Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Arch Toxicol. 2023 Sep;97(9):2303-2328. doi: 10.1007/s00204-023-03553-w. Epub 2023 Jul 5.
Genotoxicity data are mainly interpreted in a qualitative way, which typically results in a binary classification of chemical entities. For more than a decade, there has been a discussion about the need for a paradigm shift in this regard. Here, we review current opportunities, challenges and perspectives for a more quantitative approach to genotoxicity assessment. Currently discussed opportunities mainly include the determination of a reference point (e.g., a benchmark dose) from genetic toxicity dose-response data, followed by calculation of a margin of exposure (MOE) or derivation of a health-based guidance value (HBGV). In addition to new opportunities, major challenges emerge with the quantitative interpretation of genotoxicity data. These are mainly rooted in the limited capability of standard in vivo genotoxicity testing methods to detect different types of genetic damage in multiple target tissues and the unknown quantitative relationships between measurable genotoxic effects and the probability of experiencing an adverse health outcome. In addition, with respect to DNA-reactive mutagens, the question arises whether the widely accepted assumption of a non-threshold dose-response relationship is at all compatible with the derivation of a HBGV. Therefore, at present, any quantitative genotoxicity assessment approach remains to be evaluated case-by-case. The quantitative interpretation of in vivo genotoxicity data for prioritization purposes, e.g., in connection with the MOE approach, could be seen as a promising opportunity for routine application. However, additional research is needed to assess whether it is possible to define a genotoxicity-derived MOE that can be considered indicative of a low level of concern. To further advance quantitative genotoxicity assessment, priority should be given to the development of new experimental methods to provide a deeper mechanistic understanding and a more comprehensive basis for the analysis of dose-response relationships.
遗传毒性数据主要以定性方式解释，这通常导致化学物质的二元分类。十多年来，人们一直在讨论在这方面需要转变范式。在这里，我们回顾了更定量地评估遗传毒性的当前机会、挑战和观点。目前讨论的机会主要包括从遗传毒性剂量反应数据中确定参考点（例如，基准剂量），然后计算暴露量比（MOE）或推导基于健康的指导值（HBGV）。除了新的机会外，遗传毒性数据的定量解释还出现了主要挑战。这些主要源于标准体内遗传毒性测试方法检测多种靶组织中不同类型遗传损伤的能力有限，以及可测量遗传毒性效应与发生不良健康后果的概率之间的未知定量关系。此外，对于 DNA 反应性诱变剂，人们质疑广泛接受的非阈值剂量反应关系假设是否与 HBGV 的推导完全兼容。因此，目前任何定量遗传毒性评估方法都需要逐个进行评估。出于优先级目的（例如，与 MOE 方法相关）对体内遗传毒性数据进行定量解释，可以被视为常规应用的有希望的机会。然而，需要进一步研究以评估是否可以定义一个可以被认为是低关注水平的遗传毒性衍生的 MOE。为了进一步推进定量遗传毒性评估，应优先开发新的实验方法，以提供更深入的机制理解和更全面的剂量反应关系分析基础。
