Mechanistic Acute-to-Chronic Extrapolation through Sediment Toxicokinetic-Toxicodynamic Modeling

Ecological risk assessment often requires extrapolation from short-term laboratory-derived effects data to predict long-term ecological impacts of pollution exposure. This study developed a mechanistic toxicokinetic-toxicodynamic (TKTD) modeling framework to derive acute-to-chronic ratios (ACRs) for the benthic clam Ruditapes philippinarum exposed to sediment-associated Cu. To facilitate model development in the sediment context, we derived physiological parameters (k_e, C_IT, k_k) using aqueous toxicity tests and used diffusive gradients in thin-films (DGT) measurements to represent Cu bioavailability in sediments. The sediment TKTD model accurately predicted Cu accumulation in clam tissues and adequately predicted toxicity, with a 10% deviation from observed effects. Using model-predicted 7-day LC₅₀ and no-effect concentration, an ACR of 17 was determined for Cu-induced clam mortality. The framework was then applied to derive ACRs for other contaminants using literature-derived aqueous TKTD parameters, including cadmium (ACR_Cd: 11-87) and nanoplastic particles (ACR_NPs: 1.9-69). The new approach was also effective for elucidating how environmental variables (e.g., salinity, nanoplastic size) influence ACR values, thus offering insight which may be difficult to achieve by traditional empirical approaches. The study demonstrates the utility of TKTD modeling as a transparent and reproducible mechanistic method for acute-to-chronic extrapolation of toxicity as used for risk assessment applications.