The screen-and-bin approach for interpretation of genotoxicity data is predicated on three false assumptions: that genotoxicants are rare, that genotoxicity dose-response functions do not contain a low-dose region mechanistically characterized by zero-order kinetics, and that genotoxicity is not a bona fide toxicological endpoint. Consequently, there is a need to develop and implement quantitative methods to interpret genotoxicity dose-response data for risk assessment and regulatory decision-making. Standardized methods to analyze dose-response data, and determine point-of-departure (PoD) metrics, have been established; the most robust PoD is the benchmark dose (BMD). However, there are no standards for regulatory interpretation of mutagenicity BMDs. Although 5-10% is often used as a critical effect size (CES) for BMD determination, values for genotoxicity endpoints have not been established. The use of BMDs to determine health-based guidance values (HBGVs) requires assessment factors (AFs) to account for interspecies differences and variability in human sensitivity. Default AFs used for other endpoints may not be appropriate for interpretation of in vivo mutagenicity BMDs. Analyses of published dose-response data showing the effects of compensatory pathway deficiency indicate that AFs for sensitivity differences should be in the range of 2-20. Additional analyses indicate that the AF to compensate for short treatment durations should be in the range of 5-15. Future work should use available data to empirically determine endpoint-specific CES values; similarly, to determine AF values for BMD adjustment. Future work should also evaluate the ability to use in vitro dose-response data for risk assessment, and the utility of probabilistic methods for determination of mutagenicity HBGVs. Environ. Mol. Mutagen. 61:66-83, 2020. © 2019 Her Majesty the Queen in Right of Canada.

中文翻译：

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遗传毒性剂量反应数据的定量解释，用于风险评估和监管决策：现状和新兴优先事项。

用于解释遗传毒性数据的筛选和结合方法是基于三个错误的假设：遗传毒性很少，遗传毒性剂量反应功能不包含以零级动力学为特征的低剂量区域，遗传毒性为不是真正的毒理学终点。因此，需要开发和实施定量方法来解释遗传毒性剂量反应数据，以进行风险评估和监管决策。已经建立了用于分析剂量反应数据并确定出发点（PoD）指标的标准化方法；最可靠的PoD是基准剂量（BMD）。但是，对于致突变性BMD的监管解释尚无标准。尽管5-10％通常用作确定BMD的关键效应量（CES），尚未确定遗传毒性终点的值。使用BMD来确定基于健康的指导值（HBGV）需要评估因子（AF）来说明物种间的差异和人类敏感性的变异性。用于其他终点的默认AF可能不适用于解释体内致突变性BMD。公布的剂量反应数据分析显示，补偿性途径不足的影响表明，AF的敏感性差异应在2-20的范围内。进一步的分析表明，为补偿较短的治疗时间，AF应在5-15的范围内。未来的工作应使用可用数据凭经验确定特定于端点的CES值；类似地，确定用于BMD调整的AF值。未来的工作还应该评估使用体外剂量反应数据进行风险评估的能力，以及用于确定致突变性HBGV的概率方法的实用性。环境。大声笑 诱变剂。61：66-83，2020.©2019加拿大女王Queen下。