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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Appendix B Dissenting Statement and Rebuttal Dissenting Statement on Mode of Action of Tetrachloroethylene in Mouse Hepatocarcinogenesis By Rolf Schulte-Hermann The authors of the Integrated Risk Information System (IRIS) draft conclude in Chapter 4.4. That peroxisome proliferator-activated receptor-alpha (PPARα) activation is not the primary mode of action (MOA) for tetrachloroethylene-induced hepatocarcinogenesis in mice. That the specific mechanisms or MOAs for hepatocarcinogenesis are not known. That it is highly likely that more than one mechanism is operative. That conclusion is supported in Chapter 6 of the present committee review of the IRIS draft although some deficiencies in the draft are mentioned. They include the lack of coherent flow and an imbalance in critiquing the view that the PPARα MOA is not relevant for human carcinogenesis. This committee member concurs with the criticisms. However, the member disagrees with the conclusions quoted above. In the members’ opinion, the weight of evidence strongly favors a key role of PPARα activation in tetrachloroethylene-induced hepatocarcinogenesis in mice; furthermore, this MOA lacks relevance for human hepatocarcinogenesis. 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
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene 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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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Tetrachloroethylene as a Peroxisome Proliferator Tetrachloroethylene induces in mouse liver responses that are known to be mediated by PPARα—such as a 4-fold increase in CN-insensitive palmitoylCoA oxidation (PCO), morphologic evidence of peroxisome proliferation based on morphometric analysis, and hepatomegaly—at doses of 1,000 mg/kg by gavage for 10 days or 200 and 400 ppm by inhalation 6 hours/day for 14, 21, or 28 days (Goldsworthy and Popp 1987; Odum et al. 1988). Those effects also occurred, although much more weakly, in rats (Goldsworthy and Popp 1987; Odum et al. 1988). Dose-dependent increases in hepatomegaly and (not significantly) hepatocyte proliferation after oral treatment of mice were reported by Schumann et al. (1980) and Buben and O’Flaherty (1985). In male mice, tetrachloroethylene at daily oral doses of 150, 500, and 1,000 mg/kg transiently and dose-dependently increased hepatocyte DNA synthesis at 7 and 14 days; at 30 days, the increase was nearly gone (Philip et al. 2007). Tetrachloroethylene itself does not bind to PPARα (see above), so PPARα-mediated responses should be due to active metabolites, predominantly TCA. In the study by Odum (1988), 200 ppm, the higher dose in the NTP (1986) carcinogenicity study, induced pronounced increases in PCO and peroxisome proliferation that suggested that the NOAEL was much lower. Obviously, doses of tetrachloroethylene that are in the range of the carcinogenic doses are transformed to metabolites (mainly TCA) in amounts sufficient to activate PPARα in mouse liver. Evidence supporting the role of TCA is presented later. Trichloroacetic Acid as a Peroxisome Proliferator and Hepatocarcinogen in Mice TCA was shown in numerous studies to induce PPARα-mediated responses, such as PCO increases, in the livers of mice of both sexes and to produce liver tumors in mice (Goldsworthy and Popp 1987; Pereira 1996; Bull 2000; Bull et al. 2002; DeAngelo et al. 2008; further references in the IRIS draft). 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). Effects were present when TCA was given at 100 mg/kg orally over 11 days and showed some increase with dose up to 1,000 mg/kg (Dees and Travis 1994). With continued treatment, the enhancement of DNA synthesis disappeared and was reversed to depression (Pereira 1996; Stauber and Bull 1997). TCA induction of the peroxisomal enzymes PCO and acyl-CoA oxidase (by RNA expression) and of CYP 4a depended on the presence of the PPARα gene and were not seen in PPARα-null mice (Laughter et al. 2004). Some studies reported increased lipid peroxidation by TCA (Bull et al. 1990; Larson and Bull 1992; Austin et al. 1996). An increase in 8-OHdG was not found after TCA (Parrish et al. 1996) or after tetrachloroethylene (Toraason et al. 1999).
