Mechanism-Based Evaluation of the Interspecies Uncertainty Factor for Risk Assessment. K. Krishnan and M. Béliveau, Université de Montréal
The interspecies uncertainty factor (UF) is used to derive an equivalent exposure dose in one species (e.g., humans) from data in another species (e.g., rat). The UF used in risk assessment has recently been subdivided into two components to account separately for interspecies differences in toxicokinetics (UFTK) and toxicodynamics (UFTD). The former implies that the interspecies difference in toxicity is attributed to differences in tissue dose whereas the latter implies that for the same tissue dose two species would respond differently. The objective of this study was to develop algorithms for estimating the UF for various species combinations involving rat, mouse, and fish (catfish, rainbow trout, fathead minnow). The interspecies extrapolation of doses was performed for one or more of the following chemicals: benzene (BZN), 1,2 dichloroethane (DCE), 1,1,2 trichloroethane (TriCE), 1,1,2,2 tetrachloroethane (TCE), pentachloroethane (PCE), and hexachloroethane (HCE). The approach involved the derivation of mechanistic algorithms from validated physiologically-based toxicokinetic (PBTK) models to calculate interspecies differences in tissue dose for identical exposure conditions. The difference in tissue dose was quantitated and it corresponded to the toxicokinetic part of the interspecies UF. This factor was used along with the ratio of experimental data on LC50 in the appropriate species to determine the contribution of the toxicodynamic aspect of the interspecies UF. For TCE, PCE, and HCE the estimated trout-fathead minnow UFTK were 1.75, 1.09, and 1.88, respectively. The estimated UFTD was 1, 1.6, and 1, respectively. The estimated mouse-rat UFTK was 3 for BZN, while the UFTD was 1. This study represents the first attempt to quantify the chemical-specific interspecies uncertainty factor on the basis of quantitative differences in mechanistic determinants of toxicokinetics in aquatic species and mammals.
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