A Review on Pharmaceuticals and Personal Care Products Residues in the Aquatic Environment and Possibilities for Their Remediation

Abstract

Pharmaceuticals and Personal Care Products (PPCPs) are pollutants known as organic micropollutants. PPCPs belong to a group of compounds with proven biological activity used in medicine, veterinary medicine and to maintain hygiene in daily life. Their presence in the environment, even in trace concentrations, can have negative effects on living organisms, including humans. Especially relevant are the residues of pharmaceuticals such as hormonal drugs and antibiotics. PPCPs’ presence in the environment is caused by the improper production, usage and disposal of medicines. PPCPs and their residues may be introduced into the various parts of the environment such as wastewater, water and soil. Therefore, wastewater containing PPCPs, their residues and active metabolites firstly goes to a wastewater treatment plant (WWTP). However, some of these compounds may also be present in sewage sludge. This article reviews the methods and technologies used in the remediation of water and wastewater containing PPCPs residues. Among them, physical, chemical and biological methods, as well as a compilation of various techniques, can be identified. Nowadays, in a time of energy crisis, it is important to emphasize that the applied methods of wastewater and water treatment are not only effective, but also have been characterized by low energy consumption or allow for the generation of energy that could be used for the needs of the wastewater treatment plant.

1. Introduction

Recently, there has been increasing concern over and attention to the so-called contaminants of emerging concern (CECs), including endocrine disruptors (EDCs) and pharmaceuticals and personal care products (PPCPs). This growing interest is due to the fact that their presence in water reservoirs and soils triggers a negative impact on human health and aquatic organisms [1]. Pharmaceuticals belong to the group of xenobiotics of anthropogenic origin, referred to in the literature as PPCPs (pharmaceuticals and personal care products). The PPCPs group also includes food supplements and nutrients (so-called nutraceuticals) as well as various types of cosmetics and their additives, often with antiseptic and antibacterial properties (shampoos, UV blockers, toilet waters and antiseptics). This group of compounds also includes disinfectants (antibacterial and antiviral), the use of which has increased since 2020 due to the SARS-CoV-2 pandemic [2,3]. The presence of the abovementioned compounds in the environment is caused by controlled and uncontrolled discharges from households, animal farms, industry, WWTP and hospitals. Selected PPCPs (metoprolol, atenolol, carbamazepine) are mentioned as the most important substances by the USEPA (United States Environmental Protection Agency) [1].

PPCPs exhibit a variety of physicochemical properties, a complex chemical structure and stability, which usually makes their estimation, analysis and removal difficult [4]. Moreover, due to the high number of new drugs and personal hygiene products introduced into circulation, the number of studies on their removal from water and sewage and their impact on the environment is quite low [5].

The pharmaceutical industry is one of the fastest developing branches of industry. This is caused by such factors as the aging of societies, an increase in the income of the population, expenditure on research and development, as well as an increase in the incidence of civilization and chronic diseases. In many countries, changes are observed in the awareness of people who pay more and more attention to health issues and use drugs as a preventive measure. The four most important groups of drugs are the following: antihypertensive, cholesterol-lowering, antidepressant and antidiabetic drugs [6]. Moreover, due to the pandemic caused by SARS-CoV-2, there has been a significant growth in the consumption of some medications (such as antivirals, antimicrobials, and antidepressants). The abovementioned pharmaceuticals have been used to prevent infection with the virus in alleviating symptoms or improving mental health, which in turn has caused an increase in the load of pharmaceutical residues in water matrices [5]. Data provided by the Pharmaceutical Drugs Global Market [7] indicate that the global pharmaceutical drug market will grow from USD 1136.23 billion in 2022 to USD 1199.86 billion in 2023 at an assumed annual growth rate (CAGR) of 5.6%. The Russia–Ukraine war has disrupted the prospects for global economic recovery after the COVID-19 pandemic and has resulted in the imposition of economic sanctions on many countries, an increase in raw material prices and disruptions in the supply chain, which has an impact on the global market. It is estimated that in 2027, the pharmaceutical drugs market will reach USD 1848.49 billion, with a CAGR of 11.4%.

The presence of PPCPs in water and treated wastewater is not insignificant for the natural environment. The literature data indicate that it is a group of substances constituting ubiquitous, persistent and biologically active compounds which can be toxic and capable of disrupting the endocrine system. Other known consequences of the presence of PPCPs in water environments include damage to the nervous system, the feminization of reproductive functions or the inhibition of photosynthesis [8,9]. The problem of PPCPs in the environment is serious, because PPCPs in water and wastewater are detected at the ng/L-μg/L level [10]. While the presence of PPCPs in wastewater in various concentrations is not surprising, a problem arises when they are present in surface and groundwater, which are often sources of drinking water. For example, the amount of antibiotics in raw samples of wastewater on a global scale is 1–303,500 ng/L, while in freshwater, their concentration reaches 13,600 ng/L [11]. Other studies indicate that the content of detected PPCPs in drinking water treatment plants is in the range of 0.11–844 ng/L, while in tap water, it is 0.16–32.5 ng/L [12]. Generally, the concentration of common PPCPs is higher in freshwater than in groundwater or seawater. Moreover, the concentration of these compounds in water depends on the continent, country or region. One of the main routes of entry of PPCPs into drinking water sources is treated wastewater released from sewage systems [13]. Moreover, due to varying hydrophilicity, solubility, volatility and biodegradability, conventional sewage treatment plants are not effective enough in their removal [14]. This therefore necessitates the search for methods that will remove PPCPs from wastewater and water with high efficiency. In the case of purifying drinking water to remove PPCPs, technologies such as filtration, advanced oxidation processes (AOPs), granular activated carbon (GAC), membrane filtration and compilations of these methods are used [11]. In conventional WWTPs, until recently, PPCPs removal occurred mainly in primary and secondary treatment. In many WWTPs, advanced sewage treatment methods are increasingly being introduced (mainly AOPs, membrane bioreactors, microalgae-based technology and hybrid methods) as tertiary treatment, aimed primarily at removing potentially dangerous micropollutants, including PPCPs. This is mainly due to legal conditions and the required level of removal of selected micropollutants in WWTPs, which are imposed in some countries [15]. In the current reality, shaped by the uncertain geopolitical and energy situations, it is also required that the technologies used and introduced are characterized by innovation, low energy consumption and are based on a closed-loop economy. This is in line with EU policy and the communication published in 2019 setting out a strategic approach to solving the worldwide issue of the presence of pharmaceuticals in the environment and implementing Sustainable Development Goal 6 on clean water and sanitation [16].

An innovative aspect of our manuscript is the compilation of many different substances, both from the pharmaceutical group and from the personal care products group, with particular attention to the preparations and active substances used particularly intensively during the COVID-19 pandemic both for treatment and to prevent the spread of the virus.

Taking into account the above, the aim of the review is to indicate various aspects of the occurrence of PPCPs in different water bodies such as wastewater, freshwater (rivers and lakes) and groundwater, including their diversity, sources of entry, toxicity and the methods of their removal from water and wastewater. The work pays particular attention to the possibilities of applying different analytical methods, including physical and chemical and their combinations in relation to various PPCPs and energy consumption, and also highlights the importance of green technologies in removing the discussed organic micropollutants.

2. Materials and Methods

In this paper, the problem of PPCPs residues in water and wastewater, the related hazards to human and animal health and their impact on natural ecosystems are addressed. In addition, an overview of the methods used to remove of PPCPs in the production of drinking water and wastewater treatment is presented. Particular attention was paid to methods characterized by low energy input and that allow the sustainable removal of PPCPs. For this purpose, a review of the literature was carried out from the years 2000 to 2023. The literature review was performed using electronic databases such as Scopus, PubMed and Google Scholar. Among the research and review articles found, 143 were selected as the items that best reflect the nature of the topic being discussed.

3. Pharmaceutical Residues in Soil, Water and Wastewater

3.1. Sources of PPCPs

PPCPs in the environment come from households, hospitals, the pharmaceutical industry and the veterinary industry (Figure 1) [1]. There are many routes for human and veterinary drugs to enter the environment. Residues may be released during the production process, from where they may end up in surface waters. Drugs consumed by humans, after absorption and metabolism, are excreted in the form of a mixture of biologically active metabolites and end up in a sewage system. It is also common for unused, expired drugs to be thrown down the toilet or thrown into municipal waste [17,18]. Due to their complex structure and varied physicochemical properties, they do not undergo biodegradation processes and therefore are not completely eliminated during wastewater treatment processes in conventional systems, which means that they can get into water and thus be dispersed in the environment. The use of such water disturbs the balance in the body and also intensifies the problem of the already dangerous phenomenon of drug resistance, which designers of new antibiotics are constantly struggling with [19]. In addition, wastewater treated in desert and semi-desert areas is used to irrigate fields, which can cause the accumulation of drug residues in soil as well as in the plants grown there. Xenobiotics also get into the soil due to the use of sewage sludge as fertilizer or for land reclamation [20,21]. The residues of veterinary drugs used on animals grazing in meadows can get directly into water and soil. An indirect source of drugs in the environment can also be intensive animal husbandry, from where the produced manure and slurry can be used as fertilizer in the soil, after which they may end up in ground and surface water through washing and surface runoff [18,22]. Pharmaceutical residues can also get into the soil, water or air environment as a result of the improper disposal of used drug packaging and unused, often expired drugs, which often end up in landfills [23]. Pharmaceuticals such as acetaminophen (paracetamol), ibuprofen, salicylic acid, ketoprofen, and fluoxetine, carbamazepine, nimesulide and sertraline have been detected in groundwater samples from cemeteries in Portugal [24].

Municipal wastewater and breeding cycles, especially in industrial animal breeding, are still some of the most important sources of pharmaceuticals and PPCPs in the environment. Simultaneously, we should not ignore the existence of waste landfills, from which leachate leaks into the environment. To sum up, it is worth pointing out that throwing medicines into the trash contributes to an unfavorable balance for the environment.

3.2. Types of PPCPs, the Risks They Pose in the Environment and Main Regulations

PPCPs are classified into many groups according to their purpose and properties (Figure 2). The group of pharmaceuticals includes antibiotics, antiviral drugs, hormones, analgesics and beta-blockers, anti-inflammatory drugs, cytostatic drugs and regulators of blood lipid levels. Personal hygiene products include preservatives, insect repellents, bactericides and disinfectants, fragrances, and UV sun filters [25].

Most drugs are not completely metabolized by organisms, and the residues following their excretion may end up in sewage and then in surface waters and other elements of the environment and may therefore be present in the food chain (Figure 3). Moreover, excreted metabolites or incompletely degraded PPCPs can be secondary pollutants and may subsequently be directed and modified in the water bodies receiving them [18,25]. Data from 2015 show that pharmaceuticals in different parts of the environment have been recorded in over 70 countries representing all continents [26]. The total number of active pharmaceutical substances is almost 12,000. So far, about 600 different types of active drug substances were detected in different matrices (surface water, rivers, lakes and oceans, groundwater and drinking water) [26,27]. In studies conducted in Croatia, Austria, Brazil, Canada, England, Greece, Germany, Italy, Switzerland, Spain, the Netherlands and the United States, over 80 pharmaceuticals and their metabolites were detected in the water environment in amounts within the µg per 1 L range or lower [28]. Many PPCPs disperse quickly in the environment, but their widespread use causes pseudo-persistence in water environments, resulting in a negative impact on aquatic organisms [25]. Their presence, even in small amounts (nano and micrograms), in the water environment can be the cause of chronic toxicity, endocrine disorders and increase the phenomenon of resistance among bacteria. These consequences are worrisome mainly in the case of aquatic organisms, as the threats may take on a multi-generational character [29]. A study conducted by the Environmental Working Group of the United States [30] showed the presence of 16 dangerous chemicals from the PCPs group (including synthetic musk, 2-benzenedicarboxylic salt and triclosan) in the bodies of girls as a result of the use of cosmetic products.

