In recent decades, the production and consumption of pharmaceutical products have rapidly increased with the development of medicine. Approximately 3,000 compounds are used as pharmaceuticals, and the annual production quantity exceeds hundreds of tons (Carvalho and Santos, 2016; Grenni et al., 2018). Anti-inflammatory drugs, antibiotics, and analgesics are the most common drugs used around the world. Consequently, the emergence of water-soluble and pharmacologically active organic micropollutants or pharmaceutical active compounds (PhACs) has gained much attention worldwide. Humans use a variety of these pharmaceuticals for their health in everyday life, but large quantities of these drugs are also used as veterinary medicine on farms around the world, to prevent and treat animal diseases and to increase economic benefits in intensive livestock (Blanco et al., 2017; Ekpeghere et al., 2017; Gros et al., 2019; Ramírez-Morales et al., 2021).

After ingestion, pharmaceuticals are excreted in urine and feces as active substances or metabolites (Sui et al., 2015; aus der Beek et al., 2016). These pharmaceuticals are present in both influent and effluent wastewater but can also be found in surface water bodies, including freshwater ecosystems and marine environments, as well as in groundwater due to effluent leachates generated under recharge conditions (Deo, 2014; Furlong et al., 2017; Ojemaye and Petrik, 2018; Reis-Santos et al., 2018; Fekadu et al., 2019; Letsinger et al., 2019; Zainab et al., 2020). The main concern is that conventional treatment plants are ineffective in removing some of these emerging contaminants (ECs), and new techniques are being sought and studied to achieve their total elimination, particularly advances in mycoremediation (Danner et al., 2019). The importance of the study of pharmaceuticals lies in the massive increase in their consumption worldwide, as well as in the environmental repercussions that this entails, including their recalcitrance in aquatic and terrestrial ecosystems. In the contexts of wastewater and bioremediation, pharmaceutical compounds are considered as ECs due to the lack of regulation for their environmental disposal, as well as the lack of information regarding their long-term effects on the environment (Dhangar and Kumar, 2020; Valdez-Carrillo et al., 2020; Chaturvedi et al., 2021b; Rathi et al., 2021), which remains unknown (Barber et al., 2015; Ahmed et al., 2017). The fact that some drugs are marketed without medical prescription or pre-registration and, therefore, are widely consumed worldwide, meaning that they are widely distributed in the environment (Gil et al., 2017), has contributed to this growing problem.

Considering pharmaceuticals as ECs and the continual production of new PhACs, this review aims to comprehensively present the pharmaceuticals commonly detected in water, surface and groundwater and their adverse environmental effects. Advances in bioremediation technologies, which can be used as add-on treatments in wastewater treatment plants (WWTPs) to reduce unprocessed pharmaceuticals released via effluent into the environment, are presented and critically discussed with an emphasis on mycoremediation.

Pharmaceutical compounds that reach water bodies, both surface water and groundwater, came from a number of different sources (Figure 1). The first of these is urban wastewater, which contains a high load of pharmaceuticals from human excrement, and also the inadequate disposal of expired or unused drugs due to the scarce control in their management. Another major source of pharmaceuticals is agricultural and livestock waste, especially the latter, since in large farms for intensive livestock, animals are often fed with feed supplemented containing drugs and excreta are often used in agriculture as soil amendments, reaching groundwater by leaching (Kim et al., 2008; Barrios-Estrada et al., 2018). Effluents from the pharmaceutical industry are another important source, with high concentrations of pharmaceuticals being found due to discharges from factories in Asia, Europe and America, despite strict regulation of pharmaceutical production in Europe and the United States (Lin et al., 2008; Lin and Tsai, 2009; Phillips et al., 2010; Prasse et al., 2010; Sim et al., 2011; Cardoso et al., 2014). These industries are obliged to carry out treatment before discharge into the general urban sewer network (Lindberg et al., 2004; Brown et al., 2006).

