Boobis Alan, Brown Paul, Cronin Mark Timothy David, Edwards James, Galli Corrado Lodovico, Goodman Jay, Jacobs Abigail, Kirkland David, Luijten Mirjam, Marsaux Cyril, Martin Matthew, Yang Chihae, Hollnagel Heli Miriam
a Department of Medicine , Imperial College London , London , UK.
b US Food and Drug Administration , Silver Spring , MD , USA.
Crit Rev Toxicol. 2017 Sep;47(8):705-727. doi: 10.1080/10408444.2017.1318822. Epub 2017 May 16.
The threshold of toxicological concern (TTC) approach is a resource-effective de minimis method for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritize substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on the analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenic mode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicity and that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application.
毒理学关注阈值（TTC）方法是一种基于大量毒理学研究结果的分布分析，对化学品进行安全评估的资源高效的最低风险方法。它越来越多地用于筛选和优先排序低暴露且几乎没有或没有毒理学信息的物质。该方法的第一步是识别可能是DNA反应性诱变剂的物质，并应用最低的TTC值。这个TTC值基于癌症效力数据库的分析，涉及一些不再反映科学现状的假设，其中一些假设也不够透明。因此，建议使用反映当前知识的纳入和排除标准对数据库进行审查和更新。概述了一种基于对遗传毒性和致癌性证据权重的考虑来选择用于TTC测定的合适物质的策略。识别通过DNA反应性诱变作用方式致癌的物质以及那些明显通过非遗传毒性作用方式起作用的物质，将能够确定DNA反应性诱变毒性的TTC以及默认应用于可能致癌但不太可能是DNA反应性诱变剂的物质（即Cramer I-III类化合物）的保护作用。将TTC方法应用于可能是DNA反应性诱变剂的物质的关键在于用于识别此类化合物的软件工具的可靠性。本文对当前用于此任务的方法进行了综述，并对其应用提出了建议。
