Abstract
The presence of non-steroidal anti-inflammatory drugs (NSAIDs) in the aquatic environment has raised concern that chronic exposure to these compounds may cause adverse effects in wild fish populations. This potential scenario has led some stakeholders to advocate a stricter regulation of NSAIDs, especially diclofenac. Considering their global clinical importance for the management of pain and inflammation, any regulation that may affect patient access to NSAIDs will have considerable implications for public health. The current environmental risk assessment of NSAIDs is driven by the results of a limited number of standard toxicity tests and does not take into account mechanistic and pharmacological considerations. Here we present a pharmacology-informed framework that enables the prediction of the risk posed to fish by 25 different NSAIDs and their dynamic mixtures. Using network pharmacology approaches, we demonstrated that these 25 NSAIDs display a significant mechanistic promiscuity that could enhance the risk of target-mediated mixture effects near environmentally relevant concentrations. Integrating NSAIDs pharmacokinetic and pharmacodynamic features, we provide highly specific predictions of the adverse phenotypes associated with exposure to NSAIDs, and we developed a visual multi-scale model to guide the interpretation of the toxicological relevance of any given set of NSAIDs exposure data. Our analysis demonstrated a non-negligible risk posed to fish by NSAID mixtures in situations of high drug use and low dilution of waste-water treatment plant effluents. We anticipate that this predictive framework will support the future regulatory environmental risk assessment of NSAIDs and increase the effectiveness of ecopharmacovigilance strategies. Moreover, it can facilitate the prediction of the toxicological risk posed by mixtures via the implementation of mechanistic considerations and could be readily extended to other classes of chemicals.
Highlights
Millions of people worldwide use non-steroidal anti-inflammatory drugs (NSAIDs) to treat a wide variety of health conditions involving inflammation and pain (Gunaydin and Bilge, 2018)
According to the UBA database of pharmaceuticals in the environment, 19 out of 25 NSAIDs were detected in the aquatic environment, in 66 different countries around the world, supporting our hypothesis that the overall environmental risk of NSAIDs should be addressed from a mixture perspective
In the present study we provide a pharmacology-informed workflow able to guide the incorporation of pharmacokinetics and pharmacody namic considerations into the environmental risk assessment of NSAIDs and aid the implementation of predictive toxicology strategies, without the immediate need of performing additional animal testing
Summary
Millions of people worldwide use non-steroidal anti-inflammatory drugs (NSAIDs) to treat a wide variety of health conditions involving inflammation and pain (Gunaydin and Bilge, 2018). Administration of NSAIDs to humans, especially when long-term, is associated with an increased risk of adverse events in multiple organs/systems, including gastrointestinal and cardiovascular systems (Conaghan, 2012; Fanelli et al, 2017). These safety concerns led to various regulatory actions during the last twenty years in both North America and Europe, which required drug manufacturers to update product labels with explicit warnings that NSAIDs may increase the risk of serious adverse events (e.g. UK Medicines and Healthcare products Regulatory Agency, 2007, 2012; US Food and Drug Adminis tration, 2015). The regulatory and academic discussions concerning the environmental risk assessment (ERA) of NSAIDs continued and have reached the point that some stakeholders are advocating a stricter regulation of over-the-counter NSAIDs, such as diclofenac, and even the substitution with compounds associated with a lower environmental risk (OECD, 2019)
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