Interspecies extrapolation based on mechanistic determinants of chemical disposition

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Abstract
Uncertainty factors are applied in methods developed by the Environmental Protection Agency (EPA) to derive dose‐response estimates. The uncertainty factors are applied to account for uncertainties in defined extrapolations from the laboratory animal experimental data conditions to a dose‐response estimate appropriate for the assumed human scenario. The conceptual difference between these uncertainty factors and safety factors is best illustrated by how uncertainty factors can be modified as scientific data inform our understanding of the key factors that influence chemical disposition and toxicity. Mechanistic data help describe the major factors influencing chemical disposition and toxicant‐target tissue interactions, and should increase the accuracy of exposure‐dose‐response assessment. Mechanistic data on the determinants of inhaled chemical disposition were used to construct default dosimetry adjustments applied by the EPA in its inhalation Reference Concentration (RfC) methods. Because these adjustments account for interspecies dosimetric differences to some degree, the uncertainty factor for interspecies extrapolation was modified. A framework is presented that allows for incorporation of mechanistic data in order to ensure that required extrapolations are commensurate with the state‐of‐the‐science. Future applications of mechanistic data to modify additional uncertainty factors are outlined.