In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories.

IF 3.9 3区 环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES
Toxics Pub Date : 2024-09-14 DOI:10.3390/toxics12090672
David M Crizer, Julie R Rice, Marci G Smeltz, Katelyn S Lavrich, Krishna Ravindra, John F Wambaugh, Michael DeVito, Barbara A Wetmore
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Abstract

Toxicokinetic (TK) assays and in vitro-in vivo extrapolation (IVIVE) models are New Approach Methods (NAMs) used to translate in vitro points of departure to exposure estimates required to reach equivalent blood concentrations. Per- and polyfluoroalkyl substances (PFAS) are a large chemical class with wide-ranging industrial applications for which only limited toxicity data are available for human health evaluation. To address the lack of TK data, a pooled primary human hepatocyte suspension model was used with targeted liquid chromatography-mass spectrometry to investigate substrate depletion for 54 PFAS. A median value of 4.52 μL/(min x million cells) was observed across those that showed significant clearance, with 35 displaying no substrate depletion. Bayesian modeling propagated uncertainty around clearance values for use in IVIVE models. Structural evaluations showed the fluorotelomer carboxylic acids were the only PFAS carboxylates showing appreciable clearance, and per- and polyfluorosulfonamides were more readily metabolized than other PFAS sulfonates. Biotransformation product prediction, using the chemical transformation simulator, suggested hydrolysis of PFAS sulfonamides to more stable sulfonic acids, which is an important consideration for exposure modeling. This effort greatly expands the PFAS in vitro toxicokinetic dataset, enabling refined TK modeling, in silico tool development, and NAM-based human health evaluations across this important set of emerging contaminants.

多种结构类别的全氟和多氟烷基物质 (PFAS) 体外肝清除率评估。
毒物动力学(TK)测定和体外-体内外推法(IVIVE)模型是一种新方法(NAM),用于将体外出发点转化为达到等效血药浓度所需的暴露估计值。全氟烷基和多氟烷基物质 (PFAS) 是一大类化学物质,具有广泛的工业用途,但用于人体健康评估的毒性数据却十分有限。为了解决缺乏 TK 数据的问题,研究人员利用汇集的原代人类肝细胞悬浮液模型和靶向液相色谱-质谱联用技术,对 54 种 PFAS 的底物耗竭进行了研究。结果表明,有显著清除率的全氟辛烷磺酸的中位值为 4.52 μL/(分钟 x 百万细胞),其中 35 种全氟辛烷磺酸没有底物消耗。贝叶斯建模传播了用于 IVIVE 模型的清除值的不确定性。结构评估显示,氟代羧酸是唯一显示出明显清除率的全氟辛烷磺酸羧酸盐,全氟和多氟磺酰胺比其他全氟辛烷磺酸磺酸盐更容易代谢。利用化学转化模拟器进行的生物转化产物预测表明,全氟辛烷磺酸磺酰胺会水解为更稳定的磺酸,这是建立暴露模型的一个重要考虑因素。这项工作极大地扩展了全氟辛烷磺酸体外毒物动力学数据集,从而能够对这组重要的新兴污染物进行精细的 TK 建模、硅学工具开发和基于 NAM 的人类健康评估。
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来源期刊
Toxics
Toxics Chemical Engineering-Chemical Health and Safety
CiteScore
4.50
自引率
10.90%
发文量
681
审稿时长
6 weeks
期刊介绍: The Journal accepts papers describing work that furthers our understanding of the exposure, effects, and risks of chemicals and materials in humans and the natural environment as well as approaches to assess and/or manage the toxicological and ecotoxicological risks of chemicals and materials. The journal covers a wide range of toxic substances, including metals, pesticides, pharmaceuticals, biocides, nanomaterials, and polymers such as micro- and mesoplastics. Toxics accepts papers covering: The occurrence, transport, and fate of chemicals and materials in different systems (e.g., food, air, water, soil); Exposure of humans and the environment to toxic chemicals and materials as well as modelling and experimental approaches for characterizing the exposure in, e.g., water, air, soil, food, and consumer products; Uptake, metabolism, and effects of chemicals and materials in a wide range of systems including in-vitro toxicological assays, aquatic and terrestrial organisms and ecosystems, model mammalian systems, and humans; Approaches to assess the risks of chemicals and materials to humans and the environment; Methodologies to eliminate or reduce the exposure of humans and the environment to toxic chemicals and materials.
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