It was proved that the presence of PPCPs residues in waters is influenced by the season. Moreover, some processes such as photodegradation, biodegradation or hydrolysis may reduce the level of these substances in the environment [13]. Research conducted by Robinson et al. [31] showed that up to 68% of propranolol was removed from American rivers using photodegradation in the summer. Comparable data were also obtained for other PPCPs (acetaminophen, ibuprofen, etc.), confirming the purpose of photolysis in the degradation of PPCPs in surface waters [32]. In turn, O’Flynn et al. [33] indicate that, in winter, there is a decrease in the effectiveness of photodegradation in removing PPCPs from wastewater, but their higher dilution may occur due to increased precipitation, as reported by Lacey et al. [34]. It was found out that, in the presence of sunlight, triclosan may undergo photolysis, where different dichlorodioxins are generated, e.g., 4,5′-dichloro-2,2′-dihydroxybiphenyl ((OH)₂PCB-13), 2,8-dichlorodibenzo-p-dioxin, and 2,4-dichlorophenol. Compounds from the group of dichlorodioxins usually do not exhibit high toxicity, but selected factors, such as the chlorine present in the reaction environment, may cause their transformation into very toxic compounds [35].

The toxic effect of PPCPs in the environment, including water, is observed in aquatic organisms (fish, invertebrates, and algae), animals and humans (Figure 4). Genotoxic and carcinogenic effects, disruptions to the hormonal, reproductive and behavioral systems, and many other effects have been reported [18,36,37,38,39]. In addition to being toxic to aquatic organisms, pharmaceuticals can also be phytotoxic. Phytotoxicity may vary between plant species and depends primarily on sorption kinetics, soil pH and organic matter content. Physicochemical and biological PPCPs’ properties depend on a variety of environmental factors [18]. The phytotoxicity of PPCPs manifests as a reduction in growth and yield, a modification of roots, and a disruption of the photosynthetic system. Currently, little is known about the behavior of the majority of drugs in soil. The sorption of PPCPs to soil colloids depends on pH, soil temperature, the organic matter content, and granulometric composition [20].

3.2.1. Non-Steroidal Anti-Inflammatory Drugs and Analgesic Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics are among the most frequently purchased groups of drugs. This group includes painkillers, antipyretics and anti-inflammatory drugs. They are usually available without a prescription and can be purchased not only in pharmacies, but also in most stores, such as local stores, hypermarkets, kiosks and petrol stations. The data presented in Figure 5 (in DDD/1000 inhabitants/day—defined daily dosage per 1000 inhabitants per day) indicate that the average consumption of anti-inflammatory and antirheumatic products non-steroids, according to the OECD report [40], was the highest in Finland (84, 80 and 78 DDD/1000 inhabitants/day in 2010–2015, 2016–2019 and 2020–2022, respectively), while the lowest was in Greece (2010–2015: 11 DDD/1000 inhabitants/day, 2016–2019: 9 DDD/1000 inhabitants/day and 2020–2022: 8 DDD/1000 inhabitants/day). In turn, the consumption of analgesics was the highest in Denmark (96, 96 and 97 DDD/1000 inhabitants/day respectively in 2010–2015, 2016–2019 and 2020–2022).The best known and the most frequently used of this group of drugs are aspirin, diclofenac, ibuprofen, naproxen, ketoprofen and paracetamol [10]. Compounds such as diclofenac, aspirin, and ketoprofen are very often detected in water and wastewater [11]. Their concentration depends on the region and water bodies (surface water, drinking water, the influent and effluent of WWTPs. Research shows that drugs from the NSAIDs and analgesics group can also accumulate in bottom sediments of surface waters, sewage sludge and composts [41,42].

Data from the Intercontinental Marketing Services (IMS) Health indicate that the most frequently prescribed non-steroidal analgesic is diclofenac, the global consumption of which amounts to 940 Mg per year [29]. Diclofenac (known as Voltaren) is an anti-inflammatory pharmaceutical agent, and even trace amounts of this compound in water have become a very important problem from the points of view of human health and environmental hazards. It is widely used as an anti-arthritic, analgesic, and anti-rheumatic agent and is becoming one of the major pharmaceutical micropollutants in the water system [43]. The remains of this compound in water can cause changes in the kidneys and gills of fish [29].

According to the literature data, compounds like diclofenac and naproxen have antimicrobial properties and constitute a threat to the aquatic environment and human health [44]. Some drugs from the NSAIDs group are classified as endocrine disrupting pharmaceuticals [13]. Results presented by Branco et al. [45] indicate that diclofenac and ibuprom may interfere with fish reproduction by disturbing spermatogenesis and the maturation of Astyanax lacustris. In turn, research conducted by Lind et al. [46] indicated that the simultaneous use of paracetamol (APAP) and NSAIDs by a mother during pregnancy resulted in a decrease in the AGD (anogenital distance) index in male offspring without affecting the value of this index in girls.

To summarize, it is worth emphasizing that NSAIDs, as substances intended to be active in low content, have an impact on “non-target organisms”, and because of their ability to bioaccumulate, they constitute a hazard to all links of the food chain. Since the most common compound from this group is diclofenac, more and more regulations are being created, regulating its production, consumption and the control of its release into the environment, including local legal acts regarding the need to monitor its amount in the environment and estimate the effects of its action.

3.2.2. Drugs Acting on Pathogenic Microorganisms

This group of drugs includes antibiotics, antiviral, antifungal, and antiparasitic drugs, and disinfectants, used in both medicine and veterinary medicine [47]. A wide variety of antibiotics are widely used around the world as medicines to prevent or treat human and animal infections, plant infections, or as additives to animal and fish feeds, and to promote growth [20,48,49]. Antifungal agents, which include, among others, azole drugs (e.g., clotrimazole, fluconazole, and econazole) are a class of pharmaceuticals with a wide range of antifungal applications, used in medicine, veterinary medicine, agriculture and personal care products [50]. From the group of disinfectants, triclosan is very widespread and has been widely used for many years. Due to its properties, it was an important ingredient in cosmetic and hygiene preparations. It’s widespread and frequent use was the reason for the presence of large amounts of it released into the environment, constituting a serious hazard [51].

The literature data indicate that the consumption of antibiotics from 2000 to 2015 increased by 65%, and it is forecast that, by 2030, their consumption will increase by 200% [49]. According to Figure 5, the consumption of antibacterial medicines for systemic use in the years 2010–2015, 2016–2019 and 2020–2022 was the highest in Turkey (it was 41, 35 and 26 DDD/1000 inhabitants/day, respectively), while the lowest was in the Netherlands (11, 10 and 8 DDD/1000 inhabitants/day). In the case of animals, the worldwide consumption of antibiotics in 2010 was 63,151 tons and is estimated to grow by 67% in 2030 due to the consumer demand for animal products [52]. The increase in the use and consumption of antibacterial and antiviral agents occurred during the COVID-19 pandemic, especially in the early days before vaccines became available. In addition, new drugs with antiviral properties were developed at this time [1,5]. For example, in Athens (Greece), the use of antivirals increased by 170% and antibiotics by 57% [53]. During the COVID-19 pandemic, the most important antiviral drugs were ritonavir, favipiravir, lopinavir, chloroquine, ribavirin, and rapamycin [54,55]. The use of hand and surface disinfectants also increased during the pandemic [1]. As the literature data show, from January to February 2020 in Wuhan, approximately 2000 tons of disinfectants entered the sewage system [56].

Due to the increase in the consumption of drugs and antimicrobials, the presence of various substances in wastewater and water has been noted [5]. Data presented by Pei et al. [57] indicate that only 15% of antibiotics are absorbed and metabolized, while the remaining part is released into the environment. In some countries, the content of amoxicillin and other broad-spectrum antibiotics in the environment has increased since 2020 [5,58]. In the case of antivirals, it is estimated that approximately 60% of the drug dose is excreted into the sewage system in urine and feces [59]. Moreover, their concentration in the era of COVID-19 increased by 70% in urban sewage compared to previous years [60].

Antibiotics in water bodies constitute a serious problem, due to their persistence in the environment, their partial metabolism and their easy movement in the ecosystem [61]. Due to the high consumption of antibiotics, pathogenic bacteria become resistant to those antibiotics that were effective in the fight against them. This problem forces pharmaceutical companies to look for new generation drugs with increased antibacterial activity [18]. The problem of resistance in microorganisms also applies to the use of antiviral agents [62] as well as antifungal agents [50]. The phenomenon of bacterial resistance to substances with antibacterial activity also applies, to some extent, to disinfectants such as triclosan. In this case, the mechanisms of resistance can be twofold: acquired (found mainly in staphylococcal strains) or idiopathic. Cross-resistance to triclosan and antibiotics has also been identified. The literature data indicate that triclosan-resistant strains are also less sensitive to selected antibiotics. The mechanisms responsible for such a response are related to the disrupted permeability of bacterial cell membranes and the activity of the membrane pump efflux, which are responsible for the removal of various chemical compounds from the bacterial cell [63]. The presence of antibiotics in the body can be toxic, which has been found to affect several organisms such as bacteria, algae and daphnia (Daphnia magna). This applies to both high concentrations in the body as well as low concentrations and chronic tests [64]. Research conducted by Thiagarajan et al. [65] showed that tetracycline has a toxic effect on Chlorella vulgaris, Microcystis aeruginosa and Selenastrum capricornutum by inhibiting physiological processes and growth. The occurrence of antibiotics in the environment may also result in allergies and cancer in humans and aquatic organisms [66]. Antibiotics are poorly biodegradable and may remain in wastewater after treatment, which results in the long-term persistence of these compounds in the environment and their potential bioaccumulation [64]. Antibiotics in agricultural soils can have an effect on plant physiology and soil biological characteristics. However, results regarding the mobility of these compounds in the food chain are very scarce [20].

Some antimicrobial preparations may be endocrine disruptors. Such properties may be exhibited by azole antifungal agents, the symptoms of which include endocrine disorders in animals and the retardation of plant growth [50]. Several studies have shown that triclosan is an endocrine disruptor in animals because of its structural similarity to hormones, e.g., thyroxine. Animal data have indicated that even low concentrations of triclosan interfered with the thyroid-mediated development of tadpoles. In addition, triclosan may cause disturbances in the mammalian endocrine system, due to its structural similarity to estrogens. In vitro studies have shown that triclosan exhibited androgenic and estrogenic effects in human breast cancer cells, which was confirmed in animal studies [39,67].

Generally speaking, although the discovery and introduction of antibiotics into the treatment of infectious diseases was one of the most important historical achievements in medicine, their excessive use led to the spread of drug resistance genes, also among environmental strains. Currently, due to the COVID-19 pandemic, we are dealing with an unprecedented increase in the number of antiviral and other drugs used to treat and prevent the spread of the SARS-CoV-2 virus. The data presented in this subchapter indicate the need to limit and constantly monitor the amount of drugs used from the antibiotics, antiviral, antifungal and antiparasitic drugs group, which may constitute dangerous environmental pollution.

3.2.3. Hormonal Agents

Hormonal biomimetics, often referred to in the literature as EDCs (Endocrine disrupting chemicals), are substances that disrupt the functions of the endocrine system [68]. In turn, the US EPA defined endocrine disruptors as “exogenous factors that interfere with the production, release, transport, metabolism, binding, action, or elimination of natural hormones in the body responsible for maintaining homeostasis and regulating developmental processes”. EDCs include, among others, hormones of natural origin, like estrone, estradiol, as well as synthetic ones (ethinylestradiol EE2), which is the basic component of oral contraceptives. This also includes growth hormones used in animal breeding [13]. According to the OECD report and Figure 5, the highest consumption of sex hormones and modulators of the genital system in 2010–2015, 2016–2019 and 2020–2022 was recorded in France (120, 109 and 98 DDD/1000 inhabitants/day, respectively). Due to their persistence in the environment and their negative impact on the hormonal systems of humans, animals and aquatic organisms, the presence of estrogen in the environment is of great concern [69]. Most often, they end up in the environment along with excreted urine. Hormones are detected in sewage and water at low levels (ng/L–µg/L), but they can cause hormonal disorders in humans and animals.

