Assessing the impact of child/adult differences in hepatic first-pass effect on the human kinetic adjustment factor for ingested toxicants

The objective of this study was to evaluate the impact of interindividual differences in hepatic first-pass effect (FPE) on the magnitude of the human kinetic adjustment factor (HKAF) for ingested toxicants. This factor aims at replacing a default value of 3.2 used in non-cancer risk assessment. Coupled with Monte Carlo simulations, steady-state equations that account for FPE were used to obtain distributions of arterial blood concentrations (CAss) and rates of metabolism in adults, neonates, infants and toddlers continuously exposed to an oral dose of 1 μg/kg/d of theoretical CYP2E1 and CYP1A2 substrates. For such substrates exhibiting a range of blood:air partition coefficients (Pb: 1-10,000) and hepatic extraction ratios in an average adult (E(ad): 0.01-0.99), HKAFs were computed as the ratio of the 95th percentile of dose metrics for each subpopulation over the 50th percentile value in adults. The reduced hepatic enzyme content in neonates as compared to adults resulted in correspondingly diminished FPE. Consequently, HKAFs greater than 3.2 could be observed, based on CAss only, in the following cases: for some CYP2E1 substrates with E(ad) ≤ 0.3, in neonates (max.: 6.3); and for some CYP1A2 substrates with E(ad) ≤ 0.1 and 0.7, in, respectively, neonates and infants (max.: 28.3). Overall, this study pointed out the importance of accounting for child/adult differences in FPE when determining the HKAF for oral exposure.