A Safe‐by‐Design Principle Aligned Mixture INteraction TOXicity (MINTOX) Framework for Predicting the Joint Toxicity Effects in Metal Oxide Nanoparticle–Metal Ion Binary Mixtures: Toward Assessment of Innovative Advanced Materials

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.