Application of in vitro pulmonary models for hazard screening of silica particles.

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.