Nongenotoxic carcinogens in the regulatory environment.
The biological activity of many carcinogens is to directly induce mutational events, thereby altering the information encoded in the DNA. Short-term tests for potential carcinogens and risk assessment models generally rely on the assumption that the agent in question will operate through a genotoxic mechanism. However, carcinogenesis is a multistep process, and it is increasingly clear that the primary biological effect for many carcinogenic chemicals involves events other than direct DNA reactivity. For many experimental rodent models as well as human cancers, nongenotoxic mechanisms appear to be the driving force in the formation of tumors. Many of these nongenotoxic mechanisms are highly species-specific. Thus, it is increasingly important to ask if the rodent model applies to the human situation at all, in addition to the examination of appropriate, hypothetical, mathematical risk assessment models. More research is now being focused to better define the mechanisms by which the many distinctly different classes of nongenotoxic carcinogens are acting. This understanding will become the basis for new predictive assays and more realistic risk assessment models. If specific conditions are met, then a no observed effect level with a safety factor may be the most appropriate risk model for some carcinogens.