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Evaluating New Approach Methodologies for Toxicokinetics
Citation:
Wambaugh, J., B. Wetmore, R. Pearce, G. Honda, R. Sayre, K. Paul-Friedman, Woodrow Setzer, AND R. Thomas. Evaluating New Approach Methodologies for Toxicokinetics. International Society of Exposure Science annual meeting, OttawaCON, August 26 - 30, 2018. https://doi.org/10.23645/epacomptox.7072652
Impact/Purpose:
This is an abstract for a presentation in a symposium "Evaluating High-Throughput New Approach Methods (NAM) for Exposure". This symposium will be part of the International Society of Exposure Science annual meeting in Ottawa, Canada.
Description:
Toxicokinetics (TK) is required information for chemical risk assessment. Unfortunately, TK data are not available for most chemicals in commerce and the environment. New approach methods (NAMs) have been developed to predict time course concentrations in relevant tissues or plasma based upon in vitro experimental data and physico-chemical properties. These high throughput TK (HTTK) data and models are made freely available through an add-on (“httk”) to the free statistical software R as well as through the US EPA CompTox Chemistry Dashboard (http://comptox.epa.gov). Using HTTK, data from high throughput screening projects such as Tox21 and ToxCast can be compared to exposure estimates to generate risk-based prioritizations. HTTK NAMs are being evaluated through 1) uncertainty analysis and 2) comparison between in vitro predictions and in vivo measurements of both plasma concentrations and doses associated with the onset of effects (i.e., “points of departure”). Bayesian methods allow chemical-specific uncertainty estimates for in vitro TK data. Monte Carlo simulation can propagate both measurement uncertainty and biological variability into risk predictions, indicating that for most chemicals, variability contributes substantially more than uncertainty. Comparisons between in vitro predictions and in vivo observations have relied on two approaches: Comparison between HTTK predicted time course concentrations in plasma and in vivo data indicate that some properties (e.g. average and maximum concentration) can be predicted with confidence. Second, comparison between in vitro bioactivity data and HTTK-adjusted internal dose predictions for in vivo points of departure has refined assumptions of the HTTK NAMs. NAMs for TK allow risk-based prioritization of large numbers of chemicals. The views expressed here are those of the authors and do not necessarily reflect the views or policies of the U. S. EPA.
URLs/Downloads:
DOI: Evaluating New Approach Methodologies for Toxicokinetics
ISES-EVALUATINGHTTK-WAMBAUGH-082718-3.PDF (PDF, NA pp, 1027.62 KB, about PDF)