Conventional and Advanced Processes for the Removal of

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Chapter 2

Conventional and Advanced Processes for the Removal of Pharmaceuticals and Their Human Metabolites from Wastewater Nicola Montemurro,1 Manuel García-Vara,1 Juan Manuel Peña-Herrera,1 Jordi Lladó,2 Damià Barceló,1 and Sandra Pérez*,1 1Water and Soil Quality Research Group, Department of Environmental Chemistry (IDAEA), Spanish National Research Council (CSIC), Barcelona 08034, Spain 2Department of Mining, Industrial and TIC Engineering (EMIT), Universitat Politécnica de Catalunya (UPC), Manresa, Barcelona 08242, Spain *E-mail: [email protected].

Water scarcity is one of the main problems faced by many countries. In order to increase water supply in some regions, reuse of wastewater is proposed. With the purpose of obtaining safe water, more treatment has to be used. Among other pollutants, pharmaceutically active compounds and their metabolites are frequently detected in water subjected to conventional treatments. To remove them, advanced treatments should be used. Some of them are still at lab scale while others are used already at real scale. Here we review the occurrence and fate of pharmaceuticals in wastewater treatment plants with conventional treatment and also in advanced treatments applied at lab and real scale to treat wastewater.

Introduction Pharmaceuticals (pharmaceutical active compounds, PhACs) are a group of chemical compounds that are used for human and veterinarian medicines for the treatment, diagnosis and prevention of diseases. PhACs are strictly regulated for © 2018 American Chemical Society Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

patient safety, whereas adverse side effects in the environment are not yet covered by any international agreement. Generally, wastewater treatment plants (WWTPs) are the main source of PhACs and their metabolites. Consequently, as their removal from the waste stream by physical and biochemical processes is in most instances incomplete, pharmaceutical residues are discharged into the aquatic environment. Several studies of PhACs’ fate during wastewater treatment have identified drugs that are particularly resistant to elimination; their effluent concentrations are practically equal to the influent concentrations. Drugs in these category include atenolol, carbamazepine, diclofenac, iopromide, metoprolol, proponolol, sulfamethoxazole, sotalol, and trimethoprim (1–5). Therefore, treatment of sewage plays a crucial role in the elimination of pharmaceutical compounds from wastewater before their discharge into receiving streams. During the primary and secondary treatments, PhACs can be eliminated by sorption onto the sludge or through microbial degradation. The high polarity combined with the low biodegradability that some PhACs and their metabolites exhibit result in their inefficient elimination. The efficiency of contaminant removal is strongly dependent on the type of treatment technology (e.g., physicochemical vs. biological treatment) as well as on the operational parameters of the plant. Advanced technologies in wastewater treatment have been developed for improving the reduction of contaminant loads in WWTPs (6). These include biological treatments like membrane filtration, advanced oxidation processes (AOPs), and adsorption, which hold great promise to provide alternatives for more efficient elimination and better protection of the environment. Because of such different groups of chemicals, novel, efficient, and salable technologies have been reviewed in this chapter with the aim to compare the applicability of conventional treatments for pharmaceuticals’ and their metabolites’ reduction in WWTPs and also advanced treatments at lab scale and in real environments for the removal of pharmaceuticals, their human metabolites, and transformation products (TPs).

Occurrence of Pharmaceuticals in Wastewater Streams While a drug fulfills its pharmacological function, the compound affinity towards drug-metabolizing enzymes in the liver may give rise to a number of biotransformation products, which eventually are subject to excretion. The most popular pharmaceutical groups studied are antibiotics, hormones, nonsteroidal anti-inflammatory drugs (NSAID), β-blockers, blood lipid regulators, antiepileptics, antihypertensives, analgesics, antiseptics, contraceptives, anti-inflamatories, cytostatic drugs, and antidepressants (7–10). Concentrations of PhACs detected in water influents are correlated with usage/consumption of the same products. In Korea, Choi et al. (11) reported concentrations of pharmaceuticals in WWTP influent for trimethoprim, sulfamethoxazole, diltiazem, cimetidine, carbamazepine, and acetaminophen that correlate with the same order of their annual production amount in this country. Similar results were found in the correlation between concentration and doses 16 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

dispensed of acetaminophen, tramadol, codeine, gabapentin, and atenolol in the United Kingdom WWTPs by Kasprzyk-Hordern et al. (11–13).

