Consideration of Temporal Toxicity Challenges Current Default Assumptions

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Abstract
According to the 1983 NAS paradigm that serves as the basis for current health risk assessment procedures, risk characterization requires the comparison of an exposure estimate against a dose-response estimate. The types of exposure scenarios required under various regulations can be categorized as acute, subchronic, and chronic. Toxicity testing studies can also be so categorized, but such categories are defined by the exposure duration and not the underlying mechanism of action or its appropriate dose metric. Considerations of underlying mechanisms and temporal relationships of toxicity challenge current default assumptions and extrapolation approaches for derivation of dose-response estimates. This article discusses the duration adjustments used in current health risk assessment procedures and highlights the attendant assumptions. Comprehensive dosimetry model structures integrate mechanistic and temporal determinants of the exposure-dose-response continuum. Analysis of dosimetry model structures is proposed as a way to identify key parameters for development of alternative default duration adjustment procedures.