Formation of PFAAs in fish through biotransformation: A PBPK approach.

A physiologically-based pharmacokinetic (PBPK) model for perfluorinated alkyl acids (PFAAs) in rainbow trout has been updated to include formation of perfluorooctanoic acid (PFOA) from the biotransformation of 8:2 fluorotelomer carboxylic acid (8:2 FTCA). The updated model is dynamic and simulates both uptake and depuration phases. Two empirical studies are used to parameterize and test the model. In the first case, parameters related to fecal elimination and protein binding were optimized. In the second case, parameters were sourced either from literature or from optimized values based on the first study to test model performance. Optimization of parameters resulted in a decrease in the difference between experimental data and simulation results by 57 and 23 percent for the first and the second case, respectively, compared to the original case. Sensitivity analysis was performed to identify important parameters, and uncertainty in model prediction propagated by these parameters was assessed using Monte Carlo analysis. For each case, 80 and 89 percent, respectively, of median predicted values were within the limits of experimental error when comparing simulated and experimental data. This is the first toxicokinetic model that incorporates biotransformation of PFAA precursors and simultaneously predicts the distribution of the precursor and metabolite in different tissues. The model is mechanistic, and could be applied to simulate a variety of scenarios by using the organism-specific physiological properties compiled here with other chemical-specific parameters (e.g. protein interactions).