Their small concentrations in water can cause serious hormonal disorders in organisms living there. For example, ethinylestradiol may cause hormonal disorders in male fish, causing their feminization and masculinization [70,71]. Research conducted in France proved that 17-βestradiol caused a significant and rapid increase in plasma vitellogenin in both female and male chubs [72]. Similar observations regarding feminization and vitellogenin production in male fish were obtained by Mina et al. [73].

To conclude, it should be stated that the presence of EDCs in water, including hormones, is currently one of the most important environmental protection problems. In recent years, we have observed an increase in interest in the substances from this group, because it turns out that classical methods and processes of wastewater treatment are not sufficient to remove them. Therefore, it is now crucial to develop effective methods for limiting the load of these compounds in sewage discharged to surface receivers.

3.2.4. β-Blockers

This group of drugs includes atenolol, metoprolol and propanolol. They are used in the case of cardiovascular diseases, i.e., in ischemic heart disease, cardiac arrhythmias, hypertension and in the case of phaeochromocytoma of the adrenal medulla [10]. In addition, they are used in the treatment of anxiety, tremors, glaucoma, migraines and hyperthyroidism. Currently, over 20 β-blockers with a similar structure and similar physicochemical properties are used [74,75]. Drugs from this group are metabolized by humans and then reach sewage treatment plants as metabolites or parent substances, where they may undergo further transformations. β-blockers are not completely eliminated during wastewater treatment. They are biologically active compounds in the environment, often occurring in the form of a mixture of various substances whose toxicity is difficult to predict [10]

As a result of photodegradation, biotransformation and sorption, they are transformed and decomposed [2]. According to Andreozzi et al. [74], the main factors affecting the photodegradation of beta-blockers is the intensity of solar radiation related to the season and latitude.

Over the past ten years, beta blocker amounts in the influent and effluent of WWTPs have been detected below several hundred nanograms per liter [10]. They are “pseudo-persistent” aquatic pollutants with a half-life of 3–8.7 days [76]. In the era of COVID-19, there has been a growth in the consumption of β-blockers due to cardiac side effects caused by the virus, resulting in an increased release of these drugs into the environment [1]. OECD data and Figure 5 show that the highest consumption of β-blockers in 2010–2015, 2016–2019 and 2020–2022 was highest in Germany (89, 83 and 81 DDD/1000 inhabitants/day, respectively).

It has been shown that β-blockers are harmful to aquatic organisms (fish, algae, and invertebrates) even at low concentrations. Moreover, it was revealed that propranolol reduces the number of eggs released by fish [77], and in turn, metoprolol causes ultrastructural changes in the liver, gills and kidneys of rainbow trout [38].

To conclude, we must state that beta-blockers are another group of active substances whose presence in the environment promotes pollution and affects the life and functioning of entire ecosystems. Cardiac drugs, as optically active substances, undergo various chemical transformations in the environment, producing derivatives with often unknown biological activity. Therefore, understanding these processes is an important aspect of environmental monitoring.

3.2.5. Hypolipidemic Drugs (Fat Regulators)

The group of lipid metabolism regulators includes fibric acid derivatives that have the ability to reduce cholesterol and fatty acids in the liver. These include bezafibrate, gemfibrozil, and clofibrate, which is converted in the liver to its active form, clofibric acid. This group also includes atorvastatin and simvastatin. Their average consumption in 2010–2015, 2016–2019 and 2020–2022 was highest in Denmark and UK (Figure 4).

The literature data indicate that gemfibrozil is one of the endocrine disruptors. Research conducted by Mimeault et al. [78] indicated that gemfibrozil causes a reduction in plasma testosterone by more than 50% after 14 days in goldfish (Carssius auratus). Clofibric acid, like a cholesterol-lowering medicine, is considered a potential endocrine disruptor, due to it interfering with cholesterol synthesis [79].

To summarize, it should be emphasized that statins and other lipid-lowering drugs are drugs used long-term, hence their frequent detection in the environment.

3.2.6. Psychotropic and Antiepileptic Drugs

This group includes drugs such as carbamazepine and diazepam, which have anticonvulsant, antiepileptic and sedative effects. Carbamazepine (an antiepileptic drug) and antidepressants such as diazepam, fluoxetine, and venlafaxine are the most common drugs in the world from this group [10]. Research indicates that in the era of COVID-19, the consumption of mainly antidepressants has increased, resulting in an increase in their concentration in various elements of the environment [1]. OECD statistical data and Figure 5 indicate that the highest average consumption of antidepressants in the years 2010–2015, 2016–2019 and 2020–2022 was recorded in Iceland and amounted to 111, 140 and 157 DDD/1000 inhabitants/day, respectively. Approximately 13% of carbamazepine is eliminated unchanged in feces and urine [80]. Due to its high intake, low biodegradability and low elimination efficiency from wastewater, carbamezapine is detected in wastewater, sewage sludge and water at varying concentrations. The literature data also indicate that the highest concentration of carbamezapine occurs in influent and effluent areas in Europe. Furthermore, in some treatment plants around the world, higher concentrations of carbamezapine are detected in effluents than in influents [10]. In the case of fluoxetine, an antidepressant, 20–30% is metabolized, the rest of which is excreted in urine into the sewage system [81].

Some drugs in this group including the antidepressant fluoxetine and sertraline are lipophilic and have the ability to bind to solids. The literature reports the presence of these medicines also in sewage sludge [82].

Studies have shown that carbamazepine is carcinogenic to mice and fish [83]. In turn, antidepressants may be potentially harmful to aquatic organisms, including fish [10]. The literature data indicate that the presence of carbamezapine and diazepam can adversely affect endocrine and reproductive function and interfere with photosynthesis in aquatic organisms [84].

It is worth noting that the COVID-19 pandemic has not only resulted in an increase in the use of antiviral and other drugs used to treat somatic symptoms, but has also caused a huge increase in the number of mental problems. Long-term isolation had a negative impact on already diagnosed cases, and the literature data show that isolation itself was also the cause of the development of depression and other similar diseases. Therefore, the observed increase in the amount of antidepressants and their derivatives has influenced the overall toxicity of pharmaceuticals to aquatic organisms.

3.2.7. Others Pharmaceuticals

Anti-diabetic (metformin) drugs, stimulants (caffeine) and opiates (morphine, codeine, and tramadol) are also recorded in water and in influents and effluents of WWTPs around the world. One of the most commonly used stimulants is caffeine, which belongs to the methylxanthine family. It is present in coffee, energy drinks, dietary supplements and medicines [10]. As large amounts of coffee and tea are disposed of directly into the toilet, the concentration of caffeine in wastewater is estimated to be relatively high. There was no direct threat to humans and animals related to the presence of this stimulant in water. The presence of this substance in water is closely related to anthropogenic pollution and can be used as an indicator of drinking water pollution [85]. Opiates are also detected in the wastewater. This group includes compounds such as morphine, cocaine, methamphetamine and ecstasy. All of them have a strong pharmacological effect, and their presence as complex mixtures in the aquatic and terrestrial environment can be toxic to aquatic organisms [86].

The increasing consumption of drugs and other stimulants is caused by a change in society’s lifestyle and directly contributes to the growing problem of the presence of pharmaceuticals in sewage, from where they enter the environment.

3.2.8. Personal Care Products

The group of personal care products includes cosmetics and personal hygiene products, synthetic musk fragrances (nitropolycyclic musks), insect repellents (N,N-diethyl-m-toluamide (DEET)), UV blockers (methylbenzylidene camphor) and preservatives (phenols and p-hydroxybenzoic acid (parabens)) [8]. Parabens are antimicrobial preservatives with high stability and good water solubility that are used in cosmetics (e.g., shampoos and balms). Their presence in various elements of the environment is disturbing because studies have shown that parabens may cause breast cancer in women and sperm dysfunction in men [87]. Parabens belong to the group of esters; specifically, they are esters of para-hydroxybenzoic acid with an alkyl or benzyl group. For many years, they have been one of the most commonly used preservatives in cosmetics, foodstuffs and pharmaceuticals.

Among the insecticides, DEET is the most important. It is an ingredient of agents acting against mosquitoes and other insects.

Another popular ingredient of everyday products (plastic products) is the plasticizer bisphenol A. Due to its widespread use, this compound is often detected in the environment. Bisphenol A is a substance from the group of endocrine disruptors with estrogenic activity. Research indicates that it may cause early puberty in women, diabetes and reduced sperm count, etc. It may also adversely affect the reproductive organs of fish [88].

The variety of personal hygiene products is huge. When they enter a water reservoir via municipal wastewater, they may pose a real threat to the natural environment and, therefore, to human health and other living organisms.

3.2.9. The EU and International Organizations Regulations Regarding the Occurrence of PPCPs in Water and Wastewater

Due to the potential hazardous effects on the environment and human health, government and international organizations have established guidelines and strategies regarding the issue of PPCPs in wastewater treatment plants and in the environment. The most important here are the directives of the European Union (EU), the recommendations and strategies of international organizations (e.g., the World Health Organization (WHO)), the Environmental Agency (EA), the Organization of Economic Cooperation and Development (OECD) and the guidelines and measures established by individual countries [10]. Taking into account European directives, the foundation is Directive 2000/60/EC, which indicates substances potentially hazardous to the environment [89] (Figure 6). Immediately after it, the Water Framework Directive (WFD) by the European Union was created, containing the Watch List (WL) of potential water pollutants that should be monitored by EU Member States, due to their potential threat to the aquatic environment. In 2008, a second directive, Directive 2008/105/EC, was published [90], which lists 33 priority substances and presents the relevant environmental quality standards. A directive published in 2013 (2013/39/EC) [91] recommended the monitoring and removal of 45 priority substances. It also contained the WL, which listed three substances from the PPCPs group, diclofenac, E2 (estradiol), and EE2 (17α-ethinylestradiol). In 2018, the Joint Research Center (JRC) of the EU updated the WL, which included PPCPs such as amoxicillin, ciprofloxacin, erythromycin, clarithromycin, azithromycin, EE2, E2, and E1 (estrone). Additionally, diclofenac was removed from WL considering its low toxicity to the environment [92]. The inclusion of antibiotics, in line with the EU strategy, was aimed at combating antimicrobial resistance. In 2020, the EU published a new Commission Implementation Decision [93], which completed the monitoring of the following PPCPs: EE2, E2, E1 and macrolide antibiotics (erythromycin, clarithromycin and azithromycin) and included into the WL new substances such as metaflumizone, amoxicillin, ciprofloxacin, sulfamethoxazole, tri-methoprim, venlafaxine and O-desmethylvenlafaxine and azole compounds. Currently, in accordance with Decision (EU) 2022/1307, the WL of substances for Union-wide monitoring includes such PPCPs as sulfamethoxazole, trimethoprim, venlafaxine and o-desmethylvenlafaxine and azole compounds [94]. In the proposal for a directive of the European Parliament and of the Council on the quality of water intended for human consumption [95], WHO recommended including new parameters, including three substances classified as EDCs, which include bisphenol A, beta-estradiol and nonylphenol. As history shows, the EU adapts regulations on monitoring and water quality depending on the substances introduced into circulation and their potential threat to the aquatic ecosystem, but not all European Union countries implement them [96].

Regarding international organizations, several of them have debated the issue regarding pharmaceuticals and established guidelines for managing, monitoring and reducing the presence of pharmaceuticals in the environment [10]. In 2019, the European Commission (EC) imposed an obligation to conduct an environmental risk assessment related to the placing of new medicines on the market (both for humans and animals). Moreover, the next step of the EC was to implement six areas of action to manage the problem of the presence of pharmaceuticals in the environment, which included, among others, the following: recommending the control of the consumption of potentially hazardous pharmaceuticals; encouraging the introduction of “green pharmaceuticals”; improving environmental risk assessment models based on cooperation between agencies (i.e., the European Medicines Agency EMA) and Member States; improving the pharmaceutical waste management system; developing and implementing AOPs in places such as hospitals and animal farms; increasing the monitoring of pharmaceuticals in various environmental elements; filling gaps in the knowledge about the ecotoxicity and behavior of pharmaceuticals in the environment and about the relationship between the occurrence of antimicrobial compounds in the environment and resistance genes; and developing cost-effective technologies for pharmaceuticals removal [97].

