The Two-Year Rodent Carcinogenesis Bioassay - Will It Survive?

Abstract

For over 35 years, many synthetic and natural chemicals have been tested by government agencies, private companies and research institutes for carcinogenic activity in rats and mice in classical 2 year studies as part of a toxicity profile ultimately used for human toxicity and carcinogenicity risk assessment. With an increasing number of pharmaceutical and agricultural chemicals shown to be carcinogenic in these bioassays, research into the mechanisms of toxicity and carcinogenesis has intensified. The relevance of the induced tumors in rodents has been questioned after much research. Research has provided evidence to some scientists that doses used in the bioassays may represent situations where toxicity pathways do not develop in humans exposed to levels of these chemicals, toxicity itself may create situations where tumors develop only under those situations, species specific responses may exist, and tumors induced may not be relevant to human risk. Regulatory agencies have considered these and other factors when preparing regulatory decisions on regulation of these chemicals. Thus, the USA FDA often has approved drugs despite their carcinogenicity in rodents and the USA EPA has explored many situations where considerations of the mechanisms of carcinogenesis in rodents and humans play a role in their regulatory decisions. Unfortunately, much of the decisions are based on unproven and hypothetical mechanisms of carcinogenesis in rodents and humans. Despite this situation, the impact of these decisions on future considerations and decisions for regulation of chemicals suggests that the US regulatory agencies consider that the occurrence of increased incidences of tumors in standard 2 year rodent carcinogenesis bioassay is often not relevant to human carcinogenesis risk assessment.