Vol. 53, Issue 2, 177-208, June 2001

Hepatic and Renal Toxicities Associated with Perchloroethylene

Lawrence H. Lash¹ and Jean C. Parker

Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.); and National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC (J.C.P.)

I. Introduction
II. Pathways of Perchloroethylene Metabolism
    A. Cytochrome P450-Dependent Oxidation and Associated Enzymes
        1. Overview of Cytochrome P450-Dependent Pathway.
        2. Role of Specific Cytochrome P450 Enzymes in Perchloroethylene Metabolism.
        3. Role of Genetic Polymorphisms in Cytochrome P450-Dependent Metabolism of Perchloroethylene.
        4. Species Differences in Cytochrome P450-Dependent Metabolism of Perchloroethylene.
    B. Glutathione Conjugation Pathway
        1. Overview of Glutathione Conjugation Pathway.
        2. Glutathione S-Transferases.
        3. -Glutamyltransferase.
        4. Cysteine Conjugate -Lyase.
        5. Other Reactions of S-(1,2,2-trichlorovinyl)-L-cysteine and Evaluation of Relative Rates of Each Step of the Glutathione Conjugation Pathway.
    C. Relative Roles of P450 and Glutathione Conjugation Pathways in Perchloroethylene Metabolism
III. Physiologically Based Pharmacokinetic Models for Perchloroethylene
IV. Laboratory Animal Studies of Perchloroethylene Toxicity
V. Human Studies of Perchloroethylene Toxicity
    A. Occupational Studies
    B. Epidemiological Studies of the General Population Exposed to Perchloroethylene
VI. Modes of Action for Perchloroethylene in Hepatic Toxicity
    A. Overall Patterns and Metabolites Associated with Hepatic Toxicity
    B. Peroxisome Proliferation and Enzyme Induction
    C. Oncogene Activation
    D. Oxidative Stress and Genotoxicity
    E. Cell Proliferation
VII. Modes of Action for Perchloroethylene in Renal Toxicity
    A. Overall Patterns and Metabolites Associated with Renal Toxicity
    B. Peroxisome Proliferation
    C. 2u-Globulin Nephropathy
    D. Genotoxicity
    E. Acute Cytotoxicity and Cell Proliferation
VIII. Development of Reference Dose and Reference Concentration for Perchloroethylene Exposure
IX. Summary and Research Needs
Acknowledgments
References

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) -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.