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Hepatic tumorigenesis after TCA administration was studied mostly in male mice but was also demonstrated in female mice (Pereira 1996). TCA was found to promote hepatic-tumor development efficiently in mice after initiation by 1-methyl-1-nitrosourea or vinyl carbamate (Pereira and Phelps 1996; Bull et al. 2004). Foci of altered cells (presumably preneoplastic lesions) 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). Clonal expansion of anchorage-independent hepatocytes obtained from male B6C3F1mice by administration of TCA in vitro was also reported (Stauber et al. 1998). In a recent lifetime dose-response study, DeAngelo et al. (2008) found that the TCA-induced increase in PCO correlated with tumor induction, and a linear association occurred between the two effects. A TCA NOAEL of 6 mg/kg per day and a LOAEL of 58-68 mg/kg were reported. Evaluation of Effects of Trichloroacetic AcidTCA and Tetrachloroethylene for Consistency with Key Events Klaunig et al. (2003) have defined seven key events in the PPARα MOA of rodent hepatocarcinogenesis. TCA was found to induce most of the key events in mice: Causal relationship to tumor formation: Direct activation of PPARα (resistance to induction of key events in PPARα-null mice). Transient increase in hepatocyte DNA synthesis. Selective clonal expansion of the putative preneoplastic lesions and of tumors. Associative relationship to tumor formation: Peroxisome proliferation as indicated by morphologic and biochemical studies (high weight of evidence and specificity for association with tumorigenesis [Klaunig et al. 2003]). Hepatocyte oxidative stress (lipid peroxidation) (low weight of evidence and specificity for association [Klaunig et al. 2003]). Inhibition of gap junctional intercellular communication (GJIC) by TCA in a model with lucifer yellow. The same result was obtained with tetrachloroethylene (Benane et al. 1996) Dependence on Kupffer cells has apparently not been studied directly after TCA. administration. However, that is not a serious deficiency for the purpose of this discussion, because the specificity of Kupffer-cell dependence is low (Klaunig et al. 2003). This set of results was generated in several studies, and dose-response and temporal relationships are consistent with the observation of tumors. In the absence
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene of evidence on genotoxicity and other plausible MOAs, the induction of 6 of the 7 key events provide strong evidence of a PPARα-dependent MOA of TCAinduced mouse hepatocarcinogenesis. The same conclusion was reached by the National Research Council’s Committee on Human Health Risks of Trichloroethylene (2006). Data on tetrachloroethylene are less comprehensive. 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. A major argument supporting the PPARα MOA of tetrachloroethylene is related to the role of TCA as the active metabolite, as will be shown below according to several lines of evidence. SPECIES DIFFERENCES SUPPORTING THE ROLE OF TRICHLOROACETIC ACID AS THE ACTIVE METABOLITE OF TETRACHLOROETHYLENE Rats are less sensitive than mice to peroxisome-proliferator effects of the same doses of tetrachloroethylene (Goldsworthy and Popp 1987; Odum et al. 1988) and do not develop hepatic tumors in response to it (NCI 1977; NTP 1986; JISA 1993) or to TCA at doses up to 364 mg/kg per day for 104 weeks (DeAngelo et al. 1989, 1997). Those differences can be explained by the kinetics of tetrachloroethylene in the two species. Mice metabolize the agent and form TCA at concentrations several times higher than do rats (Schumann et al. 1980; Reitz et al. 1996). Thus, the area under the curve (AUC) for blood TCA after exposure to tetrachloroethylene at 400 ppm for 6 hours was 6.7 times higher in mice than in rats (Odum et al. 1988). In addition, mice are more sensitive than rats to induction of peroxisome proliferation by TCA. That may, at least partially, be due to the 10-fold higher binding capacity of rats’ than of mice’s plasma proteins for TCA (maximal binding capacity, 283 μM in rats and 29 μM in mice). As a result, the proportion of TCA available for uptake by the liver will be less in rats than in mice and will produce a weaker response in rats (Lumpkin et al. 2003). The weak peroxisome-proliferator effect seen in rats is obviously insufficient for hepatic-tumor formation. Numerous examples show that low levels of induction of peroxisomes are not necessarily associated with hepatic tumorigenesis (Klaunig et al. 2003). Overall, the striking differences between responses of mice and of rats to tetrachloroethylene can be explained by assuming TCA as the active principle. CARCINOGENICITY STUDIES WITH TETRACHLOROETHYLENE AND TRICHLOROACETIC ACID Hepatocarcinogenic doses of tetrachloroethylene in mice are displayed in