Pharmaceuticals found in high concentrations in wastewater include non-steroidal anti-inflammatory drugs (NSAIDs), β-blockers ad psychoactive compounds, analgesics, antibiotics, endocrine disruptors, antiretroviral drugs, and drugs to treat cancer (Roberts and Thomas, 2006; Gros et al., 2010; Lian et al., 2017). These are the PhACs most commonly detected due to the analytical methods available and their resolution, although new methods for identifying these compounds are increasingly being developed (Pivetta et al., 2020; Zhang et al., 2020). Table 1 shows the worldwide distribution of the drugs most commonly found in water (Supplementary Figure 1).

Non-steroidal anti-inflammatory drugs and analgesics are some of the most important groups of pharmaceutical products worldwide, with diverse chemical structures and similar therapeutic effects, having an estimated annual production of several hundred tons (Comber et al., 2018). Large amounts of anti-inflammatory drugs are prescribed in human care, but they are often sold in much higher amounts without a prescription (Ternes, 2001). NSAIDs and analgesics are often combined with antibiotics in veterinary medicine for problems such as pain, inflammation, fever, osteoarthritis and arthritis, and to reduce stress (Courtheyn et al., 2002; Bártíková et al., 2016). However, these two types of pharmaceuticals have numerous adverse effects in humans, including gastrointestinal disturbances, ulceration, renal failure with increased risk of post-operative bleeding, asthma, and rare allergic reactions (Ben Maamar et al., 2017; Morelli et al., 2017; Borgeat et al., 2018; Hurtado-Gonzalez et al., 2021). Approximately 35 million people use NSAIDs every day worldwide (Yu et al., 2013), and China increased its domestic production from 41,537 t in 2013 to 46,673 t in 2017 (Yan et al., 2021). They are currently monitored in effluents worldwide to check these drug concentrations and several studies show that both NSAIDs and analgesics are commonly detected in water bodies (Balakrishna et al., 2017; Świacka et al., 2021). In Cuernavaca (Mexico), high concentrations of naproxen (732–4,889 ng/L), acetaminophen (354–4,460 ng/L), and diclofenac (258–1,398 ng/L) have been detected in samples collected in different years, in the influent and effluent of a WWTP and in the surface waters of the Apatalco River (Rivera-Jaimes et al., 2018). Furthermore, the drugs diclofenac (10,221 ng/L highest concentration detected) and acetaminophen (1234-2346 ng/L), among others, have been detected in effluents from the Red Sea (Saudi Arabia) (Ali et al., 2017). On the other hand, in Brazil, acetaminophen (17.4–34.6 ng/L), diclofenac (19.4 ng/L), and ibuprofen (326.1–2,094.4 ng/L) have been detected in the surface and bottom water samples from Santos Bay (Pereira et al., 2016). These same drugs have also been detected in surface water on the northern Antarctic Peninsula region due to increased tourism in this area, with concentrations of 48.74, 15.09, and 10.05 ng/L of acetaminophen, diclofenac, and ibuprofen, reported respectively (González-Alonso et al., 2017).

Among the pharmaceutical compounds found in wastewater, antibiotics are of the greatest concern due to their persistent nature, partial metabolism, and easy movement through ecosystems (Mukhtar et al., 2020). Antibiotic production in China was approximately 92,700 tons, 48% destined for humans and the remaining for livestock; a total of 46% active metabolites were produced (Zafar et al., 2021). The antibiotics most commonly found in wastewater are sulfonamides, quinolones, tetracyclines, fluoroquinolones, and nitroimidazoles. The total concentrations of antibiotics vary depending on the body of water, in the case of wastewater, they can range between 0.0013 and 0.0125 μg/mL, in drinking water 0.0005 and 0.0214 μg/mL and river water 0.0003 and 0.0039 μg/mL (Zhang et al., 2015; Pan and Chu, 2017; Hanna et al., 2018). Antibiotic resistance of microorganisms to antimicrobials is becoming even stronger and more widespread over time and is expected to greatly increase human morbility and mortality in the near future (Bondarczuk and Piotrowska-Seget, 2019). Antibiotics have been found in rivers all over the world, including several in Spain (Ebro, Guadarrama and Manzanares Rivers), Italy (Arno River), South Korea (Han River), Taiwan (Xindian, Gaoping, Dahan and Po River), France (Seine River), United States (Ozark River), Sweden (Hoje River), and China (Pearl, Hai, Liao and Yellow Rivers) (Peng et al., 2008, 2011; Valcárcel et al., 2011; López-Serna et al., 2013; Bilal et al., 2020).

