Abstract:
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.
摘要:
遗传毒性数据主要以定性的方式解释,这通常导致化学实体的二元分类。十多年来,已经有关于在这方面需要转变范式的讨论。这里,我们回顾当前的机会,更定量的基因毒性评估方法的挑战和观点。当前讨论的机会主要包括确定参考点(例如,基准剂量)来自遗传毒性剂量效应数据,然后计算暴露裕度(MOE)或推导基于健康的指导值(HBGV)。除了新的机会,遗传毒性数据的定量解释出现了主要挑战。这些主要源于标准体内遗传毒性测试方法在多个靶组织中检测不同类型的遗传损伤的能力有限,以及可测量的遗传毒性作用与经历不良健康结果的可能性之间的未知定量关系。此外,关于DNA反应诱变剂,出现了一个问题,即广泛接受的非阈值剂量-反应关系的假设是否与HBGV的推导完全兼容.因此,目前,任何定量的遗传毒性评估方法仍有待逐案评估。用于优先排序目的的体内遗传毒性数据的定量解释,例如,关于教育部的方法,可以被视为常规应用的有希望的机会。然而,需要更多的研究来评估是否有可能定义一种遗传毒性来源的MOE,这种遗传毒性来源的MOE可以被认为是低水平关注的指标.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,以便为剂量反应关系的分析提供更深入的机理理解和更全面的基础。