Enabling transparent toxicokinetic modeling for public health risk assessment

Toxicokinetic modeling describes the absorption, distribution, metabolism, and elimination of chemicals by the body. Chemical-specific in vivo toxicokinetic data is often unavailable for the thousands of chemicals in commerce. However, predictions from generalized toxicokinetic models allow for extrapolation from in vitro toxicological data, obtained via new approach methods (NAMs), to predict in vivo human health outcomes and provide key information on chemicals for public health risk assessment. The httk R package provides an open-source software tool containing a suite of generalized toxicokinetic models covering various exposure scenarios, a library of chemical-specific data from peer-reviewed high-throughput toxicokinetic (HTTK) studies, and other utility functions to parameterize and evaluate toxicokinetic models. Generalized HTTK models in httk use the open-source language MCSim to describe the compartmental and physiologically based toxicokinetics (PBTK). New HTTK models may be integrated into httk with a model description code file (C script generated via MCSim) and a model documentation file (R script). httk provides a series of functionalities such as model parameterization, in vivo-derived data for evaluating model predictions, unit conversion, Monte Carlo simulations for uncertainty propagation and biological variability, and other model utilities. Here, we describe in detail how to add new HTTK models into the httk package to leverage its pre-existing data and functionality. As a demonstration, we describe the integration of a gas inhalation PBTK model. The intention of httk is to provide a transparent, open-source tool for toxicokinetics, bioinformatics, and public health risk assessment that makes use of publicly available data on more than one thousand chemicals.