Ruijter Nienke, Braakhuis Hedwig, Katsumiti Alberto, Garriz Itziar Polanco, Carriere Marie, Zanoni Ilaria, Candalija Ana, Marshall Jessica, Vermeulen Jolanda, Cassee Flemming R, Boyles Matthew
National Institute for Public Health & the Environment (RIVM), Bilthoven, The Netherlands.
TNO, Risk Analysis for Prevention, Innovation and Development, Utrecht, The Netherlands.
Arch Toxicol. 2025 Jun 25. doi: 10.1007/s00204-025-04100-5.
There is an increasing need for new approach methodologies (NAMs) for safety assessment of nanomaterials (NMs) in order to keep pace with innovation. In vitro assays are useful tools during pre-market hazard screening approaches of NMs to prioritize safe(r) candidate NMs and reduce the amount of regulatory testing required. For pre-regulatory hazard screening applications, it is crucial that in vitro assays have the capacity to distinguish between NMs based on their hazard potency and have the ability to provide accurate hazard rankings. In this paper, four types of silica particles (crystalline, pyrogenic, colloidal, and silane functionalized colloidal) were subjected to twenty-four in vitro assays to obtain hazard rankings using dose-response modelling. The assays were chosen for their relevance in the mechanism of action towards pulmonary inflammation upon inhalation of silica particles. The hazard rankings of silica particles were affected by cell type (alveolar or bronchial epithelial cells, macrophages), read-out method (cell viability, release of pro-inflammatory mediators, reactive oxygen species), and exposure method (submerged, air-liquid interface), complicating the assessment of the actual human hazard. Of particular note was an often muted in vitro response to the crystalline silica used in this study (DQ12), when in vivo data ranked this material as high hazard, due to the chronic and persistent in vivo inflammatory response to crystalline silica, highlighting an important functional discord between these models. However, the potency ranking of the silica particles to induce secretion of the pro-inflammatory mediator IL-1β by THP-1 cells differentiated to M0 macrophages as well as red blood cell haemolysis corresponded more closely to the hazard ranking based on data from rat inhalation studies. These assays should be further explored as indicators for human hazard potential of silica particles and other particles following a similar mechanism of action.
为了跟上创新的步伐，对纳米材料（NM）安全评估的新方法学（NAM）的需求日益增加。在纳米材料上市前的危害筛选方法中，体外试验是有用的工具，可用于对较安全的候选纳米材料进行优先排序，并减少所需的监管测试量。对于监管前的危害筛选应用，至关重要的是体外试验要有能力根据纳米材料的危害程度区分它们，并能够提供准确的危害排名。在本文中，对四种类型的二氧化硅颗粒（结晶型、热解型、胶体型和硅烷功能化胶体型）进行了24种体外试验，以使用剂量反应模型获得危害排名。选择这些试验是因为它们与吸入二氧化硅颗粒后引发肺部炎症的作用机制相关。二氧化硅颗粒的危害排名受细胞类型（肺泡或支气管上皮细胞、巨噬细胞）、读出方法（细胞活力、促炎介质释放、活性氧）和暴露方法（浸没、气液界面）的影响，这使得对实际人类危害的评估变得复杂。特别值得注意的是，本研究中使用的结晶二氧化硅（DQ12）在体外的反应往往不明显，而体内数据将该材料列为高危害，这是由于对结晶二氧化硅的体内慢性和持续性炎症反应，突出了这些模型之间重要的功能不一致。然而，二氧化硅颗粒诱导分化为M0巨噬细胞的THP - 1细胞分泌促炎介质IL - 1β以及红细胞溶血的效力排名与基于大鼠吸入研究数据的危害排名更为接近。这些试验应作为二氧化硅颗粒和其他具有类似作用机制的颗粒对人类潜在危害的指标进行进一步探索。
