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Appendix B: Dissenting Statement and Rebuttal
Pages 144-170

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From page 144...
... Because of the deficits in the respective presentation in the IRIS draft, the following paragraphs will briefly compile the essential data supporting the PPARα MOA 144
From page 145...
... 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)
From page 146...
... . In the first days of administration, TCA induced liver enlargement and an increase in hepatocyte DNA synthesis in male and female mice (Dees and Travis 1994; Pereira 1996; Stauber and Bull 1997)
From page 147...
... and tumors were predominantly basophilic and did not express glutathione S-transferase-pi (GSTP) , as found with other peroxisome proliferators (Pereira 1996; Pereira and Phelps 1996; Stauber and Bull 1997)
From page 148...
... An NOAEL and a LOAEL and studies in PPARα-null mice are not available. Nevertheless, the PPARα MOA is considered probable on the basis of the induction of several key events in mouse liver, including transient increases in DNA synthesis, lipid peroxidation, inhibition of GJIC, and, most important, peroxisome proliferation, an event highly specific for PPARα activation.
From page 149...
... Rats treated in parallel bioassays did not develop hepatic tumors. Long-term exposure to TCA was shown to result in hepatic-tumor formation in mice (Table 3A)
From page 150...
... . TISSUE CONCENTRATIONS OF TRICHLOROACETIC ACID AFTER ADMINISTRATION OF TETRACHLOROETHYLENE OR TRICHLOROACETIC ACID A key question in identification of the MOA of tetrachloroethyleneinduced hepatic tumors is whether sufficient TCA is formed and available in the target organ for effective induction of peroxisome proliferation and hepatocarcinogenesis.
From page 151...
... TABLE 3A Trichloroacetic Acid Drinking-Water Studies in Male Mice: Incidence of Hepatocellular Adenomas and Carcinomas Equivalent Incidence of Proportion Weeks of TCA TCA Exposure, Incidence of Incidence of Adenomas or Responding with mg/kg-day Carcinomas Carcinomas Source Exposure Exposure, g/L N Adenomas Carcinomas Bull et al.
From page 152...
... and somewhat different proportions of carcinomas. TABLE 4A Blood TCA Concentrations After Tetrachloroethylene Treatment 1)
From page 153...
... 1993 Ratios 1 2 3 1-2 2-3 Doses (mg/kg) 5 20 100 4 5 Peak concentrations (µg/mL)
From page 154...
... After 30 doses of tetrachloroethylene at 150 mg/kg, blood TCA ranged from 35 to 75 µg/mL in the 24-hour period, and after 500 and 1,000 mg/kg, from 50 to 135 µg/mL. Peak concentrations and the AUC are displayed in Table 4A.
From page 155...
... 2009) concordantly demonstrate that peak blood and liver TCA concentrations and AUC do not increase linearly with dose.
From page 156...
... 100 50 0 0 100 200 300 400 500 TCA dose (mg/kg) FIGURE 1 Peak TCA concentrations and Cmax in blood after oral administration of TCA.
From page 157...
... That is convincing evidence that TCA can be formed from tetrachloroethylene and be present in blood and target organ in amounts sufficient to induce peroxisome proliferation and hepatocarcinogenesis. Modeling the Internal Trichloroacetic Acid Dose In the IRIS draft, a quantitative comparison between hepatic-carcinoma yields after tetrachloroethylene or TCA treatment and the corresponding internal TCA doses is attempted.
From page 158...
... 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)
From page 159...
... FIGURE 2B TCA concentrations in blood of male mice after single dose of tetrachloroethylene at 0.1, 0.536, and 1.072 mg/kg in corn oil by gavage. Experimental data shown as symbols; computer simulations shown as solid lines.
From page 160...
... Therefore, the weight of evidence supports the PPARα MOA. SOME RECENT FINDINGS CONCERNING THE ROLE OF PPARα ACTIVATION IN MOUSE AND HUMAN HEPATOCARCINOGENESIS The evidence suggesting that PPARα activation plays a causal role in rodent hepatic-tumor formation by many peroxisome proliferators but is not relevant for human hepatocarcinogenesis has been compiled in recent reviews (Klaunig et al.
From page 161...
... that target constitutively activated PPARα specifically at hepatocytes. The transgenic mice exhibited various PPARα-mediated effects -- changes in fatty acid metabolism peroxisome proliferationand hepatocyte proliferation -- but, surprisingly, not hepatic tumors after 1 year.
From page 162...
... . TCA induces the three key causal events, as well as peroxisome proliferation, and other associatedkey events.
From page 163...
... This and other recent molecular data provide mechanism-based support for the concept that the PPARα MOA lacks relevance to human hepatocarcinogenesis. COMMITTEE REBUTTAL The committee greatly appreciates the dissenting member's thoughtful and careful review of the scientific literature and presentation of the arguments with respect to the MOA of tetrachloroethylene in mouse hepatic tumors and its relevance to humans.
From page 164...
...  A more critical look at the quantitative differences in metabolic activation of tetrachloroethylene to TCA between mouse and rat, species that are generally believed to be almost equally sensitive to peroxisome proliferation, and in induction of hepatic cancer by other compounds in this class should be conducted by EPA. Chapter 6 recommends that EPA consider performing additional analyses with the rat data similar to those done with the mouse in Appendix 4A of the draft and including a table that shows the quantitative differences in affinity to mouse, rat, and human PPARα of both tetrachloroethylene and its key metabolites in comparison with the known peroxisome proliferators.
From page 165...
... The dissenter cites those studies to draw a conclusion that the PPARα MOA lacks relevance to human hepatocarcinogenesis. However, alternative conclusions that can be drawn from the studies mentioned above are that the short-term carcinogenesis studies in the PPARα-null mouse model have important limitations, that activation of PPARα is necessary but not sufficient for the development of mouse hepatic tumors, and that additional molecular events may be important parts of the peroxisome-proliferator MOA.
From page 166...
... 1997. Failure of mono chloroacetic acid and trichloroacetic acid administered in the drinking water to produce liver cancer in male F344/N rats.
From page 167...
... 2001. Pharmacokinetics and Metabolism of Dichloroacetic Acid and Trichloroace tic Acid Administered in Drinking Water in Rats and Mice.
From page 168...
... 2001. Peroxisome proliferators do not increase DNA synthesis in puri fied rat hepatocytes.
From page 169...
... 1997. Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators.


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