**4. Occurrence**

Along with advances in analytical instruments and techniques, trace levels of various pharmaceuticals and their metabolites have been detected in the aquatic compartment since the latter half of the 1970s [145].

A literature review on worldwide monitoring programs in recent years, presented in Figures 2–5 and Tables S2–S5 (supporting information), clearly reveals the ubiquitous distribution of pharmaceuticals in different aquatic environment compartments, including WWIs, WWEs and surface waters, with concentrations up to mg L−<sup>1</sup> [145,147]. Usually, this occurrence is related to the gross domestic product per capita of each country and is presented as the shape of an inverted-U; i.e., pollution worsens as the economy of countries starts to grow (increased consumption of pharmaceuticals), and then it improves when countries reach a higher stage of economic growth (improved WWTPs) [101].

**Figure 2.** Boxplots with median, maximum and minimum average concentrations of pharmaceuticals in wastewater influents (WWIs). Anx—anxiolytics, Antib—antibiotics, Lip reg—lipid regulators, Antiepi—antiepileptics, SRRIs—selective serotonin uptake inhibitors, Anti-inf—anti-inflammatories and Horm—hormones [3,13,15,16,18,29,34,59,63,67,68,71,78,79,82,83,86,87,94,96,100,102,107–109,111– 115,117–120,122,123,126,128,130–133,140,147–170].

**Figure 3.** Boxplots with median, maximum and minimum average concentrations of pharmaceuticals in wastewater effluents (WWEs). Anx—anxiolytics, Antib—antibiotics, Lip reg—lipid regulators, Antiepi— antiepileptics, SSRIs—selective serotonin reuptake inhibitors, Anti-inf—anti-inflammatories, Horm— hormones and different letters represent significant statistical differences) [3,5,6,8,13,15,16,18,29,34,59, 63,67,68,71,78,79,82,83,86,87,91,94,96,100,102,103,107–109,111–115,117–120,122,126,128–133,136,139– 141,146,147,149,150,152–183].

Beside the aspects previously referred, several others can influence the concentration of pharmaceuticals in the di fferent aquatic compartments, promoting a grea<sup>t</sup> variability in the detected concentrations. In WWTPs, other aspects that can influence the detected concentrations are the flow rate, the time of the year, the temperature, the type of WWTPs, day and the type of sampling, etc. [105]. As for surface waters, the flow rate, temperature, sunlight, time of the year, day and the type of sampling are also parameters that can influence pharmaceuticals concentrations [23]. Moreover, some of these parameters can also influence the detected concentrations in other water bodies.
