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 generates tri- and dichloroacetate as metabolites of Perc, and these are associated with hepatic toxicity and carcinogenicity. The GSH conjugation pathway is associated with generation of reactive metabolites selectively in the kidneys and with Perc-induced renal toxicity and carcinogenicity. Physiologically based pharmacokinetic models have been developed for Perc in rodents and in humans. We propose the addition of a submodel that incorporates the GSH conjugation pathway and the kidneys as a target organ. Long-term bioassays of Perc exposure in laboratory animals have identified liver tumors in male and female mice, kidney tumors in male rats, and mononuclear cell leukemia in male and female rats. Increases in incidence of non-Hodgkin's lymphoma and of cervical, esophageal, and urinary bladder cancer have been observed for workers exposed to Perc. Limited, and not always consistent, evidence is available concerning the kidneys as a target organ for Perc in humans. Three potential modes of action for Perc-induced liver tumorigenesis are: 1) modification of signaling pathways; 2) cytotoxicity, cell death, and reparative hyperplasia; and 3) direct DNA damage. Four potential modes of action for Perc-induced renal tumorigenesis are: 1) peroxisome proliferation, 2) alpha-2u-globulin nephropathy, 3) genotoxicity leading to somatic mutation, and 4) acute cytotoxicity and necrosis leading to cell proliferation. Finally, the epidemiological and experimental data are assessed and use of toxicity information in the development of a reference dose and a reference concentration for human Perc exposure are presented.
Lash
L H
LH
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201-1928, USA. l.h.lash@wayne.edu
Parker
J C
JC
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D016273:Occupational Exposure; D012997:Solvents / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D013750:Tetrachloroethylene / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
D012997:Solvents; D003577:Cytochrome P-450 Enzyme System; D013750:Tetrachloroethylene