Endocrine disruptors were defined in 2002 by the International Programme on Chemical Safety (IPCS) of the United Nations Environment Programme (UNEP) and by the World Health Organization (WHO) as “an exogenous substance or mixture that alters the function(s) of the endocrine system and consequently causes adverse health effects in an intact organism or population”. Among the most common endocrine disruptors are pesticides, bisphenols and natural hormones (Gore et al., 2014; Tijani et al., 2016). These substances are not removed from water by conventional treatment processes and are found in wastewater bodies in the order of nanograms to micrograms per liter (Andrade-Eiroa et al., 2016; Gröger et al., 2020; Li et al., 2020).

Antiretroviral drugs are frequently used to treat the human immunodeficiency virus (HIV), an epidemic that has developed worldwide and has its epicenter in South Africa (Tompsett, 2020). As a result, millions of people have access to these drugs on a daily basis, with more than 40 different antiretroviral drugs being used for the treatment of HIV. These include abacavir, efavirenz, lamivudine, nevirapine, tenofovir, and zidovudine; many of which are used in combination (Russo et al., 2018; Mlunguza et al., 2020). As a consequence of the increase in the rate of HIV infection over the years, there has been a significant increase in the production and consumption of antiretroviral drugs worldwide (Nannou et al., 2020; Reddy et al., 2021). In addition, as consequence of the new pandemic coronavirus (COVID-19), antiretroviral drugs have also been used for the treatment of SARS-CoV-2. In some countries, such as China and Japan, clinical trials have been conducted to test the efficiency of using HIV drugs to treat COVID-19 (Reddy et al., 2021). At the moment, a scarcity of studies has dealt with this new issue. However, some studies have started to show a relevant problem that we will have in the very near future (Mupatsi, 2020).

In the coming decades, annual cancer cases are expected to increase to more than 20 million, which means an exponential increase in anticancer drugs and their subsequent release into wastewater (Ferlay et al., 2013). Most of these compounds are incompletely assimilated and metabolized by the human body, thus excreted in feces and urine. The most commonly administered anticancer drugs include cyclophosphamide, tamoxifen, ifosfamide and methotrexate, among others. These drugs have been detected in surface water, WWTP effluents and influents, and hospital effluents. Detected concentrations of cyclophosphamide range from 0.05 to 22,100 ng/L, ifosfamide 0.14–86,200 ng/L, methotrexate 1.6–4,756 ng/L, and tamoxifen 0.01–740 ng/L (Nassour et al., 2020). Several studies have detected these drugs in water masses, confirming that current water treatment systems fail to degrade them (Verlicchi et al., 2010; Cristóvão et al., 2019). Different international agencies have developed protocols for the handling and storing of pharmaceuticals to reduce their harmful effect on the environment (Bernabeu-Martínez et al., 2018). One of the main concerns is that these drugs may suffer biomagnification (Yadav et al., 2021).

