The Safe-by-Design (SbD) concept aims to facilitate the development of safer materials/products, safer production, and safer use and end-of-life by performing timely SbD interventions to reduce hazard, exposure, or both. Early hazard screening is a crucial first step in this process. In this review, for the first time, commonly used in vitro assays are evaluated for their suitability for SbD hazard testing of nanomaterials (NMs). The goal of SbD hazard testing is identifying hazard warnings in the early stages of innovation. For this purpose, assays should be simple, cost-effective, predictive, robust, and compatible. For several toxicological endpoints, there are indications that commonly used in vitro assays are able to predict hazard warnings. In addition to the evaluation of assays, this review provides insights into the effects of the choice of cell type, exposure and dispersion protocol, and the (in)accurate determination of dose delivered to cells on predictivity. Furthermore, compatibility of assays with challenging advanced materials and NMs released from nano-enabled products (NEPs) during the lifecycle is assessed, as these aspects are crucial for SbD hazard testing. To conclude, hazard screening of NMs is complex and joint efforts between innovators, scientists, and regulators are needed to further improve SbD hazard testing.

The concept of safe-by-design (SbD) can help toxicologists and risk assessors to keep pace with the rapidly expanding field of nanotechnology. As part of SbD, the hazard potential of a new nanomaterial (NM) is identified at the first stages of product development. For this, simple yet predictive toxicity assays are crucial. We investigated the suitability of several in vitro models and exposure methods to predict the human (pulmonary) inflammation potential of NMs. Four silica NMs were selected of which in vivo pulmonary toxicity ranking had previously been established: DQ12 (quartz) > NM-203 (fumed silica) > Colloidal silica > Silanized colloidal silica. Several cell types including a 3D human airway epithelial model, lung epithelial cell lines, and immune cell lines, either in mono- or co-culture were exposed to the four materials either in a submerged setting or at the air-liquid interface (ALI). After 24 hours of exposure, cytokine response was assessed using either 13-plex LegendPlex, ELISA, or qPCR, and toxicity rankings were compared. The results indicate differences in sensitivity between cell models and exposure methods. Submerged exposure of a cell-line seems a suitable first tier for SbD hazard testing in case of NMs that can easily be dispersed. For NMs that are not compatible with submerged testing, ALI exposure might be needed. Higher tier testing might be used to confirm the ranking.

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