Dose-response modeling of effects in mice after exposure to a polyfluoroalkyl substance (Nafion byproduct 2)

The polyfluorinated alkyl substance (PFAS) Nafion BP2 (1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid) has been detected in surface and ground water, as well as in the blood of people living near PFAS manufacturing facilities. Given that very little is known about the potential toxicity of Nafion BP2 and safe exposure levels have not yet been determined, we performed a benchmark dose analysis of phenotypic and genomic effects in mice. Male and female Balb-c mice were exposed daily to Nafion BP2 at multiple doses for 7 d by oral gavage. Full-genome transcript profiling showed that Nafion BP2 in both sexes activates a number of transcription factors linked to liver toxicity, including constitutive androstane receptor (CAR), pregnane X receptor, and NRF2, but unlike other long-chain PFAS, there was no activation of peroxisome proliferator-activated receptor α. Nafion BP2 caused hepatic steatosis in both sexes. Benchmark dose (BMD) estimates for 15 non-genomic effects were 0.25 mg/kg/d and above. BMDs for transcriptional effects were 0.04 mg/kg/d and above. The most sensitive gene sets in both males and females were related to effects on xenobiotic metabolism and the cell cycle, which are plausibly related at a mechanistic level to the activation of CAR. The xenobiotic metabolism and cell cycle findings were largely consistent when dose values based on internal dose were employed in the analysis. These values, along with the identification of molecular targets linked to hazards, may facilitate the determination of human health guidance for Nafion BP2.