A Safe-by-Design Principle Aligned Mixture INteraction TOXicity (MINTOX) Framework for Predicting the Joint Toxicity...

Toxicity assessment in Innovative Advanced Materials is challenging owing to complex interactions between components. Here we present MINTOX as a proof-of-concept framework developed and demonstrated on binary mixtures of metal oxide nanoparticles and dissolved metal ions. The MINTOX integrated dose-response modeling based on four complementary toxicity indices to predict the nonlinear joint toxicity effects of nanomaterial-ion mixtures, and its application to 18 binary mixtures (TiO₂, ZnO, Fe₃O₄ × Cu²⁺/Ag⁺/Zn²⁺) in Daphnia magna acute toxicity assays showed that it accurately classified 56% of mixture outcomes based on concentration-addition metrics and 50% based on the model deviation ratio index, revealing predominantly antagonistic interactions (notably for TiO₂-Cu²⁺) and distinct synergy "hotspots" (TiO₂-Ag⁺ and ZnO-Ag⁺). Mechanistic analysis attributed antagonism, which limited ion bioavailability, to nanoparticle (NP) surface adsorption and heteroaggregation, whereas synergy was attributed to NP-mediated ROS generation. We propose this workflow as an early-stage screening tool that can support future assessment of IAM-like multicomponent systems, but the present study is restricted to nanoparticle-ion binary mixtures.