Since almost all drugs are not completely metabolized by organisms (usually a small fraction of the active site of drug metabolic enzymes are occupied, the half-life of drugs are limited, and drugs are administrated in higher amounts than necessary to increase efficiency) (Coleman, 2020), the compounds that can cause the most damage once they are excreted and reached wastewater are PhACs. They are also called active pharmaceutical ingredients or APIs and metabolites, referring to the molecules resulting from these original compounds due to structural changes that take place in organisms. In addition, the resulting molecules are also subject to changes in the environment (such as oxidation, photolysis, or biotransformation). These changes can occur through both biotic and abiotic processes. Thus, many pharmaceutical products are biotransformed by microorganisms (Kümmerer, 2009; Wu et al., 2012). Ecotoxicologists are increasingly concerned about the worldwide detection of pharmaceutical residues in aquatic environments since their long-term toxic effects are being increasingly studied. However, it is challenging to know these effects because of the short time period these substances have been present in the environment (Nantaba et al., 2020; Ramírez-Morales et al., 2020; Gani et al., 2021).

Different studies analyzed the microbiome of wastewater where, in the case of hospitals, an abundance of anaerobes related to pathogenic threats such as Bifidobacteriales, Bacteroidales, and Clostridiales was found (Buelow et al., 2018; Ogwugwa et al., 2021; Palanisamy et al., 2021). They also noted that compared to other locations, hospital wastewater contains microorganisms with higher relative levels of antimicrobial and antibiotic resistance genes (Buelow et al., 2018). The mycobiome of hospital wastewater has also been analyzed, indicating the presence of different opportunistic phyla such as Mycosphaerella, Drechslera, Candida, or Cyphellophora (Olicón-Hernández et al., 2021), whose risk that they may acquire resistance to antibiotics is of great concern and may have great repercussions for global health.

Improving technologies for drug elimination from wastewater is an important task since pharmaceuticals have been detected in effluent from WWTPs and consequently surface water, groundwater, and drinking water globally (Bartolo et al., 2021). Although the pharmaceuticals are found in concentrations ranging from the nanogram to microgram per liter, which is too low to cause acute toxicity, they are biologically active compounds that have the potential for chronic toxicity, bioaccumulation, and biomagnification (Ruan et al., 2020). Additionally, microplastics have been shown to serve as vectors for pharmaceuticals (Santos et al., 2021), thus increasing the exposure potential. Because of incomplete elimination during conventional wastewater treatment (Reyes et al., 2021) and the potential risk posed to the environment, as discussed above, there has been pronounced interest in developing alternative treatments in recent years, specifically the biological transformation of these pollutants as a green technology (Domaradzka et al., 2015). The future inclusion of bioremediation technologies in traditional WWTP treatments is progressive as it will result in the detoxification of hazardous substances, it is less disruptive to the environment than harsh oxidative chemicals, and more cost-efficient. With perseverance, research into optimization could result in the complete eradication of target pollutants, rooting out release into the environment.

The wastewaters containing PhACs and their metabolites reaching WWTPs are commonly treated via purification systems. The potential of drug remediation via biological treatment utilizing microbes has been demonstrated (Kebede et al., 2018). Biological systems are often used in conjunction with advanced treatments and combined with conventional activated sludge (CAS) systems due to limitations associated with the process (Crini and Lichtfouse, 2019). Advanced biological treatments include modified CAS, aerobic granular systems, moving bed bioreactors (MBBRs), anammox systems, and membrane bioreactors (MBRs) (Grassi et al., 2012). However, some of these processes, such as MBRs, could result in the generation of biosolids or sewage sludge as byproducts of required maintenance. Sewage sludge, after different stabilization processes such as thermophilic anaerobic digestion, continues onto different processes, such as composting, which could facilitate the transfer of PhACs and their metabolites into various trophic levels of the food web when used as a soil amendment (Marcoux et al., 2013).

Bioremediation, utilizing native microbial monocultures or consortia or bioaugmentation, has been used for decades as a sustainable technology to manage anthropogenic pollution (Ahumada-Rudolph et al., 2021). The advantages of bioremediation include less input of hazardous chemicals, energy, and time, and it is cheap relative to other technologies (Azubuike et al., 2016). The major benefit of bioremediation is that the pollutant is chemically transformed and not only shifted from one environment to another (Mashi, 2013). However, a significant criticism of bioremediation has been that the remediation speed does not meet the requirements for the treatment capacity. Nonetheless, considering the benefits of the approach, attempts on optimizing the efficiency and decreasing retention times are being made and are reviewed below for mycoremediation. Developments in phyto- and phycoremediation of pharmaceuticals have been reported and recently reviewed (Vilvert et al., 2017; Rao et al., 2019; Kaloudas et al., 2021; Kurade et al., 2021) and thus, not included here.

