The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats

Male B6C3F1 mice metabolized inhaled trichloroethylene (TRI) (600 ppm/6 hr) to a greater extent (262% more) than male Osborne-Mendel rats. Mice metabolized more (332%) inhaled TRI to a hepatic macromolecular binding metabolite in vivo than rats. Oral administration of TRI resulted in treatment-related hepatocellular cytotoxicity in repeated dosing trials in the mouse. Hepatic effects observed in mice treated with a maximum tolerated dose of 2400 mg/kg/day TRI for 3 days were primarily centrilobular hepatocellular swelling with focal hepatocellular necrosis. These effects lead to an enhanced regenerative process as indicated by increased hepatic DNA synthesis activity (220% of control) and incidence of mitotic figures. Treatment of mice (po) with TRI for a 3-week period (5 days/week) resulted in a dose-related increase in hepatocellular swelling with giant and mineralized cells present in the 2400 mg/kg/day dosed animals. Contrasting the mouse data, rats appeared to be less sensitive to a maximum tolerated dose level of TRI, displaying enhanced hepatic DNA synthesis levels (175% of control) but no histopathology after a similar 3-week treatment with 1100 mg/kg/day TRI. Renal tissue in both species was not significantly affected by TRI. An estimate of the extent of TRI interaction with DNA was also determined by measuring the radioactivity associated with purified hepatic DNA. Only a very low level of in vivo TRI-DNA interaction was observed in mice given 1200 mg/kg TRI po which is reportedly tumorigenic upon chronic administration (maximum estimate = 0.62 ± 0.43 alkylation/10 6 nucleotides). When coupled with the very weak or negative responses of pure TRI in in vitro mutagenesis assays, the DNA alkylation data indicate a lack of genotoxic potential. These data in toto suggest an epigenetic mechanism of tumor formation in the B6C3F1 mouse, implying that a tumorigenic response to TRI exposure in these animals would only be evident upon chronic administration of high, cytotoxic dose levels of TRI.