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Tables 1 and 2. Doses that do not increase rates of hepatocarcinoma were not tested in National Cancer Institute (NCI) and National Toxicology Program (NTP) studies. 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) but not rats (DeAngelo et al. 1997). DeAngelo et al. (2008) exposed male B6C3F1 mice to TCA via drinking water at 0.05, 0.5, 4.5, and 5 g/L for 60 and 104 weeks (Table 3B). Daily doses calculated were 6-8, 58-68, and 572-602 mg/kg. The work consisted of three parts conducted in two Environmental Protection Agency (EPA) laboratories. The authors reported significant increases in the prevalence and multiplicity of hepatic tumors in the two higher dose groups. A TCA NOAEL of 6 mg/kg per day and a LOAEL of 58-68 mg/kg per day were derived for neoplastic and nonproliferative pathology. Somewhat surprisingly, the IRIS draft does not mention parts 1 and 2 of the study by DeAngelo et al. 2008), which is therefore presented completely in Table 3B. The selection of only one of the two 104-week bioassays has important implications for modeling in Appendix 4A of the IRIS draft because the control group selected shows a dramatically higher hepatic-tumor incidence (64% vs 12%; see parts 3 and 2 in Table 3B). Use of the low-tumor control would increase the fraction of animals affected by TCA (Figure 4A-1 of the IRIS draft) and increase the calculated carcinogenic potency of TCA. To add to the confusion, in the publication of DeAngelo et al. (2008), the allocation of controls and treated groups in parts 2 and 3 of the study is at variance between the methods section and Table 6 of the results section. That discrepancy should be resolved, and all pertinent data should be used in revising the IRIS document. At present, the validity of the modeled TCA potency data as used in Appendix 4A is questionable. TABLE 1 Carcinogenicity Study in B6C3F1 Mice (Tetrachloroethylene In Corn Oil Was Administered By Gavage 5 Time a Week for 78 Weeks and Followed By an Observation Period of 12 Weeks) Sex Bioassay Dose, mg/kg (TWA) Carcinoma (Incidence) Mice at Risk Male NCI 0 2 17 0 (vehicle) 2 20 536 32 49 1,072 27 48 Female NCI 0 2 20 0 (vehicle) 0 20 386 19 48 772 19 48 Source: NCI 1977.
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene TABLE 2 Incidence of Hepatocellular Adenomas and Carcinomas in B6C3F1 Mice Exposed to Tetrachloroethylene in Two Inhalation Bioassays Sex Bioassay Administered Exposures, ppm Cumulative LiverTumors at Week 104 Total at Riska Adenomas Carcinomas Adenomas or Carcinomas Male NTP (1986) 0 12 7 17 49 100 8 25 31 47 200 19 26 41 50 JISA (1993) 0 7 7 13 46 10 13 8 21 49 50 8 12 19 48 250 26 25 40 49 Female NTP (1986) 0 3 1 4 45 100 6 13 17 42 200 2 36 38 48 JISA (1993) 0 3 0 3 50 10 3 0 3 47 50 7 0 7 48 250 26 14 33 49 aAnimals that died before the first appearance of a hepatocellular tumor, but no later than week 52, were omitted from the totals because they were presumed not to have adequate time in the study to develop tumors. Source: EPA 2008 (Table 4A-3). 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. To address that question, a literature search has been conducted for analytic data on TCA concentrations in the liver and, as a surrogate, in the blood. The results are described below and displayed in Tables 4A-D and Figures 1 and 2A-C. Blood and Liver Concentrations of Trichloroacetic Acid After Administration of Tetrachloroethylene Blood concentrations of TCA after tetrachloroethylene administration were first analyzed by Odum et al. (1988). After a single exposure at 400 ppm for 6 hours, peak blood concentrations in B6C3F1 mice were 130 μg/mL 3-4 hours after the end of exposure and thereafter declined with a half-life of 7-8 hours. The AUC was calculated (Table 4A).