Taking into account the WHO, in 2012, it recommended the use of the minimum therapeutic dose (MTD) to determine the potential health risks associated with the use of pharmaceuticals. For example, the defined daily dose of acetaminophen (paracetamol) is 3 g/day, for ibuprofen 1.2 g/day and naproxen 0.5 g/day. Moreover, WHO recommended that the concentration of pharmaceuticals in surface and groundwater should not exceed 100 ng/L, while in drinking water, it should be less than 50 ng/L [1,98].

In 2019, the OECD established a policy regarding the presence of pharmaceuticals and their residues in the environment, establishing five cost-effective solutions applied in order to manage the occurrence of pharmaceuticals in water and protect water quality and ecosystems. They included deepening the knowledge about the occurrence, fate and toxicity of pharmaceuticals in water bodies and adopting a source-centric, exploitation, collaborative or lifecycle approach.

Another organization, the European Food Safety Authority (EFSA), deals with, among other responsibilities, monitoring residues of veterinary drugs in food products [99].

The US EPA regularly publishes a list of priority substances. Generally, the main task of international organizations such as the European Environmental Agency (EEA), the International Chemical Safety Program (IPCS), the WHO and the US Environmental Protection Agency (EPA) is to develop directives and regulations to ensure the protection and safety of freshwater resources [100].

It should be noted that there are currently no EU standards and regulations regarding discharges for most pharmaceuticals detected in wastewater treatment plants. Additionally, the US EPA has listed emerging pollutants as hazardous substances, but they do not have regulatory standards [101]. The exception is the Swedish Agency for Marine and Water Management, which has decided that diclofenac, estradiol, ethinylestradiol and ciprofloxacin must be considered basin-specific pollutants. Their maximum values were also established for inland surface waters (diclofenac 0.1 µg/L, ciprofloxacin 0.1 µg/L, 17-alpha-ethinylestradiol 0.000035 µg/L and 17-beta-estradiol 0.0004 µg/L) and coastal and transitional waters (diclofenac 0.01 µg/L, ciprofloxacin 0.1 µg/L, 17-alpha-ethinylestradiol 0.000007 µg/L and 17-beta-estradiol 0.00008 µg/L). However, despite the established values, there is no requirement for authorities or others to systematically measure these substances in water, and there are no legal consequences if they are exceeded [102].

PPCPs present in the environment may have an adverse effect on aquatic organisms such as bacteria or algae, but they are also one of the causes of drinking water contamination. Therefore, it is necessary to analyze the content of these biologically active substances in drinking water and to determine the level of pharmaceutical consumption and the degree of exposure of local communities. All these activities, in turn, allow for the introduction of the necessary legislation at national and European levels.

3.3. PPCPs in Water and Wastewater

3.3.1. Concentration of Selected PPCPs in Natural Waters

Monitoring the concentration of PPCPs in natural waters such as surface water, i.e., lakes, rivers, streams and estuaries and groundwater, should be an ongoing procedure. This is because the abovementioned types of surface water and groundwater are often sources of drinking water.

Table 1. Examples of concentrations of selected PPCPs in natural waters and wastewater.

Group	Classification	Examples of Compound	Country /Region	Natural Water		Wastewater (ng/L)		References
				Type	Concentration (ng/L)	Influent/Raw Wastewater	Effluent
Pharmaceuticals	NSAID and analgesic drugs	Naproxen	South Africa	Surface water	23,000	159,000	91,100	[106]
			South Korea	Surface water	230			[105]
			USA	river	0–135.2			[71]
		Ibuprofen	Global	Surface water	445–689	1060	1380	[103]
			USA	river	0–34.0			[71]
			China	Surface water	10−180			[105]
			Spain	Surface water	2.5–650			[105]
		Diclofenac	Poland	Groundwater	114	556–4001	743–5402	[107]
			-	Drinking water	1–10 (max. 56)			[104]
				Surface water	0.2–193,000			[105]
						836,000		[104]
	Antimicrobial agents	Erythromycin		Groundwater	12.3–443			[11]
				Freshwater	0.02–362.49			[11]
		Tetracyclines		Freshwater	5–712.40			[11]
		Fluconazole	South Africa			9959		[50]
		Favipiravir	Japan	Surface water	40–60			[55]
	Hormones	17β-estradiol (E2)	USA	River	0–4.5			[71]
		EE2				2193	549	[70]
	β-blockers	Atenolol		Freshwater	0.25–1237			[11]
				Groundwater	0.8–106			[11]
		Propranolol				8–76		[13]
	Hypolipidemic drugs (fat regulators)	Gemfibrozil	Global	Groundwater	1.2–1950			[11]
							<76,000	[10]
		Clofibric acid		Freshwater	0.01–450	<2593		[11]
			USA	River	3.2–26.7			[71]
		Bezafibrate					3445	[10]
	Psychotropic drugs	Carbamazepine		Groundwater	2–900			[11]
				Seawater	0.02–310			[11]
			Turkey			136	101	[108]
	Others	Caffeine	England	Freshwater	11–44,179	150,413		[11]
				Groundwater	56.8–16,249			[11]
Personal care products	Plasticizer	Bisphenol A	USA	River	147			[71]
			Italy			326.9–1317	<70	[109]
	Insect repellent	DEET		River	22–94			[8]
						600–1200	40–624	[25]
	Disinfectant	Triclosan	USA	River	8.8–26.3			[71]
			Italy			505–2210	<390	[109]

summarizes the detected concentrations of various PPCPs in natural waters. Considering substances from the group of painkillers, it is worth emphasizing that, for example, the concentration of naproxen in surface water in South Africa was 23,000 ng/L. In the case of ibuprofen, the concentration in surface water was 445–689 ng/L [103]. In drinking water, the concentration of diclofenac ranges from 1 ng/L to 10 ng/L (maximum 56 ng/L) and in groundwater from 10 ng/L to 10 µg/L [104]. Data presented by Hernández-Tenorio et al. [105] indicate that diclofenac concentrations in surface water amounted 0.2–193,000 ng/L.

Regarding the group of antibiotics, according to the literature, the concentration of erythromycin in groundwater ranged from 12.3 to 443 ng/L, while in freshwater, it ranged from 0.02 to 362.49 ng/L. In turn, the concentration of tetracyclines in freshwater ranged from 5 to 712.40 ng/L [11]. Considering the group of hormonal drugs, tests of water samples from the Mississippi River showed the presence of 17β-estradiol (E2) at levels of up to 5 ng/L [71].

The literature data focusing on the presence of β-blockers in natural water indicate that the concentration of atenolol is in the range of 0.25–1237 ng/L (freshwater) and 0.8–106 ng/L in the case of groundwater [11]. Furthermore, a very important group of compounds such as hypolipidemic drugs is also present in natural water reservoirs. Data presented by Adeleye et al. [11] indicate that gemfibrozil concentrations in groundwater range from 1.2 to 1950 ng/L. In turn, clofibric acid is detected in freshwater within the range 0.01–450 ng/L. In rivers (in the USA), the concentration of this compound was recorded at levels ranging from 3.2 to 26.7 ng/L [71].

Another group of active substances identified in water are psychotropic drugs, for example, carbamazepine, which is detected in water in different concentrations. For example, the concentration of this substance in groundwater ranges from 2 to 900 ng/L and, in seawater, from 0.02 to 310 ng/L [11]. Other active substances which are detected in natural water are other pharmaceuticals, such as stimulants, anti-diabetic drugs and personal care products, such as disinfectants. Caffeine is also commonly detected in natural waters, which is due to, among other factors, high caffeine consumption by humans. The concentration of caffeine in the aquatic environment depends on the water body. For example, in freshwater, the concentration ranges from 11 to 144,179 ng/L and, in groundwater, from 56.8 to 16,249 ng/L [11]. DEET it is also an agent that is often detected in waters, and its concentration varies. For example, in rivers, it ranges from 22 to 94 ng/L [8]. Of the disinfectant group, triclosan has been detected in surface waters at concentrations of 8.8–26.3 ng/L [71].

3.3.2. PPCPs in Wastewater

Although the presence of PPCPs in wastewater is obvious, it is a parameter that should be constantly monitored. This necessity is determined by the fact that treated wastewater may be discharged into surface water reservoirs. The literature data indicate that PPCPs residues are detected both in the influent (raw wastewater) and effluent (after treatment processes from secondary or tertiary treatment stages) of wastewater treatment plants (Table 1).

Considering pharmaceuticals from the NSAIDs and analgesics group, their average concentration in various countries in influent ranges from 3992 to 27.061 µg/L and, in treated wastewater, from 1208 to 7943 µg/L [106]. For example, the concentration of naproxen in South Africa in influent was 159,000 ng/L and, in effluent, was 91,100 ng/L. In the case of ibuprofen, the concentration was 1060 ng/L (influent) and 1380 ng/L (effluent), respectively [103]. In Poland, diclofenac concentrations were 556–4001 ng/L (in influent) and 743–5402 ng/L (in effluent) [107], and its concentration in municipal wastewater was up to 7.1 µg/L.

The group of compounds which is highly represented in wastewater are antibiotics and antifungal and antiviral drugs. Regarding antibiotics, their global concentration of antibiotics in wastewater ranges from 1 to 303,500 ng/L, with the highest values recorded in wastewater from the pharmaceutical industry, landfill leachate and farms. Studies on eight commonly used antifungal agents in various water bodies of South Africa showed that the highest concentration was recorded for fluconazole in influent samples, and its concentration was 9959 ng/L [50].

Hormonal substances are identified in wastewater, where they pose a great danger if released into the natural environment. Therefore, their content must be constantly monitored both in the influent and in the effluent leaving the WWTP. Research conducted in China showed varying contents of various natural and synthetic hormones (E1, E2, E3 and EE2) in the influent and effluent of WWTPs. The highest concentration in both influent and effluent was demonstrated for EE2 (influent: 2193 ng/L, effluent: 549 ng/L) [70].

From the group of β-blockers, propranolol is one of the most frequently isolated drugs. Its concentrations of 8–76 ng/L were recorded in wastewater (influent and effluent) [13].

The class of hydrolipidemic drugs contains active substances, which are commonly detected in the influent and effluent of WWTPs in various geographic regions. For example, concentrations up to 3445 ng/L were noticed for bezafibrate, while for gemfibrozil, concentrations up to 76,000 ng/L were recorded [10]. In turn, clofibric acid is often detected in raw wastewater at concentrations up to 2593 ng/L [11]. The increase in the frequency of identification of psychotropic drugs in wastewater is associated with the increase in their consumption in society, which is recorded all over the world. Due to its high intake, low ability in microbial degradation and low removal efficiency from wastewater, carbamazepine is detected in wastewater at varying concentrations. The literature data also indicate that the highest concentration of carbamazepine occurs in influent and effluent areas in Europe. In a municipal WWTPs in Turkey, the concentration of this compound was 136 ng/L (influent) and 101 ng/L (effluent) [108]. Furthermore, in some treatment plants around the world, higher concentrations of carbamazepine are detected in effluents than in influents [10].

Due to the widespread use of personal care products, the most common in sewage are parabens acting as preservatives, pesticides, bisphenols and disinfectants. Methyl and propyl parabens are most often identified in influents and effluents from wastewater at concentrations of up to 30 μg/L and 20 μg/L, respectively [25].

Insect repellent agents are also identified in the wastewater, which include DEET. The literature data indicate that its concentration in influent and effluent is 600–1200 ng/L and 40–624 ng/L, respectively [25].

