A model template approach for rapid evaluation and application of physiologically based pharmacokinetic models for use in human health risk assessments
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Physiologically based pharmacokinetic (PBPK) models predict the concentration of a chemical in the blood and tissues of different species as a function of dose and route of exposure. They are commonly used in chemical risk assessments to extrapolate between different species and dosing scenarios, and modelers and risk assessors frequently rely on previously published PBPK models to perform risk assessment dosimetry calculations. However, to use such models, they must first undergo quality assurance (QA) review to ensure that they are biologically plausible and that they have been implemented correctly. This review can be very time consuming particularly when model code is not available for published models under consideration. Using R and MCSim, we have developed a PBPK model template to allow for faster implementation and evaluation of published PBPK models. The model template is capable of replicating simulation results from multiple chemical-specific models using one common software implementation, which includes a generic set of model equations and logic for selecting and omitting specific model features. This allows for faster QA evaluation of models since the model equations only need to be reviewed once. Then, to complete implementation of a given chemical-specific PBPK model, simply the input parameters, including the selection of appropriate equations and logic from the template, need to be reviewed. The model template can be used to perform simulations using oral, intravenous, and inhalation exposure routes. It includes features to model a varying number of tissue compartments, renal reabsorption, saturable and first order metabolic pathways in multiple compartments, endogenous production or background exposure, and multiple excretion pathways including fecal, urinary, and biliary. The model template can also accommodate models that include a single blood compartment or separate venous and arterial blood compartments, as well as either steady state or dynamic model assumptions for each blood compartment. Using the model template, we reproduced model simulation results published for PBPK models of dichloromethane (DCM), methanol, and chloroform. When performing QA review of a PBPK model that is being considered for use in risk assessment, both the model equations and parameters must be reviewed for accuracy and scientific plausibility. However, a rigorous QA review can be time consuming to perform, particularly if model code is not available. The PBPK model template allows risk assessors to quickly implement published models and streamlines the process of QA review for the model equations, providing for faster implementation of PBPK models in chemical risk assessments.