Peroxisome proliferation: current mechanisms relating to nongenotoxic carcinogenesis

A wide variety of chemicals have been shown to produce liver enlargement, peroxisome proliferation and induction of peroxisomal and microsomal fatty acid-oxidising enzyme activities in rats and mice. Some peroxisome proliferators have also been shown to increase the incidence of liver tumours in these species. Rodent peroxisome proliferators are not considered to be genotoxic agents. Proposed mechanisms of liver tumour formation include induction of sustained oxidative stress, enhanced cell replication, promotion of spontaneous preneoplastic lesions and inhibition of apoptosis. Marked species differences in the effects of peroxisome proliferators have been observed in both in vitro and in vivo studies. Key issues concerning the risk assessment to humans of exposure to rodent peroxisome proliferators are discussed.