**1. Introduction**

Human pharmaceuticals, presenting di fferent characteristics and, consequently, producing di fferent environmental exposure profiles, represent a group of widely used chemicals that contaminate the aquatic environment. Albeit in trace amounts, they are of concern, since they are designed to perform a biological e ffect. Moreover, given their continuous introduction into the environment, their impact, both as stressors and as agents of change, is of grea<sup>t</sup> importance [1].

The main source of pharmaceuticals residues in the aquatic environment is human excretion, and consequently, the widespread presence of pharmaceuticals in environmental samples is most likely to occur from wastewater treatment plants (WWTPs), which incompletely remove these compounds. Pharmaceuticals are then released into the environment as parent compounds, metabolites, as well as transformation products [2], leading to the contamination of surface waters, seawaters, groundwater and even some drinking waters already identified by new analytical methodologies which allowed the detection at low ng L−<sup>1</sup> [3–10].

Although no legal limits have been established in water, seven pharmaceuticals and one metabolite became part of the WFD watch list established by the Directive 2013/39/EU amended by the Commission Implementing Decision from the EU 2015/495 and the EU 2018/840. This list is dynamic, changing with the awareness on the persistence in the water cycle, and its validity in time is limited. Therefore, identifying and prioritizing new pharmaceuticals are important goals to be accomplished for future updates in order to minimize the aquatic environmental contamination by pharmaceuticals [11].

Additionally, as a part of the strategy implemented by the Directive 2013/39/EU, all member states shall monitor the substances in the watch list at the selected surface waters' representative monitoring stations.

Globally, heavy contamination pressures from extensive urban activities characterize the main rivers that might lead to high aquatic contamination levels and consequent environmental and human exposure. Although the concentrations of pharmaceuticals in influents (WWIs) and e ffluents (WWEs) of WWTPs and surface waters are routinely monitored in many countries, only in recent years there has been an increase in the number of studies concerning the occurrence of pharmaceuticals in the aquatic environment [12–16]. Additionally, other aquatic compartments such as seawater, groundwater, mineral water and drinking water have a lower amount of data available regarding this contamination. However, most of these studies are primarily focused on a small number of targeted compounds in localized areas. Therefore, there is a knowledge gap which demands a comprehensive and systematic evaluation of pharmaceuticals, its metabolites and transformation products in the aquatic environment.

Thus, a systematic review, in order to provide a clear insight on pharmaceuticals' contamination of the water compartment, should embrace, not only several parent compounds, but also metabolites and transformations products belonging to di fferent therapeutic groups (Table 1).

The pharmaceuticals in study, key representatives of major classes of pharmaceuticals, were selected based on the EU watch list, their high consumption, pharmacokinetics, physicochemical properties, persistence, previous studies on the occurrence on the aquatic environment and their potential toxicological impact, both on humans and on the aquatic environment [11,17–20]. In this way, the complete scenario of the contamination of pharmaceuticals in the aquatic environment could be acquired, contributing to future improvements in minimization measures, calculation of the environmental risk assessment and legislation.

In a larger vision of future water resource managemen<sup>t</sup> sustainability, with the escalating population growth and intensified agricultural and industrial activity, water scarcity will be a reality [21–23]. Therefore, there will be the need for water/wastewater recycling, and the contamination of water resources by pharmaceuticals gains ye<sup>t</sup> another perspective. Therefore, it is important to obtain a better understanding of the context, concerning the source, fate and occurrence posed by pharmaceuticals in the aquatic environment.

#### **2. Sources and Fate of Pharmaceuticals in the Environment**