Metabolic Route of Pharmaceuticals In spite of many reviews with published data providing information about PhACs in WWTP influents and effluents (10, 11, 14–22), in the case of metabolites, the number of studies in WWTPs are scarce (15, 22–24). In mammals as well as in aquatic vertebrates, two metabolic reactions are possible: (1) phase I metabolism refers to biochemical reactions including oxidation, reduction, and hydrolysis by introducing or damasking functional groups like -OH or –COOH and (2) phase II metabolism describes biochemical reactions of the parent compound or previously generated phase I metabolites to yield conjugates such as glucuronides and sulfates. Because of higher water solubility of the latter metabolites, these are easier to excrete. Depending on the physicochemical properties of the parent compound, the renal or biliary excretion of the intact molecule is also possible. Ultimately, both the parent compound and the metabolites are collected in the sewer systems, where they can start degrading (25), and then transported to the WWTPs. In fact, in untreated sewage it is possible to detect a large number of PhACs and their metabolites occurring at wide concentration ranges (from ng L−1 to mg L−1) (26). During the stay along the treatment plant, drug concentrations of sewage may suffer a reduction in three different ways; (1) mineralization of the PhACs with the consequent result of carbon dioxide and water as products, aspirin, for example (11, 27, 28); (2) partial chemical degradation or metabolism of the PhACs during the process, penicillin, for example (27); and (3) sorption onto solid surfaces, hydrochlorothiazide or fenofibrate, for example (27, 29). However, some pharmaceuticals and their human metabolites such as carbamazepine and its hydroxilated metabolites, chloramphenicol, metoprolol, and sotalol, which are not totally removed in WWTPs by these processes, are detected in effluent waters (7, 9, 10, 12, 27–31).

Removal Mechanisms During Conventional Treatment The main goal of the wastewater treatment process is to remove chemical, physical, and microbiological contaminants from influents in order to obtain water in proper conditions to release those influents as effluents with the security that such water can be part of the environment without any risk to the ecosystem and even be reused, typically for municipal or irrigation purposes (32, 33). During wastewater treatment, in general a primary, secondary, and sometimes a third (disinfection or advanced) treatment is applied. In each step of the treatment, different physical, microbial, and chemical processes and technologies are used to reproduce natural degradation or separation processes of pollutants, but in a short limited time (34). 17 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Primary Treatment The term primary treatment is usually referred to the use of physical treatment to eliminate solid contents in the influent such as sedimentation and sorption onto coarse solids (34). But it is well studied that removal of PhACs during the primary treatment is very low (35–39). Nevertheless, some recommendations have been made about modification of the operative conditions in the primary treatment of the WWTPs in order to improve removal of PhACs in this step (10, 40). It means that the main stage where pharmaceuticals are prone to elimination is the secondary treatment of WWTPs.

Secondary Treatment Secondary or biological treatments aim at the removal of conventional chemical and microbiological pollutants from wastewater. Nonetheless, this means the microbiota developed in the treatment plant could contribute to the removal and/or degradation of PhACs present in wastewater during a specific period of time (41). Biological treatment is predominantly carried out by conventional activated sludge (CAS) systems and, in some cases, membrane biological reactors (MBR). In a recent study, it was reported that from a total of 264 WWTPs studied, 244 were based on CAS systems, whereas only 20 were MBR (31). There are many different factors affecting the efficiency on the removal of PhACs and their metabolites during biological treatment. In addition, the presence of organic pollutants at very low concentrations in influent wastewater, along with instrumental sensitivity and accuracy, could affect the veracity of the obtained values regarding removal efficiencies. The hydraulic retention time (HRT) ranges between 4 and 14 h at conventional WWTPs (41). However, the physicochemical parameters of compounds such as the half-life, biodegradability (Kbiol) or the sludge-water distribution coefficient (Kd) can affect the removal of PhACs in relation to HRT (41, 42). While substances with high Kbiol and low sludge sorption are more influenced by HRT, low Kbiol and high Kd compounds could be more affected by the sludge retention time (SRT), as their elimination would depend on their sorption to solids (43). Bioreactors in WWTPs are exposed to environmental variations such as temperature, which may also affect biological transformation of PhACs (41, 42). Wide differences in the biodegradation rates were observed between summer and winter seasons in WWTPs in Italy (17). Warmer temperatures enhance the biological treatment for many PhACs. Kot-Wasik et al. (44) studied the elimination efficiency of WWTPs and drinking water treatment plants for 25 PhACs throughout a year and detected higher effluent concentrations during the winter season than those from summer, concluding that temperature markedly affects biodegradation processes. Moreover, pH can also interfere on pharmaceuticals’ removal efficiency, as these molecules change their physicochemical and biological properties whether they are cations, anions, or neutral. 18 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

