Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene http://www.nap.edu/catalog/12863.html
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Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene
PPARα activation in mouse hepatocarcinogenesis by tetrachloroethylene via a metabolism-mediated pathway. OTHER MODES OF ACTION The operation of additional, non-PPARα-mediated mechanisms does not seem necessary to explain hepatocarcinogenesis by tetrachloroethylene but from a scientific point of view cannot be excluded. The question is whether evidence exists which supports a significant contribution of other MOAs to hepatocarcinogenesis. Cytotoxicity Tetrachloroethylene causes some hepatotoxicity in mice. It may be due to formation of reactive metabolites, including trichloroacetyl chloride, which have shown protein binding in rodents (Pähler et al. 1999; Green et al. 2001). However, hepatotoxicity has been found to disappear almost completely within 30 days (Philip et al. 2007), and the available long-term carcinogenicity studies revealed little evidence of hepatic damage or inflammation (NTP 1986; JISA 1993). Nevertheless, because the relation between cytotoxicity, inflammation, and cancer is not sufficiently understood, this point should receive attention in future studies. TCA also exerts little hepatotoxicity (Bull et al. 1990; DeAngelo et al. 1989). Overall, current evidence does not indicate that hepatotoxicity of tetrachloroethylene or TCA contributes to hepatocarcinogenesis to a substantial extent. Protein binding in humans was below the level of detection (Pähler et al. 1999). Genotoxicity Hypothetically, genotoxic activity could produce initiated hepatocytes, whose development to tumors might be promoted by TCA. Genotoxic activity could thereby enhance the carcinogenic potential of TCA. However, although some metabolites of tetrachloroethylene are genotoxic, there is no convincing evidence of genotoxic or mutagenic effects of tetrachloroethylene in vivo, and no initiating potential has been detected in appropriate assays (committee report, Chapter 5). Thus, a contribution of genotoxicity to hepatic-tumor formation by tetrachloroethylene is not supported by current evidence. DCA as the Active Metabolite As described in section on Relevance of TCA vs DCA, substantial contribution to PPARα-mediated tumor formation is unlikely. The potential MOAs of DCA include genotoxicity, but this activity is weak and probably not relevant at the low levels formed (IARC 2004).
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