]**PEER REVIEWED**
  
• A ... study investigated the possible differences in metabolism and pharmacokinetics between mice and rats exposed to trichloroethylene. A comparison of metabolized trichloroethylene on a wt basis indicates that the mouse metabolizes 2.2 times more than the rat at 10 ppm and 3.6 times at 600 ppm. Hepatic macromolecular binding was greater in the mouse than in the rat. The binding data suggest that tumor formation in the mouse exposed to trichloroethylene occurred via a nongenetic mechanism and tumors are not expected if liver injury does not occur. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986., p. 596]**PEER REVIEWED**
  

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TSCA Test Submissions

• The ability of trichloroethylene to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary toxicity determinations (exposure time=1 day), trichloroethylene was tested at 0, 4, 20, 100 and 250 ug/ml, with cell survival ranging from 125% to 96% relative to untreated controls. The test compound did not produce significantly greater transformation frequencies than untreated controls.[Arthur D. Little, Inc.; Cell Transformation Assays of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324457, Fiche No. OTS0509392 ]**UNREVIEWED**
  
• The effects of trichloroethylene were examined in the mouse hepatocyte primary culture DNA repair assay. Based on preliminary toxicity tests, trichloroethylene was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4), 1x10(-5) and 1x10(-6)% in DMSO solvent vehicle. The highest two concentrations were too cytotoxic to evaluate in the assay. The lower levels were not cytotoxic but the 0.01 and 0.001% levels caused a significant increase in the unscheduled DNA synthesis over the solvent control (DMSO).[Naylor Dana Institute; DNA Repair Tests of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324292, Fiche No. OTS0509403 ]**UNREVIEWED**
  
• The effects of trichloroethylene were examined in the rat hepatocyte primary culture DNA repair assay. Based on preliminary toxicity tests, trichloroethylene was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4) and 1x10(-5)% in DMSO solvent vehicle. The higher two levels were too cytotoxic to be evaluated in the assay. The concentrations at 0.01% or lower were not cytotoxic and did not cause a significant increase in the unscheduled DNA synthesis over the solvent control.[Naylor Dana Institute; DNA Repair Tests of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324292, Fiche No. OTS0509403 ]**UNREVIEWED**
  
• The mutagenicity of trichloroethane was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Trichloroethylene caused a positive response in strains TA100 and TA1535, both with and without added metabolic activation. Trichloroethylene did not cause a positive response in strains TA98 or TA1537 in any of the test. Trichloroethylene was evaluated using a protocol in which the test article was usually tested over a minimum of 6 dose levels, the highest nontoxic dose level being 10 mg/plate unless solubility, mutagenicity or toxicity dictated a lower limit.[SRI International; Investigation of the Species Sensitivity and Mechanism of Carcinogenicity of Halogenated Hydrocarbons. (1984), EPA Document No. 40-8424225, Fiche No. OTS0509408 ]**UNREVIEWED**
  
• The pharmacokinetics of 1,1,2-trichloroethylene (TRI) was evaluated in male B6C3F1 mice (4/exposure) and male Osborne-Mendel rats (4/exposure) receiving nominal concentrations of 14C-TRI at 10ppm or 600ppm for 6 hours in a dynamic airflow chamber. Mice and rats were placed in Roth-type metabolism cages for collection of feces, urine and expired air for 50 hours post exposure. Within 50 hours, 98-99% of the total radioactivity observed in all exposed male mice was metabolized. The primary route of elimination (approximately, 75% of total body burden) for all mice was via the urine. Approximately 9% of 14C-TRI body burden in mice was biotransformed to the 14C-carbon dioxide. No indication of saturation of 14C-TRI metabolites in the high dose mice was observed. In contrast, rats metabolism of 14C-TRI appeared to show characteristics of saturation at the high dose level. Total metabolism of 14C-TRI in rats at the high dose level (79% of absorbed dose) was decreased relative to the low dose rats (98% of the absorbed dose). Also, exhalation of 14C-TRI increased 10-fold with increased exposure in rats. The primary route of elimination of 14C-TRI in the rat was via the urine which accounted for approximately 62% and 55% of the 14C-TRI body burden in low and high doses, respectively. Mice metabolized 2.2 fold and 3.6 fold more TRI on a per kg body weight basis than rats at 10ppm and 600ppm, respectively.[Dow Toxicology Research Laboratory; The Pharmacokinetics and Macromolecular Interactions of Trichloroethylene in Mice and Rats, Final Report, (1981), EPA Document No. FYI-AX-0781-0120, Fiche No. OTS0000120-0 ]**UNREVIEWED**
  
