for tetrachloroethylene, the role of trichloroacetic acid (TCA) as the major responsible metabolite of tetrachloroethylene, the potential roles of other MOAs, new mechanistic data supporting the lack of relevance of the PPARα MOA for humans. The author hopes that the arguments collected in this dissent will be helpful in revising the IRIS draft.

EVIDENCE THAT TETRACHLOROETHYLENE AND TRICHLOROACETIC ACID ARE PEROXISOME PROLIFERATORS

Relevance of Trichloroacetic Acid vs Dichloroacetic Acid

Both TCA and dichloroaceticacid (DCA) are peroxisome proliferators. TCA is the major metabolite found in the body after exposure to tetrachloroethylene. It is eliminated slowly and therefore accumulates to some extent. In contrast, DCA is present in only tiny amounts after tetrachloroethylene exposure because of low formation and more rapid elimination (IRIS draft, Chapter 3). Thus, after tetrachloroethylene administration in mice, DCA concentrations in blood were below 10 or 25 βg/mL in the initial hours and then undetectable and were undetectable in the liver in the presence of high TCA concentrations (up to 150 βg/mL or 150 βg/g) (Philip et al. 2007; see below for experimental details). TCA and DCA have similar potency as hepatic carcinogens and tumor promoters (Bull 2000; Bull et al. 2004). Overall, therefore, DCA probably contributes little to PPARα-mediated effects of tetrachloroethylene. Other metabolites of tetrachloroethylene are not known to be peroxisome proliferators. The arguments related to the PPARα MOA should therefore focus on TCA.

Peroxisome Proliferator-Activated Receptor-Alpha Transactivation

Tetrachloroethylene (up to 5 mM) did not transactivate mouse and human PPARα in cells transfected with the PPAR genes. Likewise, chloral hydrate and trichloroethanol, minor metabolites of tetrachloroethylene, did not activate PPARα. In contrast, TCA was active at 1 and 5 mM but not at 0.1 mM. Activity was considerable at 1 mM, suggesting that the lowest observed-adverse-effect level (LOAEL) for binding activity is distinctly below 1 mM (Zhou and Waxman 1998; Maloney and Waxman 1999). The maximal activation was only about 50% of that of Wy 14643, a strong activator, but similar to that of mono(2-ethylhexyl) phthalate, the carcinogenic metabolite of di(2-ethylhexyl) phthalate (DEHP). Mouse PPARβ displayed little, and human PPARβ no, responsiveness to TCA. DCA transactivated PPARα with somewhat less potency than TCA, but it showed no effect on mouse or human PPARβ (Zhou and Waxman 1998; Maloney and Waxman 1999). In another study (Walgren et al. 2000), TCA but not DCA was found to activate mouse PPARα at 4 mM.



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