Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843-4458.
Toxicol Sci. 2020 Dec 1;178(2):391-403. doi: 10.1093/toxsci/kfaa151.
Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes are an established model for testing potential chemical hazards. Interindividual variability in toxicodynamic sensitivity has also been demonstrated in vitro; however, quantitative characterization of the population-wide variability has not been fully explored. We sought to develop a method to address this gap by combining a population-based iPSC-derived cardiomyocyte model with Bayesian concentration-response modeling. A total of 136 compounds, including 54 pharmaceuticals and 82 environmental chemicals, were tested in iPSC-derived cardiomyocytes from 43 nondiseased humans. Hierarchical Bayesian population concentration-response modeling was conducted for 5 phenotypes reflecting cardiomyocyte function or viability. Toxicodynamic variability was quantified through the derivation of chemical- and phenotype-specific variability factors. Toxicokinetic modeling was used for probabilistic in vitro-to-in vivo extrapolation to derive population-wide margins of safety for pharmaceuticals and margins of exposure for environmental chemicals. Pharmaceuticals were found to be active across all phenotypes. Over half of tested environmental chemicals showed activity in at least one phenotype, most commonly positive chronotropy. Toxicodynamic variability factor estimates for the functional phenotypes were greater than those for cell viability, usually exceeding the generally assumed default of approximately 3. Population variability-based margins of safety for pharmaceuticals were correctly predicted to be relatively narrow, including some below 10; however, margins of exposure for environmental chemicals, based on population exposure estimates, generally exceeded 1000, suggesting they pose little risk at current general population exposures even to sensitive subpopulations. Overall, this study demonstrates how a high-throughput, human population-based, in vitro-in silico model can be used to characterize toxicodynamic population variability in cardiotoxic risk.
人诱导多能干细胞（iPSC）衍生的心肌细胞是测试潜在化学危害的成熟模型。在体外也证明了毒代动力学敏感性的个体间变异性；然而，尚未充分探索人群变异性的定量特征。我们试图通过将基于人群的 iPSC 衍生心肌细胞模型与贝叶斯浓度-反应建模相结合来解决这一差距。共测试了 136 种化合物，包括 54 种药物和 82 种环境化学品，这些化合物来自 43 名非疾病个体的 iPSC 衍生心肌细胞。进行了分层贝叶斯人群浓度-反应建模，以研究 5 种反映心肌细胞功能或活力的表型。通过推导化学物质和表型特异性变异性因素来量化毒代动力学变异性。毒代动力学建模用于概率性体外至体内外推，以得出药物的人群安全性范围和环境化学物质的暴露范围。发现药物对所有表型都有效。超过一半的测试环境化学品在至少一种表型中表现出活性，最常见的是正性变时作用。功能表型的毒代动力学变异性因素估计值大于细胞活力，通常超过约 3 的普遍假定默认值。基于人群变异性的药物安全性范围预计相对较窄，包括一些低于 10；然而，基于人群暴露估计的环境化学物质的暴露范围通常超过 1000，表明即使对于敏感亚群，在当前一般人群暴露水平下，它们也不会带来风险。总体而言，这项研究表明，高通量、基于人群的体外-计算模型如何用于表征心脏毒性风险中的毒代动力学人群变异性。
