G.AI.A: An Integrated Machine-Learning Platform for Predicting Bioaccumulation and Ecotoxicity of Pharmaceuticals

Pharmaceutical pollution in aquatic environments poses a significant ecological threat due to the accumulation of bioactive compounds from human and veterinary sources. In support of the EU Green Deal's Chemicals Strategy for Sustainability, this study presents a computational framework for predicting two key environmental risk indicators in fish: bioconcentration and ecotoxicity. Bioconcentration, quantified by the bioconcentration factor (BCF), reflects a chemical's tendency to accumulate in organisms, while ecotoxicity is assessed via the median lethal concentration (LC₅₀) over defined exposure periods. We developed two high-performing machine learning (ML) models, achieving ROC AUC scores of 94.60% for bioconcentration and 96.06% for ecotoxicity, validated across both internal and external data sets. To expand the scope of risk evaluation, we incorporated metabolite prediction using the SyGMa tool, selected after benchmarking multiple alternatives. This enables the assessment of both parent compounds and their potentially toxic metabolites. Model interpretability was enhanced through molecular fingerprint analysis, which identified structural features associated with toxicity and accumulation, informing the early stages of drug design. To support practical implementation, we introduced G.AI.A (https://gaiatox.eu/), an intuitive web platform that allows users to input Simplified Molecular Input Line Entry System (SMILES) strings for rapid prediction of environmental risk end points. The application domain of G.AI.A lies in predictive toxicology, enabling researchers and regulatory bodies to assess the toxicological profiles of small organic compounds, excluding those containing heavy metals, by analyzing their chemical structures. The platform supports batch processing and offers interactive visualizations, facilitating compound screening and early stage environmental risk assessment. By integrating predictive modeling with interpretability and usability, our framework advances green-by-design pharmaceutical development and contributes to sustainable chemical management.