Simulating toxicokinetic variability to identify susceptible and highly exposed populations

Abstract

Background: Toxicokinetic (TK) data needed for chemical risk assessment are not available for most chemicals. To support a greater number of chemicals, the U.S. Environmental Protection Agency (EPA) created the open-source R package "httk" (High Throughput ToxicoKinetics). The "httk" package provides functions and data tables for simulation and statistical analysis of chemical TK, including a population variability simulator that uses biometrics data from the National Health and Nutrition Examination Survey (NHANES).

Objective: Here we modernize the "HTTK-Pop" population variability simulator based on the currently available data and literature. We provide explanations of the algorithms used by "httk" for variability simulation and uncertainty propagation.

Methods: We updated and revised the population variability simulator in the "httk" package with the most recent NHANES biometrics (up to the 2017-18 NHANES cohort). Model equations describing glomerular filtration rate (GFR) were revised to more accurately represent physiology and population variability. The model output from the updated "httk" package was compared with the current version.

Results: The revised population variability simulator in the "httk" package now provides refined, more relevant, and better justified estimations.

Significance: Fulfilling the U.S. EPA's mission to provide open-source data and models for evaluations and applications by the broader scientific community, and continuously improving the accuracy of the "httk" package based on the currently available data and literature.

Keywords: Environmental justice; Generic physiologically-based toxicokinetic (PBTK) models; Model variability and uncertainty; Modeling software tools; New approach methodologies (NAMs); Population simulator.