Hierarchy of nanoparticles toxicity factors significance as extracted from NanoCommons knowledge base: influence of compound, cell line and particle size on cell viability

The objective of the paper was to conduct a thorough statistical meta-analysis of a publicly available database by examining cell membrane damage (CMD), mitochondrial membrane potential (MMP), nuclear size (NS), nuclear intensity (NI), and cell viability (CVV) responses toward nanoparticles. The set of individual 880 and the subset of 630 measurements contained exposure dose, particle diameter, nanoparticle identity (TiO₂, Ag, SiO₂, CeO₂, ZnO, Cu), and cell type (A549, HCT116, HepaRG, HEPG2, RAW264.7) correlated to toxicity markers. The exposure dose was revealed as the most consistent predictor of toxicity across all endpoints, with higher doses significantly influencing toxicity. The compound-specific response was another important factor, where Ag, ZnO, and Cu, were consistently more cytotoxic, while ZnO and Cu correlated to loss of CVV and MMP. Contrary, TiO₂, CeO₂ and SiO₂ displayed partial protective effects, depending on cell context. The effect of particle size was compound- and endpoint-specific, e.g. smaller particles of CeO₂ displayed greater disruption to nuclear architecture (NS, NI) and MMP, while size had minimal effect on CVV for other compounds. HepaRG cells were the most sensitive, specifically from Cu and ZnO, while epithelial lines (e.g. HCT116, HEPG2) showed more complex patterns. Generally, the dose was confirmed as the most impactful predictor, due to consistent and statistically significant effects. Compounds and cell lines were determined as factors of next-highest importance, displaying mixed but significant effects, and the particle size showed lowest effects. These findings highlight the importance of multi-endpoint, multi-cell-type frameworks in nanotoxicology for compound- and cell-specific risk assessments.