Risk assessment and the use of information on underlying biologic mechanisms: a perspective

Recent years have seen the rapid expansion of scientific understanding of the underlying biologic bases of toxic reactions to chemicals. Use of this information in health risk assessment is expanding, but it has yet to reach its full potential. This article considers what has successfully been done, what approaches are now being developed, and what impediments and difficulties have been encountered in attempts to bring case-specific, mechanistic toxicological information to bear on risk estimation. In hazard identification, mechanistic information can help explain the bearing of various empirical experimental results for inferring human hazard, can increase the sensitivity of detection, and can be considered in attempts to replace 2-year animal bioassays with hazard identification methods that rest on identifying key biological properties underlying carcinogenicity rather than relying only on the experimental observation of tumors. In carcinogen potency estimation, mechanistic information can potentially extend relevant observation to lower dose levels, provide the basis for choosing among empirically based dose-response models, lead to potency estimates through relationships with quantitative measures of short-term test outcomes, and can be considered as a basis for providing direct observation of the biological parameters in biologically based dose-response modeling.