Alarms about Structural Alerts
Alarms about Structural Alerts
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有关结构警报的警报
DOI：
10.1002/chin.201640272
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
A. Tropsha
中科院分区：
文献类型：
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作者：
A. Tropsha
结构警报在化学毒理学和监管决策支持中被广泛接受，作为一种简单而透明的手段来标记潜在的化学危险或将化合物分组以供通读。然而，人们越来越关注不成比例地将化学物质标记为有毒的警报，这对它们作为毒性标志物的可靠性提出了质疑。相反，经过严格开发和适当验证的统计QSAR模型可以准确和可靠地预测化学品的毒性；然而，由于缺乏透明度和可解释性，它们在调节毒理学中的使用一直受到阻碍。我们证明，与通常认为的定量构效关系模型是“黑匣子”相反，它们可以用来识别影响毒性的统计意义重大的化学亚结构(基于定量构效关系的警报)。然而，我们通过几个案例研究表明，在一种化学物质中仅仅存在结构警报，而不考虑推导方法(基于专家或基于QSAR)，应该仅被视为可能的毒理学效应的假设。我们提出了一种新的方法，将结构警报和经过严格验证的QSAR模型协同集成，以对新化学品进行更透明和准确的安全评估。
Structural alerts are widely accepted in chemical toxicology and regulatory decision support as a simple and transparent means to flag potential chemical hazards or group compounds into categories for read-across. However, there has been a growing concern that alerts disproportionally flag chemicals as toxic, which questions their reliability as toxicity markers. Conversely, rigorously developed and properly validated statistical QSAR models can accurately and reliably predict the toxicity of a chemical; however, their use in regulatory toxicology has been hampered by a lack of transparency and interpretability. We demonstrate that contrary to the common perception of QSAR models as “black boxes” they can be used to identify statistically significant chemical substructures (QSAR-based alerts) that influence toxicity. We show through several case studies, however, that the mere presence of structural alerts in a chemical, irrespective of the derivation method (expert-based or QSAR-based), should be perceived only as hypotheses of possible toxicological effect. We propose a new approach that synergistically integrates structural alerts and rigorously validated QSAR models for a more transparent and accurate safety assessment of new chemicals.
DOI：
10.1039/c6gc01492e
发表时间：
2016-08-21
期刊：
Green chemistry : an international journal and green chemistry resource : GC
影响因子：
--
作者：
Alves V;Muratov E;Capuzzi S;Politi R;Low Y;Braga R;Zakharov AV;Sedykh A;Mokshyna E;Farag S;Andrade C;Kuz'min V;Fourches D;Tropsha A
通讯作者：
Tropsha A