Deciphering size-dependent inter-organ translocation of nanoplastics in fish using metal-labeled proxies and physiologically based toxicokinetic modeling

Nanoplastics (NPs) are extensively ingested by aquatic organisms, but quantitative inter-organ translocation kinetics remain poorly characterized, hindering their environmental risk assessment. We used metal-labeled NPs as proxies to trace bioaccumulation, biodistribution and depuration processes of two-sized NPs (200 nm L-NPs and 50 nm S-NPs) in zebrafish under environmentally relevant concentrations via waterborne (100 μg/L) and dietary (1000 μg/kg) exposure. Subsequently, we developed a physiologically based toxicokinetic model with seven compartments: blood, brain, gills, intestine, liver, gonad, and carcass. The model accurately described NPs toxicokinetics across compartments (overall R 2 ranging from 0.916 to 0.993). Organ exchange rates were quantified, revealing that NPs size determines inter-organ translocation capacity, with smaller NPs exhibiting stronger translocation capability. This model mathematically confirmed gills as the primary uptake route for aqueous NPs (>70 % mean contribution) and intestine as the major elimination route regardless of exposure pathway. Enterohepatic circulation was identified, with S-NPs showing enhanced recirculation capacity. Differential biological half-lives ( t 1/2 ) across organs caused tissue-specific residual patterns. Specifically, intestine dominated NPs distribution during exposure, whereas organs with longer t 1/2 (e.g., carcass) dominated residual NPs after depuration. This study provides a framework to quantify inter-organ translocation of NPs, elucidating the size-driven mechanisms governing tissue-specific burdens and environmental risks from different route exposures. • This is the first whole-body PBTK model for nanoplastics in fish. • Contributions of waterborne and dietary exposure to NPs bioaccumulation were quantified. • Smaller NPs demonstrated greater susceptibility to biotranslocation. • The gills as the primary uptake route for aqueous NPs and intestine as the major elimination route. • This model explains the tissue-specific residual patterns of NPs of different sizes.