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Mechanisms Involved in Trichloroethylene Induced Liver Cancer: Importance to Environmental Cleanup.

DE2004827061

Publication Date	2004
Page Count	30
Abstract	Trichloroethylene (TCE) is a common contaminant of groundwater as a result of poor disposal practices of the past. As a consequence, this solvent is the focus of many clean-up operations of hazardous waste sites. The finding that TCE induces liver cancer in mice has been a primary driver for current environmental regulations of this contaminant. Under the proposed cancer risk guidelines of the Environmental Protection Agency, identifying the dose-response behavior of key events involved in carcinogenic responses can be used for developing alternative risk assessments, which ultimately impact environmental standards and remediation costs. A critical issue in addressing the mechanism by which TCE induces liver cancer is to identify the metabolites produced by TCE that contribute to the tumor response. It has been proposed that dichloroacetate (DCA) and trichloroacetate (TCA) are potential metabolites that have been produced from TCE, and both metabolites are carcinogenic in mice. Understanding the relative contributions of TCA and DCA in TCE-induced liver cancer is an important variable when considering the potential risk to humans. This task was accomplished primarily through three approaches. First, metabolism and kinetic studies were performed to evaluate the potential formation rates of DCA and TCA in mice exposed to TCE. Second, a comparative study was performed to evaluate whether the pattern of mutations in the H-ras gene in tumors induced by TCE, DCA, and TCA would reveal the relative roles of these metabolites in tumor induction. Third, studies were performed using isolated mouse liver cells in an effort to understand which signaling pathways are modulated by these chemicals and how these pathways regulate cell division. Results from these experiments demonstrated that because DCA is very rapidly metabolized within the liver, blood levels of DCA after administration of carcinogenic doses of either DCA or TCE are much lower than previously appreciated. However, studies using isolated liver cells as a model system demonstrated that even low micromolar concentrations of DCA are sufficient to promote the growth of cells with precancerous characteristics.
Keywords	Environmental management Trichloroethylene Neoplasms Risk assessment Health hazards Ground water Dose-response relationships Mice Metabolites Mutations Tumors Genotype Oncogenes Pharmacokinetics Liver cancer Cleanup
Source Agency	Technical Information Center Oak Ridge Tennessee
Corporate Authors	Pacific Northwest National Lab., Richland, WA.; Department of Energy, Washington, DC.
Supplemental Notes	Sponsored by Department of Energy, Washington, DC.
Document Type	Technical Report
NTIS Issue Number	200511

Mechanisms Involved in Trichloroethylene Induced Liver Cancer: Importance to Environmental Cleanup.

Mechanisms Involved in Trichloroethylene Induced Liver Cancer: Importance to Environmental Cleanup.
DE2004827061

Publication Date	2004
Page Count	30
Abstract	Trichloroethylene (TCE) is a common contaminant of groundwater as a result of poor disposal practices of the past. As a consequence, this solvent is the focus of many clean-up operations of hazardous waste sites. The finding that TCE induces liver cancer in mice has been a primary driver for current environmental regulations of this contaminant. Under the proposed cancer risk guidelines of the Environmental Protection Agency, identifying the dose-response behavior of key events involved in carcinogenic responses can be used for developing alternative risk assessments, which ultimately impact environmental standards and remediation costs. A critical issue in addressing the mechanism by which TCE induces liver cancer is to identify the metabolites produced by TCE that contribute to the tumor response. It has been proposed that dichloroacetate (DCA) and trichloroacetate (TCA) are potential metabolites that have been produced from TCE, and both metabolites are carcinogenic in mice. Understanding the relative contributions of TCA and DCA in TCE-induced liver cancer is an important variable when considering the potential risk to humans. This task was accomplished primarily through three approaches. First, metabolism and kinetic studies were performed to evaluate the potential formation rates of DCA and TCA in mice exposed to TCE. Second, a comparative study was performed to evaluate whether the pattern of mutations in the H-ras gene in tumors induced by TCE, DCA, and TCA would reveal the relative roles of these metabolites in tumor induction. Third, studies were performed using isolated mouse liver cells in an effort to understand which signaling pathways are modulated by these chemicals and how these pathways regulate cell division. Results from these experiments demonstrated that because DCA is very rapidly metabolized within the liver, blood levels of DCA after administration of carcinogenic doses of either DCA or TCE are much lower than previously appreciated. However, studies using isolated liver cells as a model system demonstrated that even low micromolar concentrations of DCA are sufficient to promote the growth of cells with precancerous characteristics.
Keywords	Environmental management Trichloroethylene Neoplasms Risk assessment Health hazards Ground water Dose-response relationships Mice Metabolites Mutations Tumors Genotype Oncogenes Pharmacokinetics Liver cancer Cleanup
Source Agency	Technical Information Center Oak Ridge Tennessee
Corporate Authors	Pacific Northwest National Lab., Richland, WA.; Department of Energy, Washington, DC.
Supplemental Notes	Sponsored by Department of Energy, Washington, DC.
Document Type	Technical Report
NTIS Issue Number	200511