A model template approach for rapid evaluation and application of physiologically based pharmacokinetic models: extension to volatile organic compounds

Abstract

AbstractChemical 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.