5P42ES027706 Sources, Transport, Exposure, and Effects of PFASs (STEEP) SRP

全氟和多氟烷基物质(PFAS)是一类高度氟化的化学物质 人为化学物质。接触全氟烷基化合物与许多 肝脏和免疫方面的不良后果。多氟烷基化合物，可降解 转化为全氟烷基化合物并具有相似的化学性质，得到的最低限度 科学和监管方面的关注。聚氟烷基6：2含氟弹性体的广泛应用 磺酸盐(6：2 FTSA)及其前体(6：2 FT)在水性成膜泡沫(AFFF)和 金属电镀中使用的抑雾剂已导致地下水广泛污染 和浪费基础设施。在对这些化学品处置的理解上存在严重差距 体外，它们的代谢物，可能的健康影响，以及对人体的潜在贡献 全氟烷基羧酸(PFCA)的负担阻碍了正在进行的风险评估。这项建议 旨在通过在CD-1小鼠身上测量这些化合物及其代谢物来解决这些差距 暴露在AFFF中使用的6：2 FTSA和6：2 FT混合物中。我们的团队将首先评估PFAS 在这些小鼠体内产生PFCA的生物积累和代谢途径。老鼠们将会是 经口灌胃暴露于10微米F 6：2 FTSA或AFFF 28天，并测定PFAS和 可提取的有机氟(EOF)将在血清、肝脏和其他器官中用液体定量 层析、串联质谱仪和燃烧离子层析。总蛋白质， 将同时测量脂质和磷脂，以评估组织之间的分布 使用混合效果模型。使用高分辨率质谱学的非目标分析将 以确定未知的代谢物和降解机制。一项随访研究 将用于评估发育和慢性疾病期间的剂量-反应关系 小鼠暴露于6：2 FTSA。怀孕小鼠将暴露于0至1微米F，相当于6：2 FTSA 通过经口灌胃，它们的幼崽将被分成急性(不含PFAS)或慢性(0.001微米F，按6：2 FTSA)暴露组。全氟辛烷磺酸和EOF将在母亲的母乳和 仔犬出生后第4、21和126天的血清和肝脏。

Per- and polyfluoroalkyl substances (PFAS) are a chemical class of highly fluorinated anthropogenic chemicals. Exposures to perfluoroalkyl compounds have been linked to numerous adverse hepatic and immunological outcomes. Polyfluoroalkyl compounds, which can degrade into perfluoroalkyl compounds and share similar chemical properties, have received minimal scientific and regulatory attention. Extensive use of the polyfluoroalkyl 6:2 fluorotelomer sulfonate (6:2 FTSA) and its precursors (6:2 FT) in aqueous film-forming foams (AFFF) and mist suppressants used in metal plating has resulted in widespread contamination of groundwater and waste infrastructure. Critical gaps in understanding of the disposition of these chemicals in vitro, their metabolites, possible health effects, and potential contributions to the human body burden of perfluoroalkyl carboxylic acids (PFCA) hinder ongoing risk assessment. This proposal aims to address these gaps by measuring these compounds, and their metabolites, in CD-1 mice exposed to 6:2 FTSA and 6:2 FT mixtures used in AFFF. Our team will first evaluate PFAS bioaccumulation and metabolic pathways for PFCA production in these mice. The mice will be exposed for 28 days to 10 µM F 6:2 FTSA or AFFF via oral gavage and levels of PFAS and extractable organofluorine (EOF) will be quantified in serum, liver, and other organs using liquid chromatography tandem mass spectroscopy and combustion ion chromatography. Total protein, lipids, and phospholipids will be simultaneously measured to assess distribution among tissues using a mixed effects model. Nontargeted analysis using high resolution mass spectroscopy will be performed to identify unknown metabolites and degradation mechanisms. A follow-up study will be performed to assess dose-response relationships during developmental and chronic exposure to 6:2 FTSA in the mice. Pregnant mice will be exposed to 0 to 1 µM F as 6:2 FTSA via oral gavage and their pups will be split into acute (PFAS free) or chronic (0.001 µM F as 6:2 FTSA) exposure groups. PFAS and EOF will be quantified in the mothers’ breast milk and the pup’s serum and liver at postnatal day 4, 21, and 126.