Petkov Petko I, Patlewicz Grace, Schultz Terry W, Honma Masamitsu, Todorov Milen, Kotov Stefan, Dimitrov Sabcho D, Donner E Maria, Mekenyan Ovanes G
Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria.
DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE 19711, USA.
Regul Toxicol Pharmacol. 2015 Jun;72(1):17-25. doi: 10.1016/j.yrtph.2015.03.003. Epub 2015 Mar 16.
Carcinogenicity is a complex endpoint of high concern yet the rodent bioassay still used is costly to run in terms of time, money and animals. Therefore carcinogenicity has been the subject of many different efforts to both develop short-term tests and non-testing approaches capable of predicting genotoxic carcinogenic potential. In our previous publication (Mekenyan et al., 2012) we presented an in vitro-in vivo extrapolation workflow to help investigate the differences between in vitro and in vivo genotoxicity tests. The outcomes facilitated the development of new (Q)SAR models and for directing testing. Here we have refined this workflow by grouping specific tests together on the basis of their ability to detect DNA and/or protein damage at different levels of biological organization. This revised workflow, akin to an Integrated Approach to Testing and Assessment (IATA) informed by mechanistic understanding was helpful in rationalizing inconsistent study outcomes and categorizing a test set of carcinogens with mutagenicity data on the basis of regulatory mutagenicity classifications. Rodent genotoxic carcinogens were found to be correctly predicted with a high sensitivity (90-100%) and a low rate of false positives (3-10%). The insights derived are useful to consider when developing future (non-)testing approaches to address regulatory purposes.
致癌性是一个备受关注的复杂终点指标，但目前仍在使用的啮齿动物生物测定法在时间、金钱和动物使用方面成本高昂。因此，致癌性一直是许多不同努力的主题，旨在开发能够预测遗传毒性致癌潜力的短期测试和非测试方法。在我们之前的出版物（Mekenyan等人，2012年）中，我们提出了一种体外-体内外推工作流程，以帮助研究体外和体内遗传毒性测试之间的差异。这些结果促进了新的（定量）构效关系模型的开发，并指导了测试。在这里，我们通过根据特定测试在不同生物组织水平检测DNA和/或蛋白质损伤的能力将它们分组，对这个工作流程进行了优化。这个经过修订的工作流程类似于一种基于机制理解的综合测试与评估方法（IATA），有助于使不一致的研究结果合理化，并根据监管致突变性分类对一组具有致突变性数据的致癌物测试集进行分类。发现啮齿动物遗传毒性致癌物能够以高灵敏度（90-100%）和低假阳性率（3-10%）被正确预测。在开发未来用于满足监管目的的（非）测试方法时，所获得的见解是值得考虑的。
