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Modelling kinetics and dynamics of chemicals at the U.S. Environmental Protection Agency using the httk open-source platform
Citation:
Wambaugh, J., S. Davidson-Fritz, A. Meade, M. Breen, R. Sayre, T. Wall, E. Kenyon, M. Evans, B. Wetmore, AND C. Ring. Modelling kinetics and dynamics of chemicals at the U.S. Environmental Protection Agency using the httk open-source platform. Eurotox 2023, Ljubljana, SLOVENIA, September 10 - 13, 2023. https://doi.org/10.23645/epacomptox.24101718
Impact/Purpose:
An abstract has been prepared by John Wambaugh for an invited presentation to EuroTox annual meeting as part of a symposium on “Next generation risk assessment of food chemicals, environmental contaminants and pharmaceuticals using open-source modelling platforms: Perspectives from regulatory agencies, academia and industry”. The presentation is entitled “Modelling kinetics and dynamics of chemicals at the US-EPA using the httk open-source platform”.
Description:
There is a need to rapidly assess the potential risk of chemicals in our environment. Toxicokinetic (TK) predictions provide key information for chemical risk assessment, including interspecies and in vitro-in vivo extrapolation (IVIVE). However, chemical-specific in vivo data (for example., measurements from animal studies) are often unavailable for the thousands of chemicals in commerce. Over the last decade, several regulatory agencies have worked to integrate new approach methodologies (NAMs) into next generation risk assessment (NGRA). High Throughput TK (HTTK) methods provide a toxicokinetic NAM with the ability to characterize large numbers of chemicals by combining generic TK models with in vitro measurements and in silico predictions of chemical-specific TK properties. HTTK allows incorporation of chemical-specific TK predictions into bioinformatic workflows using hazard/bioactivity NAMs to predict adverse effect in vivo. IVIVE of bioactivity NAMs with HTTK is key to enabling NGRA. In HTTK chemicals are first characterized by standardized in vitro measurements or in silico predictions for items such as intrinsic metabolic clearance and fraction of the chemical unbound in plasma. Then, pre-made generic TK models designed to use those descriptors allow a variety of IVIVE approaches and other TK predictions to relate external chemical exposures to internal tissue doses. These models provide a quantitative means to link exposure assessment, internal dose, and toxicological outcomes. To support the adoption of HTTK and NAMs, the U.S. EPA provides HTTK methods through an open-source R package “httk. The R package “httk” provides a library of chemical-specific data from peer-reviewed and published studies, along with a suite of tools for parameterizing, executing, and evaluating toxicokinetic models. Ongoing expansion of the models aims to cover several relevant exposure scenarios including general population ingestion of semi- and non-volatile chemicals and inhalation of volatile chemicals from ambient sources. Occupational chemical exposures are addressed through inclusion of inhalation and dermal routes of exposure. The predictive ability of the models included within the R package is evaluated through systematic evaluation of predictions across pre-existing in vivo TK data sets compiled by EPA’s CvTdb (TK Concentration vs. Time database) which covers hundreds of chemicals in commerce. In addition, the quantitative root mean squared error (RMSE) provides empirical uncertainty factors for using HTTK NAMs and IVIVE within NGRA. Altogether, the “httk” R package provides free access to data and models, which are continually updated, that can be easily used, evaluated, and traced to enable robust TK assessments for NGRA. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Modelling kinetics and dynamics of chemicals at the U.S. Environmental Protection Agency using the httk open-source platform
PRESENTATION.PDF (PDF, NA pp, 3555.95 KB, about PDF)