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Quantitating population toxicokinetic variability utilizing recombinant enzyme-specific clearance rates (ASCCT 2020)
Citation:
Kreutz, A. AND B. Wetmore. Quantitating population toxicokinetic variability utilizing recombinant enzyme-specific clearance rates (ASCCT 2020). American Society for Cellular and Computational Toxicology 2020 Virtual meeting, Virtual, Virtual, October 20 - 22, 2020. https://doi.org/10.23645/epacomptox.19172177
Impact/Purpose:
Poster presented to the American Society for Cellular and Computational Toxicology (ASCCT) Virtual meeting October 2020. Uncertainty factors are utilized in high-throughput screening methods and used to inform regulatory assessments, but it is unclear whether default uncertainty factors are relevant for particular subpopulations. Potential vulnerable subpopulations include infants and young children, the elderly, diseased states, and ethnic variations. To better understand population variability, we are calculating clearance rates of chemicals and using these rates to inform steady state plasma concentrations and the its oral dose equivalent, which can be compared to exposure estimates. This information will be incorporated into the HTTK package and could help inform regulators as to when alternate uncertainty factors might need to be considered.
Description:
When toxicokinetic (TK) variability occurs across different populations or lifestages, identical external chemical exposures may yield differing systemic concentrations, and may subsequently result in differing health impacts. In vitro -in vivo extrapolation (IVIVE) modeling that combines in vitro TK data with population-specific physiologic and ontogenetic information during Monte Carlo simulations can be used to predict in vivo exposures. A previous proof of concept applied this approach and successfully predicted exposures for drugs for which in vivo data were available and demonstrated how interindividual variability could be quantitated. In this follow-up, enzymatic clearance data has been generated for 6 chemicals --ametryn, dimethenamid, fenbuconazole, fenhexamid, glyphosate, and n-butylparaben --across 6 isozymes we previously found to be the predominant contributors to metabolism. The resulting data are being used to further our understanding of whether particular isozyme metabolic profiles may drive greater TK variability. Prediction of steady state concentrations and human-specific TK adjustment factors (HKAFs) thus far show the pediatric lifestage is often the most sensitive, with HKAFs values falling above the 3.2 default uncertainty factor typically assigned for TK variability. Sensitivity in the pediatric lifestages decreases with age, coinciding with maturation of the metabolic enzymes. We also noted an inverse relationship between HKAF variability and the number of enzymes with fraction of compound metabolized exceeding 3% for these chemicals. Future work will continue to expand the chemical space analyzed and our assessments of the relationship of isozyme metabolic profiles to TK variabilities. This abstract doesn't necessarily reflect the views of the EPA.
URLs/Downloads:
DOI: Quantitating population toxicokinetic variability utilizing recombinant enzyme-specific clearance rates (ASCCT 2020)
ASCCT_KREUTZ_1020.PDF (PDF, NA pp, 1085.472 KB, about PDF)