CANCER AND NONCANCER RISK ASSESSMENT - NOT SO DIFFERENT IF YOU CONSIDER MECHANISMS

Default risk assessment procedures use threshold models for non-carcin ogens and a non-threshold model for carcinogens. This a priori distinc tion reflects the fact that the default procedures do not consider mec hanisms of action of specific chemicals. When mechanisms are considere d, the distinction is not necessary. Starting with the premise that th e goal of risk assessment is to identify actual risk for specific chem icals, three major, generic components of the overall mechanism transl ating exposure into a response of regulatory interest are identified. These are the specific mechanisms linking (1) exposure with dose to ta rget tissue, (2) target tissue dose with short-term responses such as cytolethality or mutation, and (3) short-term responses with ensuing l ong-term responses such as cancer or cirrhosis. (Short-term responses may be regulatory end points of interest, or they may be intermediate steps on the way to longer-term sequelae). On-going research on formal dehyde and chloroform is described to illustrate how these three compo nents of the overall mechanism can be examined experimentally and used in specific models. The impact of mechanism-based risk assessment on uncertainty is also considered. Uncertainty is a function of the exten t to which the model used for risk assessment misspecifies the actual mechanism of action for the chemical in question. There is a trade-off between (a) mechanism-based models that may reduce uncertainty but ar e expensive and time-consuming to develop and (b) default models that are not chemical-specific but can be used with minimal data sets. Expe rience with mechanism-based risk assessment may allow modification of default procedures to minimize this trade-off. A future default proced ure for carcinogen risk assessment might allow specification of mode o f action. For example, while DNA reactive-carcinogens would still be a ssumed to have linear low-dose risk,carcinogens acting through purely cytotoxic mechanisms might be assumed to have sharply non-linear or ev en threshold dose-response curves.