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene TABLE 3A Trichloroacetic Acid Drinking- Water Studies in Male Mice: Incidence of Hepatocellular Adenomas and Carcinomas Source Weeks of Exposure TCA Exposure, g/L Equivalent TCA Exposure, mg/kg- day N Incidence of Adenomas Incidence of Carcinomas Incidence of Adenomas or Carcinomas Proportion Responding with Carcinomas Bull et al. (1990)a 37 2 330 11 0 3 3 0.27 52 0 0 35 0 0 0 0.0 1 170 11 2 2 NR 0.18 2 330 24 1 4 NR 0.17 Bulll et al. (2002) 52 0 0 20 0 0 0 0.0 0.5 NR 20 5 3 6 0.15 2 NR 20 6 3 8 0.15 Herren-Freund et al. (1987) 61 0 0 22 2 0 2 0.0 5 NR 22 8 7 NR 0.32 Ferreira-Gonzalez et al. (1995) 104 0 0 16b NR 3b NR 0.19 4.5 NR 11 NR 8 NR 0.73 DeAngelo et al. (2008) 104 0 0 56 10 26 31 0.55 0.05 8 48 10 14 21 0.44 0.5 68 51 20 32 36 0.71 aCumulative TCA exposures were provided in grams per kilogram for the mice evaluated at 52 weeks. Those exposures were converted to milligrams per kilogram per day by (1,000 mg/g)/(7 days/[week][52 weeks]). bEstimated from the reported proportion responding by selecting the smallest group size and incidence value consistent with the precision of the reported proportion. NR = not reported. Source: EPA 2008 (Table 4A-1).
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene TABLE 3B Complete Presentation of Results of the TCA Carcinogenicity Study of DeAngelo et al. (2008) Weeks TCA, g/L Equivalent TCA, mg/kg Na Number with Denoma Number with Carcinoma Number with Adenoma or Carcinoma 60 (part1) 0 (NaCl) 0 30 7 7 13 0.05 8 27 15 4 15 0.5 68 29 21 21 38 5.0 602 29 38 38 55 104 (part 2) 0 (NaCl) 0 25 0 12 12 4.5 572 36 59 78 89 104 (part 3) 0 (1.5 g of acetic acid) 0 42 21 55 64 0.05 6 35 23 40 57 0.5 81 37 51 78 87 aNumber of animals examined. Note: Table 3A from EPA (2008) contains only part 3 and reports higher numbers of animals examined than the publication by De Angelo et al. and somewhat different proportions of carcinomas. TABLE 4A Blood TCA Concentrations After Tetrachloroethylene Treatment 1) 1x 400 ppm for 6 hours Odum et al. 1988 Doses (ppm x 6 hours) 400 Peak concentrations (μg/mL) a 130 AUC0-24 (μg/mL per hour) b 1,760 2) 1x i.g. Gearhart et al. 1993 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 100 536 1,072 5.36 2.0 Peak concentrations (μg/mL) a 23 80 157 3.48 1.96 AUC0-24 (μg/mL per hour) b 368 1,317 2,840 3.58 2.16 3) 1x, i.g.; SW mice Philip et al. 2007 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 150 500 1,000 3.33 2.0 Peak concentrations (μg/g) a 150 160 170 1.07 1.06 AUC0-24 (μg/mL per hour) a 2,583c 2,229 3,208 0.86 1.44 4) 30x, daily i.g.; SW mice Philip et al. 2007 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 150 500 1,000 3.33 2.0 Peak concentrations (μg/g) a 75 128c 130 1.71 1.02 AUC0-24 (μg/mL per hour) a 864 2197c 2,439 2.54 1.11 aNumbers read from figure. bCalculated from figure. cData of the first two time points were excluded from the calculation. Note: If not indicated otherwise, male B6C3F1 mice were used. Ratios between doses, peak TCA concentrations, and AUC are indicated. i.g. = intragastric application. Further technical data on the studies is given in the text.
