Abstract：
Per- and poly-fluoroalkyl substances (PFAS) have a wide range of elimination half-lives (days to years) in humans, thought to be in part due to variation in proximal tubule reabsorption. While human biomonitoring studies provide important data for some PFAS, renal clearance (CLrenal) predictions for hundreds of PFAS in commerce requires experimental studies with in vitro models and physiologically-based in vitro-to-in vivo extrapolation (IVIVE). Options for studying renal proximal tubule pharmacokinetics include cultures of renal proximal tubule epithelial cells (RPTECs) and/or microphysiological systems. This study aimed to compare CLrenal predictions for PFAS using in vitro models of varying complexity (96-well plates, static 24-well Transwells and a fluidic microphysiological model, all using human telomerase reverse transcriptase-immortalized and OAT1-overexpressing RPTECs combined with in silico physiologically-based IVIVE. Three PFAS were tested: one with a long half-life (PFOS) and two with shorter half-lives (PFHxA and PFBS). PFAS were added either individually (5 μM) or as a mixture (2 μM of each substance) for 48 h. Bayesian methods were used to fit concentrations measured in media and cells to a three-compartmental model to obtain the in vitro permeability rates, which were then used as inputs for a physiologically-based IVIVE model to estimate in vivo CLrenal. Our predictions for human CLrenal of PFAS were highly concordant with available values from in vivo human studies. The relative values of CLrenal between slow- and faster-clearance PFAS were most highly concordant between predictions from 2D culture and corresponding in vivo values. However, the predictions from the more complex model (with or without flow) exhibited greater concordance with absolute CLrenal. Overall, we conclude that a combined in vitro-in silico workflow can predict absolute CLrenal values, and effectively distinguish between PFAS with slow and faster clearance, thereby allowing prioritization of PFAS with a greater potential for bioaccumulation in humans.
摘要：
全氟烷基和多氟烷基物质（PFAS）在人类中具有广泛的消除半衰期（几天到几年），认为部分是由于近端小管重吸收的变化。虽然人类生物监测研究为一些PFAS提供了重要数据，商业上数百种PFAS的肾清除率（CLreal）预测需要使用体外模型和基于生理的体外到体内外推（IVIVIVE）进行实验研究。研究肾近曲小管药代动力学的选择包括肾近曲小管上皮细胞（RPTEC）和/或微生理系统的培养。本研究旨在使用不同复杂性的体外模型（96孔板，静态24井Transwells和流体微生理模型，全部使用人端粒酶逆转录酶永生化和OAT1过表达的RPTEC与基于计算机生理学的IVIVIVE。测试了三种PFAS:一种具有长半衰期(PFOS),两种具有较短半衰期(PFHxA和PFBS)。将PFAS单独（5μM）或作为混合物（每种物质2μM）添加48小时。使用贝叶斯方法将培养基和细胞中测量的浓度拟合到三隔室模型，以获得体外通透性。然后将其用作基于生理的IVIVE模型的输入，以估计体内CLreal。我们对PFAS的人CLrenal的预测与体内人体研究的可用值高度一致。缓慢和较快清除PFAS之间的CLreal相对值在2D培养物的预测与相应的体内值之间是最高度一致的。然而,来自更复杂模型(有或无血流)的预测与绝对CLreal表现出更大的一致性.总的来说,我们得出的结论是，组合的体外计算机工作流程可以预测绝对CLreal值，并有效区分具有缓慢和较快清除的PFAS，从而允许优先考虑在人类中具有更大的生物积累潜力的PFAS。
