A Mechanistic Approach for Determining Uncertainty Factors Specific to Species Combinations. M. Béliveau, M. L. Pelekis, and K. Krishnan, TOXHUM, Université de Montréal, Montréal, Québec, Canada
The interspecies uncertainty factor, UF, is used to derive human equivalent doses from animal data. The UF has recently been subdivided into two components to account separately for interspecies differences in toxicokinetics (UFTK) and toxicodynamics (UFTD). Although the composite UF (i.e., 10) has been commonly used for extrapolations of NOAEL dose levels from various animal species to humans, this number appears to have originated from rodent-human differences in body surfaces and basal metabolic rates. Recently, steady-state equations derived from physiologically-based pharmacokinetic models have been used to quantify the magnitude of rat-human UF. The objective of this study was to generalize this algorithmic approach to quantify the magnitude of the toxicokinetic component of the UF (UFTK) for various species combinations involving rat, mouse, fish and humans. The species extrapolation of doses were performed from rat, mouse or fish to humans for one or more of the following chemicals: styrene, 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene, benzene, dichloromethane, vinyl chloride, and chloroform. The exercises involved the determination of the overall magnitude of UFTK and the magnitude of its components, namely, the UFTK-ABS, accounting for interspecies differences in dose absorbed for identical exposure conditions, the UFTK-MET , the factor by which the blood concentration of unchanged parent chemical differs between species when both receive identical doses, and the UFTK-DIS , the magnitude of difference in chemical concentrations distributed in target tissues of two species when the arterial blood concentration in both of them is identical. Data on species differences in body weight, ventilation rate, fraction of cardiac output flowing to the liver, blood:environment partition coefficient and hepatic extraction ratio were required to determine chemical-specific UFTK for each species combination. This study represents the first effort to determine the magnitude of species-combination specific UFTK based on knowledge of mechanistic determinants.
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