PhACs’ Removal During Conventional Secondary Treatment During the secondary treatment, many organic contaminants can be transformed or retained according to their physicochemical properties. Major degradation occurs during activated sludge, whereas sorption arises into organic matter (2, 9, 23, 30). The WWTPs can be more effective for one or other compounds according to the configuration and use of technology. Data of individual studies regarding the percentage of removal of PhACs around the world are shown in Figure 1 (11, 13–17, 28, 39, 45–87). The wide black dashes represent the average of those data. In Figure 1 it is possible to observe remotion of more than 90% for some compounds such as salicylic acid (93.3% remotion), acetylsalicylic acid (also known as Aspirin, 90.3% remotion), or acetaminophen (also known as paracetamol or ApAp for acetyl-para-aminophenol, 94.4% remotion). Moreover, many nonprescription drugs that are used frequently as self-medication are removed from the influent water with a rate of 30–90% in WWTPs during primary and secondary treatment. Examples of those PhACs are represented in the same Figure 1, for example, naproxen (anti-inflammatory, 69%), ibuprofen (also known as Advil or Motrin; analgesic anti-inflammatory and painkiller 84.2% remotion), and diclofenac (also known as Voltaren; NSAIDs, 44.6% remotion). In most cases, at least 20% of PhACs are still present in the effluent if no specific, tertiary, or advanced treatment is applied in the WWTPs (9, 12, 29, 88). There are many studies and reviews on the concentration of drugs in influents and effluents, but specifically, in the cases of salicylic acid, acetylsalicylic acid, acetaminophen, naproxen, ibuprofen, and diclofenac, concentrations of influent waters were in the ranges of 110–63,700 ng L−1, 470–18,100 ng L−1, 18–172,000 ng L−1, 2–21,000 ng L−1, 4–1.5 × 106 ng L−1, 1–4114 ng L−1, respectively (references in Figure 1). In Figure 1, there are also prescription drugs, like ketoprofen (NSAID), gemfibrozil (a lipid regulator), carbamazepine (a psychiatric drug), ranitidine (a receptor antagonist), propranolol (a beta-blocker drug), salbutamol (a beta agonist), erythromycin, and clarithromycin (antibiotics), of which concentrations in influent wastewaters are in the ranges of 4–8560 ng L−1, 24–17,100 ng L−1, 15–4600 ng L−1, 330–5060 ng L−1, 49–1090 ng L−1, 0–13,000 ng L−1, 44–1050 ng L−1, and 228-1300 ng L−1 for each compound, respectively. Moreover, their removal from the wastewater influents is not effective. The average removal for ketoprofen is 46.6%, gemfibrozil 46.8%, carbamazepine 11.2%, ranitidine 39.3%, propranolol 50.4%, salbutamol 47.5%, erythromycin 18.8%, and clarithromycin 46.6% (12, 29–31). In general, most compounds are removed in WWTPs between 40 and 80% (the blue zone in Figure 1). During the secondary treatment, drugs are removed from the water to be adsorbed by the sludge or are transformed during the process (29). The average percentages of removal, adsorption, and discharge of pharmaceutical products from three different WWTPs are shown in Figure 2. In this figure, it is possible to observe the different fate of some PhACs; for example, in this case, enalapril is practically 100% removed from the wastewater during the process, and drugs such as metronidazole or chloramphenicol are nearly 100% discharged into the effluents. The combination of treatments can help reduce drug discharges, 19 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

as shown in Figure 2 for fenofibrate, whose combination of degradation and adsorption (40 and 60% respectively) helps to eliminate almost 100% of the drug from the effluent.

Figure 1. Percentage of removal for different pharmaceuticals reported in different studies. In the blue zone is depicted the pharmaceutical removals ranging between 40 and 80% (11, 13–17, 28, 39, 45–87).

Figure 2. Distribution of pharmaceuticals during water treatment in a WWTP. (A) Percentage of pharmaceuticals removed during treatment; (B) percentage of pharmaceuticals sorbed onto sludge; (C) Percentage of pharmaceuticals discharged from WWTP (29).

20 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Table 1. Pharmaceutical and Hormone Metabolites of Human Origin Detected in WWTPs Parent compound

Human Metabolite

Matrix

Met Conc (ng/L)

Ref

21

Amitriptyline

Nortriptyline

Raw Sewage/Effluent

3.1–4.5/1.5–3.8

(90, 94)

Carbamazepine

2-hydroxycarbamazepine

Influent/Effluent

59–121/70–132

(101, 102)

Carbamazepine

3-hydroxycarbamazepine

Influent/Effluent

55–94/69–101

(101, 102)

Carbamazepine

10,11-dihydro-10,11-epoxycarbamazepine

Influent/Effluent

39–47/19–52

(101, 102)

Carbamazepine

10,11-dihydro-10,11-dihydroxycarbamazepine

Influent/Effluent

1001–1571/ 1081–1325

(101, 102)

Carbamazepine

10,11-dihydro-10-hydroxycarbamazepine

Influent/Effluent

8.5–22/9.3–32

(101, 102)

Caffeine

Paraxanthine

Influent/Effluent

55,000–79,000/ 18,000–25,000

(74, 93)

Clofibrate

Clofibric acid

Influent/Effluent

1–170/5–110

(13, 39, 45, 61, 97, 99, 103)

Cocaine

Benzoylecgonine

Influent/Effluent

612–893/90–452

(100)

Erythromycin

Erythromycin-H2O

Influent/Effluent

79–2530/12–1385

(13, 65, 96, 104, 105)

Estrone

Estrone-3-glucuronide

Influent/Effluent

4.3/0.7

(92)

Estriol

Estriol-3-sulfate

Influent/Effluent

14–34.1/2.2–29

(92, 98)

Fluoxetine

Norfluoxetine

Influent/Effluent

4.2–12 /1.8–12

(39, 65, 94)

Ibuprofen

Hydroxy-ibuprofen

Influent/Effluent

990–6840/ 50–1130,

(15, 103) Continued on next page.

Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Table 1. (Continued). Pharmaceutical and Hormone Metabolites of Human Origin Detected in WWTPs Parent compound

Human Metabolite

Matrix

Met Conc (ng/L)

Ref

Ibuprofen

Carboxy-ibuprofen

Influent/Effluent

10,750–23,000/ 430–1270

(15, 103)

Methadone

2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine

Influent/Effluent

3.3–1029/ 2.7–1150

(91)

Sertraline

Desmethylsertraline

Raw Sewage/Effluent

4.2–5.0/3.6–4.7

(94)

Sulfamethoxazole

N4-acetylsulfamethoxazole

Influent/Effluent

390–1600/5–1200

(40, 95)

Venlafaxine

O-desmethyl-venlafaxine

Influent/Effluent

274–346 /222–330

(94)


It is known that compounds of the same therapeutic class may have different physicochemical properties and different behavior during wastewater treatment (29, 31). Another reason of the variation in total removals are changes in composition of the influent waters or even the season of the year (89). Thus, there is no a general rule or trend to predict the proportion of the retention or removal of some PhACs in a specific WWTP. The proportion of PhACs that continues to be active in the effluent water its quite considerable.

Occurrence and Removal of Human Metabolites in Conventional Treatments Despite the fact that studies of drug removal in WWTPs are published with more frequency, very little attention is given to drug human metabolites. As reported in the section “Metabolic Route of Pharmaceuticals,” the presence of human metabolites in influent water is due to the excretion of the body. Pharmaceutical drug metabolites found in WWTPs samples are reported in Table 1 (13, 15, 39, 45, 49, 61, 66, 72, 74, 90–105). In some cases, the concentration of the metabolites is higher than the parent compound or presents a higher concentration in effluents than influents, such as the case of carbamazepine metabolites. The reduction of the metabolite concentration occurs during biological treatment or to a lesser extent by sorption to the sludge. In some cases, the drug metabolite can be retransformed into the parent compound as in the case of sulfamethoxazole, carbamazepine, erythromycin, and diclofenac (12, 13, 31, 60, 106–109).

Presence and Removal of TPs of PhACs As it happens with metabolites, TPs formed during the biological treatment are pushed into the background despite their importance. In fact, regardless of the applied technology, PhACs and their human metabolites could be degraded to TPs. Knowledge on the formation of stable TPs in WWTPs is an essential part in the understanding of the environmental fate of the parent compound (110). Once in the environment, TPs can be transported and distributed in rivers and streams and possibly be further biodegraded. For most PhACs and their biotransformation products, the pathways in the WWTPs are yet largely unknown, and publications focused on their occurrence in environmental compartments are still scarce. However, in the last years, an increasing number of studies have put their efforts on the study of biodegradation of pharmaceuticals, mainly in aerobic activated sludge, identifying their TPs and elucidating their chemical structures. According to the high levels of consumption, antibiotics, analgesics, anti-inflammatory agents, iodinated X-ray contrast media, anticonvulsants, and psychiatric drugs are the most common drugs detected in environmental samples and, thus, analyzed. In addition, despite the lack of conclusive data, some studies have observed a 23 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

higher antibiotic resistance on microbiota from effluent waters in areas close to WWTPs (111, 112). This could be due to the presence of antibiotics in the wastewater, which stay together with the microbiota during the SRT established on the WWTP, allowing it to express antibiotic resistance genes. PhACs are mainly biodegraded through the oxidative pathway, which is carried out by a wide range of microbial enzymes including oxidases, esterases, hydrolases, reductases, and transferases. The most common reactions are hydroxilations, oxidations of alcohols, reduction of ketones, or dealkylations. Antineoplasic methotrexate biodegradation was studied by Kosjek et al. (113), finding 9 TPs formed through reactions such as hydrolysis, aldehyde oxidations, N-demethylations, or hydroxylations under aerobic conditions in activated sludge. There has also been observed hydroxylations and demethylations in biodegradations of codeine (114) and metoprolol (115). On the other hand, diazepam is transformed to nordazepam through a N-desmethylation and to temazepam via C-hydroxylation (116). Other pathways are the N-oxidation or N-methylation that anticonvulsant lamotrigine suffers in WWTP activated sludge and the oxidation of the glucuronic moiety of metabolite lamotrigine N2-glucuronide (117). In some cases, TPs formed during microbial degradation in WWTPs are identical to human metabolites produced by the same PhACs. This is the case of metoprolol acid: one of the main metabolites from beta-blockers metoprolol and atenolol, also formed during batch biodegradations of metoprolol (115, 118). The same can also be observed with citalopram-N-oxide and N-desmethyl-citalopram (116); oxazepam, nordazepam, and temazepam (119); or OH-diclofenac (120). As observed in the previous section, human metabolites can be detected in influent wastewater at higher concentrations than their parent compounds (25, 115, 121). However, very little has been reported about the biodegradation of metabolites in WWTPs, and few have studied their TPs. To our knowledge, Table 2 (2, 117, 119–121) encompasses all the identified TPs coming from the biodegradation of these metabolites. Reactions involved were similar to those observed in the parent compounds, including hydroxilations, demethylations, oxidations, and so forth. Mass balances between influent and effluent waters are frequently incomplete because of the transformation back of metabolites to their parent compounds or because of the formation of TPs (117). This fact reveals the importance of including metabolites on the global studies of degradation of pharmaceuticals in WWTPs.


