Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among...

Trichloroethylene (TCE) is a well-known environmental and occupational toxicant that is classified as carcinogenic to humans based on the epidemiological evidence of an association with higher risk of renal-cell carcinoma. A number of scientific issues critical for assessing human health risks from TCE remain unresolved, such as the amount of kidney-toxic glutathione conjugation metabolites formed, interspecies and interindividual differences, and the mode of action for kidney carcinogenicity. It was postulated that TCE renal metabolite levels are associated with kidney-specific toxicity. Oral dosing with TCE was conducted in subacute (600 mg/kg/d; 5 d; 7 inbred mouse strains) and subchronic (100 or 400 mg/kg/d; 1, 2, or 4 wk; 2 inbred mouse strains) designs. The quantitative relationship was evaluated between strain-, dose, and time-dependent formation of TCE metabolites from cytochrome P-450-mediated oxidation (trichloroacetic acid [TCA], dichloroacetic acid [DCA], and trichloroethanol) and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione], and various kidney toxicity phenotypes. In subacute study, interstrain differences in renal TCE metabolite levels were observed. In addition, data showed that in several strains kidney-specific effects of TCE included induction of peroxisome proliferator-marker genes Cyp4a10 and Acox1, increased cell proliferation, and expression of KIM-1, a marker of tubular damage and regeneration. In subchronic study, peroxisome proliferator-marker gene induction and renal toxicity diminished while cell proliferative response was elevated in a dose-dependent manner in NZW/LacJ but not C57BL/6J mice. Overall, data demonstrated that renal TCE metabolite levels are associated with kidney-specific toxicity and that these effects are strain dependent.