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Incorporating Population Variability and Susceptible Subpopulations into Dosimetry for High-Throughput Toxicity Testing
Citation:
Wetmore, B., B. Allen, H. Clewell III, T. Parker, John F. Wambaugh, L. Almond, M. Sochaski, AND Russell S. Thomas. Incorporating Population Variability and Susceptible Subpopulations into Dosimetry for High-Throughput Toxicity Testing. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 142(1):210-224, (2014).
Impact/Purpose:
This manuscript describes research using in vitro methods to incorporate known human variability (i.e. between demographics and life stages) into in vitro to in vivo (IVIVE) extrapolation for the ToxCast project (i.e. reverse toxicokinetics or RTK).
Description:
Momentum is growing worldwide to use in vitro high-throughput screening (HTS) to evaluate human health effects of chemicals. However, the integration of dosimetry into HTS assays and incorporation of population variability will be essential before its application in a risk assessment context. Previously, we employed in vitro hepatic metabolic clearance and plasma protein binding data with in vitro in vivo extrapolation (IVIVE) modeling to estimate oral equivalent doses, or daily oral chemical doses required to achieve steady-state blood concentrations (Css) equivalent to media concentrations having a defined effect in an in vitro HTS assay. In this study, hepatic clearance rates of selected ToxCast chemicals were measured in vitro for 13 cytochrome P450 (CYP) and 5 uridine 5’-diphospho-glucuronysyltransferase (UGT) isozymes using recombinantly expressed enzymes. The isozyme-specific clearance rates were then incorporated into an IVIVE model that captures known differences in isozyme expression across several life stages and ethnic populations. Comparison of the median Css for a healthy population against the median or the upper 95th percentile for more sensitive populations revealed differences of 1.3 to 4.3-fold or 3.1 to 13.1-fold, respectively. Such values may be used to derive chemical-specific pharmacokinetic adjustment factors. The IVIVE model was also used to estimate subpopulation-specific oral equivalent doses which were directly compared to subpopulation-specific exposure estimates. This study successfully combines isozyme and physiologic differences to quantitate subpopulation pharmacokinetic variability. Incorporation of these values with dosimetry and in vitro bioactivities provides a viable approach that could be employed within a high-throughput risk assessment framework.
URLs/Downloads:
http://toxsci.oxfordjournals.org/content/early/2014/08/21/toxsci.kfu169.full.pdf+html