Bacterial remediation has been reviewed to some extent (Shah and Shah, 2020), and, therefore, a brief overview of previously undiscussed advances are included here alongside mycoremediation. Bacterial communities have the ability to degrade and mineralize many xenobiotic compounds and have thus been used for centuries in wastewater-activated sludge (Xu et al., 2018). Bioremediation technologies have been advanced by studies elucidating the importance of facilitating biofilm growth in achieving maximum efficiency and community stability and survival (Edwards and Kjellerup, 2013). The majority of the available literature on bacterial remediation has focused on the aerobic degradation of pharmaceuticals by individual bacteria or consortia in which oxygenases are reported to be involved (Ferreira et al., 2018). Activated sludge, in which an uncharacterized bacterial consortium in suspension is responsible for the remediation, is one of the most widely used biological methods to treat pharmaceutical wastewater at a large scale (Bis et al., 2019). However, due to operational issues associated with the development of large amounts of sludge, research has been invested in developing bespoke bacterial consortia for remediation, including microalgae and bacterial-microalgae consortia (Mamta et al., 2020).

In the environment, fungi are excellent decomposers through the nonspecific nature of enzymes, both intracellular and extracellularly secreted, which exhibit significant capabilities to degrade organic material (Rouches et al., 2016). More specifically, the ligninolytic (including peroxidases and laccases) and cytochrome P450 systems have been proven to be involved in the exceptional capacity of white-rot fungi to degrade recalcitrant pollutants (Park and Choi, 2020). The nonspecific nature of these enzymes also makes them an ideal approach to deal with the diverse chemical structures of the many classes of pharmaceuticals. Many fungal species are also hyperaccumulators, capable of absorbing and bioaccumulating xenobiotics from their environment, as demonstrated by the ability of mushrooms (Braeuer et al., 2020). Furthermore, fungi are known for their capacities to adapt to severe environmental constraints (Jiao and Lu, 2020), making them more tolerant to environmental changes than other bioremediation organisms. Thus, mycoremediation, which results in the reduced toxicity of wastewater (Jelic et al., 2012; Akhtar and Mannan, 2020), offers a comparatively cost-effective, eco-friendly, and effective approach to pollution remediation.

Macromycetes, aka mushrooms or polypores, were previously proven efficient in remediating various pharmaceuticals (Migliore et al., 2012; Cruz-Morató et al., 2014), including β-blockers and psychoactive drugs, anti-inflammatory drugs, antibiotics and hormones (Table 3). Mostly, investigations into the efficiency of fungi to remediate pharmaceuticals have been performed in flask batch experiments with white-rot fungi, especially Trametes versicolor, which exhibited impressive capacities for eliminating a vast range of pharmaceuticals. In bioreactors-based studies, T. versicolor was equally efficient, able to degrade various pharmaceuticals, including codeine, diazepam, carbamazepine, and metoprolol (Asif et al., 2017). The role of redox-mediators has also been extensively studied in improving the performance of laccase-based treatments (Ashe et al., 2016; Shao et al., 2019), including the treatment of pharmaceuticals (Nguyen et al., 2013; Vasiliadou et al., 2019). Studies employing filamentous micromycetes have shown potential for pharmaceutical remediation from wastewaters as reviewed by Olicón-Hernández et al. (2017) but are limited compared to the literature on macromycetes (Table 3). The efficiency of bacteria and fungi to remediate different classes of pharmaceuticals is discussed in more detail below.

