Use of mode of action in risk assessment: past, present, and future

The evolution of chemical risk assessment has been marked by a steadily increasing expectation for the use of chemical-specific dosimetric and mechanistic information to tailor the risk assessment approach. The information to be used can range from the broad physical properties of the chemical to detailed information on the mechanism by which it causes a particular toxic outcome, and the risk assessment decisions effected can in turn range from how to define equivalent exposures across species to whether a particular animal outcome is relevant to a human health assessment. A concept that has proven useful in support of these considerations is the "mode of action," a term coined by the USEPA in their new guidelines for carcinogen risk assessment. This paper describes the increasing use of mode-of-action considerations in risk assessment, beginning with early examples involving quantitative dosimetry on the one hand, and qualitative relevance on the other, which foreshadowed the current interest in mode of action. It then describes more recent developments regarding the use of the mode-of-action concept for the selection of a low-dose extrapolation approach, for harmonization of cancer and noncancer risk assessment approaches, and for cross-chemical evaluations. Finally, examples of recent controversies associated with the use of mode-of-action information in risk assessment are provided to demonstrate the challenges that must be overcome to assure the continued viability of the mode-of-action approach.