| A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants Kathryn Z. Guyton, Weihsueh A. Chiu, Thomas F. Bateson, Jennifer Jinot, Cheryl Siegel Scott, Rebecca C. Brown, and Jane C. Caldwell National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA Abstract
Background: Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl) phthalate (DEHP) , are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk. Data synthesis: Herein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis. Conclusions: Our review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation. Key words: carcinogenesis, mode of action, peroxisome proliferators, risk assessment. Environ Health Perspect 117:1664–1672 (2009) . doi:10.1289/ehp.0900758 available via http://dx.doi.org/ [Online 15 May 2009]
Address correspondence to K.Z. Guyton, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Mail Code: 8623P, Washington, DC 20460 USA. Telephone: (703) 347-8562. Fax: (703) 347-8692. E-mail: guyton.kate@epa.gov We thank L. Birnbaum and I. Cote for their critical review of the manuscript, and P. Preuss, J. Vandenberg, D. Bussard, B. Sonawane, and P. White for providing management support for this work. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. The authors declare they have no competing financial interests. Received 4 March 2009 ; accepted 14 May 2009.
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