• The ability of 1,1,2-trichloroethylene to alkylate hepatic DNA was evaluated in four male B6C3F1 mice receiving a carcinogenic dose (1200mg/kg) of 14C-TRI orally by gavage. Mice were sacrificed 5 hours post exposure, and liver were excised. 1,1,2-Trichloroethylene alkylated hepatic DNA in mice to a very small degree, with the maximum estimate average DNA alkylation of 0.62 (+/-0.42) alkylations/10(6) nucleotides for three mice and no 14C-associated bases were detected in the fourth mouse.[Dow Toxicology Research Laboratory; The Pharmacokinetics and Macromolecular interactions of Trichloroethylene in Mice and Rats as Related to Oncogenicity, Final Report, (1981), EPA Document No. FYI-AX-0781-0120, Fiche No. OTS0000120-0 ]**UNREVIEWED**
  
• The ability of trichloroethylene (TCE) to cause unscheduled DNA synthesis was evaluated in 3 sets of male B6C3F1 mice (10-12/group) exposed by gavage using 3 regimes: Set 1, 0 or 2400 mg/kg/day for 3 days; Set 2, 0 or 2400 mg/kg/day for 5 days/week for 3 weeks; and Set 3, 0 , 250, 500, 1200 or 2400 mg/kg/day for 5 days/week for 3 weeks. Mice were injected subcutaneously with radiolabelled thymidine, Set 1 daily, and Sets 2 and 3 on the last 5 and 4 days of TCE treatment, respectively. The animals were sacrificed upon termination of treatment and the kidneys (Set 1 only) and livers examined. There were statistically significant differences noted between treated and control mice in the following: Sets 1 and 2 (p < 0.01, Dunnett's or Student's t-test), increased liver/body weight ratio and hepatic DNA synthesis, and decreased ug DNA/g tissue; Set 3, dose-related increase in liver/body weight ratio (500 mg/kg/day and above, p < 0.01), and a dose-related decrease in hepatic DNA synthesis (500 mg/kg/day and above, p < 0.01). No significant differences were observed between the kidneys of treated and control mice of Set 2. Histopathological changes in hepatic tissue were observed in all treated animals (dose-related in Set 3 animals). Five mice treated with 1200 mg radiolabelled TCE/kg by gavage and sacrificed 3 hrs later indicated that TCE alkylated hepatic DNA only to a small degree.[Dow Chemical USA; The Pharmacokinetics and Macromolecular Interactions of Trichloroethylene in Mice and Rats as Related to Oncogenicity. (1981), EPA Document No. FYI-AX-0781-0120, Fiche No. OTS0000120-0 ]**UNREVIEWED**
  
• The ability of trichloroethylene (TCE) to cause unscheduled DNA synthesis was evaluated in 2 sets of male Osborne-Mendel rats (4/group) exposed by gavage using 2 regimes: Set 1, 0 or 1100 mg/kg/day for 3 days, and Set 2, 0 or 1100 mg/kg/day for 5 days/week for 3 weeks. The rats were injected subcutaneously with radiolabelled thymidine, Set 1 daily, and Set 2 on the last 5 days of TCE treatment. The animals were sacrificed upon termination of treatment and the kidneys (Set 1 only) and livers examined. There were statistically significant differences noted between treated and control rats in the following: Set 2 (p < 0.01, Dunnett's or Student's t-test), increased liver/body weight ratio and hepatic DNA synthesis. No significant differences were observed between the kidneys of treated and control rats of Set 2 or the livers of treated and control rats of Set 1. No significant histopathological changes in hepatic tissue were observed in any of the groups of animals.[Dow Chemical USA; The Pharmacokinetics and Macromolecular Interactions of Trichloroethylene in Mice and Rats as Related to Oncogenicity. (1981), EPA Document No. FYI-AX-0781-0120, Fiche No. OTS0000120-0 ]**UNREVIEWED**
  
• The macromolecular binding of 1,1,2-trichloroethylene (TRI) was evaluated in male B6C3F1 mice (12/exposure) and male Osborne-Mendel rats (12/exposure) receiving nominal concentrations of 14C-TRI at 10ppm or 600ppm for 6 hours in a dynamic air flow chamber. Four rats and four mice were sacrificed at 0, 6 and 24 hours post exposure, and liver and kidneys were excised. Additional mice and rats were sacrificed at 50 hour post exposure from a previous study under the same conditions. The mice had greater binding of radiolabel from TRI than the rat after exposure to 10 or 600ppm of 14C-TRI. Macromolecular binding as measured by pmole Eq C14-TRI per ug protein was three to four times greater in both hepatic and renal tissue in mice following 600ppm exposure than rats. Only a modest increase was observed in hepatic tissue of the mouse following 10ppm exposure relative to the rat. Maximum binding in the liver for both species was observed immediately following exposure (3 hours for the kidneys) and decreased steadily over the next 48 hours.[Dow Toxicology Research Laboratory; The Pharmacokinetics and Macromolecular Interactions of Trichloroethylene in Mice and Rats, Final Report, (1981), EPA Document No. FYI-AX-0781-0120, Fiche No. OTS0000120-0 ]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.