Development of edible sorbent therapies to mitigate dietary exposures to per- and polyfluoroalkyl substances (PFAS)

摘要 全氟烷基和多氟烷基物质（PFAS），也被称为“永久化学品”，是新出现的污染物， 由于其患病率（在美国99%的血液样本中），半衰期长，对健康有不良影响 在人类身上。PFAS可以在紧急情况下释放，动员和重新分布在环境中，例如 火灾、工业事故、飓风和洪水，从而增加了人类接触和健康影响。一个主要 与这些紧急情况相关的挑战是保护弱势群体，包括第一反应者， 前线人员和受影响地区的社区。迫切需要发展 采取切实可行的策略，尽量减少从饮用水和食物中摄入PFAS，这占90%， 人体暴露。在饮食中使用可食用吸附剂的缓解策略对人类消费是安全的。的 长期目标是建立治疗吸附剂干预措施，减少口服和吸入暴露于 复杂的环境污染物和微生物该项目的总体目标是开发可食用， 多组分吸附剂，将有效地减少PFAS暴露的饮食。在这个项目中，6 已选择代表性PFAS及其混合物用于体外、计算机模拟和体内补充 问题研究在目标1中，多组分吸附剂，包括加工和营养改良的粘土，将来自于 天然存在的材料，或公认安全的材料。体外吸附研究将 在模拟胃肠道模型中进行，以表征表面相互作用。解毒 吸附剂处理的功效将在哺乳动物细胞模型和活生物体（水螅）中验证。 在目标2中，分子动力学（MD）模拟，能量分析，极简MD模拟和数据驱动 模型将被用来研究复杂的系统包含PFAS和多组分吸附剂的混合物。 计算研究将验证吸附机制和热力学，并与目标1相结合， 吸附剂选择和表征。在目标3中，将测试所选吸附剂的有效性和安全性， vivo.雄性和妊娠雌性大鼠将暴露于PFAS，并将吸附剂以不同的剂量包含在饲料中。 剂量为3周。最有效降低PFAS生物利用度且无干扰的3种吸附剂 将被纳入为期6个月的安全性研究。待确定的参数包括：1）PFAS 血液、尿液和母乳中的生物利用度，2）营养水平，3）体重，相对器官与体重， 和婴儿出生体重，4）饲料转化率，和5）临床血液生化。预计在 在这项研究中开发的治疗吸附剂将是现场实用的，易于口服，以中和 在紧急情况下保护和治疗脆弱人群的膳食暴露PFAS混合物。

ABSTRACT Per- and polyfluoroalkyl substances (PFAS), also known as “forever chemicals”, are emerging contaminants of concern due to their prevalence (in 99% of blood samples in the U.S.), long half-life, and adverse health effects in humans. PFAS can be released, mobilized, and redistributed in the environment during emergencies such as fires, industrial incidents, hurricanes, and flooding, thus enhancing human exposures and health effects. A major challenge associated with these emergencies is protecting vulnerable populations including first responders, frontline personnel, and communities at the impacted sites. There is a critical need for the development of practical strategies to minimize dietary exposures to PFAS from drinking water and food, which account for 90% of human exposures. Mitigation strategies using edible sorbents in the diet are safe for human consumption. The long-term goal is to establish therapeutic sorbent interventions that will reduce oral and inhalation exposures to complex environmental contaminants and microbes. The overall objective of this project is to develop edible, multicomponent sorbents that will effectively reduce PFAS exposures from the diet. In this project, six representative PFAS and their mixtures have been selected for complementary in vitro, in silico, and in vivo studies. In Aim 1, multicomponent sorbents including processed and nutrient-amended clays will be derived from materials that are naturally occurring, or generally recognized as safe. The in vitro adsorption studies will be conducted in simulated gastrointestinal tract models to characterize surface interactions. The detoxification efficacy of sorbent treatment will be validated in mammalian cell models and a living organism (Hydra vulgaris). In Aim 2, molecular dynamics (MD) simulations, energetic analysis, minimalistic MD simulations, and data-driven models will be used to study complex systems containing mixtures of PFAS and multicomponent sorbents. Computational studies will validate sorption mechanisms and thermodynamics and integrate with Aim 1 for sorbent selection and characterization. In Aim 3, the efficacy and safety of selected sorbents will be tested in vivo. Male and pregnant female rats will be exposed to PFAS and sorbents will be included in the diet at varying doses for 3 weeks. The 3 sorbents that most effectively reduce the PFAS bioavailability and show no interference with nutrients will be included in a 6-month safety study. Parameters to be determined include 1) PFAS bioavailability in blood, urine, and breast milk, 2) nutrient levels, 3) body weight, relative organ-to-body weight, and infant birth weight, 4) feed conversion efficiency, and 5) clinical blood biochemistry. It is expected that therapeutic sorbents developed in this research will be field-practical and easily delivered orally to neutralize PFAS mixtures from dietary exposures to protect and treat vulnerable populations during emergencies.