Table 2. Identification of Biotransformation Products from Human Metabolites of Pharmaceuticals and Biochemical Reactions Involved Compound Diazepam Oxazepam Bromazepam

Number of TPs

Reactions

Biological Process

Analysis Method

Ref

25

5

N-demethylation, hydroxylations, loss of oxygen

Oxic and anoxic bioreactors

UPLC-QqToF-MS

(119)

Diclofenac Aceclofenac 4’-hydroxy-Diclofenac 4’-hydroxy-Aceclofenac

3

O-nitrosation, ester cleavage, nitration of aromatic ring, N-dealkylation and carboxylation

Aerobic activated sludge

UPLC-QqToF-MS

(2)

Diclofenac 4’-hydroxy-Diclofenac

4

Hydroxylation, dehydration

MBR

HPLC-Q-ExactiveHRMS

(120)

7

Oxidation, hydroxylation, α-ketol rearrangement, benzylic acid rearrangement


UPLC-LTQ-Orbitrap Velos-MS

(121)

5

Oxidation of glucuronide moiety, amidine hydrolysis, N-oxidation, glucuronide hydrolysis, N-methylation


UPLC-Q-Exactive Orbitrap-MS

(117)

Dihydroxy-Carbamazepine 10’-hydroxy-Carbamazepine Oxcarbazepine

Lamotrigine-N2-glucuronide Lamotrigine


After studying the occurrence of pharmaceuticals in batch reactors and the identification of TPs, analysis of real samples has to be done. However, the identification of TPs in environmental samples becomes an arduous task because of their complex matrices, which interfere with detection. Furthermore, these substances are present at very low concentrations, and the unavailability of reference standards make their analysis difficult. Some authors have detected the presence of TPs on effluent samples (116, 117, 120–122) or even in drinking water (121), confirming that monitoring pharmaceuticals uniquely is not enough to assess the impact of wastewater treatment deficiencies in the environment. Disinfection Disinfection of wastewater includes all those specific tertiary treatments to reduce or prevent the risk of spreading diseases when the treated effluents are released into the environment or being considered for a possible reuse. Conventional wastewater disinfection technologies include chlorination, peracetic acid (PAA), UV light, ozone, and wetlands. The choice between these different disinfection technologies depends on the required quality of wastewater, existing standards, specific reuse applications, and wastewater treatment work capacity.

Chlorination Chlorination is a well-developed and widely used disinfection process used to kill certain bacteria and other microbes in water that uses either sodium hypochlorite (liquid chlorine), chlorine gas, chlorine dioxide, or chloramines. It is applied in water treatment processes in WWTPs, drinking water facilities, or in hospital effluents. Chlorine disinfectants may react with the organic matter present in the wastewater and form organochlorine by-products, which are highly toxic for aquatic organisms (123). The most attractive chlorination in water treatment is achieved with gaseous chlorine and hypochlorite. These substances are dissolved in water to form a weak acid, hypochlorous acid, which can partially dissociate to form hypochlorite ions depending its formation on the pH of the medium (124). Sodium hypochlorite is a liquid chlorine solution commonly known as bleach. Sodium hypochlorite is the dominant reactive species during chlorination reacting with organic compounds in three types of reactions: (1) oxidation, (2) addition reactions to the unsaturated bond, and (3) electrophilic substitution. However, liquid chlorine is a mild oxidant not capable of completely mineralizing organic contaminates. Instead, the formation of numerous TPs is observed. TPs originating from disinfection processes have received particular attention owing their high toxicity (125, 126). A prominent example are the generally nontoxic iodinated X-ray contrast media (ICM), which upon treatment with chlorine or monochloramine can form genotoxic and cytotoxic iodo-disinfection byproducts (DBPs) (127–130). Another source of DBPs are reactions of chlorine with dissolved natural organic matter (NOM). 26 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Reactions of oxidizing chlorine with drug molecules are frequently observed for structures with activated aromatic rings such as (130) sulfamethoxazole (131, 132), diclofenac (133, 134), gemfibrozil (135, 136), cimetidine (137) and erlotinib (138). As mentioned before, as alternatives to chlorination, chloramine and chlorine dioxide are also used for water disinfection purposes. Because of its lower potential to generate trihalometanes and haloacetic acids, chloramination is considered a good alternative to chlorination (139). Unfortunately, it is directly linked to the formation of nitrosamines like the carcinogenic N-nitrosodimethylamine (NDMA). Although, as in the case of chlorination, they can be formed from NOM precursors, several studies have shown that PhACs that have dimethylamine groups are susceptible to form NDMA under chloramination (130, 140, 141). For instance, among a set of PhAC containing a dimethylamine group, the antacid ranitidine was demonstrated to have a strong potential to form NDMA via nucleophilic substitution (142, 143). In contrast to chlorination and chloramination, chlorine dioxide tends to form few halogenated DBPs. As a result, when PhACs are exposed to chlorine dioxide, the majority of TPs originate from oxidation rather than halogenation (130).

