In vivo genotoxicity testing strategies: Report from the 7th International workshop on genotoxicity testing (IWGT)
In vivo genotoxicity testing strategies: Report from the 7th International workshop on genotoxicity testing (IWGT)
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DOI：
10.1016/j.mrgentox.2019.03.008
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发表时间：
2019-11-01
影响因子：
1.9
通讯作者：
Williams, Andrew
中科院分区：
文献类型：
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作者：
Kirkland, David;Uno, Yoshifumi;Williams, Andrew
工作组在许多问题上达成了完全或多数一致。91种化学物质的TGR和体内彗星试验结果表明，它们本身具有类似的检测细菌诱变剂和Ames阳性致癌物本身的体内遗传毒性的能力。TGR和彗星试验结果与IARC第1组、2B组和未分类的致癌物相比没有显著差异。对于2B组化学物质以及IARC分类和未分类致癌物的组合，彗星试验的阳性反应明显更多，这是意料之中的，因为突变是遗传毒性的一个子集。肝脏彗星试验与骨髓/血液微核试验(MNviv)相结合将在体内检测到不表现出组织特异性或接触部位效应的遗传毒素，并且适合于常规的体内遗传毒性测试。通常，对于口服药物，只需要在接触胃肠道组织的一个部位(胃或十二指肠/空肠)进行彗星试验。在MNviv试验中，可以通过许多不同的方式获得目标组织暴露的证据根据ICH S2(R1)和EFSA(Hardy等人，2017)的建议。试验路线不适合活体试验；对于风险评估，应给予生理相关给药途径的数据更多的权重。肝脏MN试验对于制定OECD指南是充分有效的。然而，给6周龄的动物注射药物的影响需要评估。胃肠道MN试验显示了希望，但需要对OECD指南进行更多验证。Pig-a试验检测系统可用诱变剂，是体外阳性结果的有价值的后续行动。新的冻融协议提供了更大的灵活性。突变的网织红细胞和红细胞的频率都应该测定。在雄性大鼠生殖细胞中进行猪A试验的初步数据需要验证，包括生殖细胞DNA突变来源。
The working group reached complete or majority agreement on many issues.Results from TGR and in vivo comet assays for 91 chemicals showed they have similar ability to detect in vivo genotoxicity per se with bacterial mutagens and Ames-positive carcinogens.TGR and comet assay results were not significantly different when compared with IARC Group 1, 2 A, and unclassified carcinogens. There were significantly more comet assay positive responses for Group 2B chemicals, and for IARC classified and unclassified carcinogens combined, which may be expected since mutation is a subset of genotoxicity.A liver comet assay combined with the bone marrow/blood micronucleus (MNviv) test would detect in vivo genotoxins that do not exhibit tissue-specific or site-of-contact effects, and is appropriate for routine in vivo genotoxicity testing.Generally for orally administered substances, a comet assay at only one site-of-contact GI tract tissue (stomach or duodenum/jejunum) is required.In MNviv tests, evidence of target tissue exposure can be obtained in a number of different ways, as recommended by ICH S2(R1) and EFSA (Hardy et al., 2017).Except for special cases the i.p. route is inappropriate for in vivo testing; for risk evaluations more weight should be given to data from a physiologically relevant administration route.The liver MN test is sufficiently validated for the development of an OECD guideline. However, the impact of dosing animals > 6 weeks of age needs to be evaluated. The GI tract MN test shows promise but needs more validation for an OECD guideline.The Pig-a assay detects systemically available mutagens and is a valuable follow-up to in vitro positive results. A new freeze-thaw protocol provides more flexibility. Mutant reticulocyte and erythrocyte frequencies should both be determined. Preliminary data are available for the Pig a assay in male rat germ cells which require validation including germ cell DNA mutation orgin.