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene TABLE 4B Blood TCA Concentrations after TCA Treatment 1) 1x i.g., 4-hour fast Larson and Bull 1992 Ratios 1 2 3 1 - 2 Doses (mg/kg) 20 100 5 Cmax (μg/mL) 38 ± 1.65 130 ± 9.9 3.4 AUC0-24 (μg/mL per hour) 333 ± 9.9 1185 ± 34.7 3.5 2) 1x i.g., 8-hour fast Templin et al. 1993 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 5 20 100 4 5 Peak concentrations (μg/mL) a 10.1 40.3 80.6 4.0 2.0 AUC0-24 (μg/mL per hour) a 87 374 934 4.3 2.5 3a) 1x i.v., 16-hour fast Gonzalez-Leon 1999 Doses (mg/kg) 100 Cmax (μg/mL) 179 ± 30 AUC0-24 (μg/mL per hour) 2,516 ± 289 3b) Pretreatment with TCA at 2 g/L for 14 days, then 1x i.v., 16-hour fast Doses (mg/kg) 100 Cmax (μg/mL) 214 ± 17 AUC0-24 (μg/mL per hour) 2,964 ± 418 4) Drinking water, 14 days Mahle et al. 2001 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 11.6 110 268 9.5 2.4 Peak concentrations (μg/mL) 10.3 72.9 79.9 7.1 1.1 5) Drinking water for 5 or 14 days Green 2003 (Data from Sweeney et al. 2009) Ratios 1 2 3 1 - 2 2 – 3 Doses (mg/kg), 5 days 180 443 2.5 Peak concentrations (μg/mL) 71.6 127 1.8 Doses (mg/kg), 14 days 181 497 2.8 Peak concentrations (μg/mL) 97.5 133 1.4 aNumbers read from figure. Note: For explanations, see Table 4A.
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene TABLE 4C Liver TCA Concentrations after Treatment with Tetrachloroethylene 1) 1x, i.g.; SW mice Philip et al. 2007 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 150 500 1,000 3.33 2.0 Peak concentrations (μg/g) a 53 100 175 1.89 1.75 AUC0-24 (μg/mL per hour) a 956 1,690 3,233 1.77 1.91 1) 30x, daily i.g.; SW mice Philip et al. 2007 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 150 500 1,000 3.33 2.0 Peak concentrations (μg/g) a 25 34 42 1.36 1.24 AUC0-24 (μg/mL per hour) a 388 563 694 1.45 1.23 aNumbers read from figure. Note: For explanations, see Table 4A. TABLE 4D Liver TCA Concentrations after Treatment with TCA 2) 1x i.g., 8-hour fast Templin et al. 1993 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 5 20 100 4 5 Peak concentrations (μg/g) 6.4 21.1 28.4 3.3 1.3 AUC0-24 (μg/mL per hour) 55 199 386 3.6 1.9 4) Drinking water, 14 days Mahle et al. 2001 Ratios 1 2 3 1 - 2 2 - 3 Doses (mg/kg) 11.6 110 268 9.5 2.4 Peak concentrations (μg/mL) 6.2 48.2 61.6 7.77 1.28 Note: For explanations, see Table 4A. Gearhart et al. (1993) administered a single dose of tetrachloroethylene to male B6C3F1 mice by gavage in corn oil at of 0.1, 0.536, and 1.072 mg/kg. The two higher doses correspond to those used in the NCI oral-carcinogenicity study (Table 1). TCA reached peak blood concentrations of 23, 80, and 157 mg/l; these and the AUC are shown in Table 4A. In a similar study of male Swiss Webster mice, Philip et al. (2007) applied tetrachloroethylene in aqueous gavage (with Emulphor) daily in three dosages (150, 500, and 1,000 mg/kg) for up to 30 days. Concentrations of tetrachloroethylene, TCA, DCA, and trichloroethanol were analyzed after one and 30 treatments. After the first treatment, peak blood TCA was similar with all three dosages. 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. Peak hepatic TCA and AUC tended to be lower than the corresponding blood concentrations, particularly after 30 days of treatment (Table 4C).