PAA PAA (C2H4O3) is synthesized by an acid-catalyzed reaction between acetic acid (CH3COOH) and hydrogen peroxide (H2O2) in an aqueous solution. The storage and distribution system of PAA is very similar to the sodium hypochlorite system. However, the PAA normally is used at a dose of about half that of sodium hypochlorite for the wastewater effluent and requires a contact time of about 5 min. Recently, the U.S. Environmental Protection Agency has considered the use of PAA as a valid alternative to hypochlorite for the disinfection of wastewater, since it is more effective than NaOCl in controlling a number of pathogens (including viruses and spores) and is arousing a growing attention (144). It is a strong oxidant with an oxidation potential and an effectiveness of disinfection superior to chlorine. Unlike chlorinated products, it does not generate toxic compounds. Once added to water, it is divided into acetic acid and hydrogen peroxide, and its oxidation products are water, oxygen, and carbon dioxide. Because of the sensitivity to pH and high temperatures (which compromise performance) and high costs, PAA disinfection is rarely used. Although PAA has not been extensively studied for the removal of pharmaceutical products during wastewater treatment, it is believed that its strong oxidizing power has the potential to be an alternative technique for treating PhACs in wastewater (145). The same authors report a study comparing the efficacy of ClO2 and PAA on the removal of four NSAIDs (ibuprofen, naproxen, diclofenac, and mefenamic acid) and two lipid-regulating agents (gemfibrozil and clofibric acid) in biologically treated wastewater collected from two treatment plants in Sweden. However, this study concludes that ClO2 is more effective than PAA in removing PhACs in wastewater, especially in the case of naproxen and diclofenac, while the mefenamic acid has been degraded by low-dose PAA. However, when combined 27 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

with UV light, the disinfection of wastewater with PAA can be a cost-effective practice compared to traditional disinfection (144). In fact, the UV light can activate the PAA generating radicals (Photolysis of PAA); therefore, the UV/PAA process can be classified as an AOP. In addition, the formation of •OH and other radicals from UV/PAA may significantly contribute to the elimination of Contaminants of Emerging Concern, such as bezafibrate, carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen (144). The drugs’ degradation rate was more than 93.5% in the UV/PAA. However, a relatively high number of TPs (similar to AOPs) was also observed. Surely the use of PAA deserves a more detailed study in the near future.

UV Treatment The UV disinfection system is a physical process that transfers electromagnetic energy from the mercury arc lamp to the cells of the pathogenic microorganisms harming the DNA and affects their activity and replication capacity (146). The source of UV radiation consists of either low-pressure or medium-pressure mercury arc lamps with low or high intensities submerged in the effluent. Compared to chemical-based disinfection, UV disinfection does not present the problem of creating or releasing carcinogenic DBPs into the environment. Besides the disinfection activity, the UV light can remove PhACs from wastewater by biological processes (147–152). In a bench study (150) using a laboratory system with a low-pressure lamp, the degradation of five pharmaceuticals was investigated: amidotrizoic acid, carbamazepine, diclofenac, metoprolol, and sulfamethoxazole. The fastest degradation was observed for amidotrizoic acid, diclofenac, and sulfamethoxazole, whereas for carbamazepine and metoprolol (both more stable), the elimination rate was slower. The effectiveness of UV-based and UV/H2O2 processes for the removal of PhACs in real wastewater using a bench-scale experimental setup was also evaluated in a japanese study (148). Among 41 PhACs tested, only 12 (including ketoprofen, diclofenac, and antipyrine) were effectively removed during only the UV process. In particular, the removal efficiencies of macrolide antibiotics clarithromycin, erythromycin, and azithromycin were found to be very low. Contrarily, a removal efficiency of 90% could be achieved in 39 PhACs during the combination of H2O2 with the UV process with a significant reduction in energy costs.

Ozone Treatment (AOPs) Chlorine, chlorine dioxide, and ozone disinfection are oxidation processes (153). Among the three oxidants, ozone is the most reactive with many organic chemicals and has been applied to water treatment mainly because of its strong disinfection and sterilization properties (154). In fact, because of its strong oxidative capacity, ozone damages the cell walls, enters the cells, and causes their lysis, contributing to the removal of pathogenic organisms. However, because of the high installation costs, the use of ozone is rarely considered as a 28 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

disinfectant. However, for a long time, ozone was considered a very effective oxidant and disinfectant, as it can rapidly oxidize and decompose most of the organic substance in water. As a result, ozone can effectively remove organic pollutants such as drugs from water. In fact, ozonation, which is an AOP, may be appropriate to remove trace levels of PhACs and other anthropic organic contaminants in treated wastewater (155).

