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Letter to the editor regarding the review article by Yamada et al. (2021) titled “Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)”

comprehensive review article by Yamada et al. (2021) on a topic that is a matter of scientific debate for quite some years now: the human relevance of the mode of action (MoA) for liver tumor formation by chemicals that are activators of the constitutive androstane receptor (CAR). Following a critical analysis of currently available data concerning this topic the authors conclude that this MoA is qualitatively not plausible for humans. Their conclusion is based on a pivotal species difference in hepatocellular proliferation (a key event in CAR-mediated rodent liver tumor formation), supported by negative epidemiology data for the archetypical CAR activator phenobarbital (PB). According to the authors