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene FIGURE 2C TCA concentrations in blood of male mice after single doses of TCA at 20 or 100 mg/kg by gavage. Data read from figure. Source: Larson and Bull 1992. Reprinted with permission; copyright 1992, Toxicology and Applied Pharmacology. Other Mechanisms Several other effects of tetrachloroethylene or TCA have been discussed as potential MOAs. Among these, changes in DNA methylation occur during PPARα activation. Therefore, that effect, although not specific for the PPARα MOA, does not necessarily support a contribution of other MOAs to hepatocarcinogenicity of tetrachloroethylene. TCA slightly transactivated mPPARβ, but this effect was much weaker than seen with PPARα and therefore is considered to have little or no relevance in mouse hepatocarcinogenesis. Importantly,TCA had no effect on human PPARβ (see section on PPARα Transactivation). In conclusion, there is no evidence available tosuggest that MOAs other than PPARα activation have asignificant impact on mouse hepatocarcinoma formation by tetrachloroethylene. 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. 2003; Meek et al. 2003; Peters et al. 2005; EU 2008; Corton 2008).
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene The authors of the IRIS draft present two recent publications that in their opinion raise questions about the causal relationship between activation of PPARα and rodent hepatic-tumor formation (p. 4-31). First, Yang et al. (2007) used transgenic mice (LAP-VP16PPARα) 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. Transgenic mice showed no hepatocyte hypertrophy and eosinophilia and no induction of proliferation of nonparenchymal liver cells. Those results indicate that PPARα-dependent induction of hepatocyte proliferation alone is not sufficient for hepatocarcinogenesis and that additional effects, such as activation of nonparenchymal cells, are required. Activation of Kupffer and other nonparenchymal cells had been found necessary for optimal induction of proliferation of normal and preneoplastic hepatocytes (Rose et al. 1997; Parzefall et al. 2001; Hasmall et al. 2001; Drucker et al. 2006). Thus, the study of Yang et al. does not refute the PPARα MOA but confirms and extends current knowledge. Second, Ito et al. (2007) found that a low dose of DEHP (0.05% in diet) known to be noncarcinogenic in wild-type mice produced a low rate (26%) of hepatic adenomas in PPARα-null mice after 22 months. The tumors apparently were induced by oxidative stress and inflammation, as indicated by histopathologic changes and increases in 8-OHdG, NF-ĸB, and c-jun RNA, all of which were particularly high in the null mice. Activation of PPARα can have anti-inflammatory effects, resulting in higher vulnerability to tumorigenesis in PPARα-null mice (Ito et al. 2007). 8-OHdG was not increased after tetrachloroethylene or TCA (see earlier section on TCA as a Peroxisome Proliferator and Hepatocarcinogen in Mice). Thus, the results of Ito et al. suggest that DEHP, an agent unrelated to tetrachloroethylene, can induce (benign) hepatic tumors through a second, previously unsuspected PPARα-independent pathway. They do not contradict the causal role of PPARα activation in many instances of rodent hepatocarcinogenesis induced by peroxisome proliferators, which is supported by overwhelming evidence. Some important new findings are missing in the IRIS draft. Thus, the generation of transgenic mice in which the mouse PPARα is replaced by the human counterpart provided substantial progress. The hPPARα mice were essentially resistant to hepatocarcinogenesis when fed a potent peroxisome proliferator (WY-14643) for 44 weeks, whereas corresponding wild-type mice developed tumors in 38 weeks. Gene-expression analysis for peroxisomal fatty-acidmetabolizing enzymes revealed that both receptors were functional. The findings suggest that structural differences between human and mouse PPARα are responsible for the different susceptibility of mice and humans to hepatocarcinogenesis by peroxisome proliferators (Morimura et al. 2006). Furthermore, it was shown that induction of hepatocellular proliferation by peroxisome proliferators involves downregulation of the microRNA let-7c gene by mPPARα. That in turn allows increased expression of c-myc protein, which is essential for hepatocyte proliferation and tumor formation. Human PPARα
