Transformation products of diclofenac: Formation, occurrence, and toxicity implication in the aquatic environment

Diclofenac (DCF) is the first drug on the EU Watch List of Priority Substances due to its extensive uses, incomplete removal in wastewater treatment plants (WWTPs), and toxic effects. Once in the environment, DCF undergoes processes that yield various transformation products (TPs) or metabolites, whichcan be more toxic than DCF. While these TPs or metabolites often dominate the majority of the drug load in municipal wastewater, they have been largely ignored. This review critically examines recent data on the formation, occurrence, fate, and toxicology of DCF TPs in the aquatic environment. This review reveals some important findings. First, DCF TPs may constitute >57 % of DCF in wastewater influent, ∼60 % in effluent, and ∼30 % in surface waters. Second, TPs persistently retain the core structure of DCF and may pose greater environmental risks than the parent drug. Third, some metabolites may revert back to the parent drug. Fourth, WWTPs serve as a consistent source that release DCF and its by-products into the environment. Fifth, mixtures of DCF and its metabolites, along with other contaminants, may pose elevated and synergistic environmental risks than individual compounds. These findings suggest that current risk assessment practices, which ignore the impacts of the metabolites and the chemical interactions/synergies, may seriously underestimate the overall toxicity of DCF and likely other pharmaceuticals. Further studies are needed to monitor the long-term fate and toxicity of the metabolites, as well as new analytical methods and standards to unveil the hidden metabolites and the associated environmental risks.