Factors affecting species differences in the kinetics of metabolites of trichloroethylene

The hepatocarcinogenicity of trichloroethylene (TRI) in mice has been attributed to a metabolite, trichloroacetate (TCA). Rats of various strains appear to be resistant to TRI-induced hepatocarcinogenesis and produce lower peak concentrations of TCA. Mice, however, also form significant amounts of another carcinogenic metabolite, dichloroacetate (DCA). The present study was conducted to investigate the interspecies differences in the metabolism of TRI between the mouse, rat, and dog and to gain further insight into the role metabolic factors may play in the apparent species specificity of liver tumor induction by TRI. Fischer 344 rats and beagle dogs were dosed orally with TRI and blood was analyzed for TRI, DCA, TCA, and trichloroethanol (TCE). Data on the metabolism of TRI in mice have been previously published. Limited data are available on the metabolism of TRI in humans. Dogs produce higher peak concentrations and have a larger area under the concentration-time curve (AUC) for TCA as compared to rats given similar doses of TRI. Dichloroacetate was not found in measurable concentrations, that is, above 4 nmol/ml, the minimal quantifiable concentration, in the blood of either rats or dogs. Appreciable concentrations of DCA were found in the blood of mice administered TRI in previous studies. Trichloroethanol was found to be present in the blood, urine, and bile, primarily as the glucuronide conjugate. In all species, peak TCA concentrations were observed beyond the disappearance of TRI. The AUC for TCE glucuronide is consistent with its acting as a precursor for TCA and probably contributes to the continued increase in TCA concentration after TRI disappears from the system. Investigations into the binding of TCA to plasma constituents in the rat, dog, mouse, and human suggest that binding also plays a role in species differences in the distribution and elimination of TCA.