Consideration of Temporal Toxicity May Modify Default "Duration-Adjustment." A. M. Jarabek, National Center for Environmental Assessment, U.S. EPA, Research Triangle Park, NC 27711
Risk assessment requires the comparison of an exposure estimate against a dose-response estimate. The types of exposure scenarios requiring assessment under various regulations run the gamut from acute to lifetime exposures. Toxicity testing studies used to characterize response can be categorized as acute, subchronic, or chronic, but these categories are defined by the exposure duration and not informed by consideration of the underlying mechanism of toxicity or its appropriate dose metric. A typical default for "duration-adjustment" of inhalation exposures is to linearly prorate the laboratory animal effect level by the # hours/24 hours and the # days/week of the animal exposure regimen (e.g., by 6/24 x 5/7). The rationale for this adjustment is that the resultant human equivalent concentration should be the concentration times time (C x T) product equivalent of the animal exposure level. The assumption that an equivalent (C x T) exposure product is as an appropriate dose metric is tenuous since steady-state conditions may not have been reached under some exposure conditions and is not consistent with different toxicity mechanisms (e.g., an effect mediated by peak blood concentration versus integrated tissue dose). Comprehensive dosimetry models integrate mechanistic and temporal determinants of the exposure-dose-response continuum to define interactions between C and T. Dosimetry models for dichloromethane and perchloroethylene, chemicals with different physicochemical characteristics (partition coefficients), metabolic parameters (Vmax, Km and Kf), effects, and presumed mechanisms of toxicity, are exercised at various exposure levels and durations to illustrate discrepancies of the current default approaches with respect to internal dose metrics. Sensitivity analyses identify key parameters and suggest revisions to current default approaches.