Evaluating parameter availability for physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoic acid...

Physiologically based pharmacokinetic (PBPK) models are considered useful tools to describe the absorption, distribution, metabolism and excretion of xenobiotics. For accurate predictions, PBPK models require species-specific and compound-specific parameters. Zebrafish are considered an appropriate vertebrate model for investigating the toxicity of a wide variety of compounds. However, no specific mechanistic model exists for the pharmacokinetics of perfluoroalkyl acids (PFAAs) in zebrafish, despite growing concern about this class of ubiquitous environmental contaminants. The purpose of this study was to evaluate the current state of knowledge for the parameters that would be needed to construct such a model for zebrafish. We chose perfluorooctanoic acid (PFOA) as a model PFAA with greater data availability. We have updated a previous PBPK model for rainbow trout to simulate PFOA fate in zebrafish following waterborne exposure. For the first time, the model considers hepatobiliary circulation. In order to evaluate the availability of parameters to implement this model, we performed an extensive literature review to find zebrafish-specific parameters. As in previous approaches, we broadened our search to include mammalian and other fish studies when zebrafish-specific data were lacking. Based on the method used to measure or estimate parameters, or based on their species-specific origin, we scored and ranked the quality of available parameters. These scores were then used in Monte Carlo and partial rank correlation analyses to identify the most critical data gaps. The liver, where fatty acid binding proteins (FABPs) and plasma proteins are considered, represented the best model-data agreement. Lack of agreement in other tissues suggest better parameters are needed. The results of our study highlight the lack of zebrafish-specific parameters. Based on sensitivity and uncertainty analysis, parameters associated with PFAA-protein interactions and passive diffusion need further refinement to enable development of predictive models for these emerging chemicals in zebrafish.