Department of Biomedicine and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7028, SE-750 07 Uppsala, Sweden.
Institute for Environmental Research, RWTH Aachen, Worringerweg 1, D-52074 Aachen, Germany.
Environ Sci Technol. 2021 Jan 5;55(1):447-457. doi: 10.1021/acs.est.0c04872. Epub 2020 Dec 15.
Linking cellular toxicity to low-tier animal toxicity and beyond is crucial within the adverse outcome pathway concept and the 3R framework. This study aimed to determine and compare the bioavailable effect concentrations in zebrafish cell lines and embryos. Acute, short-term toxicity (48 h) of eight veterinary pharmaceuticals was measured in two zebrafish cell lines (hepatocytes, fibroblasts) and zebrafish embryos. Seven endpoints of cytotoxicity were recorded. The fish embryo acute toxicity test was modified by adding sublethal endpoints. Chemical distribution modeling (mass balance) was applied to compute the bioavailable compound concentrations in cells () and embryos () based on nominal effect concentrations (). Effect concentration ratios were calculated (cell effects/embryo effects). A low correlation was observed between cytotoxicity and embryo toxicity when nominal concentrations were used. Modeled bioavailable effect concentrations strongly increased correlations and placed regression lines close to the line of unity and axis origin. Cytotoxicity endpoints showed differences in sensitivity and predictability. The hepatocyte cell line depicted closer proximity to the embryo data. Conclusively, the high positive correlation between the cell- and embryo-based test systems emphasizes the appropriate modulation of toxicity when linked to bioavailable concentrations. Furthermore, it highlights the potential of fish cell lines to be utilized in integrated testing strategies.
将细胞毒性与低等动物毒性联系起来，并超越这一点，是不良结局途径概念和 3R 框架中的关键。本研究旨在确定和比较斑马鱼细胞系和胚胎中的生物有效效应浓度。在两种斑马鱼细胞系（肝细胞、成纤维细胞）和斑马鱼胚胎中，测量了八种兽药的急性短期毒性（48 小时）。记录了 7 个细胞毒性终点。通过添加亚致死终点，对鱼类胚胎急性毒性试验进行了修改。应用化学分布建模（质量平衡），根据名义效应浓度（）计算细胞（）和胚胎（）中的生物有效化合物浓度。计算了效应浓度比（细胞效应/胚胎效应）。当使用名义浓度时，观察到细胞毒性与胚胎毒性之间的相关性很低。模型化的生物有效效应浓度强烈增加了相关性，并使回归线接近单位线和轴原点。细胞毒性终点表现出敏感性和可预测性的差异。肝细胞系更接近胚胎数据。总之，细胞和胚胎测试系统之间的高度正相关强调了将毒性与生物有效浓度联系起来时的适当调节。此外，它还突出了鱼类细胞系在综合测试策略中的潜在应用。
