With the increasing human exposure to nanoparticles (NP), the evaluation of their genotoxic potential is of significant importance. However, relevance for NP of the routinely used in vitro genotoxicity assays is often questioned, and a nanoparticulate reference positive control would therefore constitute an important step to a better testing of NP, ensuring that test systems are really appropriate. In this study, we investigated the possibility of using tungsten carbide-cobalt (WC-Co) NP as reference positive control in in vitro genotoxicity assays, including 2 regulatory assays, the mouse lymphoma assay and the micronucleus assay, and in the Comet assay, recommended for the toxicological evaluation of nanomedicines by the French Agency of Human Health Products (Afssaps). Through these assays, we were able to study different genetic endpoints in 2 cell types commonly used in regulatory genotoxicity assays: the L5178Y mouse lymphoma cell line and primary cultures of human lymphocytes. Our results showed that the use of WC-Co NP as positive control in in vitro genotoxicity assays was conceivable, but that different parameters have to be considered, such as cell type and treatment schedule. L5178Y mouse lymphoma cells did not provide satisfactory results in the 3 performed tests. However, human lymphocytes were more sensitive to genotoxic effects induced by WC-Co NP, particularly after a 24-h treatment in the in vitro micronucleus assay and after a 4-h treatment in the in vitro Comet assay. Under such conditions, WC-Co could be used as a nanoparticulate reference positive control in these assays.

译文

随着人类对纳米颗粒 (NP) 的暴露增加,对其遗传毒性潜力的评估非常重要。然而,通常使用的体外遗传毒性测定与NP的相关性经常受到质疑,因此,纳米颗粒参考阳性对照将构成更好地测试NP的重要步骤,从而确保测试系统确实合适。在这项研究中,我们研究了在体外遗传毒性试验中使用碳化钨-钴 (WC-Co) NP作为参考阳性对照的可能性,包括2项调节试验,小鼠淋巴瘤试验和微核试验,以及在彗星试验中,法国人类健康产品局 (Afssaps) 推荐用于纳米药物的毒理学评估。通过这些测定,我们能够研究调节性遗传毒性测定中常用的2种细胞类型的不同遗传终点: L5178Y小鼠淋巴瘤细胞系和人类淋巴细胞的原代培养物。我们的结果表明,在体外遗传毒性测定中使用WC-Co NP作为阳性对照是可以想象的,但是必须考虑不同的参数,例如细胞类型和治疗时间表。L5178Y小鼠淋巴瘤细胞在3次进行的测试中均未提供令人满意的结果。然而,人类淋巴细胞对WC-Co NP诱导的遗传毒性作用更为敏感,尤其是在体外微核试验中进行24小时处理后以及在体外彗星试验中进行4小时处理后。在这种条件下,WC-Co可以在这些测定中用作纳米颗粒参考阳性对照。

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