Wetlands Constructed wetlands (CWs) are an alternative and low-cost wastewater treatment system consisting of inundated vegetated beds designed to mimic the well-known water depurative capacity of natural wetlands (156–164). CWs appear as a cost-effective tertiary treatment since they will reduce most of the pathogens and other constituents such as nutrients and metals. Moreover, wetlands can be very effective denitrification systems. Furthermore, CWs represent a potential economic solution for the removal of PhACs in wastewater effluents (160). In fact, in these natural environments, several physical, chemical, and biological processes occur simultaneously, such as adsorption, photolysis, volatilization, plant uptake and accumulation, plant exudation, and microbial degradation (156–158, 161, 162, 164). Generally, the removal efficiency of PhACs in wetlands is affected by several parameters including type of flow, feeding strategies, presence of plants, type of plants, type of substrate, HRT, and hydraulic loading rates. In addition to the design parameters, other variables that could also influence the removal efficiencies of CWs are temperature, pH, amount of sunlight, type and number of microbes, the age of the wetland, and seasonality of the high microbial biomass. The capability of CWs for removal of the antibiotics enrofloxacin and oxytetracycline, belonging to two the most common families used in aquaculture (fluoroquinolones and tetracyclines), and antibiotic resistant bacteria from saline aquaculture effluents were tested by Boto et al. (157). The presence of the macrophyte P. australis can contribute significantly to the removal of the tested antibiotics above 99% from saline aquaculture effluents, attenuating the impact of these effluents into the aquatic environment. The efficiency of a laboratory-scale CW system planted with P. australis was also studied for the removal of PhACs carbamazepine, ibuprofen, and sulfadiazine from a synthetic domestic wastewater (159). The results revealed that carbamazepine was present in plant tissues, confirming the low tendency to degrade, whereas ibuprofen and sulfametazine were not present suggesting that other mechanisms such as biodegradation have a role in their removal. Removal and transformation of some common pharmaceuticals in CWs were also investigated by Lee et al. (163). Different transformation patterns of PhACs were observed, especially of ibuprofen, whereas no specific change of pharmaceutical metabolites was detected in the case of carbamazepine.


Emission and Transformation in Natural Environments In the final step, after water is treated, and effluents are released, PhACs that were not removed during treatment start to be part of the aquatic bodies where the effluents are discharged. As a result, in many waters bodies PhACs can be detected and quantified (11, 21, 22, 43, 88, 165–168). Even more, the concentration of the PhACs varies along the river, for attenuation effect, or accumulation of different effluent and/or discharges in the river (43, 166, 167); for example, the Adige river (Italy) and Ebro river (Spain) have been studied along the river, and as a result, variation of analgesics, NSAIDs, lipid regulators, psychiatric drugs, antihistaminic drugs, cardiovascular drugs, beta-antagonist drugs, barbiturates, antidiabetics, beta-blocking agents, diuretics, antihypertensives, calcium channel blockers, and antibiotics were detected, including some of their metabolites that were also studied (89, 169). Nevertheless, more research and studies about behavior and fate on the occurrence of PhACs in rivers and environmental waters are needed concerning environmental attenuation and effects of pharmacological activity in the ecosystem. Performance and Implementation of Advanced Treatment Technologies Modern living requires an increasing per capita use of water for coverage of individual needs. Today, the average amount of consumption is about 200 L per capita per day. The increase in the population and the significant rise in living standards cause a large increase in water demand, constantly reducing stocks of clean water and increasing stocks of reused water. In this way, the recycling of reused water becomes necessary, after appropriate treatment, which will contribute to the increase of water supplies (170). With the current attention on environmental health and water pollution issues, there is an increasing awareness of the need to dispose of wastewater safely and beneficially. Wastewater reuse may result in the conservation of high-quality water and its use for purposes other than irrigation. Properly planned use of treated wastewater alleviates the water pollution that affects surface water and preserves valuable water resources but also takes advantage of the nutrients contained in sewage to grow crops. Many countries have included wastewater reuse as an important dimension of water resources planning. Reuse of wastewater can provide a vital link in meeting needs in water-short areas. However, the chemical risk remains for humans and the environment, deriving from the possible presence of toxic and/or harmful compounds in the wastewater that are poorly degradable, which tend to accumulate and persist in the components of the biotic and abiotic ecosystems (171). Given the wide range of properties represented by trace chemical constituents, there is no single treatment process that provides an absolute barrier to all chemicals. To minimize their presence in treated wastewater, a sequence of diverse treatment processes capable of tackling the wide range of physiochemical properties is needed (172). Full scale and pilot studies have demonstrated that this can be accomplished by combinations of different processes: biological 30 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

processes coupled with chemical oxidation or activated carbon adsorption, physical separation followed by chemical oxidation, or natural processes coupled with chemical oxidation or carbon adsorption (173). The question is whether all of these technologies are necessary to assure health protection or whether a particular sequence is over-treatment, especially when the water will be returned to the environment via a reservoir or aquifer. In the previous section, the presence, elimination, and biodegradation of pharmaceuticals and their human metabolites in conventional treatments have been reviewed. In general terms, a complete WWTP can consist in four common parts: pre-treatment, primary, secondary, and tertiary. During the process in WWTPs, the quality of the water increases and the tertiary part is basically used when water is highly contaminated because of the presence of pollutants of emerging concern such as PhACs and their human metabolites, which cannot be degraded. Furthermore, the tertiary part can represent a high cost for small WWTPs. The most useful technologies in the tertiary treatment at real scale are MBR, UV-disinfection, ozone, and chlorination and at lab scale advanced oxidation and adsorption with carbonaceous materials, AOPs, and MBR. Some of the processes developed at lab scale have not yet been introduced at real scale. In this section, the evaluation of advanced treatments at lab scale and full scale is described.

