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“httk”: EPA’s Tool for High Throughput Toxicokinetics (CompTox CoP)
Citation:
Wambaugh, J. “httk”: EPA’s Tool for High Throughput Toxicokinetics (CompTox CoP). Presented at CompTox Community of Practice, Research Triangle Park, NC, April 27, 2017.
Impact/Purpose:
This is a webinar presentation to the CompTox community of practice. The goal of this presentation is to familiarize researchers with EPA's open source models and data for toxicokinetics, including reverse dosimetry and physiologically-based pharmacokinetic (PBPK) modeling.
Description:
Thousands of chemicals have been pro?led by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentrations resulting from chemical exposure, and a \reverse dosimetry" approach can be used to predict exposure doses sufficient to cause tissue concentrations that have been identified as bioactive by high-throughput screening. We have created four toxicokinetic models within a new R software package, httk. These models are designed to be parameterized using high-throughput in vitro data (plasma protein binding and hepatic clearance), as well as structure-derived physicochemical properties and species-specific physiological data. The package contains tools for Monte Carlo sampling and reverse dosimetry along with functions for the analysis of concentration vs. time simulations. The package can currently use human in vitro data to make predictions for 543 chemicals in humans, rats, mice, dogs, and rabbits, including 95 pharmaceuticals and 416 ToxCast chemicals. For 66 of these chemicals, the package includes rat-specific in vitro data. This package is structured to be augmented with additional chemical data as they become available. httk enables the inclusion of toxicokinetics in the statistical analysis of chemicals undergoing high-throughput screening.