Kirkland et al. [Mutation Research/Genetic Toxicology and Environmental Mutagenesis 847 (2019) 403035, https://doi.org/10.1016/j.mrgentox.2019.03.008; Mutation Research/Genetic Toxicology and Environmental Mutagenesis 839 (2019): 21–35, https://doi.org/10.1016/j.mrgentox.2019.01.007] made recommendations on the use of the in vivo comet and transgenic rodent (TGR) gene mutation assays to screen for in vivo mutagenicity. Although it is not directly stated in either of these publications, we are concerned that the reports could potentially be used to support assertions that it is equally acceptable to follow up a positive bacterial reverse mutation (Ames) finding for an investigational drug with either the in vivo TGR mutation assay or an in vivo comet assay. For regulatory genotoxicity assessment, the in vivo follow-up for an in vitro bacterial mutation-positive drug, drug-related metabolite, or impurity should be based upon evaluating a similar endpoint (i.e., mutagenicity) as the intent is to determine if the findings of in vitro gene mutation correlate with findings of in vivo gene mutation (i.e., biologically relevant to the in vitro results). Thus, the most scientifically appropriate in vivo assays would be the TGR mutation assay or, in some circumstances, the in vivo Pig-a assay. An in vivo rodent comet assay or combination of the in vivo micronucleus and in vivo rodent comet assays would generally not be an appropriate follow-up test.

柯克兰等人。[突变研究/遗传毒理学和环境诱变847（2019）403035，https://doi.org/10.1016/j.mrgentox.2019.03.008；Mutation Research/Genetic Toxicology and Environmental Mutagenesis 839 (2019): 21–35, https://doi.org/10.1016/j.mrgentox.2019.01.007] 就体内彗星和转基因啮齿动物 (TGR ) 的使用提出了建议) 基因突变测定以筛选体内致突变性。尽管在这些出版物中都没有直接说明，但我们担心这些报告可能会被用来支持这样的断言，即对具有体内TGR 突变测定或体内彗星试验。对于监管遗传毒性评估，体外细菌突变阳性药物、药物相关代谢物或杂质的体内随访应基于评估类似终点（即致突变性），因为目的是确定是否体外基因突变的发现与体内基因突变的发现相关（即，与体外结果生物学相关）。因此，最科学的体内试验是 TGR 突变试验，或者在某些情况下是体内 Pig-a试验。体内_啮齿动物彗星试验或体内微核和体内啮齿动物彗星试验的组合通常不是合适的后续试验。