Judson Richard S, Martin Matthew T, Patlewicz Grace, Wood Charles E
U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
Regul Toxicol Pharmacol. 2017 Jun;86:74-92. doi: 10.1016/j.yrtph.2017.02.015. Epub 2017 Feb 24.
Predictive toxicity models rely on large amounts of accurate in vivo data. Here, we analyze the quality of in vivo data from the U.S. EPA Toxicity Reference Database (ToxRefDB), using chemical-induced anemia as an example. Considerations include variation in experimental conditions, changes in terminology over time, distinguishing negative from missing results, observer and diagnostic bias, and data transcription errors. Within ToxRefDB, we use hematological data on 658 chemicals tested in one or more of 1738 studies (subchronic rat or chronic rat, mouse, or dog). Anemia was reported most frequently in the rat subchronic studies, followed by chronic studies in dog, rat, and then mouse. Concordance between studies for a positive finding of anemia (same chemical, different laboratories) ranged from 90% (rat subchronic predicting rat chronic) to 40% (mouse chronic predicting rat chronic). Concordance increased with manual curation by 20% on average. We identified 49 chemicals that showed an anemia phenotype in at least two species. These included 14 aniline moiety-containing compounds that were further analyzed for their potential to be metabolically transformed into substituted anilines, which are known anemia-causing chemicals. This analysis should help inform future use of in vivo databases for model development.
预测毒性模型依赖于大量准确的体内数据。在此，我们以化学诱导贫血为例，分析了美国环境保护局毒性参考数据库（ToxRefDB）中体内数据的质量。考虑因素包括实验条件的变化、术语随时间的变化、区分阴性结果与缺失结果、观察者和诊断偏差以及数据转录错误。在ToxRefDB中，我们使用了1738项研究（亚慢性大鼠或慢性大鼠、小鼠或犬）中一项或多项研究里测试的658种化学物质的血液学数据。贫血在大鼠亚慢性研究中报告最为频繁，其次是犬、大鼠的慢性研究，然后是小鼠的慢性研究。不同研究（相同化学物质，不同实验室）中贫血阳性结果的一致性范围为90%（大鼠亚慢性预测大鼠慢性）至40%（小鼠慢性预测大鼠慢性）。经人工整理后，一致性平均提高了20%。我们鉴定出49种在至少两个物种中表现出贫血表型的化学物质。其中包括14种含苯胺部分的化合物，对其代谢转化为已知的致贫血化学物质取代苯胺的潜力进行了进一步分析。该分析应有助于为未来体内数据库在模型开发中的应用提供参考。
