# Pharmaceuticals in Coastal Waters: An UHPLC-TOF-MS Multi-Residue Approach
## 1 Introduction  
Coastal pollution has quickly become a global environmental concern. Natural ecosystems worldwide have been struggling with the continuous release of substances and energy that subsequently induce changes in their physical, chemical and biological characteristics, altering functions and processes that often lead to biodiversity and habitats degradation [1, 2, 3]. The balance between economic growth and sustainable development spends chronically towards the first, aggravated by the fact that over 50% of the world's population is settled within 200 km of the shoreline [4]. Thus, anthropogenic pressure is even more problematic in coastal ecosystems, with countless forms of pollutants discharged constantly in the water. Pharmaceuticals are among these pollutants, regarded as emergingcontaminants ubiquitous to the aquatic environment, with multiple origins including urban and hospital effluents, veterinary runoffs, pharmaceutical industries and wastewater treatment plants. Although many may be swiftly degraded, due to their continuously release to the environment they are considered pseudo-persistent [2; 5; 6; 7; 8]. Moreover, they are listed as hazardous substances due to the fact that they retain biological activity capable of inducing effects in non-target organisms even after digestion and excretion [5; 7; 9], easily permeating cell barriers, which increases the risks of bioaccumulation and biomagnification throughout the food web [7; 9]. Therefore, monitoring pharmaceuticals in the environment is paramount. In this sense, the European Water Framework Directive mandates the surveillance of several substances in all member states to evaluate their risk as contaminants (EU Commission Decision 2020/1161). When a chemical has potential environmental risk but not enough data for adequate assessment, it can be proposed for inclusion as a priority substance in the Surface Water Watch List [10]. When monitoring data sets are enough to establish risk assessment, then substances are excluded from the list [10]. Currently, the revised form of the Watch List mandates the surveillance of eight pharmaceutical substances comprising four antibiotics, one antidepressant and its metabolite and three fungicides, which is a very low number compared to the thousands reaching the aquatic environment daily. Moreover, current legislation is aimed at freshwaters and transitional waters (including estuarine and coastal waters up to 1 nautical mile from the shore). Regarding marine waters, although guidelines with recommendations have been proposed under the OSPAR Commission, legislation is still lacking [5; 11]. It comes, then, as no surprise that the majority of surveillance studies available pertain mainly to freshwaters. Another reason for this is the complexity of seawater and estuarine samples due to the presence of salt ions and dissolved organic matter and due to the much lower concentrations as a result of the dilution of contaminants as they are carried away from the coast. All these constraints have pushed advances in the analytical field aiming at the detection and monitoring of a large suite of pharmaceutical compounds at very low concentrations (ng/L). Hence, the development and validation of new analytical tools is essential. In particular, given that the number of contaminants keeps rising and that such compounds are present in mixtures, the use of multi-residue mass spectrometry methods represents a valuable tool to detect and quantify very low concentrations of multiple substances from a single sample analysis. The use of ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry detector time-of-flight (UHPLC-TOF-MS), enables the detection of an unlimited number of compounds with the powerful advantage that it allows reevaluating data to assess the presence of initially untargeted substances.