A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models: Extension to Volatile Organic Compounds.

Chemical risk assessors use physiologically based pharmacokinetic (PBPK) models to perform dosimetric calculations, including extrapolations between exposure scenarios, species, and populations of interest. Assessors should complete a thorough quality assurance (QA) review to ensure biological accuracy and correct implementation prior to using these models. This process can be time-consuming, and we developed a PBPK model template that allows for faster, more efficient QA review. The model template consists of a single model "superstructure" with equations and logic commonly found in PBPK models, allowing users to implement a wide variety of chemical-specific PBPK models. QA review can be completed more quickly than for conventional PBPK model implementations because the general model equations have already been reviewed and only parameters describing chemical-specific model and exposure scenarios need review for any given model implementation. We have expanded a previous version of the PBPK model template by adding features commonly included in PBPK models for volatile organic compounds (VOCs). We included multiple options for representing concentrations in blood, describing metabolism, and modeling gas exchange processes to allow for inhalation exposures. We created PBPK model template implementations of published models for seven VOCs: dichloromethane, methanol, chloroform, styrene, vinyl chloride, trichloroethylene, and carbon tetrachloride. Simulations performed using our template implementations matched published simulation results to a high degree of accuracy (maximum observed percent error: 1%). Thus, the model template approach can now be applied to a broader class of chemical-specific PBPK models while continuing to bolster efficiency of QA processes that should be conducted prior to using models for risk assessment applications.

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.

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.