**1. Introduction**

The environmental impact of medicinal products has been recognized worldwide, and as its use cannot be avoided, a sound risk assessment of their presence in the environment is a key issue that must be tackled to meet the European Union (EU) Water Framework Directive (WFD) [1]. The potential of human pharmaceuticals for negative ecotoxicological effects, even at sublethal concentrations, in the aquatic environment has been of concern since the issue was first brought to attention in 1985 [2]. Nonetheless, the ecotoxicological risks associated to the ubiquitous occurrence of pharmaceuticals in aquatic ecosystems are far from being fully known [3].

According to the European Medicines Agency (EMA) legislation, and since 2006, before a pharmaceutical obtains a marketing authorization approval, it must be demonstrated that it poses no risk to the environment through an environmental risk assessment (ERA). ERA compares the predicted environmental concentrations (PECs), with the predicted no effect concentrations (PNECs) of three trophic levels of aquatic organisms [4,5]. When the pharmaceutical is already on the market, instead of using the PEC, which predict the environmental concentration, we can use the measured environmental concentrations (MEC) reflecting the real concentration in the aquatic environment [6]. Therefore, for

marketed pharmaceuticals, high-quality monitoring data, along with data on ecotoxicological and toxicological e ffects are crucial to perform the ERA, which associates the presence of pharmaceuticals with their impact on the aquatic ecosystem and human health, supporting the selection of possible new priority substances to be monitored [7–9].

Thus, a systematic review, in order to provide a clear insight on pharmaceuticals toxicology and on ERA, should embrace, not only several parent compounds, but also, metabolites and transformations products belonging to di fferent therapeutic groups such as: the anxiolytics and hypnotics, further referred only as anxiolytics, alprazolam (ALP), lorazepam (LOR) and zolpidem (ZOL); the antibiotics azithromycin (AZI), ciprofloxacin (CIP), clarithromycin (CLA) and erythromycin (ERY); the lipid regulators bezafibrate (BEZ), gemfibrozil (GEM) and simvastatin (SIM); the antiepileptic carbamazepine (CAR); the selective serotonin reuptake inhibitors (SSRIs) citalopram (CIT) and its main metabolite desmethylcitalopram (N-CIT), escitalopram (ESC), fluoxetine (FLU) and its main metabolite norfluoxetine (Nor-FLU), paroxetine (PAR), sertraline (SER) and its main metabolite desmethylsertraline (Nor-SER); the anti-inflammatories and/or analgesics and antipyretics, further referred only as anti-inflammatories, diclofenac (DIC) and its main metabolite 4-hydroxydiclofenac (4-OH-DIC), ibuprofen (IBU), naproxen (NAP), paracetamol (PARA) and its transformation product 4-aminophenol (4-PARA); and the hormones 17β-estradiol (E2) and its main metabolite estrone (E1) and 17 α-ethinylestradiol (EE2; Table 1).




**Table 1.** *Cont*.

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 [10–14]. This review will provide a more realistic water quality assessment contributing for a more integrative approach to rank and prioritize pharmaceuticals, based on an integrated assessment of ERA and exposure in the aquatic environment.

"Water is not a commercial product like any other but, rather, a heritage which must be protected, defended and treated as such", the claim by the EU WFD contrasts with the poor ecological status of European freshwater bodies, where only 43% achieve a good ecological status. In addition, and despite the enormous efforts, the picture that emerges regarding ecological status is still incomplete, fragmented and with contradictory assessments of the situation. Therefore, it is important to obtain a better understanding of the regional and global context, concerning the environmental risk posed by pharmaceuticals in the aquatic environment.
