Quantitative Structure-Activity Relationship Models for Predicting Inflammatory Potential of Metal Oxide Nanoparticles

B ACKGROUND : Although substantial concerns about the in fl ammatory e ff ects of engineered nanomaterial (ENM) have been raised, experimentally assessing toxicity of various ENMs is challenging and time-consuming. Alternatively, quantitative structure - activity relationship (QSAR) models have been employed to assess nanosafety. However, no previous attempt has been made to predict the in fl ammatory potential of ENMs. O BJECTIVES : By employing metal oxide nanoparticles (MeONPs) as a model ENM, we aimed to develop QSAR models for prediction of the in fl am- matory potential by their physicochemical properties. M ETHODS : We built a comprehensive data set of 30 MeONPs to screen a proin fl ammatory cytokine interleukin (IL) -1 beta (IL -1 b ) release in THP-1 cell line. The in vitro hazard ranking was validated in mouse lungs by oropharyngeal instillation of six randomly selected MeONPs. We established QSAR models for prediction of MeONP-induced in fl ammatory potential via machine learning. The models were further validated against seven new MeONPs. Density functional theory (DFT) computations were exploited to decipher the key mechanisms driving in fl ammatory responses of MeONPs. R ESULTS : Seventeen out of 30 MeONPs induced excess IL -1 b production in THP-1 cells. In vivo disease outcomes were highly relevant to the in vitro data. QSAR models were developed for in fl ammatory potential, with predictive accuracy (ACC) exceeding 90%. The models were further validated experimentally against seven independent MeONPs (ACC = 86 % ). DFT computations and experimental results further revealed the underlying mech- anisms: MeONPs with metal electronegativity lower than 1.55 and positive f -potential were more likely to cause lysosomal damage and in fl ammation. C ONCLUSIONS : IL -1 b released in THP-1 cells can be an index to rank the in fl ammatory potential of MeONPs. QSAR models based on IL -1 b were able to pre- dict the in fl ammatory potential of MeONPs. Our approach overcame the challenge of time- and labor -consuming biological experiments and allowed for com- putational assessment of MeONP in fl ammatory potential by characterization of their physicochemical properties. https://doi.org/10.1289/EHP6508