Integrating structure annotation and machine learning approaches to develop graphene toxicity models

Modern nanotechnology provides efficient and cost-effective nanomaterials (NMs). The increasing usage of NMs brings great concerns regarding nanotoxicity in humans. Traditional animal testing of nanotoxicity is expensive and time-consuming. Modeling studies using machine learning (ML) approaches are promising alternatives to direct evaluation of nanotoxicity based on nanostructure features. However, NMs, including two-dimensional nanomaterials (2DNMs) such as graphenes, have complex structures making them difficult to annotate and quantify the nanostructures for modeling purposes. To address this issue, we constructed a virtual graphenes library using nanostructure annotation techniques. The irregular graphene structures were generated by modifying virtual nanosheets. The nanostructures were digitalized from the annotated graphenes. Based on the annotated nanostructures, geometrical nanodescriptors were computed using Delaunay tessellation and used for ML modeling. Partial least squares regression (PLSR) models for the graphenes were built and validated using a leave-one-out cross-validation (LOOCV) procedure. The resulted models showed good predictivity in four toxicity-related endpoints with the coefficient of determination (R2) ranging from 0.558 to 0.822. This study provides a novel nanostructure annotation strategy that can be applied to generate high-quality nanodescriptors for ML model developments, which can be widely applied to nanoinformatics studies of graphenes and other NMs.