Nanosized titanium dioxide (TiO₂) has been investigated in numerous studies on genotoxicity, including comet assay endpoints and oxidatively damaged DNA in cell cultures and animal models. The results have been surprisingly mixed, which might be attributed to physico-chemical differences of the tested TiO₂. In the present review, we assess the role of certain methodological issues and publication bias. The analysis shows that studies on DNA strand breaks without proper assay controls or very low intra-group variation tend to show statistically significant effects. Levels of oxidatively damaged DNA, measured by the enzyme-modified comet assay, tend to show no effect in studies that have not included proper assay controls or they have uncertainty about the measurement. In addition, there are indications of publication and reporting bias. Nevertheless, the analysis shows that Aeroxide P25 generates DNA strand breaks in a concentration-dependent manner, which is not dependent on the duration of exposure. The standard comet assay seems to be able to discriminate between the genotoxicity of different types of TiO₂, where anatase TiO₂ seems to be the form with strongest genotoxic potential. Cell culture studies also demonstrate increased levels of oxidatively damaged DNA after exposure to TiO₂. There are relatively few studies on animal models where DNA strand breaks and oxidatively damaged DNA have been tested with reliable methods. Collectively, this review shows that exposure to nanosized TiO₂ is associated with genotoxicity in cells, whereas there are still too few reliable studies to assess the genotoxic potential in animal models.

中文翻译：

---

评估纳米二氧化钛产生的DNA链断裂和细胞和动物模型中的DNA氧化损伤的证据

纳米二氧化钛（TiO ₂）已在许多关于基因毒性的研究中进行了研究，包括彗星分析的终点以及细胞培养物和动物模型中的氧化损伤的DNA。结果令人惊讶地混合在一起，这可能是由于所测试的TiO _2的物理化学差异所致。在本综述中，我们评估了某些方法论问题和出版偏见的作用。分析表明，对DNA链断裂的研究如果没有适当的分析控制或极低的组内变异，往往会显示出统计学上的显着效果。通过酶修饰的彗星试验测定的氧化损伤DNA的水平，在没有包括适当的试验对照或对测定结果不确定的研究中往往没有效果。此外，还有迹象表明发布和报告存在偏差。然而，分析表明，Aeroxide P25以浓度依赖的方式产生DNA链断裂，这与暴露的持续时间无关。标准彗星试验似乎能够区分不同类型的TiO ₂的遗传毒性，其中锐钛矿TiO ₂似乎是具有最强遗传毒性的形式。细胞培养研究还表明，暴露于TiO ₂后，DNA氧化损伤水平增加。在动物模型中，很少有研究使用可靠的方法对DNA链断裂和氧化损伤的DNA进行测试。总的来说，这项综述表明，暴露于纳米级的TiO ₂与细胞的遗传毒性有关，而评估动物模型的遗传毒性潜力的可靠研究仍然很少。