4. An Overview of Methods for Removal of Selected PPCPs Residues from Water and Wastewater

WWTPs, as a rule, operate a single-stage, two-stage and optionally three-stage wastewater treatment system. A three-stage wastewater treatment system is most often used when high-quality water is obtained for specific purposes (e.g., for reuse, for irrigation or recreation). This is usually associated with a higher cost of treatment [11,110]. In general, techniques for the elimination of PPCPs residues in the drinking water production process include slow filtration with sand filters, ozonation, techniques based on the advanced oxidation process (AOPs) and electrochemical oxidation, adsorption on granular activated carbon (GAC) and membrane techniques, in particular nanofiltration and reverse osmosis. In the case of wastewater treatment, conventional biological processes are often insufficient. Therefore membrane bioreactors are recommended [111].

4.1. Techniques Used in Water Treatment

Conventional drinking water treatment techniques are aimed at removing pathogens, reducing color, turbidity, and controlling odor and taste. However, these methods are not efficient in completely eliminating organic micropollutants. Therefore, it is necessary to introduce advanced methods [112]. Among the currently used advanced methods of water purification and drinking water production, the main ones include adsorption methods, AOPs, membrane separation techniques and combined technologies [113] (Figure 7). Examples of various technologies used in water purification from PPCPs residues, taking into account their energy consumption, are listed in Table 2.

4.1.1. Electrocoagulation

One of the methods being used in order to remove antibiotics from water is electrocoagulation. The main processes used in electrocoagulation are charge adsorption and neutralization. The main reactions occurring in the electrocoagulation process are the dissolution of metal in the anodic part and the production of hydroxyl anion in the cathodic part. Oxytetracycline hydrochloride was removed via this method using iron and aluminum as anode materials, and stainless steel was applied as the cathode. Studies have shown that aluminum is more effective than iron as an anode material for removing oxytetracycline hydrochloride and is less energy intensive [114].

4.1.2. Advanced Oxidation Processes in Water Treatment

Nowadays, commonly used methods that allow for the elimination of micropollutants from wastewater and water are the advanced oxidation processes (AOPs). AOPs are defined as processes in which a strong oxidant—the hydroxyl radical—is produced and used (HO•), which has the property of oxidizing virtually any organic compound to carbon dioxide, water and inorganic compounds. Hydrogen peroxide, ozone, UV radiation, additives of catalysts (MnO₂, Fe²⁺, TiO₂) and their combinations are used to obtain radicals. Better results are obtained using systems containing, e.g., two (O₃/UV, O₃/H₂O₂, H₂O₂/UV) or three (O₃/H₂O₂/UV) components [5,15]. Technologies based on advanced oxidation have been more and more intensively developed for some time, and more and more attention is paid to them. This is due to the fact that they result in the complete oxidation of pollutants with the simultaneous absence of harmful byproducts. The literature data indicate many advantages of methods included in this group, including high efficiency, safety, lack of toxicity, low costs and good photochemical stability [115]. In recent years, plasma methods have become a potential alternative to the technology of conventional AOPs methods, the operation of which is based on the generation of a wide group of highly reactive molecules (O₃, H₂O₂) and ions (O⁺, O⁻, H⁻), including several radicals (HO•, HO₂•, O•, H•) involved in the decomposition of microparticles. Comparative studies using plasma ozonation and AOP techniques based on O₃ and UV in water purification from selected pharmaceuticals (atrazine, alachlor, bisphenol A and 1,7-α-ethinylestradiol) in a batch experiment were conducted by Wardenier et al. [116]. The obtained results showed that O₃-based AOPs are characterized by a higher efficiency than UV-based techniques, taking into account energy efficiency. In turn, the plasma technique is placed between UV and O₃ techniques regarding energy, but the authors suggest that improving mass transfer in the plasma-ozonation system will reduce energy consumption.

Among the many types of advanced oxidation technologies, the photocatalytic method of water treatment seems to be the most promising, due to its high degree of degradation and ability to mineralize. Based on this technology, with the use of sunlight, even impurities resistant to decomposition (including organic matter, inorganic matter, etc.) are broken down and mineralized to simple compounds including CO₂ and H₂O [117]. The degradation of diclofenac in water was studied using a photocatalytic process in the presence of ultraviolet radiation at room temperature, using active nanocomposite catalysts in the form of titanium oxide and zirconia in a batch reactor. Titanium–zirconium nanocomposites showed greater catalytic activity than titanium oxide alone without zirconium. Maximum diclofenac removal of approx. 92.5% was achieved with a Zr/Ti weight ratio of 11.8% [43]. There are also known studies on the advanced oxidation process, in which titanium dioxide TiO₂ is used as a catalyst. As a result of this process, the following substances were removed from the water: amoxicillin, ampicillin, and paracetamol [47]. In the last decade, nano-TiO₂ was recognized as an excellent photocatalytic material, but the high cost of using this compound initiated the search for cheaper equivalents. ZnO turned out to be an appropriate substitute due to its similar bandgap energy and lower price. In addition, it has a high chemical stability and sensitivity to ultraviolet radiation, which makes photocatalysis a promising, sustainable and environmentally friendly method [118]. Eryildiz et al. [119] indicated that the efficiency of the elimination of antiviral drugs using UV-based photocatalysis depends on factors such as pH, chemical properties of water and light source. Jia et al. [120] showed that as the pH increased (5–9), the ratio of the molecular form of acyclovir decreased and the ratio of the ionic form of acyclovir increased, which resulted in a faster photodegradation of acyclovir.

As reported by Alfonso-Muniozguren [101], the implementation of a photochemical AOP approach (i.e., photo-Fenton, UVC/H₂O₂) is associated with such difficulties as iron precipitation, the contamination of UVC lamps and the need for H₂O₂ storage. To minimize these problems, a compilation of AOPs with an ultrasound (US) approach is proposed. The disadvantage of this solution is the fact that minerals in water may be the cause of the formation of toxic byproducts.

4.1.3. Advanced Electrochemical Oxidation Processes in Water Treatment

There are reports in the literature on the conduct of advanced electrochemical oxidation processes (EAOPs), such as anodic oxidation (AO), electro-Fenton (EF) and photoelectro-Fenton (PEF), to remove PPCPs from water. Electrochemical oxidation, due to its strong oxidation performance, environmental compatibility, and mild reaction conditions, seems to be a very promising method of wastewater treatment. However, its high energy consumption significantly limits its use [121]. Reis et al. [122] studied the effectiveness of electrochemical EAOPs to eliminate EE2 from water. Using this technology, 99.9% removal was achieved. EAOPs technology also include membrane technologies. Electrodialysis is the simplest membrane method based on electrochemical technology that uses ion exchange membranes. It is used to separate water from contaminants such as heavy metals and organic compounds. Studies indicate that the purification of pharmaceutical ethinylestradiol in the urine via electrodialysis led to a positive reduction in toxicity, with a removal efficiency of approximately 99.7%. Recently, integrated electrochemical technologies that can support membrane processes (micro/nano/ultrafiltration and reverse osmosis) with EAOPs have gained attention [123]. Son et al. [124] checked the performance of the membrane capacitive deionization (MCDI) system for removing acetaminophen, atenolol and sulfamethoxazole from water in a batch experiment. The results showed that MCDI could effectively remove pharmaceuticals such as atenolol and sulfamethoxazole with low energy requirements. The removal efficiency of the tested pharmaceuticals is related to the nature of the compound. The highest removal rate was recorded for cationic atenolol (97.65%), followed by anionic sulfamethoxazole (93.22%), and the lowest for neutral acetaminophen (68.08%).

4.1.4. Adsorption in Water Treatment

Adsorption methods are also effective in removing organic micropollutants from water. Various substances can be used as adsorbents, e.g., activated carbon, chitosan, resins, zeolites or waste-based adsorbents. There are reports of ibuprofen adsorption on activated carbon obtained from cork waste. Other bioadsorbents, such as graphene-based nanoadsorbents, carbon nanotubes, and materials, such as biochar, have also been studied [125]. Naproxen was effectively removed via an adsorbent made from apricot waste, chemically activated with ZnCl₂ [126]. One of the types of tested adsorbents is the cyclodextrin polymer. In the work of Moulahcene et al. [127], the effectiveness of the use of insoluble cyclodextrin polymers cross-linked with citric acid to remove progesterone from water was studied.

Zhang et al. [128] studied the use of magnetic chitosan as an adsorbent to remove selected pharmaceutical agents, such as diclofenac, clofibric acid and carbamazepine from aqueous solutions. It was found that magnetic chitosan had a high sorption capacity and affinity for drugs with a carboxyl group, i.e., with diclofenac and clofibric acid.

Ahsan et al. [129] used a bioadsorbent based on sulfonated coffee waste to remove bisphenol A and sulfamethoxazole. The process was carried out at pH 4 for 30 min and the adsorption capacity was 256 mg/g (sulfamethoxazole) and 271 mg/g (bisphenol A).

Generally, adsorption methods, including those using biochar, are less efficient but, at the same time, are low cost and use low-demanding technologies. In addition, the adsorbent may be waste from different materials which lowers the costs of production and thus supports a sustainable waste management approach [130]. Czech et al. [131] conducted studies on the removal of triclosan, diclofenac and naproxen using sewage sludge-derived biochars in water systems. The highest adsorption capacity was obtained for naproxen (127 mg/g). In studies presented by Zungu et al. [132], the adsorption efficiency of salicylic acid and diclofenac present in water was tested using biochar based on coffee waste. The capacity of adsorption was 40.47 mg/g (salicylic acid) and 38.52 mg/g (diclofenac).

4.1.5. Membrane Filtration in Water Treatment

Among the methods used to purify water from micropollutants, PPCP, nanofitration (NO) and reverse osmosis are used [133]. Microfiltration and ultrafiltration membranes with biological treatment have been compiled as membrane bioreactors [101]. The limitation in the use of micro- and ultrafiltration membranes for the elimination of PPCPs from water is the higher molecular weight of the membrane as compared to the molecular weight of most PPCPs. Currently used technologies use various membrane modifications and hybrid systems [134]. Data show that polyimide ultrafiltration membranes enriched with silica nanoparticles allowed the removal of up to 99.9% of acetaminophen and 87% of ibuprofen from water [135]. On the other hand, Zhou et al. [136] applied photocatalysis (with TiO₂) and membrane techniques (ultrafiltration membrane) for the elimination of sulfonamide antibiotics from water. The removal efficiency of sulfadiazine in pure water was 91.4% with a first-order rate.

4.1.6. Microalgae and Phytoremediation Technology in Water Treatment

Currently, algae are one of the key biotechnological methods used in water reclamation, due to their simplicity of culture, biological properties and environmental friendliness. The technology also has applications in the removal of PPCPs from water.

In an incubation study [137], the elimination of five PPCPs (trimethoprim, sulfamethoxazole, carbamazepine, ciprofloxacin and triclosan) from Lake Mead water was assessed using the green alga Nannochloris sp. The results showed that carbamazepine was highly resistant to uptake by the algae (only 10% was removed). A low removal rate (up to 40%) was recorded for sulfamethoxazole, and its removal was additionally caused by photolysis in the presence of algae. Ciprofloxacin and triclosan were significantly dispersed, and almost 100% of the compounds were eliminated from water after 7 days of incubation within 24 h in the presence of light. There are also reports on the elimination of PPCPs residues from water in the phytoremediation process. An attempt was made to remove clofibric acid, naproxen and ibuprofen from the water medium using lettuce and spathiflora. After 30 days, a decrease in pharmaceuticals in the culture medium was found (85–99% in lettuce and 51–81% in spathiphyllum). It was also reported that the partial degradation of these micropollutants could occur as a result of photodegradation [20]. Ranieri et al. [138] used P. australis and T. latifolia to remove acetaminophen (paracetamol), obtaining efficiencies of ~51–99% (P. australis) and 46.7–99.9% (T. latifolia), respectively.

The occurrence of pharmaceuticals in drinking water is particularly dangerous to human health and life. The above analysis of various purification methods allows us to conclude that it is possible to eliminate most pharmaceuticals using advanced purification methods, but conventional sewage treatment plants are not adapted to carry out such processes. Therefore, legislative issues are important and require quick solutions. Since the European Medical Agency, the European Environmental Agency, the US Environmental Protection Agency and the World Health Organization are interested in the occurrence of pharmaceuticals in the environment, there is a chance to solve this problem.

