A Generalized Physiologically Based Kinetic Model for Fish forEnvironmental Risk Assessment of Pharmaceuticals

An increasing number of pharmaceuticals found in the environment potentially impose adverseeffects on organisms such asfish. Physiologically based kinetic (PBK) models are essential risk assessment tools,allowing a mechanistic approach to understanding chemical effects within organisms. However,fish PBKmodels have been restricted to a few species, limiting the overall applicability given the countless species.Moreover, many pharmaceuticals are ionizable, andfish PBK models accounting for ionization are rare. Here,we developed a generalized PBK model, estimating required parameters as functions offish and chemicalproperties. We assessed the model performance forfive pharmaceuticals (covering neutral and ionic structures).With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were withina 10-fold and a 3-fold difference from measurements, respectively. The performance improved usingexperimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances weremore accurate than any of the existing species-specific PBK models. The present study is thefirst to develop ageneralizedfish PBK model focusing on mechanism-based parameterization and explicitly accounting forionization. Our generalized model facilitates its application across chemicals and species, improving efficiencyfor environmental risk assessment and supporting an animal-free toxicity testing paradigm.