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Interpreting ToxCast HTS data
Citation:
Paul-Friedman, K. Interpreting ToxCast HTS data. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 10 - 14, 2019.
Impact/Purpose:
Session proposal abstract for 2019 Society of Toxicology annual meeting
Description:
The US Environmental Protection Agency (EPA) ToxCast data pipeline (tcpl) has been applied to >1000 assay endpoints as first tier data processing of bioactivity data from high-throughput screening (HTS) stored in the “invitrodb” database. First, tcpl and the structure of invitrodb will be reviewed with a discussion of data “levels,” formatted data for preparation and completion of curve-fitting. Curve-fitting analysis (levels 4-6) generates concentration-response parameters, including the 50% activity concentration (AC50). Often the data available in level 5, including the AC50 or positive hitcall, may be useful in addressing toxicological questions. However, there are multiple sources of potential variability in these AC50s, resulting from biological variance, experimental error, or curve-fitting procedures. A robust bootstrap resampling method, available as the toxboot R package, has been implemented for generation of curve-fit reproducibility and uncertainty for AC50s from tcpl. Such uncertainty information may be useful in interpreting ToxCast data for various uses, e.g. supporting biological key event relationships or for use in preliminary screening level risk assessment. To this end, in vitro bioactivity data in ToxCast may be used to estimate point-of-departures (PODs) and has the potential to accelerate human health risk assessments when integrated with high-throughput predictions of exposure. In vitro toxicokinetic assays and in vitro-to-in vivo extrapolation modeling enable conversion of in vitro bioactive concentrations to estimated administered dose equivalents (mg/kg/day) for a comparison to possible exposure. Advancement toward the goal of accelerated risk assessment by incorporated high-throughput predictions of bioactivity, toxicokinetics, and exposure for risk assessment will be discussed, with details on how to compute these values and possibilities for filtering ToxCast data to fit the intended purpose. This abstract does not necessarily reflect U.S. EPA policy.