Trichloroethylene is an industrial solvent used primarily for vapor degreasing and cold cleaning. It was selected for study because of its industrial use and for potential for human exposure. (An estimated 3.5 million workers are exposed to trichloroethylene.) In an earlier study trichloroethylene (stabilized with epichlorohydrin and 1,2-epoxybutane) administered by gavage caused hepatocellular carcinomas in male and female B6C3F1 mice. Trichloroethylene administration did not increase the incidence of tumors in male or female Osborne-Mendel rats. However, the survival of dosed rats was reduced, thereby compromising the sensitivity of the study to detect a carcinogenic effect.
The studies described in this report were conducted to compare the sensitivities of four strains of rats (ACI, August, Marshall, and Osborne-Mendel) to diisopropylamine-stabilized trichloroethylene. The results of the present studies demonstrate that long-term administration of trichloroethylene produces nephrotoxicity in four strains of rats and that the susceptibilities of these strains to the nephrotoxic effects of the chemical are similar. Because of chemically induced toxicity, reduced survival, and incomplete documentation of the experimental data, the studies are considered inadequate for either comparing or assessing trichloroethylene-induced carcinogenesis in these strains of rats.
Toxicology and carcinogenesis studies of trichloroethylene (more than 99% pure, stabilized with 8 ppm diisopropylamine) were conducted by administering the chemical in corn oil gavage at doses of 0, 500, or 1,000 mg/kg per day, 5 day per week, for 103 weeks to groups of 50 male and 50 female ACI, August, Marshall, and Osborne-Mendel rats. The doses were selected on the basis of results from 13-week gavage studies in which groups of 10 male and 10 female ACI, August, and Marshall rats received daily doses or trichloroethylene (male: 125-2,000 mg/kg; female: 63-1,000 mg/kg). Doses for Osborne-Mendel rats were selected to conform with doses used in an earlier carcinogenicity study in that strain (TR-2).
In the 13-week studies, male ACI and August rats receiving 2,000 mg/kg trichloroethylene and male and female Marshall rats receiving 1,835 mg/kg had final mean body weights 12%-17% lower than those of the vehicle controls. All other dose groups had body weights comparable to those of the vehicle controls. Three male August rats dosed with 2,000 mg/kg died. Histopathologic evaluation of tissues revealed no lesions attributable to trichloroethylene administration in the 13-week studies. This absence of histopathologic findings did not accurately predict the nephrotoxic effects of long-term administration of trichloroethylene to rats.
Body Weight and Survival in the Two-Year Studies: In the 2-year studies, all dosed groups exhibited some reduction in mean body weights relative to the vehicle controls. Survival relative to vehicle controls was significantly reduced in 7/16 dosed groups (see page 6 of the Technical Report). Also, the survival of high dose male Marshall rats was reduced by a large number of accidental deaths. Nephrotoxicity, reduced survival, and central nervous system toxicity (characterized by sedation, loss of consciousness, tremors, and convulsions) showed that the doses of trichloroethylene selected for the 2-year studies were too high.
Renal Effects in the Two-Year Studies: Trichloroethylene caused tubular cell cytomegaly in 82%-100% of all dosed animals. In addition, trichloroethylene produced toxic nephropathy (which was distinguishable from age-related nephropathy) in 17%-80% of the dosed animals. Cytomegaly, karyomegaly, or toxic nephropathy was not found in untreated or vehicle control animals. Trichloroethylene administration was also associated with increased incidences of renal tubular cell adenomas and adenocarcinomas. The incidences of renal lesions are shown in the following table (see page 7 of Technical Report).
Other Pathologic Effects in the Two-Year Studies: An increased incidence of interstitial cell tumors of the testis was observed in high dose male Marshall rats (untreated control, 16/46; vehicle control, 17/46; low dose, 21/48; high dose, 32/48; P=0.002). The incidences of pheochromocytomas of the adrenal gland were significantly reduced in male ACI, female August, female Marshall, and male and female Osborne-Mendel rats.
Genetic Toxicology: Trichloroethylene did not cause mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In Chinese hamster ovary cells, trichloroethylene did not induce chromosomal aberrations; the results for sister chromatid exchanges were considered positive. Trichloroethylene was mutagenic to mouse L5178Y lymphoma cells in the presence of rat liver S9.
Data Audit: Audits of the experimental data for these 2-year studies of trichloroethylene were conducted by the National Toxicology Program (see Appendix Q of the Technical Report). The results of the audits revealed evidence that the doses of trichloroethylene were too high. In addition, there was insufficient documentation of animal breeding, clinical observations, environmental conditions, and analytical chemistry data. Also, individual animal identification was not always verifiable.
Conclusions: Under the conditions of these 2-year gavage studies of trichloroethylene in male and female ACI, August, Marshall, and Osborne-Mendel rats, trichloroethylene administration caused renal tubular cell cytomegaly and toxic nephropathy in both sexes of the four strains. However, these are considered to be inadequate studies of carcinogenic activity because of chemically induced toxicity, reduced survival, and deficiencies in the conduct of the studies. Despite these limitations, tubular cell neoplasms of the kidney were observed in rats exposed to trichloroethylene and interstitial cell neoplasms of the testis were observed in Marshall rats exposed to trichloroethylene.