A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants.
BACKGROUND
Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) 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-alpha agonists is irrelevant to human carcinogenic risk.


RESULTS
Herein, we review recent studies that experimentally challenge the PPAR-alpha activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-alpha-null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-alpha activation in a transgenic mouse model. We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-alpha 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-alpha activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-alpha agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-alpha. 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.
Guyton
Kathryn Z
KZ
National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.
Chiu
Weihsueh A
WA
Bateson
Thomas F
TF
Jinot
Jennifer
J
Scott
Cheryl Siegel
CS
Brown
Rebecca C
RC
Caldwell
Jane C
JC
D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000633:toxicity; D018570:Risk Assessment / Q000379:methods; D013045:Species Specificity
D004785:Environmental Pollutants; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D004051:Diethylhexyl Phthalate