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High Throughput Determination of Critical Human Dosing Parameters (SOT)
Citation:
Nicolas, C., B. Ingle, M. Bacolod, J. Gilbert, B. Wetmore, C. Ring, Woodrow Setzer, R. Tornero-Velez, M. Martin, AND J. Wambaugh. High Throughput Determination of Critical Human Dosing Parameters (SOT). Presented at SOT 55th Annual Meeting and ToxExpo, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
Poster presentation at the SOT 2016 annual meeting. Reverse dosimetry (i.e., reverse toxicokinetics or RTK) based on HTTK data converts high throughput in vitro toxicity screening (HTS) data into predicted human equivalent doses that can be linked with biologically relevant exposure scenarios.
Description:
High throughput toxicokinetics (HTTK) is a rapid approach that uses in vitro data to estimate TK for hundreds of environmental chemicals. Reverse dosimetry (i.e., reverse toxicokinetics or RTK) based on HTTK data converts high throughput in vitro toxicity screening (HTS) data into predicted human equivalent doses that can be linked with biologically relevant exposure scenarios. Thus, HTTK provides essential data for risk prioritization for thousands of chemicals that lack TK data. One critical HTTK parameter that can be measured in vitro is the unbound fraction of a chemical in plasma (Fub). However, for chemicals that bind strongly to plasma, Fub is below the limits of detection (LOD) for high throughput analytical chemistry, and therefore cannot be quantified. A novel method for quantifying Fub was implemented for 85 strategically selected chemicals: measurement of Fub was attempted at 10%, 30%, and 100% of physiological plasma concentrations using rapid equilibrium dialysis assays. Varying plasma concentrations instead of chemical concentrations makes high throughput analytical methodology more likely to be successful. Assays at 100% plasma concentration were unsuccessful for 34 chemicals. For 12 of these 34 chemicals, Fub could be quantified at 10% and/or 30% plasma concentrations; these results imply that the assay failure at 100% plasma concentration was caused by plasma protein binding for these chemicals. Assay failure for the remaining 22 chemicals may be due to chemical insolubility, susceptibility to enzymatic or other degradation, and ability to bind to assay plate walls. ~35% of missing Fub values were captured as a result of using this new approach and would have been missing with the use of previous HTTK protocols. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
NICOLAS-SOT-POSTER-030816_DRAFT KMC_FINAL.PDF (PDF, NA pp, 768.203 KB, about PDF)NICOLAS_2016_SOTABSTRACT_093015_FINAL_CIN.PDF (PDF, NA pp, 94.084 KB, about PDF)