Understanding mechanisms of inhaled toxicants: Implications for replacing default factors with chemical-specific data

Assessing risk of inhaled materials is a challenging endeavor because of the profound interspecies differences in respiratory tract anatomy, physiology, and biochemistry. Recent advances in the availability of mechanistic data and mathematical models for describing dosimetry behavior of particles and gases has lead to improvements in default approaches to risk assessment of inhaled materials. An overview of some of the more well-understood differences between species in factors controlling dosimetry and response, and the default approach of the U.S. Environmental Protection Agency that accounts for many of these factors, are presented. The default methodology also creates a framework which inhalation toxicologists can use to direct research at reducing uncertainty in risk assessments that might otherwise be handled through default uncertainty factors. The optimal approach to risk assessment is to develop chemical-specific mode of action and dosimetry data that can be used quantitatively to replace the entire default approach. The toxicology of vinyl acetate and recent efforts to develop data to supplant assumptions made in the default approach are presented. The conclusion is drawn that the future of inhalation toxicity risk assessment lies in reducing uncertainties associated with interspecies extrapolation and that to do this effectively requires approaches to toxicology that are outside of routine testing paradigms, and are aimed at elucidating mechanisms of action through hypothesis-driven research.