Species differences in response to trichloroethylene. I. Pharmacokinetics in rats and mice

The elimination of radioactivity in two strains of rats and mice following a single po dose of trichloro[14C]ethylene at dose levels from 10 to 2000 mg/kg has shown a marked dose dependence in rats but not in mice. The metabolism of trichloroethylene in the mouse was linear over the range of doses used, whereas in the rat it became constant and independent of dose at 1000 mg/kg and above. At the 10-mg/kg dosage, both species metabolized trichloroethylene almost completely, 60% of the dose being excreted in urine with only 1 to 4% being eliminated unchanged in expired air in the first 24 hr. At 2000 mg/kg, 78% of the dose was eliminated unchanged in the rat, but only 14% in the mouse. Consequently at high dosages, the mouse was exposed to significantly higher concentrations of trichloroethylene metabolites than the rat. Blood level kinetics of trichloroethylene and its metabolites confirmed a faster rate of metabolism in the mouse than in the rat. Peak concentrations of the metabolites were reached within 2 hr of dosing in the mouse compared to 10 to 12 hr in the rat. The concentrations of both trichloroethanol (4X) and trichloroacetic acid (7X) were significantly higher in the mouse than in the rat. Whereas trichloroethanol was rapidly eliminated from blood, the higher concentrations of trichloroacetic acid were maintained for over 30 hr. The high blood quantities of trichloroethylene-derived trichloroacetic acid are known to induce hepatic peroxisome proliferation in mice but are insufficient to induce this response in rats. These data suggest that trichloroacetic acid blood amounts, peroxisome proliferation, and the link between peroxisomes and liver cancer are the basis of species difference in response to trichloroethylene.