Mechanistic Ecotoxicology of Pharmaceuticals via Target Conservation and AOPs

Abstract

Design ligands which are pharmaceutical, specific and bind at low concentrations to a molecular target. For non-target species, the compounds can interact with conserved orthologues of human targets that result in molecular initiating events (MIEs), which cascade to adverse outcome pathways (AOPs) in the environment. This review aims to give a molecular understanding of the ecotoxicity of pharmaceutical products, including environmental fate, internal dose, target conservation and mechanistic evidence. The cornerstone studies and the newest developments are included in the body of literature. Focus on the evidence from 2020–2026. The physicochemical principles of controlling the environmental behaviour and internal exposure of ionizable active pharmaceutical ingredients (APIs), such as pH-dependent partitioning, active transport, molecular descriptors and three-dimensional shape, are first discussed. The principles of the environmental behaviour and internal exposure of ionisable active pharmaceutical ingredients (APIs) such as pH-dependent partitioning, active transport, molecular descriptors and three-dimensional shape are first reviewed. This is followed by the formalisation of target conservation, the usefulness of read-across methods, e.g., Fish Plasma Model and SeqAPASS are discussed. Mechanistic case studies of the framework are included such as mechanism of action of the estrogen receptor agonist 17?-ethinylestradiol, mechanism of action of the antibiotic class that inhibit bacterial targets, mechanism of action of the cyclooxygenase inhibitor diclofenac, and mechanism of action of serotonin transporter blocker fluoxetine, including the controversy surrounding the endocrinically related mechanism of action of metformin. In parallel examples both in avian and invertebrate systems, the same pharmacological logic has led to disastrous ecological consequences, where exposure routes were linked to high levels of internal exposure. As part of the review, transformation products, mixture effects, effect directed analysis and mechanistic biomarkers are also discussed. The mechanism-based prioritization, internal-dose informed testing and effect-based monitoring for environmental risk assessment is facilitated by the framework. For green pharmacy it offers suggestions on the selection of molecules with therapeutic activity that have lower persistence, degradation profile and lower non-target activity. Therefore, molecular descriptors and target conservation and quantitative AOPs provide a pragmatic approach to shift from environment detection to mechanistic prediction, regulation and safer drug design.