A review of in vitro genotoxicity studies on titanium dioxide nanoparticles (TiO₂-NPs) published between 2010 and 2016 was performed by France in the framework of the CLP Regulation 1272/2008/EC. Neither the few in vivo studies of low quality nor the larger number of acceptable in vitro studies available for genotoxicity allowed France to conclude on the genotoxicity of TiO₂-NPs. Based on this work, it was decided to compare the acceptable in vitro studies to understand the reasons for the diverging results observed, such as the materials tested or of the protocols used and their inherent interferences. The systematic review performed on in vitro genotoxicity data for TiO₂-NPs was then restricted to studies with the highest level of confidence among studies following OECD guidelines and the largely applied comet assay. Indeed, the aim of this article is to understand why, even if judged of good quality, the 36 publications selected and analyzed did not lead to a clear picture. Some recommendations to be taken into account before performing new in vitro genotoxicity assays for insoluble particles such as TiO₂-NPs are proposed. Although secondary genotoxic effects consequent to oxidative stress seem to be the major mechanism responsible for the genotoxicity of TiO₂-NPs reported in some studies, primary genotoxic effects cannot be excluded. Further studies are needed to clarify the exact mode of action of TiO₂-NPs and to highlight which physicochemical properties lead to their genotoxicity in vitro to ultimately identify a specific combination of parameters that could represent a risk in vivo.

中文翻译：

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在监管背景下评估TiO ₂纳米粒子的体外遗传毒性

法国在CLP法规1272/2008 / EC的框架内对2010年至2016年发表的二氧化钛纳米粒子（TiO ₂ -NPs）的体外遗传毒性研究进行了综述。很少有质量低下的体内研究或大量关于遗传毒性的可接受的体外研究都不能使法国得出TiO ₂ -NPs的遗传毒性的结论。基于这项工作，决定比较可接受的体外研究，以了解观察到结果分歧的原因，例如测试的材料或所用规程及其固有干扰。对体外进行的系统评价然后将TiO ₂ -NPs的遗传毒性数据限制在遵循OECD指南和广泛应用的彗星试验的研究中，其置信度最高。的确，本文的目的是要理解，即使评判为高质量，为什么选择和分析的36篇出版物并没有清晰的画面。提出了对不溶性颗粒（如TiO ₂ -NPs）进行新的体外遗传毒性试验之前要考虑的一些建议。尽管氧化应激导致的继发性遗传毒性作用似乎是造成TiO ₂遗传毒性的主要机理-在一些研究中报道了NP，不能排除主要的遗传毒性作用。需要进一步的研究来阐明TiO ₂ -NPs的确切作用方式，并强调哪些理化性质导致其体外遗传毒性，以最终确定可能代表体内风险的参数的特定组合。