The modes of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR) and the peroxisome proliferator-activated receptor alpha (PPARα) are not relevant to human cancer risk: an updated critical evaluation

). Peroxisome proliferator-activated receptor alpha (PPARα) activators induce rodent liver tumors through a similar MOA, again involving increased hepatocellular proliferation, but are generally considered not relevant to human cancer risk. As with CAR activators, PPARα activators are mitogenic in rodent liver but not in other species, including humans. This species-specific effect of CAR and PPARα activators provides critical information useful for the overall risk assessments of these molecules, including pharmaceuticals, agrochemicals, food additives, and other chemicals. Overall, based on the available data for the specific molecular effects of these agents, the time has come to consider that chemicals for which the MOA of liver carcinogenicity observed in rodents has been clearly identified as either CAR- or PPARα-mediated (with other MOAs having been excluded) can be judged as having no relevance to human cancer risk without further investigations being necessary.