QIVIVE APPROACHES TO EVALUATE INTERINDIVIDUAL TOXICOKINETIC VARIABILITY

摘要

Toxicokinetic (TK) variability across life-stages and populations can significantly impact the amount of chemical available systemically to elicit an effect despite similar external exposures. This variability is driven by physiologic (e.g., liver weights, blood flow rates, etc.), ontogenetic (e.g., immature or developing metabolic enzyme capabilities) and genetic (e.g., polymorphisms) differences. Recent advances in experimental tools, in vitro - in vivo extrapolation (IVIVE) and in silico modeling approaches have laid the groundwork for the development of strategies that can quantitate chemical-specific TK variability that may be present across different populations. Metabolic clearance of nine ToxCast chemicals were measured in vitro using 13 cytochrome P450 (CYP) and 5 UDP-glucuronosyltransferase (UGT) isozymes that were recombinantly expressed. Together with plasma protein binding data, these isozyme-specific clearance rates were used in an IVIVE modeling approach that incorporates known differences in xenobiotic metabolizing isozyme abundances among various life-stage or ethnic-based populations to estimate the resulting systemic chemical steady-state concentrations, thus providing a strategy to quantitate TK variability. CYPs 3A4, 3A5, 2C9, and 2C19 were the most active isozymes, contributing to the clearance of all of the chemicals tested. Chemicals metabolized primarily by CYP1A2 displayed the greatest TK variability across the populations assessed. Children, in particular the newborn to 6 months of age life-stage, displayed the highest steady-state levels given a similar external exposure, identifying them as a sensitive population. Next, these steady state values were incorporated with ToxCast in vitro bioactivity concentrations to estimate the daily oral dose for each population, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to these in vitro bioactivity values. These external, population-specific oral equivalent doses were then compared against life-stage or population-specific external exposure estimates to provide a margin of exposure assessment that could be applied in risk-based prioritization. This study demonstrates the feasibility and value of using isozyme-specific clearance data to tailor dosimetric values for a wide range of populations. Moreover, such strategies may enable a shift away from default uncertainty factors toward chemical-specific safety factors.