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Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor

J Christopher Corton1, Michael L Cunningham, B Timothy Hummer

  • 1US Environmental Protection Agency , Research Triangle Park, NC , USA .

Critical Reviews in Toxicology
|November 5, 2013
PubMed

Insights

PPARα (peroxisome proliferator-activated receptor alpha) activators cause liver tumors in rodents. However, the mode of action is unlikely to be relevant to humans due to significant species differences in toxicodynamics and biological responses.

Area of Science:

  • Toxicology
  • Hepatocarcinogenesis
  • Receptor Biology

Background:

  • Peroxisome proliferator-activated receptor alpha (PPARα) activators are known to induce liver tumors in rodents.
  • The mechanisms underlying PPARα activator-induced rodent hepatocarcinogenesis have been extensively studied.

Purpose of the Study:

  • To review the evidence for the mode of action (MOA) of PPARα activator-induced rodent hepatocarcinogenesis.
  • To identify knowledge gaps in this MOA.
  • To assess the relevance of the rodent MOA to humans.

Main Methods:

  • Review of chemical-specific and mechanistic data for PPARα activators.
  • Comparison of temporal and dose-response relationships in rodents and human surrogate species.
  • Evaluation of toxicodynamic and biological differences between rodents and humans.

Main Results:

  • Data support concordance of key events for PPARα activators like DEHP and gemfibrozil in rodents.
  • Biologically plausible MOA events in rodents are unlikely to induce liver tumors in humans.
  • Human surrogate species show minimal or no effects on growth pathways, hepatocellular proliferation, and liver tumors at relevant doses.

Conclusions:

  • Significant quantitative differences exist in PPARα activator-induced liver cancer formation between rodents and humans.
  • The rodent MOA for PPARα activator-induced hepatocarcinogenesis is considered "not relevant" or "unlikely to be relevant" to humans.
  • Differences in confidence levels among experts stem from perceived limitations in understanding species-specific quantitative and mechanistic data.

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