title: Evaluating the Impact of Uncertainties in Clearance and Exposure When Prioritizing Chemicals Screened in High-Throughput Assays.
abstract: The toxicity-testing paradigm has evolved to include high-throughput (HT) methods for addressing the increasing need to screen hundreds to thousands of chemicals rapidly. Approaches that involve in vitro screening assays, in silico predictions of exposure concentrations, and pharmacokinetic (PK) characteristics provide the foundation for HT risk prioritization. Underlying uncertainties in predicted exposure concentrations or PK behaviors can significantly influence the prioritization of chemicals, though the impact of such influences is unclear. In the current study, a framework was developed to incorporate absorbed doses, PK properties, and in vitro dose-response data into a PK/pharmacodynamic (PD) model to allow for placement of chemicals into discrete priority bins. Literature-reported or predicted values for clearance rates and absorbed doses were used in the PK/PD model to evaluate the impact of their uncertainties on chemical prioritization. Scenarios using predicted absorbed doses resulted in a larger number of bin misassignments than those scenarios using predicted clearance rates, when comparing to bin placement using literature-reported values. Sensitivity of parameters on the model output of toxicological activity was examined across possible ranges for those parameters to provide insight into how uncertainty in their predicted values might impact uncertainty in activity.
authors.affiliation: Oak Ridge Institute for Science and Education , Oak Ridge, Tennessee 37831, United States.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Leonard
authors.affiliation: Department of Biological Sciences, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Ashley
authors.initials: A
authors.lastname: Sobel Leonard
authors.affiliation: Chemical Computing Group, Montreal, QC H3A 2R7, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.affiliation: National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Edwards
authors.affiliation: Oak Ridge Institute for Science and Education , Oak Ridge, Tennessee 37831, United States.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Lu
authors.affiliation: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Scholle
authors.affiliation: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Key
authors.affiliation: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Winter
authors.affiliation: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Kristin
authors.initials: K
authors.lastname: Isaacs
authors.affiliation: National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
mesh_terms: D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008962:Models, Theoretical; D018675:Toxicity Tests; D035501:Uncertainty