Can a mechanistic rationale be provided for non-genotoxic carcinogens identified in rodent bioassays?

Abstract

In a recent survey of the results of the National Cancer Institute/National Toxicology Program's Carcinogenesis Bioassay Program, Ashby and Tennant (1988) drew attention to the high proportion of carcinogens that were non-genotoxic insofar as their response to the Salmonella-microsome test was concerned. The present review contrasts these findings with what is known mechanistically about non-genotoxic carcinogens that affect the tissues which are considered to be particularly prone to non-genotoxic tumor induction. Excessive and often thresholded increases in cellular proliferation in the affected tissues appear to be one common feature in tumor induction by these agents, which act either through cytotoxicity followed by regeneration or through hormone-mimetic action. It is suggested that a weight of the evidence approach on a chemical by chemical basis is necessary to decide the relevance of these agents to the human situation.