MECHANISMS INVOLVED IN TRICHLOROETHYLENE INDUCED LIVER CANCER: IMPORTANCE TO ENVIRONMENTAL CLEANUP

Bull, Richard J. ; Thrall, Brain D.

Pacific Northwest National Laboratory (U.S.)

关键词: 63 Radiation, Thermal, And Other Environmental Pollutant Effects On Living Organisms And Biological Materials;    Dna Damages;    Genotype;    54 Environmental Sciences;    Carcinogens;   

DOI  :  10.2172/827061
RP-ID  :  EMSP-54684
RP-ID  :  827061

美国|英语

来源: UNT Digital Library

【 摘 要 】

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 uncontrolled hazardous waste sites. TCE is carcinogenic in both mice and rats, but at different sites, the liver and kidney, respectively (NCI 1976; NTP 1988; NTP 1990). Liver tumor induction in mice has been the tumor most critical from the standpoint of environmental regulation (Bull 2000). Under the proposed cancer risk guidelines of the Environmental Protection Agency (EPA 1996), identifying the dose-response behavior of key events involved in carcinogenic responses can be used for developing alternative risk assessments. A major difficulty in developing alternative approaches for TCE is the fact that three of its metabolites are capable of inducing liver cancer in mice (Bull et al. 1990; Daniel et al. 1992; DeAngelo et al. 1999; Pereria 1996). Two of these metabolites have distinct modes of action, dichloroacetate (DCA) and trichloroacetate (TCA). The third metabolite, chloral hydrate, is probably active as a result of its conversion to one or both of these two metabolites. Ordinarily, the first approach to assigning causality to a metabolite in tumorigenesis would be an attempt to measure its concentration in the body and associate that with tumorigenic concentrations observed when the compound is itself administered. This can be done with relative ease with TCA. However, it has been more difficult with DCA since blood levels of this metabolite after exposure to carcinogenic doses of DCA fall rapidly below detection limits (Kato-Weinstein et al. 1998; Merdink et al. 1998). Mutations in the ras protooncogene have been used to determine if distinct patterns of DNAsequence alterations can provide indications of the type of DNA damage that might be produced by carcinogens. The presence of ras mutations in chemically-induced tumors was suggested as a means o f determining whether a chemical was genotoxic (Wiseman et al. 1986). However, the 7 discovery that spontaneous tumors also contain this oncogene indicated that this assumption may not be correct (Fox and Watanabe 1985). Several non-genotoxic carcinogens have been shown to produce tumors with a H-ras mutation frequency considerably below those that result spontaneously (Maronpot et al. 1995). Among these chemicals are a class called peroxisome proliferators, of which TCA and TCE are members. DCA and TCE were found to induce tumors with similar H-ras mutation spectra (Anna et al. 1994), whereas only limited data have been available on TCA (Fereira-Gonzalez et al. 1995). Thus, a major focus of this research was to evaluate whether the pattern and frequency of H-ras mutations in TCE-induced tumors could be explained by the same parameters in tumors induced by the metabolites TCA or DCA. The present project was organized around three interrelated objectives: The first objective addressed the pharmacokinetic questions regarding the formation and elimination of DCA and TCA in mice administered TCE and whether levels of these metabolites may account for the tumors induced by TCE. The second objective was to investigate potential molecular mechanisms by which TCA and DCA may, in the absence of directly causing mutations, promote the clonal growth and expansion of precancerous cell populations within mouse liver. The third objective was to investigate whether the genotype of tumors induced by TCA and DCA can be used to establish the relative roles of these metabolites in TCE-induced cancer. In particular, the focus of the latter studies was to compare the incidence and spectra of mutations in the H-ras gene (codon 61) to determine if the reported similarities in the genotype of DCA- and TCE-induced tumors have a causal relationship.