Numeric uptake drives nanoplastic toxicity: Size-effects uncovered by toxicokinetic-toxicodynamic (TKTD) modeling.

Predicting nanoplastic bioaccumulation and toxicity using process-based models is challenging due to the difficulties in tracing them at low concentrations. This study investigates the size-dependent effects of nanoplastic exposure on Daphnia magna using a toxicokinetic-toxicodynamic (TKTD) model. Palladium-doped fluorescent nanoplastics in three sizes (30-nm, 66-nm, 170-nm) were tested at two numeric exposure concentrations. The TK model reproduced nanoplastic uptake and elimination, indicating a uniform elimination rate constant (0.035 h) across sizes, while uptake rate constants (k) varied by size and concentration. Fluorescence analysis revealed larger nanoplastics (66-nm, 170-nm) accumulated primarily in the intestine, while smaller nanoplastics (30-nm) were more widely distributed. Re-modeling uptake specifically for the intestine showed consistent trends in the uptake rate constants, with larger nanoplastics exhibiting higher ingestion efficiency. Toxicity effects mirrored the order of whole-organism nanoplastic uptake: 30-nm nanoplastics were most toxic, 170-nm nanoplastics showed slight toxicity, and 66-nm nanoplastics were non-toxic. The TD model suggested similar hazard potentials across sizes, with observed toxicity differences likely driven by whole-organism particle uptake. The TKTD model predicted no-effect concentrations at 1.8 × 10 and 6.0 × 10 particles L for 30-nm and 170-nm nanoplastics, respectively, corresponding to mass concentrations of 2.54 and 1540 mg L. These values are significantly higher than reported environmental levels, indicating a low current toxicity risk to D. magna. Overall, this study enhances understanding of how size-dependent uptake behaviors influence nanoplastic toxicity, stressing the need for more accurate assessment of hazards linked to low-size nanoplastics and supporting more informed decision-making in nanoplastic pollution management.