A Theoretical Protein Surface-Binding Model for Toxicokinetic Predictions in Aquatic Species

Abstract Understanding the relationship between external exposure and internal concentration is fundamental to environmental safety assessment. A key measure of chemical accumulation in aquatic species is the ratio between the organism’s internal concentration and the external water concentration. Current methods for estimating species-specific long-exposure steady-state ratios are semiempirical, relying on calibration of mathematical models to experimental in vivo toxicokinetic data. However, this approach has limited applicability for novel chemicals lacking such data. Here, we present a new theoretical model that can predict chemical accumulation for novel compounds without requiring in vivo data. An expression for steady-state was derived from differential equations describing chemical lipid partitioning and protein surface-binding. The derived protein contribution term introduces a novel relationship between the protein fraction and external concentration. The predicted steady-state concentration ratios were validated against historical in vivo data. A calibration-free special-case expression provided conservative estimates (∼70-fold higher on average) of chemical accumulation in 99% of 1973 steady-state ratios across 50 aquatic species, including vertebrates and invertebrates. Future work will address overprediction by incorporating biotransformation. This approach supports next-generation safety assessment by enabling safety decisions without calibration to in vivo data, thereby reducing the burden of generating chemical-specific information.