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.

• Di(2-ethylhexyl) phthalate (DEHP)
• human relevancy framework
• key events
• liver cancer
• mode of action
• NF-kB
• oxidative stress
• peroxisome proliferator-activated receptor alpha (PPARα)

Acknowledgements

The authors would like to thank the Nuclear Receptor Workshop Steering Committee members (Dr. Melvin Andersen, Dr. Richard Becker, Dr. Robert Budinsky, Dr. Michael Cunningham, Dr. Vicki Dellarco, Dr. Michael Dourson, Dr. Cliff Elcombe, Dr. Michael Honeycutt and Dr. Julian Preston) for their input in workshop development, along with the Case Study Leaders. The authors thank Ms. Alison Willis, Dr. John F. Reichard and Dr. Ted Simon for compiling drafts prior to submission and for their role in the dose–response analysis of DEHP and gemfibrozil, and Drs. Susan Hester and Barbara Abbott for their review of the manuscript.