A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models for Use in Human Health Risk Assessments: A Case Study on Per- and Polyfluoroalkyl Substances
Citation:
Bernstein, A., D. Kapraun, AND P. Schlosser. A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models for Use in Human Health Risk Assessments: A Case Study on Per- and Polyfluoroalkyl Substances. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 182(2):215-228, (2021). https://doi.org/10.1093/toxsci/kfab063
Impact/Purpose:
This manuscript describes a physiologically based pharmacokinetic (PBPK) model template that is capable of implementing multiple published PFAS PBPK models, which is a class of chemicals for which there are common features. Using the template, only one primary model file needs to undergo quality assurance testing, and then only the input files for model-specific parameters require separate review for individual chemical models. Using such a template allows for faster, more efficient evaluation of PFAS PBPK models for risk assessment, and the success of this template shows the promise of using the general template approach for a broader set of PBPK models.
Description:
Physiologically based pharmacokinetic (PBPK) models are commonly used in risk assessments to perform inter- and intraspecies extrapolations as well as to extrapolate between different dosing scenarios; however, they must first undergo quality assurance review, which can be a time-consuming process, especially when model code is not readily available. We developed and implemented (using R and MCSim) a PBPK model template capable of replicating published model results for several chemical-specific PBPK models. This model template allows for faster quality assurance review because the general model equations only need to be reviewed once, and application to a specific chemical then only requires reviewing input parameters. The model template can implement PBPK models with oral and intravenous exposure routes, varying numbers of tissue compartments, renal reabsorption, and multiple elimination pathways, including fecal, urinary, and biliary. Using the model template, we reproduced published model simulation results for perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorodecanoic acid, perfluorooctanoate, and perflouorooctane sulfonate. We also show that the template can be a useful tool for identifying potential model errors. Thus, the model template allows for faster evaluation and review of published PBPK models and provides a proof of concept for using this approach with broader classes of chemical-specific PBPK models.
