Quantitative In Vitro-to-In Vivo Extrapolation for Mixtures: A Case Study of Superfund Priority List Pesticides.
Quantitative In Vitro-to-In Vivo Extrapolation for Mixtures: A Case Study of Superfund Priority List Pesticides.
复制标题
混合物的体外到体内定量外推：超级基金优先清单农药的案例研究。
DOI：
10.1093/toxsci/kfab076
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Rusyn,Ivan
中科院分区：
文献类型：
--
作者：
Valdiviezo,Alan;Luo,Yu-Syuan;Chen,Zunwei;Chiu,WeihsuehA;Rusyn,Ivan
在基于试管细胞的毒性测试方法中，会产生大量的数据，为基于风险的评估提供信息。为了能够将基于细胞的测试的定量输出外推到人体中的等量暴露水平，使用反向毒代动力学模型从体外有效浓度到活体剂量当量进行体外到体内的外推(IVE)。针对单个化学品的IVIVE建模方法已经建立得很好；然而，混合环境中的化学对化学相互作用对IVIVE的潜在影响在很大程度上仍未被探索。我们假设，化学联合暴露可以调节混合物中化学物质的蛋白质结合效率和肝细胞清除量，这反过来又会影响IVE的定量毒代动力学参数。为了验证这一假设，我们使用了来自有毒物质和疾病登记物质优先列表的20种杀虫剂，分别作为等摩尔混合物，并研究了化学相互作用在体外毒素动力学参数中的浓度依赖效应。采用超速离心法测定血浆蛋白结合率，并测定冻存原代人肝细胞悬液中肝细胞的清除率。我们发现，对于单一的化学物质，在不同的测试浓度下，蛋白质结合效率是相似的。然而，在混合物中，蛋白质结合效率和肝细胞清除率都受到影响。当IVE使用混合物衍生的毒代动力学数据进行IVE时，与使用单一化学实验的数据相比，对活度/暴露比的估计更保守。由于人类暴露在化学品混合物中，这项研究具有重要意义，因为它证明了将混合物衍生参数纳入体外生物活性数据中的重要性，以便准确地确定风险的优先顺序，并促进基于科学的决策。
In vitrocell-based toxicity testing methods generate large amounts of data informative for risk-based evaluations. To allow extrapolation of the quantitative outputs from cell-based tests to the equivalent exposure levels in humans, reverse toxicokinetic modeling is used to conductin vitro-to-in vivoextrapolation (IVIVE) fromin vitroeffective concentrations toin vivooral dose equivalents. IVIVE modeling approaches for individual chemicals are well-established; however, the potential implications of chemical-to-chemical interactions in mixture settings on IVIVE remain largely unexplored. We hypothesized that chemical coexposures could modulate both protein binding efficiency and hepatocyte clearance of the chemicals in a mixture, which would in turn affect the quantitative IVIVE toxicokinetic parameters. To test this hypothesis, we used 20 pesticides from the Agency for Toxic Substances and Disease Registry Substance Priority List, both individually and as equimolar mixtures, and investigated the concentration-dependent effects of chemical interactions onin vitrotoxicokinetic parameters. Plasma protein binding efficiency was determined by using ultracentrifugation, and hepatocyte clearance was estimated in suspensions of cryopreserved primary human hepatocytes. We found that for single chemicals, the protein binding efficiencies were similar at different test concentrations. In a mixture, however, both protein binding efficiency and hepatocyte clearance were affected. When IVIVE was conducted using mixture-derived toxicokinetic data, more conservative estimates of activity-to-exposure ratios were produced as compared with using data from single chemical experiments. Because humans are exposed to mixtures of chemicals, this study is significant as it demonstrates the importance of incorporating mixture-derived parameters into IVIVE forin vitrobioactivity data in order to accurately prioritize risks and facilitate science-based decision-making.