Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans,Environmental Science & Technology

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Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2023-04-18 , DOI: 10.1021/acs.est.2c05642
Jieying Lin _{1,

2} , Sheng Yuan Chin _{1,

3} , Shawn Pei Feng Tan _{1,

2} , Hor Cheng Koh _{1,

2,

4} , Eleanor Jing Yi Cheong _{2,

3} , Eric Chun Yong Chan _{1,

4} , James Chun Yip Chan _{1,

2,

3}

Affiliation

Perfluorooctanoic acid (PFOA) is an environmental toxicant exhibiting a years-long biological half-life (t_1/2) in humans and is linked with adverse health effects. However, limited understanding of its toxicokinetics (TK) has obstructed the necessary risk assessment. Here, we constructed the first middle-out physiologically based toxicokinetic (PBTK) model to mechanistically explain the persistence of PFOA in humans. In vitro transporter kinetics were thoroughly characterized and scaled up to in vivo clearances using quantitative proteomics-based in vitro-to-in vivo extrapolation. These data and physicochemical parameters of PFOA were used to parameterize our model. We uncovered a novel uptake transporter for PFOA, highly likely to be monocarboxylate transporter 1 which is ubiquitously expressed in body tissues and may mediate broad tissue penetration. Our model was able to recapitulate clinical data from a phase I dose-escalation trial and divergent half-lives from clinical trial and biomonitoring studies. Simulations and sensitivity analyses confirmed the importance of renal transporters in driving extensive PFOA reabsorption, reducing its clearance and augmenting its t_1/2. Crucially, the inclusion of a hypothetical, saturable renal basolateral efflux transporter provided the first unified explanation for the divergent t_1/2 of PFOA reported in clinical (116 days) versus biomonitoring studies (1.3–3.9 years). Efforts are underway to build PBTK models for other perfluoroalkyl substances using similar workflows to assess their TK profiles and facilitate risk assessments.

中文翻译：

基于生理学的人体全氟辛酸转运体依赖性配置的毒代动力学模型

全氟辛酸 (PFOA) 是一种环境毒物，具有长达数年的生物半衰期 ( t _1/2) 在人类中，并与不利的健康影响有关。然而，对其毒代动力学 (TK) 的了解有限阻碍了必要的风险评估。在这里，我们构建了第一个基于生理学的毒代动力学 (PBTK) 模型来机械解释 PFOA 在人类中的持久性。使用基于定量蛋白质组学的体外到体内外推法，对体外转运蛋白动力学进行了彻底表征并扩大到体内清除率。PFOA 的这些数据和物理化学参数用于参数化我们的模型。我们发现了一种新的 PFOA 摄取转运蛋白，很可能是单羧酸转运蛋白 1，它在身体组织中普遍表达，并可能介导广泛的组织渗透。我们的模型能够概括来自 I 期剂量递增试验的临床数据以及来自临床试验和生物监测研究的不同半衰期。模拟和敏感性分析证实了肾脏转运蛋白在驱动广泛的 PFOA 重吸收、减少其清除率和增加其清除率方面的重要性吨_1/2。至关重要的是，包含一个假设的、可饱和的肾脏基底外侧流出转运蛋白，首次统一解释了临床（116 天）与生物监测研究（1.3-3.9 年）中报告的 PFOA t _{1/2的差异。}正在努力使用类似的工作流程为其他全氟烷基物质建立 PBTK 模型，以评估其 TK 概况并促进风险评估。

更新日期：2023-04-18

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