ToxStrategies scientist Caroline L. Ring, Ph.D,, along with co-authors from the US Environmental Protection Agency, recently published the article, “Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability” in Environment International. This manuscript describes a new open-source software package to simulate inter-individual physiological variability for in vitro-in vivo extrapolation (IVIVE) of data from in vitro high-throughput toxicity screening (HTS) assays, with the aim of conducting rapid risk-based chemical prioritization for potentially sensitive sub-populations. The software is freely available as part of the R package “httk” (https://cran.r-project.org/package=httk).
Under the Toxic Substances Control Act (TSCA), as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act (LCSA), the US EPA is required to conduct detailed risk evaluations, initially on high-priority chemicals. One component of a risk evaluation under LCSA will include consideration of exposure to sensitive subpopulations (e.g., children or senior citizens). To consider potentially sensitive subpopulations, IVIVE must be performed in a way that reflects toxicokinetic variability among these subpopulations. Dr. Ring and colleagues address this issue within the httk software package through the simulation of population variability using physiological parameters relevant to toxicokinetic modeling, based on recent data from the Centers for Disease Control National Health and Nutrition Examination Survey (CDC NHANES). By integrating these data with the US EPA’s ToxCast and ExpoCast data, the httk software is used to investigate differences in the AER among ten subpopulations of interest.
Identification of “high-priority” chemicals for risk evaluation is based on EPA’s chemical prioritization process. However, in the fall of 2017, US EPA will consider new methods to rapidly screen the thousands of existing chemicals and the hundreds of new chemicals introduced into commerce each year for which the available hazard data may be limited. The httk package leverages a promising framework for rapid risk-based chemical prioritization, through the combination of in vitro HTS assay data (e.g., US EPA’s ToxCast HTS data) with data from high-throughput (HT) exposure modeling frameworks (e.g. US EPA’s ExpoCast). In this prioritization framework, the bioactive in vitro concentrations identified through HTS are converted to equivalent external doses using IVIVE. The bioactive-equivalent external doses are then compared to HT exposure estimates, and the ratio (the activity-exposure ratio, or AER) yields a rough estimate of potential risk (analogous to a margin of exposure). AERs can then be used as a factor in the priorization process.
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