Size-dependent sensitization of copper toxicity by polystyrene nanoplastics revealed by toxicokinetic–toxicodynamic modeling

Nanoplastics (NPs) and heavy metals coexist widely in aquatic environments, yet the quantitative mechanisms by which NP size regulates their combined toxicity remain unclear. Here, we applied a toxicokinetic-toxicodynamic (TK-TD) modeling approach to investigate the individual and combined effects of copper (Cu) and polystyrene NPs (PS-NPs, 50 and 300 nm) on zebrafish. TK analysis revealed that 50 nm PS-NPs (PS) exhibited a 5.6% higher uptake rate and a 33.2% slower elimination rate than 300 nm PS-NPs (PS). The prolonged internal residency of PS (12.1 h; 8.1 h for PS) revealed their superior vector ability, which culminated in a 2.05-fold increase in the Cu body burden compared to the Cu-only control. Critically, TD modeling revealed a sensitization effect, whereby co-exposure to 2 mg L of PS and Cu significantly reduced the critical internal threshold of Cu, indicating compromised organismal tolerance. This sensitization was driven by exacerbated oxidative stress and intestinal barrier damage, as evidenced by lipid peroxidation, antioxidant depletion, and goblet cell loss. Therefore, the enhanced toxicity of Cu by smaller NPs is not merely due to increased internal burden but results from the consequential sensitization of the host. This study revealed the heightened ecological risks posed by smaller NPs and their interactions with heavy metals, underscoring the urgent need to prioritize these co-exposure scenarios in environmental risk assessments.