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 st rains appear to be resistant to TRI-induced hepatocarcinogenesis and p roduce lower peak concentrations of TCA. Mice, however, also form sign ificant amounts of another carcinogenic metabolite, dichloroacetate (D CA). The present study was conducted to investigate the interspecies d ifferences in the metabolism of TRI between the mouse, rat, and dog an d to gain further insight into the role metabolic factors may play in the apparent species specificity of liver tumor induction by TRI. Fisc her 344 rats and beagle dogs were dosed orally with TRI and blood was analyzed for TRI, DCA, TCA, and trichloroethanol (TCE). Data on the me tabolism of TRI in mice have been previously published. Limited data a re available on the metabolism of TRI in humans. Dogs produce higher p eak concentrations and have a larger area under the concentration-time curve (AUC) for TCA as compared to rats given similar doses of TRI. D ichloroacetate was not found in measurable concentrations, that is, ab ove 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. Trichloroethan ol was found to be present in the blood, urine, and bile, primarily as the glucuronide conjugate. In all species, peak TCA concentrations we re observed beyond the disappearance of TRI. The AUC for TCE glucuroni de is consistent with its acting as a precursor for TCA and probably c ontributes to the continued increase in TCA concentration after TRI di sappears from the system. Investigations into the binding of TCA to pl asma constituents in the rat, dog, mouse, and human suggest that bindi ng also plays a role in species differences in the distribution and el imination of TCA.