Pharmaceuticals

Pharmaceuticals are used for diagnosis, treatment, or prevention of health conditions in both humans and animals by interacting with the binding site of a receptor and the consequent formation of a drug-receptor complex, thus promoting the desired pharmacological activity (Stringer, 2006). Although the pharmacological activity is generally well known, their effects in non-target organisms are still not completely understood (Daughton and Ternes, 1999). In this context, there is a great environmental concern about chiral pharmaceuticals in particular due to the additional complexity in comparison to achiral ones, based on the possible different pharmacokinetic and pharmacodynamics of enantiomers and consequent dissimilar toxicological and ecotoxicological properties. Chiral illicit drugs have been receiving a great attention due to their high toxicity to aquatic organisms and in this topic, Kasprzyk-Hordern et al. have published several papers (Bagnall et al., 2013, 2012; Castrignano et al., 2016; Evans et al., 2016, 2015; Evans and Kasprzyk-Hordern, 2014; Petrie et al., 2017,2014; Vazquez-Roig et al., 2014). Interestingly, a very recent study described evidence on the effects of co-existing microplastics in the increasing toxic effects and enantioselectivity behavior of methylamphetamine to green alga and freshwater snail (Qu et al., 2020), as verified for many pesticides.

There are chiral pharmaceuticals commercialized as racemates, as single enantiomers, and as both racemic and enantiopure forms, depending on the interaction of the enantiomers w'ith the receptors (Ribeiro et al.. 2012b). There is a trend of commercialization of enantiopure pharmaceuticals and the chiral switching (re-evaluation of the license of the enantiomeric pure substances commercialized as racemate) has played an important role in this shift (Pavlinov et al., 1990). Other approach to obtain enantiopure substances is de novo development of pure enantiomers, which can be achieved by three processes: (i) screening enantiomerically pure natural drugs, also known as “chiral pool”; (ii) asymmetric synthesis; and (iii) chiral resolution that also complements the other two processes (Song et al., 2020). However, there are a number of pharmaceuticals that are commercialized both as racemic mixture and enantiopure forms, as example: bupivacaine/(S)- bupivacaine (levobupivacaine), cetirizine/(/?)-cetirizine (levocetirizine), citalopram/(S)-citalopram (escitalopram), ibuprofen/(S)-ibuprofen (dexibuprofen), ketoprcfen/(S)-ketoprofen (dexketoprofen), ofloxacin/(S)-ofloxacin (levofloxacin), omeprazole/(S)-omeprazole (esomeprazole), salbutamol/ (S)-salbutamol (levalbuterol) (Tiritan et al., 2016). A less frequent alternative is the production of chiral pharmaceuticals with a proportion of enantiomers different from 1:1 (Ribeiro et al., 2012b). Another important aspect is that although the tendency to use enantiopure pharmaceuticals is driven by the low'er therapeutic doses, less adverse effects, higher safety range, less interindividual variability, and less drug-drug interactions, the option of using enantiopure pharmaceuticals can also lead to unforeseen toxic effects (Ribeiro et al.. 2012c). As an example, an unsuccessful chiral switching occurred with fluoxetine. The attempts of chiral switching for the development of a market license for (R)-fluoxetine led to an adverse cardiac effect, resulting in its abandonment (McConathy and Owens, 2003).

Chiral pharmaceuticals, and also chiral illicit drugs that follow the same pathways of pharmaceuticals, are metabolized and excreted by humans and animals and the parent compounds and the respective metabolites can reach the aquatic environment through their passage in wastewater treatment plants (WWTPs). Moreover, unused or expired drugs may be incorrectly dumped as solid waste or in toilets or sinks, reaching landfills and WWTPs, respectively (Sousa et al., 2018). The footprint of pharmaceutical industries cannot be disregarded even when industrial effluents are released into WWTPs, since the pharmaceuticals are not completely removed by the conventional treatment occurring in the WWTPs (Barbosa et al., 2016). Therefore, the release of effluents from municipal WWTPs is considered the most important pathway of pharmaceuticals in the aquatic environment (Ribeiro et al., 2012b, 2013). As the conventional WWTPs are not designed to completely remove residual organic compounds, those compounds not removed or partially degraded in WWTPs can reach surface waters that are interconnected to ground w'ater and drinking water (Escuder-Gilabert et al., 2018; Ribeiro et al., 2013, 2012a). On the other hand, many industries are still not regulated in some countries and their non-treated effluents are often discharged into the environment (Sousa et al., 2018). The runoff from livestock areas and the release from aquaculture are other relevant sources of pharmaceuticals and estrogens (Barbosa et al., 2016). The use of reclaimed wastewater in agriculture can also be a source of chiral pharmaceuticals that may leach into receiving waters. Similarly, landfill leachates and septic tanks cannot be disregarded as a source of this type of chiral pollutants.

The general polar nature of pharmaceuticals as a wanted characteristic to promote their distribution and excretion w'ithin organisms makes them prone to be mostly removed in WWTP by adsorption, biodegradation, hydrolysis, and photodegradation, the same mechanisms occurring in the surface water (Ribeiro et al., 2020). In the case of chiral pollutants, biodegradation is an important degradation route since microorganisms are able to remove them enantioselectively (Ribeiro et al., 2012b). Despite the recent advances on the knowledge about environmental chirality and its recognition as an important research field, chiral pharmaceuticals and illicit drugs are mostly studied as unique molecular entities and EF is often neglected, therefore underestimating the enantioselective environmental behavior (e.g., occurrence, fate, distribution, degradation, uptake) and toxicological effects (Ribeiro et al., 2020). Many review papers have been published in this field, namely on their environmental determination (Dogan et al., 2020; Evans and Kasprzyk-Hordern. 2014; Ribeiro et al., 2020), occurrence and fate (Kasprzyk-Hordern, 2010;

Petrie et al., 2014; Sanganyado et al., 2017), biodegradation (Hashim et al., 2010; Maia et al., 2017; Wong, 2006; Xu et al.. 2018), potential human health impacts and remediation (Sanganyado, 2019; Stanley and Brooks, 2009; Zhou et al., 2018b), and forensic application (Ribeiro et al., 2018; Sanganyado et al., 2020).