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The PPARα-dependent rodent liver tumor response is not relevant to humans: Addressing misconceptions
Citation:
Corton, C., J. Peters, AND J. Klaunig. The PPARα-dependent rodent liver tumor response is not relevant to humans: Addressing misconceptions. Archives of Toxicology. Springer, New York, NY, 92(1):83-119, (2017).
Impact/Purpose:
A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasm. Studies of the rodent mode of action and human relevance are discussed in this review. Criticisms of the rodent MOA for compounds which activate PPARα (Klaunig et al., 2003) have been suggested in two reviews (Kesheva and Caldwell, 2006; Guyton et al., 2009). These reviews have been criticized by experts in the field for misleading investigators and regulators into believing that there is no defensible rodent MOA and therefore we cannot judge whether the MOA is relevant to humans or not. We performed an analysis into the impact of these review articles on the field and were shocked to find out that they have had a major impact. Many primary papers and a recent risk assessment of diisononyl phthalate (DINP) by Cal-EPA have incorporated the conclusions of the Kesheva and Caldwell (2006) and Guyton et al. (2009) reviews almost verbatim into their analyses in the absence of a comprehensive assessment of all of the data. We have written this review article in response to what we feel is the misinterpretation of a number of studies. Our review article is structured such that regulators can better understand why perceived inconsistencies in the MOA do not mean that they outweigh the 40+ years of research which support the MOA and lack of human relevance for this class of compounds. The review will be most helpful to regulators (EPA and otherwise) who have to determine whether the liver cancer caused by a compound through the PPARα MOA is relevant to human health.
Description:
A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. The weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis is summarized here. Chemical-specific and mechanistic data support concordance of temporal and dose–response relationships for the key events associated with many PPARα activators. The key events (KE) identified in the MOA are PPARα activation (KE1), alteration in cell growth pathways (KE2), perturbation of hepatocyte growth and survival (KE3), and selective clonal expansion of preneoplastic foci cells (KE4), which leads to the apical event—increases in hepatocellular adenomas and carcinomas (KE5). In addition, a number of concurrent molecular and cellular events have been classified as modulating factors, because they potentially alter the ability of PPARα activators to increase rodent liver cancer while not being key events themselves. These modulating factors include increases in oxidative stress and activation of NF-kB. PPARα activators are unlikely to induce liver tumors in humans due to biological differences in the response of KEs downstream of PPARα activation. This conclusion is based on minimal or no effects observed on cell growth pathways and hepatocellular proliferation in human primary hepatocytes and absence of alteration in growth pathways, hepatocyte proliferation, and tumors in the livers of species (hamsters, guinea pigs and cynomolgus monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Despite this overwhelming body of evidence and almost universal acceptance of the PPARα MOA and lack of human relevance, several reviews have selectively focused on specific studies that, as discussed, contradict the consensus opinion and suggest uncertainty. In the present review, we systematically address these most germane suggested weaknesses of the PPARα MOA.
