Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Department of Biological Sciences and Statistics, North Carolina State University, Raleigh, NC 27695, USA; Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27695, USA.
Toxicology. 2024 Mar;503:153763. doi: 10.1016/j.tox.2024.153763. Epub 2024 Feb 27.
Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both the environment and humans. Because of this, PFAS as a class (composed of hundreds to thousands of chemicals) are contaminants of very high concern. Little information is available for the vast majority of PFAS, and regulatory agencies lack safety data to determine whether exposure limits or restrictions are needed. Cell-based assays are a pragmatic approach to inform decision-makers on potential health hazards; therefore, we hypothesized that a targeted battery of human in vitro assays can be used to determine whether there are structure-bioactivity relationships for PFAS, and to characterize potential risks by comparing bioactivity (points of departure) to exposure estimates. We tested 56 PFAS from 8 structure-based subclasses in concentration response (0.1-100 μM) using six human cell types selected from target organs with suggested adverse effects of PFAS - human induced pluripotent stem cell (iPSC)-derived hepatocytes, neurons, and cardiomyocytes, primary human hepatocytes, endothelial and HepG2 cells. While many compounds were without effect; certain PFAS demonstrated cell-specific activity highlighting the necessity of using a compendium of in vitro models to identify potential hazards. No class-specific groupings were evident except for some chain length- and structure-related trends. In addition, margins of exposure (MOE) were derived using empirical and predicted exposure data. Conservative MOE calculations showed that most tested PFAS had a MOE in the 1-100 range; ∼20% of PFAS had MOE<1, providing tiered priorities for further studies. Overall, we show that a compendium of human cell-based models can be used to derive bioactivity estimates for a range of PFAS, enabling comparisons with human biomonitoring data. Furthermore, we emphasize that establishing structure-bioactivity relationships may be challenging for the tested PFAS.
全氟和多氟烷基物质（PFAS）广泛应用于商业领域，因此在环境中普遍存在。由于其化学稳定性，PFAS 被认为是持久性和生物累积性的；它们经常在环境和人类中被检测到。因此，PFAS 作为一个类别（由数百到数千种化学物质组成）是高度关注的污染物。对于绝大多数 PFAS，几乎没有信息可用，监管机构缺乏安全数据来确定是否需要暴露限制或限制。基于细胞的测定是一种向决策者提供潜在健康危害信息的务实方法；因此，我们假设可以使用靶向的人类体外测定组来确定 PFAS 是否存在结构-生物活性关系，并通过比较生物活性（起点）与暴露估计值来表征潜在风险。我们用六种从目标器官中选择的人类细胞类型（具有 PFAS 不良影响的人诱导多能干细胞（iPSC）衍生的肝细胞、神经元和心肌细胞、原代人肝细胞、内皮细胞和 HepG2 细胞）测试了 8 个结构基类的 56 种 PFAS，浓度范围为 0.1-100µM。虽然许多化合物没有效果；某些 PFAS 表现出细胞特异性活性，这突出表明需要使用综合的体外模型来识别潜在危害。除了一些链长和结构相关的趋势外，没有明显的类别特定分组。此外，还使用经验和预测暴露数据得出了暴露倍数（MOE）。保守的 MOE 计算表明，大多数测试的 PFAS 的 MOE 在 1-100 范围内；约 20%的 PFAS 的 MOE<1，为进一步研究提供了分层优先级。总体而言，我们表明，综合的人类基于细胞的模型可用于为一系列 PFAS 得出生物活性估计值，从而可以与人体生物监测数据进行比较。此外，我们强调，对于测试的 PFAS，建立结构-生物活性关系可能具有挑战性。
