Hepatic and renal toxicities associated with perchloroethylene

Metabolism of perchloroethylene (Perc) occurs by cytochrome P450-dependent oxidation and glutathione (GSH) conjugation. The cytochrome P450 pathway ge nerates tri- and dichloroacetate as metabolites of Perc, and these are asso ciated with hepatic toxicity and carcinogenicity. The GSH conjugation pathw ay is associated with generation of reactive metabolites selectively in the kidneys and with Perc-induced renal toxicity and carcinogenicity. Physiolo gically based pharmacokinetic models have been developed for Perc in rodent s and in humans. We propose the addition of a submodel that incorporates th e GSH conjugation pathway and the kidneys as a target organ. Long-term bioa ssays of Perc exposure in laboratory animals have identified liver tumors i n male and female mice, kidney tumors in male rats, and mononuclear cell le ukemia in male and female rats, increases in incidence of non-Hodgkin's lym phoma and of cervical, esophageal, and urinary bladder cancer have been obs erved for workers exposed to Perc. Limited, and not always consistent, evid ence is available concerning the kidneys as a target organ for Perc in huma ns. Three potential modes of action for Perc-induced liver tumorigenesis ar e: 1) modification of signaling pathways; 2) cytotoxicity, cell death, and reparative hyperplasia; and 3) direct DNA damage. Four potential modes of a ction for Perc-induced renal tumorigenesis are: 1) peroxisome proliferation , 2) alpha -2u-globulin nephropathy, 3) genotoxicity leading to somatic mut ation, and 4) acute cytotoxicity and necrosis leading to cell proliferation . Finally, the epidemiological and experimental data are assessed and use o f toxicity information in the development of a reference dose and a referen ce concentration for human Perc exposure are presented.