The use of isolated fungal enzymes could also overcome some limitations associated with mycoremediation. Fungal enzymes, specifically the ligninolytic enzymes, have been recognized for their abilities to transform a broad range of recalcitrant PhACs. However, difficulties in growing fungi on a large scale, together with the long incubation processes, extensive growth phase, and spore formation, have prompted the exploration of extracted crude and isolated enzymes (Stadlmair et al., 2018). Though, to date, the main limiting factor has been the high cost of the enzyme purification procedure.

Commercially available laccases from T. versicolor efficiently degraded diclofenac, trimethoprim, carbamazepine and sulfamethoxazole as individual drugs, but the remediation efficiency decreased when applied to mixtures of the drugs (Alharbi et al., 2019). Kang et al. (2021) isolated laccases from Bjerkandera spp., which could efficiently remediate acetaminophen under a range of pH conditions (Kang et al., 2021). In a study employing immobilized laccases from Trametes hirsuta, Hachi et al. (2017) reported better remediation efficiencies for carbamazepine and acetaminophen (40 and 70%) in single compared to in mixtures (5 and 25%) (Hachi et al., 2017).

Using laccases (2,000 U/L) isolated from Myceliophthora thermophile, 94.1 and 95.5% of estrone E1 and 17β-estradiol E2 could be degraded within 8 h in the presence of a natural mediator in a fed-batch bioreactor. In an enzymatic membrane reactor (EMR) with a stir-tank configuration, this percentage was increased to 95% for E1 and near total E2 degradation (Lloret et al., 2010). This indicates that the bioreactor type significantly impacts the remediation efficiency regarding isolated enzymes. In a study by Becker et al. (2017), immobilized laccase from T. versicolor and M. thermophila could degrade 83 and 87%, respectively, of estrogenic compounds (E1 estrone; E2 17β-estradiol; EE2 17α-ethinylestradiol) in mixtures with other endocrine-disrupting compounds within 6h (Becker et al., 2017). Golveia et al. (2018) reported 96.5% remediation of 10 mg/L 17-α-ethinylestradiol by Pycnoporus sanguineus laccase (1,642 U/mL) after 8 h (Golveia et al., 2018). It would be noted that 1% (v/w) was added to the fungal culture to promote optimal laccase production concentration before extraction.

Utilizing isolated enzymes has the advantages of reducing the remediation time by avoiding the lag phase of fungal growth, reducing sludge production, and facilitating process control (Jebapriya and Gnanadoss, 2013). Apart from the high cost as a disadvantage, a study by Nguyen et al. (2014) demonstrated another drawback of using isolated enzymes (Nguyen et al., 2014). In a direct comparison, whole-cell culture degraded trace organic compounds with higher efficiency, which is said to be facilitated by biosorption and the activity of both intracellular and mycelium associated enzymes.

The environmental impact of pharmaceuticals and their proper elimination from wastewaters have gained interest in recent years, mostly due to the intrinsic characteristics of these compounds, their massive use, and the negative effects on the environment and humans. Although they are medicinal substances developed to aid in the well-being of organisms, their indiscriminate use can lead to irreversible environmental problems. Therefore, it is important to create legislation according to the current standards of using substances and eco-friendly trends. More versatile and efficient systems for eliminating PhACs such as mycoremediation are being developed to lessen or avoid the problems associated with pharmaceutical pollution in the environment. However, these promising techniques are still at a laboratory scale and data regarding the application in WWTPs are still lacking. Even though new techniques for the remediation of PhAC are being developed and optimized, relative to the development of new drugs, implementing these techniques into practice is slow. New promising approaches for this purpose, such as genetic engineering, are still in their infancy. Thus, the new editing tool, such as CRISPR-Cas9, could help to introduce metabolic genes focused on target recalcitrant compounds. Much more studies are still necessary to deal with the problem of PhACs.

ME, EA, DRO-H: conceptualization. MO and ME: literature search and data analysis and original draft preparation. MO, ME, DRO-H, JG-L, and EA: critical revision of the work. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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