Safety assessment for non-genotoxic rodent carcinogens: curves, low-dose extrapolations, and mechanisms in carcinogenesis

The most frequent biologic events associated with multispecies multisite rodent non-genotoxic carcinogenesis include robust liver P450 enzyme induction without liver toxicity. This cancer process is not relevant for humans as exemplified by phenobarbital. A host of other pharmaceuticals, including loratidine and atorvastatin, with current sales in the billions of dollars attests to the lack of relevance of our rodent models acting via this specific process. Hopefully, the mechanism of phenobarbital will no longer draw research money in further probing the irrelevant in human carcinogenesis. The known human carcinogens not linked with genetic injury all perturb tissue growth/replication in humans as well as in rodent short-term tests at doses ultimately linked with cancer. Clearly identifying exposures perturbing growth/replication versus exposures not perturbing growth provides an effective tool for demonstrating the threshold for cancer risk in refining the risk assessment as capably described by Dr. Klaunig. Hopefully, we can begin to increasingly use data-based decisions in risk assessment versus hypothetical low-dose extrapolations and mathematical modeling, building on the wealth of current understanding in human and rodent cancer processes in arenas beyond pharmaceutics.