Studying mixture effects on uptake and tissue distribution of PFAS in zebrafish (Danio rerio) using physiologically based kinetic (PBK) modelling

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously distributed in the aquatic environment. They include persistent, mobile, bioaccumulative, and toxic chemicals and it is therefore critical to increase our understanding on their adsorption, distribution, metabolism, excretion (ADME). The current study focused on uptake of seven emerging PFAS in zebrafish (Danio rerio) and their potential maternal transfer. In addition, we aimed at increasing our understanding on mixture effects on ADME by developing a physiologically based kinetic (PBK) model capable of handling co-exposure scenarios of any number of chemicals. All studied chemicals were taken up in the fish to varying degrees, whereas only perfluorononanoate (PFNA) and perfluorooctanoate (PFOA) were quantified in all analysed tissues. Perfluorooctane sulfonamide (FOSA) was measured at concerningly high concentrations in the brain (C-max over 15 mu g/g) but also in the liver and ovaries. All studied PFAS were maternally transferred to the eggs, with FOSA and 6:2 perfluorooctane sulfonate (6,2 FTSA) showing significant (p < 0.02) signs of elimination from the embryos during the first 6 days of development, while perfluorobutane sulfonate (PFBS), PFNA, and perfluorohexane sulfonate (PFHxS) were not eliminated in embryos during this time-frame. The mixture PBK model resulted in >85 % of predictions within a 10-fold error and 60 % of predictions within a 3-fold error. At studied levels of PFAS exposure, competitive binding was not a critical factor for PFAS kinetics. Gill surface pH influenced uptake for some carboxylates but not the sulfonates. The developed PBK model provides an important tool in understanding kinetics under complex mixture scenarios and this use of New Approach Methodologies (NAMs) is critical in future risk assessment of chemicals and early warning systems.