*3.3. Mitigation Measures*

The RQs obtained for all the water compartments, particularly the RQs higher than 1 in surface waters and in the other water bodies, raise not only the issue of toxicity for the aquatic environment but also for humans using these aquatic bodies as a source of drinking water and also for whom eating animals living in these contaminated environments. Therefore, mitigation measures should be implemented to prevent high RQs in these important water resources. These measures should begin through the awareness of the problem. For example, in Sweden, an environmental classification system for drugs has been established through collaboration between producers, authorities and the public health care. This system assesses the environmental risk of pharmaceuticals being publicly available, therefore, the market can demand for medicines with less environmental impact, stimulating producers to design more environmentally friendly medicines [17]. This includes the concept of green pharmacy, where the design of pharmaceutical products focus also on their high metabolization and environmental degradation, reducing the environmental burden and improving environmental safety and health impacts [138].

Additionally, the ERA guideline on human pharmaceuticals should be revised in order to: enter the risk benefit analysis; impose its revision every five years with the new available data; incorporate the pharmaceuticals marketed before 2006 and include metabolites and transformation products [6].

Another issue already referred is the possible improvement of WWTPs removal e fficiencies and the improvement of toxicity studies. The main challenges regarding the assessment of ecotoxicity are the scarce information available for some of the selected pharmaceuticals, namely chronic data and e ffects on multiple life stages or even multiple generations, which mimics the environmental exposure. Behavior studies are also lacking, before death and other major toxicity e ffects there can be diminished sexual interest, fear or activity, increased curiosity, etc. Although this seems like small behavior changes, it can be enough to unbalance an ecosystem eliminating one or more species by being unable to escape from predators or by lack of reproduction. This leads to another point that ecotoxicity studies should also be performed in ecosystems, because some e ffects previously referred are more evident in this type of studies. It should also be considered the increase of species tested and mixture e ffects, not only between di fferent pharmaceuticals of the same therapeutic group but also from di fferent groups and with other substances, like heavy metals. Given the pharmaceutical environmental presence in mixtures and with other substances, additive or even synergistic e ffects occur; therefore, the real hazard may be greater than that calculated [24,33,180,181]. Another issue that is neglected with the traditional ecotoxicity studies is the emergence of bacterial resistance. We are testing antibiotics in algae, invertebrates and fish but probably the biggest impact will be on bacteria, namely on the emergence of resistant bacteria that can reach not only aquatic animals but also

humans. Additionally, the emergence of bacterial resistance is a major concern involving the presence of pharmaceuticals in the aquatic compartment, which is more prone in this environment [6,182].

This could generate benefits in water resource management, by providing the means for cross-compliance measures in environmental regulation and providing an adequate risk assessment for pharmaceuticals mixtures [183]. In this way, the complete scenario of the contamination of pharmaceuticals in the aquatic environment and their risk could be performed, contributing to future improvements in minimization measures and legislation.
