Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study

Abstract

Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Overall, the panel concluded that significant quantitative differences in PPARα activator-induced effects related to liver cancer formation exist between rodents and humans. On the basis of these quantitative differences, most of the workgroup felt that the rodent MOA is "not relevant to humans" with the remaining members concluding that the MOA is "unlikely to be relevant to humans". The two groups differed in their level of confidence based on perceived limitations of the quantitative and mechanistic knowledge of the species differences, which for some panel members strongly supports but cannot preclude the absence of effects under unlikely exposure scenarios.

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis

“…In our model, the high dietary protein consumption did not contribute significantly to blood glucose. These results are in agreement with previous studies in humans and rats that, despite the intrinsic differences in the metabolic response of PPARa ligands between species (Albrecht et al 2013;Corton et al 2014), show that the contribution of AA to glucose production via gluconeogenesis is quite modest (Fromentin et al 2013;Stepien et al 2011 The lack of PPARa up-regulates lipogenesis in a greater extent in a low-protein/high-carbohydrate diet…”

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

“…The first two modes of action are considered of doubtful, if any, significance to humans (Corton et al 2014;Elcombe et al 2014). Substances acting via these agreed modes of action, but excluding any possible DNA-reactivity/genotoxicity, could be used to identify a priority list of human-relevant (and potentially relevant) non-genotoxic carcinogens.…”

“…While, in general it is assumed, in the absence of evidence to the contrary, that the carcinogenicity of compounds acting by a DNA-reactive MOA will be relevant to humans, for those acting by other modes of action this is often not the case. A number of carcinogenic effects in rodents are now considered not to be relevant to humans, such as thyroid follicular cell tumors in rats resulting as a consequence of induced clearance of thyroid hormones by glucuronosyltransferase (UGT) (Cohen et al 2004), renal tumors in male rats resulting from binding to alpha 2U -globulin (Meek et al 2003), rodent liver tumors arising from the activation of constitutive androstane receptor (CAR) or peroxisome proliferator-activated receptor (PPAR)-alpha (Klaunig et al 2003;Corton et al 2014;Elcombe et al 2014). Those compounds that are carcinogenic by a MOA not relevant to humans should be excluded from the specific dataset used to determine an appropriate TTC value for genotoxic (i.e.…”

Integrating emerging technologies into chemical safety assessment: progress since the 2012 report of the expert panel on the integrated testing of pesticides

“…Case studies of AOPs for liver cancer to identify human relevant MOA and key events for: 1 aryl hydrocarbon receptor (AHR) (Budinsky et al, 2014) 2 peroxisome proliferator-activated receptor alpha (PPARα) (Corton et al, 2014) 3 constitutive androstane receptor (CAR) and pregnane X receptor (PXR) (Elcombe et al, 2014) were recently published.…”