Table 2. Selected technologies for the elimination of PPCPs from water with consideration of the energy aspect.

Methods	Examples of PPCPs	Removal (%)	Energy Consumption (kWh/m3)	References
Electrocoagulation with iron anode	Oxytetracycline hydrochloride	93.2	1.4	[114]
Electrocoagulation with aluminum anode	Oxytetracycline hydrochloride	87.75	190
O3	Atrazine	5.1–22.7	0.73	[116]
	Alachlor	>90	0.055
	Bisphenol A	>90	0.041
	1,7-α-ethinylestradiol	>90	0.084
O3/H2O2	Atrazine	6.96–92.3	5.96
	Alachlor	-	0.86
	Bisphenol A	-	1.29
	1,7-α-ethinylestradiol	-	0.89
UV	Atrazine	5.1	499
	Alachlor	32.5	73.1
	Bisphenol A	18.1	139
	1,7-α-ethinylestradiol	35.6	65.5
	Acyclovir	32.22	-	[120]
UV/H2O2	Atrazine	7.6–9.1	322	[116]
	Alachlor	-	48.2
	Bisphenol A	-	102
	1,7-α-ethinylestradiol	-	49.5
UV/O3	Atrazine	8.61–36.0	65.3
	Alachlor	>80	4.75
	Bisphenol A	>80	5.27
	1,7-α-ethinylestradiol	>80	10.6
UV/O3/H2O2	Atrazine	16–51.1	44.1
	Alachlor	>80	5.28
	Bisphenol A	>80	13.2
	1,7-α-ethinylestradiol	>80	8.8
Plasma-ozonation	Atrazine	95.5–99.2	19.8
	Alachlor	>80	15.7
	Bisphenol A	100	5.65
	1,7-α-ethinylestradiol	100	4.48
Membrane capacitive deionization (MCDI)	Acetaminophen Atenolol	68.1 97.7	0.27 (control)—0.03	[124]
	Sulfamethoxazole	93.2
Electro-oxidation	17α-ethinylestradiol (EE2)	99.9	-	[122]
Cyclodextrin polymers (PolyCyC®)-based adsorption	Progresterone	92% (for 500 mg adsorbent amount)	-	[127]
Magnetic chitosan-based adsorption	Diclofenac and	Capacity: 57.5 mg/g	-	[128]
	Clofibric acid	Capacity: 191.2 mg/g	-
Spent coffee-based adsorbents	Sulfamethoxazole	Adsorption capacity: 256 mg/g		[129]
	Bisfenol A	Adsorption capacity: 271 mg/g
Biochar	Diclofenac	Maximum adsorption capacity: 92.7 mg/g	-	[131]
	Naproxen	113 mg/g
	Triclosan	127 mg/g
Biochar from biowaste coffee grounds	Salicylic acid	41 mg/g	-	[132]
	Diclofenac	39 mg/g	-
Microalgae	Trimethoprim	0–10%	-	[137]
	Sulfamethoxazole	40%	-
	Carbamazepine	0–10%	-
	Ciprofloxacin	~100%	-
	Triclosan	~100%	-
Phytoremediation	Acetaminophen	~51–99% (Phragmites australis)	-	[138]
		46.7–99.9% (Typha latifolia)	-

Table 2. Selected technologies for the elimination of PPCPs from water with consideration of the energy aspect.

Methods	Examples of PPCPs	Removal (%)	Energy Consumption (kWh/m3)	References
Electrocoagulation with iron anode	Oxytetracycline hydrochloride	93.2	1.4	[114]
Electrocoagulation with aluminum anode	Oxytetracycline hydrochloride	87.75	190
O3	Atrazine	5.1–22.7	0.73	[116]
	Alachlor	>90	0.055
	Bisphenol A	>90	0.041
	1,7-α-ethinylestradiol	>90	0.084
O3/H2O2	Atrazine	6.96–92.3	5.96
	Alachlor	-	0.86
	Bisphenol A	-	1.29
	1,7-α-ethinylestradiol	-	0.89
UV	Atrazine	5.1	499
	Alachlor	32.5	73.1
	Bisphenol A	18.1	139
	1,7-α-ethinylestradiol	35.6	65.5
	Acyclovir	32.22	-	[120]
UV/H2O2	Atrazine	7.6–9.1	322	[116]
	Alachlor	-	48.2
	Bisphenol A	-	102
	1,7-α-ethinylestradiol	-	49.5
UV/O3	Atrazine	8.61–36.0	65.3
	Alachlor	>80	4.75
	Bisphenol A	>80	5.27
	1,7-α-ethinylestradiol	>80	10.6
UV/O3/H2O2	Atrazine	16–51.1	44.1
	Alachlor	>80	5.28
	Bisphenol A	>80	13.2
	1,7-α-ethinylestradiol	>80	8.8
Plasma-ozonation	Atrazine	95.5–99.2	19.8
	Alachlor	>80	15.7
	Bisphenol A	100	5.65
	1,7-α-ethinylestradiol	100	4.48
Membrane capacitive deionization (MCDI)	Acetaminophen Atenolol	68.1 97.7	0.27 (control)—0.03	[124]
	Sulfamethoxazole	93.2
Electro-oxidation	17α-ethinylestradiol (EE2)	99.9	-	[122]
Cyclodextrin polymers (PolyCyC®)-based adsorption	Progresterone	92% (for 500 mg adsorbent amount)	-	[127]
Magnetic chitosan-based adsorption	Diclofenac and	Capacity: 57.5 mg/g	-	[128]
	Clofibric acid	Capacity: 191.2 mg/g	-
Spent coffee-based adsorbents	Sulfamethoxazole	Adsorption capacity: 256 mg/g		[129]
	Bisfenol A	Adsorption capacity: 271 mg/g
Biochar	Diclofenac	Maximum adsorption capacity: 92.7 mg/g	-	[131]
	Naproxen	113 mg/g
	Triclosan	127 mg/g
Biochar from biowaste coffee grounds	Salicylic acid	41 mg/g	-	[132]
	Diclofenac	39 mg/g	-
Microalgae	Trimethoprim	0–10%	-	[137]
	Sulfamethoxazole	40%	-
	Carbamazepine	0–10%	-
	Ciprofloxacin	~100%	-
	Triclosan	~100%	-
Phytoremediation	Acetaminophen	~51–99% (Phragmites australis)	-	[138]
		46.7–99.9% (Typha latifolia)	-

4.2. Techniques Used in Wastewater Treatment

4.2.1. Primary, Secondary and Tertiary Treatment of Wastewater

In many WWTPs in Europe, conventional methods of treating wastewater from pharmaceuticals still dominate and are based on two stages of treatment: physical and chemical, including coagulation, volatilization, adsorption, sedimentation and filtration. There is a small number of treatment plants using more advanced treatment methods such as ultrafiltration, flocculation, ozonation, advanced oxidation or reverse osmosis or nanofiltration. This is due to the high costs of running these processes. However, these methods are constantly being improved and tested, due to the high efficiency of wastewater treatment from organic micropollutants [86]. In countries, such as Switzerland, the abovementioned technology is already being used on a large scale as a tertiary treatment to remove PPCPs [139]. The primary removal stage of PPCPs (Figure 8) is intended to remove large, coarse solids and fats/greases via sedimentation and/or clarification. The removal of PPCPs in this step may occur as a result of adsorption on settling particles or absorption on fat floating on the surface of the wastewater. However, conventional pretreatment has a low PPCPs elimination efficiency, and in some cases, even negative efficiency. In the case of primary treatment, parameters such as hydrophobicity, acid dissociation constant (pKa) and temperature are important. The octanol–water partition coefficient (log Kow), which is an indicator of the hydrophobicity of most PPCPs, is less than four, which means that they will not adsorb to solids or absorb on fats to a large extent. In most cases, a lower temperature reduces the removal efficiency of pharmaceuticals during pretreatment, but this is not the case for carbamazepine and diazepam [140]. Secondary treatment is biological treatment including technologies such as conventional activated sludge, biological oxidation lagoons, rotating biological contact chambers and membrane bioreactors. The elimination of PPCPs in this step is related to biological and chemical degradation and adsorption on sludge carriers (for example, flocks) [11]. Tertiary treatment includes technologies used to obtain very good quality wastewater, which can then be discharged directly into the environment, used for irrigation or recreation, or even intended for drinking. AOP technologies and membrane bioreactors are used here. Currently, hybrid systems are often used in sewage treatment plants, which allow the removal of a wide range of PPCPs with a variety of properties and at different stages of purification.

Table 3 presents the methods used in wastewater treatment to eliminate PPCPs contamination. According to Samal et al. [141], PPCPs that enter wastewater treatment plants cannot always be removed 100% and may therefore end up back in water systems, polluting the environment. The degree of elimination of pharmaceutical contaminants will mainly depend on the wastewater treatment method used and the compound contained in the wastewater matrix.

By recognizing the ability of pharmaceuticals and their metabolites to degrade in WWTPs, it is possible to lower the level of their release into the environment and thus reduce the risk associated with their presence. In conventional WWTPs, PPCPs micropollutants may be biodegraded to carbon dioxide and water, adsorbed on sewage sludge (mainly lipophilic and hardly biodegradable compounds), or in unchanged forms or metabolites, released into the environment [1,141].

4.2.2. Conventional Wastewater Treatment Using Activated Sludge

Kosjek et al. [142] studied the removal efficiency of four pharmaceuticals belonging to non-steroidal anti-inflammatory drugs such as diclofenac, ibuprofen, naproxen, ketoprofen and active metabolites (clofibric acid) in a pilot WWTPs using activated sludge from a sewage treatment plant in Slovakia. The authors obtained a high degree of success in the elimination of ibuprofen, naproxen and ketoprofen (<87%), while the efficiency of diclofenac removal was much lower and ranged from 49 to 59%. Clofibric acid has been eliminated to a small extent. The occurrence and removal of various drugs (e.g., naproxen, ibuprofen, clofibric acid) was analyzed by Zorita et al. [21] in the influent and effluent of a wastewater treatment plant in Sweden, depending on the different stages of treatment, which included a three-stage wastewater treatment system, including one based on the conventional activated sludge method. The authors found that the degree of purification of these compounds, apart from clofibric acid and ofloxacin, was above 90%. Diclofenac was not removed, and an even higher content of it was found in the effluent than in the influent of the treatment plant.

Table 3 shows that in the case of biological wastewater treatment using the activated sludge method, higher pharmaceutical removal efficiencies are recorded than in the case of mechanical treatment. Generally, during wastewater treatment in conventional systems with activated sludge chambers, pharmaceuticals are removed both by adsorption and biodegradation with varying efficiencies, generally in the range of 20–90% [143]. As Huang et al. [144] pointed out, activated sludge microorganisms occurring in the biological part of wastewater treatment also do not guarantee satisfactory results regarding the decomposition of pharmacological micropollutants. Moreover, during the degradation of pharmaceuticals, a number of byproducts of their decomposition are produced, which are often more harmful to the environment and people than the initial substrates [145]. Moreover, it should be remembered that the efficiency of the removal of pharmaceuticals is significantly influenced not only by the type of pharmaceutical, but also by the age of the sludge, which should not be lower than 5 d (preferably 10–15 d).

4.2.3. Adsorption Methods in Wastewater Treatment

Fu et al. [146] analyzed the removal efficiency of 29 PPCPs in two WWTPs in China using ozonation and granulated activated carbon (GAC) filtration after coagulation and sedimentation (wastewater treatment plant 1) and using anthracite filtration and GAC (treatment plant 2). PPCP removal varied significantly among compounds and treatment systems. Coagulation, filtration and GAC worked ineffectively and removed the detected PPCPs by less than 50%, which was due to the hydrophilic nature of the compounds. In turn, ozonation was 90% effective for most PPCPs but limited mineralization and caused the formation of byproducts.

