Quantifying the Amplification of Organophosphate Ester-Induced Visual Risk by Nanoplastics Considering Dual Mechanisms of Vector Effects and Efflux Inhibition

Nanoplastics (NPs) are pervasive in aquatic environments, where they co-occur with chemical contaminants, potentially modulating their toxicological behaviors. However, the combined risks of these mixtures remain poorly characterized due to complex interactions and challenges in extrapolating laboratory findings to realistic scenarios. Here, using the representative flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) as a model co-contaminant, we evaluated the combined toxicity of TDCIPP and NPs with varying aging and modification properties at environmentally relevant concentrations by integrating transcriptomics, bioassays, molecular dynamics, and mechanistic modeling. We demonstrated that NPs significantly amplified the bioaccumulation and visual toxicity of TDCIPP in zebrafish larvae. This chemosensitization was driven by dual mechanisms: NPs served as vectors enhancing TDCIPP uptake and concurrently inhibited cellular efflux transporters via downregulation and competitive binding. Aged and amino-modified NPs exhibited stronger effects. We further developed a mechanism-based predictive framework coupling a refined toxicokinetic model to a quantitative adverse outcome pathway for visual impairment. This framework substantially improved toxicity predictions and, when supported by field data, indicated that 1 mg/L NPs amplify the TDCIPP-induced visual impairment risk by 21.35%. This work provides a dynamic and cross-scale perspective from molecular interactions to individual-level risks, offering an extrapolatable approach for assessing the NP-contaminant combined effects on aquatic health.