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene apparently cannot suppress let 7c expression, and c-myc was not increased in hPPARalpha mice after WY-14643 treatment (Shah et al. 2007; Gonzalez and Shah 2008). Overall, the findings provide mechanism-based support for the concept that the PPARα MOA of rodent-hepatocarcinoma induction is not relevant to human hepatocarcinogenesis. SUMMARY This dissent has critically reviewed evidence related to MOAs of mouse hepatocarcinogenesis after exposure to tetrachloroethylene. The following conclusions can be drawn from findings in the literature: TCA is the major metabolite in the body after exposure to tetrachloroethylene. DCA concentrations in blood and liver were lower than those of TCA by an order of magnitude, or DCA was completely undetectable. TCA transactivates PPARα, while tetrachloroethylene does not. DCA also activates PPARα, but, because of its low occurrence, arguments related to the PPARα MOA should focus on TCA as the dominant active metabolite. Effects of tetrachloroethylene and TCA associated with peroxisome proliferation were compiled and evaluated for consistency with the PPARα MOA as suggested by Klaunig et al. (2003). TCA induces the three key causal events, as well as peroxisome proliferation, and other associatedkey events. Data were generated in several studies, and dose-response and temporal relationships are consistent with the observation of tumors. The weight of evidence of this MOA was considered strong for TCA (in agreement with the National Research Council trichloroethylene committee) and probable for tetrachloroethylene although studies of PPARα-null mice are not available. Major support of the PPARα MOA of tetrachloroethylene rests on the role of TCA as the active metabolite. Rats are less sensitive than mice to PPARα-mediated effects of tetrachloroethylene and do not develop hepatocarcinoma in response to tetrachloroethylene or TCA. That species difference can be explained by kinetic differences in TCA formation and availability in the target organ. In mice, formation of TCA is much higher and binding to plasma proteins much lower than in rats. Therefore, the mouse-rat difference can be explained by assuming that TCA is the active metabolite of tetrachloroethylene. A key question is whether sufficient TCA is produced from tetrachloroethylene to induce peroxisome proliferation and tumor formation in the liver. To address that question, analytic data on blood and liver concentrations of TCA were collected from the literature. The data revealed that peak and AUC levels of TCA in mouse blood after tetrachloroethylene were similar to or even higher than those after TCA when carcinogenic doses of the two agents were compared. That constitutes direct evidence that TCA can be generated from tetra-
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene chloroethylene and be present in blood and target organ in amounts sufficient to induce peroxisome proliferation and hepatocarcinogenesis. Analytic data from all of five available studies consistently demonstrate that absorption of TCA after oral application is incomplete and decreases with increasing dose. Moreover, published modeling work based on some of those studies suggests that only 25-10% of oral TCA bioavailable. The analytic and modeling data are not compatible with the estimate in the IRIS draft that 95% of oral TCA is absorbed—an estimate apparently not founded on experimental data. Apparently, the internal TCA doses derived from that estimate are too high. Consequently, the tumor yields predicted for tetrachloroethylene-derived TCA would be too low. Indeed, modeling studies taking into account the limited bioavailability of TCA suggest that TCA generated from tetrachloroethylene is sufficient to explain the incidence of hepatic tumors. In conclusion, the weight of evidence clearly favors a key role of PPARα activation by TCA in tetrachloroethylene-induced mouse hepatocarcinogenesis. The available evidence does not support a substantial contribution of other MOAs to hepatocarcinogenesis by tetrachloroethylene. Transgenic mice carrying the human PPARα gene were found to be essentially resistant to hepatocarcinogenesis by a model peroxisome proliferator. 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. As noted by the dissenter and in Chapter 6 of the committee’s report, the committee agrees that the EPA MOA characterization for hepatic cancer is inadequate and should be revised to provide a more focused and integrated analysis of the available evidence on tetrachloroethylene and its metabolites. The dissenter’s statement is an attempt to provide an example of how such an analysis might be performed. The committee supports much of the dissenter’s approach, but the dissenting member’s conclusions go beyond those drawn by the full committee. The dissenting member holds the opinion that PPARα mediation of tetrachloroethylene-induced hepatocarcinogenesis in mice is the plausible predominant MOA and that this MOA lacks relevance to human hepatocarcinogenesis. The committee believes that the arguments presented are reasonable and advises EPA to review the considerations presented by the member and the recent literature cited carefully. However, the committee does not support the apparent conclusions regarding mouse hepatic cancer that TCA is the sole carcinogenic metabolite of tetrachloroethylene, that the only MOA of TCA is peroxisome proliferation, and that there is unmistakable concordance in the carcinogenic
