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.

Abstract

Constitutive androstane receptor (CAR) activators have long been known to enhance hepatocellular carcinogenesis in rodents, with the prototypic chemical being phenobarbital (PB). This has raised an ongoing controversy for the past 50 years as to whether this is relevant to human cancer risk. The established mode of action (MOA) for rodent liver tumor formation by CAR activators includes receptor activation, increased hepatocellular proliferation, altered liver foci and ultimately liver tumors. We previously published a critical review indicating the pivotal species difference that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate hepatocellular proliferation in humans based on molecular downstream interaction differences, thus CAR activators pose no liver carcinogenic risk to humans (Yamada et al. Crit Rev Toxicol 2021). 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.