According to Adeleye et al. [11], a high degree of adsorption corresponds to a high value of the n-octanol/water ratio (logKow). Yang et al. [147] report that removal of pharmaceuticals with high logKow values (i.e., diclofenac and fluoxetine) may not be effective due to their pKa values, which are lower than the pH of the wastewater (pH 6.8–8.3). Moreover, as noted by Grover et al. [148], the values of the logKow coefficient of the pharmaceutical, pH and temperature also have a significant impact on the adsorption efficiency. At higher logKow values and lower pH and temperature, the degree of removal of pharmaceutical substances from wastewater is generally greater [120]. However, in the case of ibuprofen, despite relatively high values of this coefficient, they have a low degree of adsorption on activated sludge.

The other possibility to eliminate PPCPs from wastewater is adsorption, which uses activated carbon, magnetic nanoparticles, aerogels and hybrid systems [14,149,150]. Puga et al. [151] conducted research related to the removal of non-ionic PPCPs (fluoxetine, sulfamethazine and antipyrine) via conventional adsorption using carbon aerogel granules as adsorbents. The results showed that >96% removal of sulfamethizole and antipyrine was achieved, while only 2.5% of fluoxetine was removed.

4.2.4. AOP Technologies in Wastewater Treatment

Studies conducted by Silva et al. [152] indicate that the ozonation technology carried out in the case of amoxicillin was more effective at a high pH, which was the most cost-effective approach applied in order to remove the antibiotic.

Table 3. The selected methods of PPCPs removal from wastewater with consideration of energy aspect.

Methods	Examples of PPCPs	Groups	Concentration in Wastewater [ng/L]		Removal Rate [%]	Energy Consumption (kWh/m3)	Comments	References
			Influent	Effluent
Activated sludge	Naproxen	Analgesics	0.25 mg/L	-	>87%	-	small-scale pilot wastewater treatment plant	[142]
	Ketoprofen			-	>87%	-
	Diclofenac	Anti-inflammatory		-	49–59%	-
	Ibuprofen	Non-steroidal		-	>87%	-
	Clofibric Acid	Lipid regulators		-	30%	-
	Musk Ketone	Fragrances	74.5–161.3	6.7–18.5	<60%	-	-	[153]
	Galaxolide		-	2310–3490	-	-	-
	Tonalide		-	nd—360	-	-
	N,N-diethyl-3-methylbenzamide	Mosquito and insect repellants	1220–2520	574–886	40%	-	-	[154]
Flocculation and sedimentation	Erythromycin	Antibiotics	251–515	239–432	4.7–16	-	-	[146]
	Sulfamethazine		2.4–3.2	0.9–1.4	50–72	-	-
	Roxithromycin		0.59–1.31	0.62–1.36	−1.3	-	-
	Carbamazepine	Anticonvulsant	3.1	2.98	3.6	-	-
	Diclofenac	Anti-inflammatory	-	-	10–38	-	-	[143]
	Ibuprofen	Non-steroidal	-	-	9–27	-	-
	Estrone	Hormones	13–315	3–83	43–82	-	-	[149]
	17-β-Estradiol		20–199	4–107	>52	-	-
	Progesterone		163–904	0.2–25	89–98	-	-
	Oseltamivir	Antiviral	>42.7	>17.3	>42	-	-	[155]
	Methylphenidate	Central nervous system	50–270	>50–170	>81	-	-
	Paraben	Preservatives	12–61	6.9	-	-	-
	Triclosan	Soaps and shampoos	2–98	>22	-	-	-
	Synthetic musks	Fragrances	-	-	61–97	-	-	[153]
	Polycyclic musks	Fragrances	-	-	46–63%	-	-
Ozonation	Erythromycin	Antibiotics	-	-	<20	-	Ozone dosages of 2.5 and 7 g/m3	[156]
	Trimethoprim		-	-	>80
	Amoxycylin		-	-	-	-	highest removal efficiency at high pH	[152]
	Ketoprofen	Analgesics	70–220		0–80	0.73–0.084		[145]
	Sertraline	Antidepressants	-	-	20–80		Ozone dosages of 2.5 and 7 g/m3	[156]
	Ibuprofen	Non-steroidal	-	-	20–80
	17-β-Estradiol	Hormones	-	-	>80
Ozonation and granular activated carbons	Erythromycin	Antibiotics	251–515	23–42	90–92	30% more expensive than ozonation	-	[146]
	Sulfamethazine		2.4–3.2	0.28–0.33	86–91		-
	Trimethoprim		-	-	>80		-	[156]
	Roxithromycin		0.59–1.31	0.5–0.9	18–30		-	[146]
	Carbamazepine	Anticonvulsant	3.1	ND	-		-
	Sertraline	Antidepressants	-	-	>80		-	[156]
	Diclofenac	Anti-inflammatory			96–98			[143]
	Ibuprofen	Non-steroidal	-	-	>80		-	[156]
	17-β-Estradiol	Hormones	-	-	>80		-
Secondary effluent–ozonation–sand filtration	Atenolol	β-blockers	-	-	100	0.035	-	[157]
	Bisphenol A	Sunscreen agents	834	338	>95	0.117	-	[158]
	N,N-diethyl-3-methylbenzamide	Mosquito and insect repellants	805	290	48		-
Biofiltration–ozonation–soil aquifer treatment	Primidone	Anticonvulsant	-	-	65		Ozone dose 10 mg O3·/L	[155]
	Iopromide	Agent for intravascular	-	-	52	0.12
Activated carbon ultrafiltration (PCA-UF)	Sulfamethoxazole	Antibiotic	-	-	<80%	-	at <5000 BV *	[145]
	Ciprofloxacin		2291	779	63	-		[158]
	Carbamazepine	Anticonvulsant	-	-	>80%	-	carbon usage of approx. 25–35 g/m3	[145]
	Primidone		-	-	<80%	-		[145]
	Atenolol	β-blockers	1274	682	88	-	-	[158]
	17β-Estradiol	Hormones	14	1.3	>61	-	-
Nanofiltration	Naproxen	Analgesics	-	-	86.9%	-	Green-synthesized copper nanoparticles (Cu NPs)	[150]
	Ibuprofen	Non-steroidal	-	-	74.4%	-
	Ibuprofen		-	-	>90	-	-	[159]
Ultrafiltration membrane bioreactor	Metformin	Antihyperglycemic	-	-	95	Ultrafiltration required higher costs compared to sand filtration	-	[160,161]
	Hydroxybupropion	Antidepressant	-	-	82		-
Electrochemical advanced oxidation processes (EAOPs)	Venlafaxine	Antidepressant	40–2987	60–2563	>68			[162]
	Metoprolol	β-blockers	4–810	3–435	>52
Anerobic digestion with algal bioreactor	Diclofenac	Anti-inflammatory	-	-	50	-	C. sorokiniana	[133]
	Ibuprofen	Non-steroidal	-	-	100
	Carbamazepine	Anticonvulsant			30

* BV—bed volumes (in m³/m³).

Table 3. The selected methods of PPCPs removal from wastewater with consideration of energy aspect.

Methods	Examples of PPCPs	Groups	Concentration in Wastewater [ng/L]		Removal Rate [%]	Energy Consumption (kWh/m3)	Comments	References
			Influent	Effluent
Activated sludge	Naproxen	Analgesics	0.25 mg/L	-	>87%	-	small-scale pilot wastewater treatment plant	[142]
	Ketoprofen			-	>87%	-
	Diclofenac	Anti-inflammatory		-	49–59%	-
	Ibuprofen	Non-steroidal		-	>87%	-
	Clofibric Acid	Lipid regulators		-	30%	-
	Musk Ketone	Fragrances	74.5–161.3	6.7–18.5	<60%	-	-	[153]
	Galaxolide		-	2310–3490	-	-	-
	Tonalide		-	nd—360	-	-
	N,N-diethyl-3-methylbenzamide	Mosquito and insect repellants	1220–2520	574–886	40%	-	-	[154]
Flocculation and sedimentation	Erythromycin	Antibiotics	251–515	239–432	4.7–16	-	-	[146]
	Sulfamethazine		2.4–3.2	0.9–1.4	50–72	-	-
	Roxithromycin		0.59–1.31	0.62–1.36	−1.3	-	-
	Carbamazepine	Anticonvulsant	3.1	2.98	3.6	-	-
	Diclofenac	Anti-inflammatory	-	-	10–38	-	-	[143]
	Ibuprofen	Non-steroidal	-	-	9–27	-	-
	Estrone	Hormones	13–315	3–83	43–82	-	-	[149]
	17-β-Estradiol		20–199	4–107	>52	-	-
	Progesterone		163–904	0.2–25	89–98	-	-
	Oseltamivir	Antiviral	>42.7	>17.3	>42	-	-	[155]
	Methylphenidate	Central nervous system	50–270	>50–170	>81	-	-
	Paraben	Preservatives	12–61	6.9	-	-	-
	Triclosan	Soaps and shampoos	2–98	>22	-	-	-
	Synthetic musks	Fragrances	-	-	61–97	-	-	[153]
	Polycyclic musks	Fragrances	-	-	46–63%	-	-
Ozonation	Erythromycin	Antibiotics	-	-	<20	-	Ozone dosages of 2.5 and 7 g/m3	[156]
	Trimethoprim		-	-	>80
	Amoxycylin		-	-	-	-	highest removal efficiency at high pH	[152]
	Ketoprofen	Analgesics	70–220		0–80	0.73–0.084		[145]
	Sertraline	Antidepressants	-	-	20–80		Ozone dosages of 2.5 and 7 g/m3	[156]
	Ibuprofen	Non-steroidal	-	-	20–80
	17-β-Estradiol	Hormones	-	-	>80
Ozonation and granular activated carbons	Erythromycin	Antibiotics	251–515	23–42	90–92	30% more expensive than ozonation	-	[146]
	Sulfamethazine		2.4–3.2	0.28–0.33	86–91		-
	Trimethoprim		-	-	>80		-	[156]
	Roxithromycin		0.59–1.31	0.5–0.9	18–30		-	[146]
	Carbamazepine	Anticonvulsant	3.1	ND	-		-
	Sertraline	Antidepressants	-	-	>80		-	[156]
	Diclofenac	Anti-inflammatory			96–98			[143]
	Ibuprofen	Non-steroidal	-	-	>80		-	[156]
	17-β-Estradiol	Hormones	-	-	>80		-
Secondary effluent–ozonation–sand filtration	Atenolol	β-blockers	-	-	100	0.035	-	[157]
	Bisphenol A	Sunscreen agents	834	338	>95	0.117	-	[158]
	N,N-diethyl-3-methylbenzamide	Mosquito and insect repellants	805	290	48		-
Biofiltration–ozonation–soil aquifer treatment	Primidone	Anticonvulsant	-	-	65		Ozone dose 10 mg O3·/L	[155]
	Iopromide	Agent for intravascular	-	-	52	0.12
Activated carbon ultrafiltration (PCA-UF)	Sulfamethoxazole	Antibiotic	-	-	<80%	-	at <5000 BV *	[145]
	Ciprofloxacin		2291	779	63	-		[158]
	Carbamazepine	Anticonvulsant	-	-	>80%	-	carbon usage of approx. 25–35 g/m3	[145]
	Primidone		-	-	<80%	-		[145]
	Atenolol	β-blockers	1274	682	88	-	-	[158]
	17β-Estradiol	Hormones	14	1.3	>61	-	-
Nanofiltration	Naproxen	Analgesics	-	-	86.9%	-	Green-synthesized copper nanoparticles (Cu NPs)	[150]
	Ibuprofen	Non-steroidal	-	-	74.4%	-
	Ibuprofen		-	-	>90	-	-	[159]
Ultrafiltration membrane bioreactor	Metformin	Antihyperglycemic	-	-	95	Ultrafiltration required higher costs compared to sand filtration	-	[160,161]
	Hydroxybupropion	Antidepressant	-	-	82		-
Electrochemical advanced oxidation processes (EAOPs)	Venlafaxine	Antidepressant	40–2987	60–2563	>68			[162]
	Metoprolol	β-blockers	4–810	3–435	>52
Anerobic digestion with algal bioreactor	Diclofenac	Anti-inflammatory	-	-	50	-	C. sorokiniana	[133]
	Ibuprofen	Non-steroidal	-	-	100
	Carbamazepine	Anticonvulsant			30

* BV—bed volumes (in m³/m³).

