A comprehensive approach for integration of toxicity and cancer risk assessments

Experimental observations and theoretical considerations indicate a dose threshold for most chemically induced noncancer toxic effects below which the increased risk of toxicity is zero. Thus, the historical approach for minimizing risk from toxic chemicals has been to experimentally determine a no-observed-adverse-effect-level (NOAEL) and then to apply safety or uncertainty factors to estimate a dose not expected to produce that toxic effect in humans. In contrast, for radiation and chemically induced cancer, it has been assumed that all agents operate by a genotoxic mode of action and that some risk can be assigned to even vanishingly small doses. Accordingly, risk assessments for carcinogens have commonly been based on the assumption that the tumor dose-response curve at low doses is linear and passes through the origin. Mode of action is defined as a fundamental obligatory step in the induction of toxicity or cancer. It is now clear that tumor induction can arise in a variety of ways including not only a DNA-reactive genotoxic mode of action, but also non-DNA-reactive nongenotoxic-cytotoxic and nongenotoxic-mitogenic modes of action. Initial risk assessment approaches that recognized this distinction identified a chemical carcinogen as either genotoxic or nongenotoxic, with no middle ground. The realization that there is a continuum whereby different chemicals can act by a combination of modes of action and the recent explosion of research into molecular mechanisms of carcinogenesis indicate that all relevant information should be integrated into the risk assessment process on a case by case basis. A comprehensive approach to risk assessment demands that default assumptions be replaced with an integrated understanding of the rate-limiting steps in the induction of toxicity or cancer along with quantitative measures of the shapes of those dose-response curves. The examples of more contemporary risk assessments are presented for chloroform and vinyl acetate.