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene potency of tetrachloroethylene in the National Toxicology Program and Japan Industrial Safety Association bioassays and the corresponding studies of TCA. Overall, the committee judges that many gaps in knowledge remain with regard to the MOA of tetrachloroethylene and that the relevance of the peroxisomeproliferator MOA to tetrachloroethylene-induced mouse hepatic cancer and to tetrachloroethylene-induced human hepatic cancer remains hypothetical and requires further rigorous testing. The committee generally supports the comprehensive literature review and analyses conducted by the dissenting member and recommends that EPA use them when reassessing its own evaluation. However, there are aspects of the dissenter’s analysis that the committee believes require more rigorous assessments before definitive conclusions can be drawn. They include the following: The committee does not agree that a role of DCA in tetrachloroethylene-induced hepatic carcinogenesis in mice can be ruled out solely on the grounds that it is detected at much lower concentrations than TCA in the blood and liver. First, there are few data on DCA formation from tetrachloroethylene. Second, there is some evidence that DCA is formed via a metabolic pathway that does not involve the liver. Third, there is some debate on whether DCA is formed from TCA. In Chapter 6, the committee stated that the conclusions regarding potential relevance or lack of relevance of DCA to hepatic carcinogenesis by tetrachloroethylene would be strengthened by the comparison of tetrachloroethylene hepatocellular-tumor data with predictions based on DCA carcinogenesis studies (in a way similar to that presented in Appendix 4A of the draft IRIS assessment). Such an analysis would provide a strong quantitative rationale for DCA’s potential involvement, or lack thereof, in hepatic cancer. 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. Such analyses and data would greatly facilitate the discussion of quantitative differences between compounds and species. The committee supports the use of the weight-of-evidence analysis and the need for evaluation of the key events in hepatic carcinogenesis by tetrachloroethylene and its key metabolites. However, important knowledge gaps remain to be addressed with regard to key events in the PPARα MOA, especially those with causal and associative relationship to tumor formation and tetrachloroethylene or its key metabolites (see dissenter’s statement and Chapter 6). Indeed, the committee is not yet convinced of the proof of the hypothesis that
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene the PPARα MOA is the sole MOA of tetrachloroethylene in inducing mouse hepatic cancer. Hence, it is premature to draw conclusions on the relevance of the PPARα MOA to tetrachloroethylene-induced human hepatic carcinogenesis. The committee agrees that the issues of TCA bioavailability, absorption, and blood and liver concentrations in various exposure scenarios are critical for the consideration of MOA of tetrachloroethylene. The current analysis by EPA is important but is inadequate in its current form. The committee recommends that EPA reconsider the analyses performed and consider using the data suggested by the dissenting member. The committee disagrees with the dissenter that the available evidence is sufficient to conclude that other MOAs are unlikely to contribute substantially to hepatocarcinogenesis by tetrachloroethylene. As noted in Chapter 6, the committee recommends that EPA strengthen and clarify the description of the degree, rather than the “significance,” of the contribution of other plausible molecular events, in addition to activation of PPARα, to mouse hepatic tumors produced by tetrachloroethylene. The committee agrees with the dissenter that recent findings reported with PPARα-null mice (Ito et al. 2007; Takashima et al. 2008; Eveillard et al. 2009), PPARα humanized transgenic mice (Morimura et al. 2006), and hepatocyte-specific constitutively activated PPARα transgenic mice (Yang et al. 2007) are valuable contributions to the discussion of the relevance of the PPARα MOA in human hepatic carcinogenesis. 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. Thus, the committee believes that it is premature to draw definitive conclusions regarding the relevance of the PPARα MOA to human hepatocarcinogenesis. In Chapter 6, the committee has encouraged EPA to strengthen the discussion of this matter in the draft IRIS assessment. REFERENCES Austin, E.W., J.M. Perrish, D.H. Kinder, and R.J. Bull. 1996. Lipid peroxidation and formation of 8-hydroxydeoxyguanosine from acute doses of halogenated acetic acids. Fundam. Appl. Toxicol. 31(1):77-82. Benane, S.G., C.F. Blackman, and D.E. House. 1996. Effect of perchloroethylene and its metabolites on intercellular communication in clone 9 rat liver cells. J. Toxicol. Environ. Health 48(5):427-437. Buben, J.A., and E.J. O’Flaherty. 1985. Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: A dose-effect study. Toxicol. Appl. Pharmacol. 78(1):105-122. Bull, R.J. 2000. Mode of action of liver tumor induction by trichloroethylene and its me-
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