Rodent carcinogenicity of peroxisome proliferators and issues on human relevance

A variety of substances such as hypolipidemic drugs, phthalate ester plasticizers, pesticides, and industrial solvents have been shown to increase the size and number of peroxisomes in rats and mice. They are grouped under the generic term peroxisome proliferators (PP) because of their unique property of inducing peroxisome proliferation. There are marked species differences in response to PP. Rats and mice are most sensitive, and banisters show an intermediate response while guinea pigs, monkeys, and humans appear to be relatively insensitive or non-responsive at dose levels that produce a marked response in rodents. Out of over 100 PP identified to date, about 30 have been adequately tested and shown to be carcinogenic, inducing tumors (primarily in the liver) upon chronic administration to rats and/or mice; hence, chemicals which induce the proliferation of peroxisomes have formed a unique class of chemical carcinogens. It is now well documented that activation of the "peroxisome proliferator-activated receptor alpha" (PPARalpha) is involved in PP-induced liver growth and carcinogenesis in rodents. PPARalpha is also present in human cells; however, the levels reported are about 10% of those found in the liver of rodents. The human relevance of rodent tumors induced by PP has been the subject of debate over the last decade. Review of the existing evidence on PPAR-alpha agonists by a recent International Life Science Institute (ILSI) workgroup following a human relevance mode of action (MOA) framework has concluded that despite the presence of similar pathways in humans, it is unlikely that the proposed MOA for rodent tumors is plausible in humans, taking into account kinetic and dynamic factors. The data, however, did not permit a definitive conclusion that the animal MOA is not plausible in humans. While these agents appear unlikely to be hepatocarcinogens in humans at expected levels of human exposure, it remains uncertain to some experts in the field whether there is no possibility of carcinogenic potential under any circumstance of PP exposure, and if the potential human carcinogenicity of these chemicals can be summarily ignored. A number of remaining issues on human relevance of rodent tumors induced by PP are discussed.