The comprehensive monitoring of pharmaceutically active compounds (PhACs) in the environment is challenging given the myriad of substances continuously discharged, the increasing number of new compounds being produced (and released), or the variety of the associated human metabolites and transformation products (TPs). Approaches such as high-resolution mass spectrometry (HRMS)-based suspect analysis have emerged to overcome the drawbacks of classical target analytical methods, e.g., restricted chemical coverage. In this study, we assess the readiness of HRMS-based suspect screening to replace or rather complement target methodologies by comparing the performance of both approaches in terms of i) detection of PhACs in various environmental samples (water, sediments, biofilm, fish plasma, muscle and liver) in a field study; ii) PhACs (semi)quantification and iii) prediction of their environmental risks. Our findings revealed that target strategies alone significantly underestimate the variety of PhACs potentially impacting the environment. However, relying solely on suspect strategies can misjudge the presence and risk of low-level but potentially risky PhACs. Additionally, semiquantitative approaches, despite slightly overestimating concentrations, can provide a realistic overview of PhACs concentrations. Hence, it is recommended to adopt a combined strategy that first evaluates suspected threats and subsequently includes the relevant ones in the established target methodologies.

Peer reviewed