Citation:

Corton, C., M. Cunningham, B. Hummer, C. Lau, B. Meek, J. Peters, J. Popp, L. Rhomberg, J. Seed, AND J. Klaunig. Mode of action framework analysis for receptor-mediated toxicity: the Peroxisome Proliferator-Activated Receptor alpha (PPARα) as a case study. CRITICAL REVIEWS IN TOXICOLOGY. CRC Press LLC, Boca Raton, FL, 44(1):1-49, (2014).

Impact/Purpose:

The review reemphasizes the key events in the PPARalpha MOA for rodent liver tumors as well as to highlight some persistent data gaps. The consensus of the panel was that for weak to moderately potent activators, the rodent MOA is not relevant to humans. Some of the panel members thought that potent human PPARalpha activators could still have the potential to modulate cell fate in the human liver. One key conclusion from a dose-response analysis for two activators was that exposures less than those at points of departure for any of the hypothesized key events would consequently protect against subsequent tumors in all species including the human liver.

Description:

Therapeutic hypolipidemic agents and industrial chemicals that cause peroxisome proliferation and induce liver tumors in rodents activate the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Research has elucidated the cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis. This review summarizes an expert panel’s current views, from a workshop held in late 2010, on the weight of evidence relevant to the hypothesized mode of actions (MOAs) for PPARα activator-induced rodent hepatocarcinogenesis and identifies persistent gaps in knowledge. Reevaluation of the mechanistic data support key events in the hypothesized MOA leading to liver tumors. Chemical-specific data supports temporal and dose-response relationships for the key events by exposure to many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil used to treat hypertriglyceridemia in humans. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for relatively weak PPARα activators, such as DEHP, are unlikely to induce liver tumors in humans at anticipated exposure levels. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species that are more appropriate human surrogates than mice and rats. However, even with the lack of evidence some of the panel felt that potent compounds may be capable of activating PPARα and altering hepatocyte fate in human livers. Overall, it was concluded that PPARaactivator-induced effects related to cancer formation in rodents cannot be completely ruled out for the human. However, the concordance analysis of the key events in rodents and humans has shown quantitative differences in the key events between rodents and humans which should be considered in the risk assessment process. Exposures less than those at points of departure for any of the hypothesized key events would consequently protect against subsequent tumors in all species including the human liver.

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