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Modes of action of trichloroethylene for kidney tumorigenesis
L H Lash1, J C Parker, C S Scott
1Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. l.h.lash@wayne.edu
Abstract:
This article focuses on the various models for kidney toxicity due to trichloroethylene (TCE) and its glutathione-dependent metabolites, in particular S-(1,2-dichlorovinyl)-l-cysteine. Areas of controversy regarding the relative importance of metabolic pathways, species differences in toxic responses, rates of generation of reactive metabolites, and dose-dependent phenomena are highlighted. The first section briefly reviews information on the incidence and risk factors of kidney cancer in the general U.S. population. Epidemiological data on incidence of kidney cancer in male workers exposed occupationally to TCE are also summarized. This is contrasted with cancer bioassay data from laboratory animals, that highlights sex and species differences and, consequently, the difficulties in making risk assessments for humans based on animal data. The major section of the article considers proposed modes of action for TCE or its metabolites in kidney, including peroxisome proliferation, alpha(2u)-globulin nephropathy, genotoxicity, and acute and chronic toxicity mechanisms. The latter comprise oxidative stress, alterations in calcium ion homeostasis, mitochondrial dysfunction, protein alkylation, cellular repair processes, and alterations in gene expression and cell proliferation. Finally, the status of risk assessment for TCE based on the kidneys as a target organ and remaining questions and research needs are discussed.
Insights
Trichloroethylene (TCE) kidney toxicity is complex, involving various metabolic pathways and species differences. Understanding these mechanisms is crucial for accurate human risk assessment of TCE exposure.
Area of Science:
- Toxicology
- Environmental Health
- Carcinogenesis
Background:
- Kidney toxicity from trichloroethylene (TCE) and its metabolites, particularly S-(1,2-dichlorovinyl)-l-cysteine, is a significant concern.
- Controversies exist regarding metabolic pathways, species-specific responses, reactive metabolite generation, and dose-dependent effects.
- Epidemiological data on kidney cancer incidence in the general population and occupationally exposed workers are reviewed.
Purpose of the Study:
- To analyze various models of kidney toxicity induced by TCE.
- To highlight areas of scientific controversy in TCE toxicology.
- To discuss the challenges in extrapolating animal bioassay data to human risk assessment.
Main Methods:
- Review of existing literature on TCE metabolism and kidney toxicity.
- Analysis of epidemiological data on TCE-related kidney cancer.
- Comparison of human epidemiological data with animal cancer bioassay findings.
- Examination of proposed mechanisms of TCE-induced kidney damage.
Main Results:
- Significant sex and species differences complicate risk assessment based on animal data.
- Proposed mechanisms of kidney toxicity include peroxisome proliferation, alpha(2u)-globulin nephropathy, genotoxicity, oxidative stress, and mitochondrial dysfunction.
- Dose-dependent phenomena and reactive metabolite generation rates are key areas of investigation.
Conclusions:
- Kidney toxicity models for TCE are diverse and debated.
- Accurate human risk assessment requires further research into TCE's modes of action and species-specific responses.
- Identifying remaining questions and research needs is essential for future studies on TCE's nephrotoxicity.