Cobalt Institute, Guildford GU1 4AP, UK.
Williams Chemical Consultancy Limited, Dublin, Ireland.
Toxicol Sci. 2020 Apr 1;174(2):311-325. doi: 10.1093/toxsci/kfz249.
Based on the wide use of cobalt substances in a range of important technologies, it has become important to predict the toxicological properties of new or lesser-studied substances as accurately as possible. We studied a group of 6 cobalt substances with inorganic ligands, which were tested for their bioaccessibility (surrogate measure of bioavailability) through in vitro bioelution in simulated gastric and intestinal fluids. Representatives of the group also underwent in vivo blood kinetics and mass balance tests, and both oral acute and repeated dose toxicity (RDT) testing. We were able to show a good correlation between high in vitro bioaccessibility with high in vivo bioavailability and subsequent high in vivo toxicity; consequently, low in vitro bioaccessibility correlated well with low in vivo bioavailability and low in vivo toxicity. In vitro bioelution in simulated gastric fluid was the most precise predictor of the difference in the oral RDT lowest observed adverse effect levels of 2 compounds representing the highly and poorly bioaccessible subset of substances. The 2 compounds cobalt dichloride hexahydrate and tricobalt tetraoxide differed by a factor of 440 in their in vitro bioaccessibility and by a factor of 310 in their RDT lowest observed adverse effect level. In summary, this set of studies shows that solubility, specifically in vitro bioelution in simulated gastric fluid, is a good, yet conservative, predictor of in vivo bioavailability and oral systemic toxicity of inorganic cobalt substances. Bioelution data are therefore an invaluable tool for grouping and read across of cobalt substances for hazard and risk assessment.
基于钴物质在一系列重要技术中的广泛应用，尽可能准确地预测新的或研究较少的物质的毒理学性质变得尤为重要。我们研究了一组 6 种具有无机配体的钴物质，通过在模拟胃液和肠液中的体外生物洗脱来测试它们的生物可利用性（生物利用度的替代测量）。该组的代表还进行了体内血液动力学和质量平衡测试以及口服急性和重复剂量毒性（RDT）测试。我们能够证明高体外生物可利用性与高体内生物利用度和随后的高体内毒性之间存在良好的相关性；因此，低体外生物可利用性与低体内生物利用度和低体内毒性密切相关。体外生物洗脱在模拟胃液中是预测口服 RDT 最低观察到不良效应水平的 2 种化合物（代表高和低生物可利用性物质子集）之间差异的最准确预测因子。2 种化合物六水合二氯化钴和四氧化三钴在体外生物可利用性方面相差 440 倍，在 RDT 最低观察到不良效应水平方面相差 310 倍。总之，这组研究表明，溶解度，特别是在模拟胃液中的体外生物洗脱，是无机钴物质体内生物利用度和口服全身毒性的良好但保守的预测因子。因此，生物洗脱数据是对钴物质进行危害和风险评估的分组和跨类推断的宝贵工具。
