A toxicokinetic model for gill processes affecting the uptake of perfluoroalkyl acids by freshwater fish

Perfluoroalkyl acids (PFAA) are a well-studied subclass of per- and polyfluoroalkyl substances (PFAS). Some PFAA bioaccumulate in food webs, and fish consumption is an important vector of human exposure. However, mechanistic studies investigating the relative importance of branchial uptake, tissue partitioning, and renal excretion of PFAA in fish are limited. We developed a mechanistic toxicokinetic (TK) model to examine gill transport as a potential rate-limiting step for PFAA uptake and elimination in fish. The model simulates laboratory conditions and explicitly accounts for transport across the aqueous boundary layer (ABL) at the gill epithelial membrane and co-transport with dissolved organic carbon (DOC). Modeled bioconcentration factors (BCFs) for PFAA containing 4-10 perfluorinated carbons (η_pfc) agreed with laboratory data within one standard deviation of the median. BCFs were most sensitive to by tissue binding (normalized sensitivity coefficients [NSCs] across PFAA: 69% to 102%). Elimination half-lives were sensitive to both tissue binding (57% to 76%) and effective gill permeability (-30% to -96%). ABL thickness at the gill epithelial membrane, rather than the epithelial membrane itself, determines the diffusion barrier for short-chain PFAA (η_pfc < 6) and was the most sensitive parameter (97%) affecting elimination half-lives. The gills accounted for 5-47% of tissue-bound PFAA, driven by binding to proteins and partitioning to phospholipids. At an aqueous DOC concentrations of 100 mg L^-1, modeled BCFs decreased by up to 22%. Together, these results suggest tissue binding and gill permeability are both important for PFAA bioconcentration, and that uptake and exchange are affected by flow-dependent transport across the ABL at the gill epithelial membrane.