Considering ozonation, a problem with this study is that an appropriate ozone dosage is very hard to obtain. The usage of energy in the ozonation process (about 19 MWh/year of full activity) was rather low, and therefore it may consist as an insignificant factor considering the aspect of costs. The work by Yuan et al. indicate that UV/H₂O₂ demands lower energy costs than ozonation [163]. Rosal et al. [29] studied the effectiveness of removing such pharmaceuticals as β-blockers (atenolol, metoprolol and propranolol), lipid regulators (esafibrate and fenofibric acid), antibiotics (erythromycin, sulfamethoxazole and trimethoprim), anti-inflammatory drugs (diclofenac, indomethacin, ketoprofen and mefenamic acid), antiepileptics (carbamazepine) and antacids (omeprazole) using ozonation [64,152,164]. Ozonation at doses lower than 90 µmol/L allowed the elimination of micropollutants almost completely, including compounds characterized by higher resistance to biological removal (ketoprofen and bezafibrate). In the removal of antibiotics (e.g., penicillin) from wastewater, ozonation methods in combination with oxidation (O₃ + H₂O₂) have proved effective [64,157,165]. Svebrant et al. [166] investigated the effectiveness of removing active pharmaceutical ingredients from hospital sewage in Uppsala, Sweden, after the ozonation process. The degree of removal varied, but the total energy consumption measured for 63 days during ozonation was 342 kWh. The literature data shows that ozonation is more beneficial compared to, e.g., reverse osmosis and adsorption, due to the fact that pollutants are decomposed and not concentrated and transferred to the other phase [160,165]. Ozonation generates lower operating costs compared to reverse osmosis and adsorption. In turn, membrane separation requires higher energy costs as well as solving problems with membrane contamination compared to ozonation. However, it should be remembered that ozonation is not 100% effective, and the resulting byproducts may have even higher toxic properties compared to the parent substance [15,159]. Currently, research is underway on the use of perovskite-based oxides, which constitute a heterogeneous catalyst in AOP technologies, in which both free and non-free radicals can occur [167]. The non-free radical pathway is more preferred due to the complex matrix of wastewater. The study used Ruddlesden–Popper layered perovskite oxides to activate peroxymonosulfate in AOPs. The interaction of perovskite and rock salt layers in Ruddlesden–Popper perovskite oxides stabilizes transition metals, resulting in the formation of large amounts of lattice oxygen. The resulting oxygen species are characterized by high activity and facilitate the formation of non-free singlet oxygen. AOP technology based on perovskite oxides is a functional, environmentally friendly and effective solution for removing pollutants, including PPCPs [168,169].

4.2.5. Membrane Technology in Wastewater Treatment

In recent years, membrane bioreactors have become very popular, the main advantage of which is the ability to remove many types of micropollutants from wastewater [160]. Rosal et al. [29] indicate that the implementation of new competitive technologies for the biological degradation of organic matter, such as a membrane bioreactor, will ensure the retrieval of safe treated wastewater. In addition, three-stage treatment technologies are needed to ensure the safe use of already treated wastewater. The estimated total energy consumption (kWh/m³) in membrane bioreactors is 4.2 kWh/m³, while in osmotic membrane bioreactors it is 2.8 kWh/m³ for wastewater treated. Moreover, the electrical energy requirement for reverse osmosis will increase as feed solution salinity increases, whereas membrane distillation is only minimally affected by feed solution salinity [156,158]. Some studies suggest that the introduction of nanoparticles or activated carbon to the membrane surface improves the removal of PPCPs from wastewater. Moreover, such substances can additionally capture and remove highly water-soluble PPCPs such as sulfamethazine from the solution, the removal percentage of which exceeds 90% when usually it is approx. 50% [170]. This is also confirmed by research conducted by Kovalova et al. [171] in which the combination of activated carbon with nanofiltration additionally retained micropollutants on the membrane, contributing to the better removal of contaminants.

4.2.6. Biotechnological Methods in Wastewater Treatment

The future solution for wastewater treatment (effluents) from PPCPs residues in the third stage of wastewater treatment seems to be the so-called “green technologies” using biotechnological methods, which include membrane bioreactors, algae-based technology, activated sludge and phytotechnology [20,157,165]. Technologies using microalgae are becoming more and more popular. Their advantages are high biomass production, bioconversion and high carbon uptake [141].

Wastewater treatment technologies from PPCPs using such algae as C. sorokiniana, C. vulgaris, T. dimorphus or Chlorella sp. have recently become very popular. The advantage of such technology is the reduction of greenhouse gas emissions compared to conventional wastewater treatment systems. The elimination of PPCP from wastewater occurs through the process of sorption, biodegradation, photodegradation and volatilization using algae-based techniques (Table 2) [141]. The different methods of PPCP removal by microalgae are generally divided into bio-adsorption, bioaccumulation, intracellular and extracellular biodegradation, and the method can be further improved by introducing microbial consortia (e.g., B. cepacia, C. luteola, P. fluorescens, B. subtilis, B. megaterium, Sterothermophilus, C. freundii). The mechanism of PPCP capture by algae species can last from 1 h to several days and involves the active transport of pollutants into the cell through the cell wall, where it binds to intracellular proteins and other compounds. Microalgae cells can take up PPCP in three main ways: passive diffusion, passive-facilitated spread and energy-dependent/active uptake. According to Peng et al. [172], the use of pure cultures of microalgae Chlorella pyrenoidosa and Scenedesmus obliquus resulted in the biodegradation of the hormone progesterone and norgestrel at a level of >95%. However, the microalgae Chlamydomonas reinhardtii and Selenastrum capricornutum used significantly reduced the content of the hormones 17ά-ethinylestradiol and 17β-estradiol in wastewater [173]. In turn, according to Bai and Acharya [137], algae used in the sewage treatment plant removed 100% of antimicrobials such as triclosan. Microalgae technology is successfully used to eliminate heavy metals and recover nutrients from wastewater. The main disadvantage of biotechnological methods is the high investment and operational costs related to maintaining the farm and providing appropriate lighting, etc. [14]. Encarnação et al. [14] investigated the efficiency and effectiveness of free and immobilized microalgae Nannochloropsis sp. cells in the removal of paracetamol, ibuprofen, olanzapine and simvastatin. It was found that free Nannochloropsis sp. cells removed olanzapine from wastewater to a greater extent, while ibuprofen and paracetamol were better removed by immobilized cells. Other bioremediation methods use mycoremediation, i.e., the removal of organic micropollutants using fungi. This method is environmentally friendly, relatively low energy consuming and not time consuming [18]. The use of white rot fungi has been proposed for the elimination of PPCPs, which is possible due to the secretion of oxidative extracellular enzymes, such as lignin peroxidase, manganese peroxidase, and laccase. This is a future-proof method that has been used to eliminate several persistent pollutants from the environment. The potential ability of these fungi to degrade such pharmaceuticals as antidepressants (citalopram and fluoxetine), antibiotics (sulfamethoxazole), anti-inflammatory drugs (diclofenac, ibuprofen, naproxen), antiepileptic drugs (carbamazepine), sedatives (diazepam) was investigated. The authors obtained the complete degradation of all PPCPs except fluoxetine and diazepam, the degree of the removal of which ranged from 23 to 57% [174].

Another green technology that is becoming increasingly important in removing PPCPs from wastewater is phytoremediation, characterized as a cheap and environmentally friendly approach involving the use of plants. The advantage of in situ phytoremediation is the creation of a habitat and the production of biomass, which can then be used as a raw material for bioenergy production. Improving the efficiency of the phytoremediation process is related to the interaction of endophytic and rhizosphere microorganisms with the plant. There is a lot of data on the removal of PPCPs from wastewater, and the effectiveness of this process depends mainly on the type of pollutant and the plant species [175]. A high phytoremediation effect (84–96%) was achieved in the case of triclosan and plants such as Ipomoea aquatica, Brassicaceae and cane shoot. This compound was mainly accumulated in the roots [176]. A high degree of naproxen removal (98%) was achieved using Scirpus validus [177].

Generally, the selection of the wastewater treatment method in order to eliminate PPCPs depends primarily on the requirements related to the quality of the treated wastewater, on the time of treatment, the availability of reagents and the cost. Therefore, it is important to use an appropriate method to remove as many pharmaceuticals as possible from wastewater. Taking ibuprofen as an example, its content after the ozonation process in treated sewage ranged from 20 to 80%, while after the ozonation and granular activated carbon process, it was almost 80%, and after nanofiltration, it was above 90%. Conversely, the use of an anaerobic digester along with the algal bioreactor method in sewage treatment plants allowed for the removal of 100% of ibuprofen [157,160,161,165]. In analyzing the presented wastewater treatment methods in terms of eliminating pharmaceutical substances from them, it should be stated that they are characterized by varying effectiveness, depending primarily on the type, structure and properties of pharmaceuticals present in wastewater treatment plants and the conditions of the process. Due to the huge diversity of these substances, it seems impossible to indicate a universal method for everyone.

5. Future Perspectives

Among others causes, the COVID-19 pandemic is a reason why the pharmaceutical industry is currently the most intensively developing branch of industry in the world. The value of sales in this sector has doubled in the last decade and has reached almost USD 1.2 trillion annually. The literature data clearly shows a huge increase in the number of reports detecting pharmaceuticals in environmental samples. Hence, there can only be one conclusion—drugs are and will be detected in all types of water bodies: lakes, seas and oceans, and in agricultural areas. Therefore, it should be expected that with the development of this economic sector, which is the pharmaceutical industry, the problem of the presence of drugs in the environment will become more and more common and, at the same time, more and more difficult to solve. Therefore, filling the knowledge gaps regarding the properties of PPCPs introduced to the market and understanding the removal mechanisms and the effectiveness of the introduced technologies are important in the future to increase the level of the efficiency of PPCPs removal from both wastewater and water. It is also important that future technologies coping with the global energy crisis caused by the Russian–Ukrainian war are characterized by low energy consumption and are designed to operate on the principle of a closed-loop economy.

6. Conclusions

The problem of PPCPs residues in water, sewage, sewage sludge and soil concerns the whole world. Due to the fact that the pharmaceutical industry is constantly developing and is resistant to the global crisis, the progress of medicine is visible, the number of civilization diseases is increasing, drug-resistant bacteria appear, and due to the increase in pro-health prevention among society, the number of drugs and their variety will constantly increase. Related to this is an increase in the amount of PPCPs residues in wastewater, water and the environment. This poses a serious threat to human and animal health, even from a multi-generational perspective. So far, there are no consistent standards or legal documents specifying acceptable concentrations of certain PPCPs delivered to wastewater treatment plants and released into ecosystems. In addition, there are no effective methods to remove a wide range of PPCPs from water or wastewater. Hence, a big challenge for technologists of environmental engineering and related sciences (chemistry, biology, biotechnology) is to develop innovations or improve the existing methods of detecting and removing PPCPs residues already at the stage of wastewater treatment to reduce their release into the environment. Based on the technologies presented in the review for removing PPCPs residues from water and sewage, it can be concluded that AOP technologies and hybrid systems are the future. Their undoubted advantage is their relatively low energy consumption and high removal efficiency of most PPCPs. Biotechnologies based on phytoremediation or microalgae are also worth attention, but in this case, one should take into account a reduction in the efficiency of PPCPs removal (depending on seasonality) or an increase in energy consumption related to, among other factors, maintaining the farm. Therefore, when selecting methods or introducing technologies and devices, a compromise must be found between the efficiency of removing PPCPs in water and sewage and ensuring low energy consumption and environmental friendliness.