Modes of action of trichloroethylene for kidney tumorigenesis

This article focuses on the various models for kidney toxicity due to trich loroethylene (TCE) and its glutathione-dependent metabolites, in particular S-(1,2-dichlorovinyl)-L-cysteine. Areas of controversy regarding the relat ive importance of metabolic pathways, species differences in toxic response s, rates of generation of reactive metabolites, and dose-dependent phenomen a are highlighted. The first section briefly reviews information on the inc idence and risk factors of kidney cancer in the general U.S. population. Ep idemiological data on incidence of kidney cancer in male workers exposed oc cupationally to TCE are also summarized. This is contrasted with cancer bio assay data from laboratory animals, that highlights sex and species differe nces and. consequently, the difficulties in making risk assessments for hum ans based on animal data. The major section of the article considers propos ed modes of action for TCE or its metabolites in kidney, including peroxiso me proliferation, alpha(2u)-globulin nephropathy, genotoxicity, and acute a nd chronic toxicity mechanisms. The latter comprise oxidative stress, alter ations in calcium ion homeostasis, mitochondrial dysfunction, protein alkyl ation, cellular repair processes, and alterations in gene expression and ce ll proliferation. Finally, the status of risk assessment for TCE based on t he kidneys as a target organ and remaining questions and research needs are discussed.