THE RELEVANCE OF HEPATIC PEROXISOME PROLIFERATION IN RATS TO ASSESSMENT OF HUMAN CARCINOGENIC RISK FOR PHARMACEUTICALS

There exists a strong association between the ability of drugs and oth er chemicals to induce hepatic peroxisomes in rodents and to increase the frequency of liver tumors in these same species. Despite several y ears of intensive investigation, a plausible mechanism causally relati ng peroxisome induction to tumor formation has not been found. Two maj or theories of how such compounds produce tumors-prolonged oxidative s tress and cellular growth dysregulation-have limited experimental supp ort. The oxidative stress demonstrated in rodents as a consequence of peroxisomal activity may be irrelevant to man since primates appear to be much less susceptible to peroxisome proliferation than are rats or mice. Cellular growth dysregulation and other effects of test materia ls that often accompany-but are not directly attributable to-peroxisom e proliferation in rodents can be assessed in other, more relevant spe cies ifa causal relationship between their presence and tumor developm ent is ultimately shown in rodents. Currently, there is no reason to s pecifically avoid the clinical assessment and commercial development o f new therapeutic drugs that induce peroxisomes in rodents if other me asurements indicate the absence of DNA damage or growth dysregulation at reasonable exposures in relevant species. (c) 1994 Academic Press, Inc.