Table 2.

Selected key mode-of-action hypotheses and support.

End point/hypothesized mode of action	Summary of weight of evidence
Kidney tumors
Mutagenicity	Data sufficient to conclude a mutagenic mode of action is operative.
GSH conjugation–derived metabolites are produced in the kidney.	Studies demonstrate TCE metabolism via GSH conjugation pathway; availability of metabolites to the kidney in laboratory animals and humans.
Metabolites directly induce mutations in kidney cells, advancing acquisition of critical traits contributing to carcinogenesis.	Predominance of positive genotoxicity data for GSH pathway metabolites in experimental systems.
Cytotoxicity and regenerative proliferation	Data consistent with cytotoxicity contributing to carcinogenesis in rodents, but the evidence is not as strong as that for a mutagenic mode of action.
GSH conjugation–derived metabolites are produced in kidney.	Studies demonstrate TCE metabolism via GSH conjugation pathway; availability of metabolites to the kidney in humans and laboratory animals.
Metabolites directly induce death in kidney cells (cytotoxicity).	Studies demonstrating TCE-induced rare form of nephrotoxicity in laboratory animals; similarity of renal tubular effects induced by TCE and its GSH metabolites. However, cytopathology involves changes in cell and nuclear sizes.
Compensatory cell proliferation occurs to repair damage.	Data linking TCE-induction of proliferation and clonal expansion are lacking.
Clonal expansion of initiated cells occurs, leading to cancer.
Liver tumors
Mutagenicity	Data are inadequate to support a mutagenic mode of action
Oxidation-pathway–derived metabolites are produced in and/or distributed to the liver.	Studies demonstrate TCE metabolism via oxidative pathway: availability of numerous metabolites to the liver.
Metabolites directly induce mutations in liver, advancing acquisition of critical traits contributing to carcinogenesis.	Strong data for mutagenic potential is CH, but difficult to assess the contributions from CH along with genotoxic and non-genotoxic effects of other oxidative metabolites.
PPARα activation	Data are inadequate to support a PPARα activation mode of action.
Oxidation-pathway–derived PPAR agonist metabolites (TCA and/or DCA) are produced in and/or distributed to the liver.	Studies demonstrate TCE metabolism via oxidative pathway: availability of some metabolites that are PPAR agonists to the liver.
Metabolites activate PPARα in the liver.	Studies demonstrating activation of hepatic PPARα in rodents exposed to TCE and TCA.
Alteration of cell proliferation and apoptosis occurs.	However, inadequate evidence that PPARα is necessary for liver tumors induced by TCE or that hypothesized key events are collectively sufficient for carcinogenesis.
Clonal expansion of initiated cells occurs, leading to cancer.
Other end points and/or modes of action
Inadequate data to support one or more of the following:
An identified sequence of key events.
TCE or metabolites induce key events.
Key events are individually necessary for inducing the end point.
Key events are collectively sufficient for inducing the end point.
Abbreviations: CH, chloral hydrate; DCA, dichloroacetic acid; PPARα, peroxisome proliferator activated receptor α; TCA, trichloroacetic acid. Data from U.S. EPA (2011d).