Performance of Current Advanced Technologies at Bench/Pilot Scale Adsorption Process in a Lab Scale In this section, the adsorption of PhACs and their human metabolites with activated carbon and new advanced carbonaceous materials as carbon xerogels is the technology focused on. Adsorption is a process in which, for example, a pharmaceutical molecule or their metabolites are retained in the surface of a solid material (considered as the adsorbent). This process is based on the mass transfer phenomenon between molecules and the surface of the adsorbent, and it consists in three different steps: macrotransport, microtransport, and sorption (physical and chemical attachment in the surface and in the pore structure).

Adsorbent Materials Activated Carbons Activated carbon is a carbonaceous material that has both a high degree of porosity and extended surface area available for adsorption or chemical reactions (174–176). Activated carbon materials are mainly composed of the element carbon and low percentages of oxygen, nitrogen, hydrogen, and sulphur. Carbon atomic structure allows different bonding possibilities, both with other elements and with itself (177). So every activated carbon shows different unique characteristics. 31 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Carbon Xerorgels Carbon xerogel is a synthetic carbonaceous material that it is synthesized by means of policondesation of resorcinol and formaldehyde. The process of production of carbon xerogels involves different stages: (1) formation of a gel polymer in a solvent, (2) formation of particles (curing step), (3) the drying step, and (4) carbonization (elimination of remaining oxygen and hydrogen). Carbon xerogels with different pore structure are obtained depending on the initial conditions (resorcinol/formaldehyde ratio, methanol content, dilution ratio (178), and pH (179–181)).

Textural and Chemical Properties of the Adsorbents Often information on the physical and chemical properties such as pore texture, surface area, elemental composition, surface functional groups, pH, charge, and hydrophobicity of the adsorbents helps to know whether a PhAC can be adsorbed easily in the adsorbent. Pore Texture Activated carbons and carbon xerogels have a different porous structure. According to International Union of Pure and Applied Chemistry this structure is formed by pores of different sizes (macropores Ø > 50 nm, mesopores Ø 2–50 nm, micropores Ø < 2 nm, supermicropores Ø 0.7–2 nm, and ultramicropores Ø < 0.7 nm). In activated carbons, micropores can represent between 50 and 90% of the total surface area; mesopores enhance the conduction to the micropore (5–25% of the total surface) and macropores facilitate the access to the inner of meso- and micropores. On the other hand, mesopore and macropore structures in carbon xerogels are predominant in the total surface (60–80%). Furthermore, the average mesopore diameter of these materials is from 5 to 55 nm depending on the purpose (179, 180, 182, 183). Pore volume and surface area are the other two important textural properties. Pore volume is the space that occupies the different pores, which can show values from 0.1 to more than 2 cm3 g−1 for activated carbons and from larger than 0.7 cm3 g−1 for carbon xerogels. Surface area is basically determined for the micropores. In the case of activated carbons, it ranges from 500 to 2000 m2 g−1, whereas in carbon xerogels, it is about 600–700 m2 g−1 (178, 181). Chemical Composition and Surface Chemistry Activated carbons are made from polycondensated aromatic species in which carbon is the major element. Moreover, other elements such as nitrogen, hydrogen, oxygen, and sulphur can be present giving different functionalities in the surface. The most abundant functional groups are from oxygen (carbonyl, phenolic, etc.) and nitrogen (nitro, pyridine, etc.) (184). These groups increase the polarity of the carbon surface and give the ability to set different interactions depending on the functional groups, making every activated carbon different (185, 186). 32 Cledon et al.; Integrated and Sustainable Environmental Remediation ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

Furthermore, some activated carbons also contain mineral matter (ash content) depending on the nature of the raw material used as precursor. On the other hand, carbon xerogels show a polymeric structure with a high percentage of carbon (>95%) and low quantity of oxygen ( activated carbon/Norit SAE Super (PAC)

WWTP and Effluent Features

Water consumption: 232.8 m3/day DOC: 6–8 mg/L COD: 30 mg/L pH: 8.1-8.5

Number of Compounds Detected and Studied

56

Common Compounds

Removal (%)

Atenolol

>88

Carbamazepine

100

Ciprofloxacin

>99

Diatrizoate

18 ± 9

Iopromide

91

Ioxitalamic acid

1 ± 16

Morphine

>63

Sulfadiazine

>40

Tramadol

100

Venlafaxine

100

Ref

(271)

Continued on next page.


Table 4. (Continued). Characteristics of the Tertiary Treatments in Different WWTPs, Number of Pharmaceutical Compounds Detected, Common Compounds, and Percent of Removal Type of System/ Type of Carbon

44

Secondary effluent -> Activated Carbon + Ultrafiltration/Organosorb 10 (GAC)


Flow rate: 48 m3/day Removal (TOC: 12%, COD: 38%, NH4+ : 87%)


13

Common Compounds

Removal (%)

Atenolol

93

Azithromycin

65

Carbamazepine

87

Ciprofloxacin

86

Irbesartan

79

Metropolol

92

Propanolol

87

ofloxacin

77

Trimethoprim

94

Venlafaxine

78


Ref

(276)

Type of System/ Type of Carbon

45

Biological treatment -> Activated Carbon + Ultrafiltration/Norit SAE Super/Sorbopor MV-125 (PAC)


95,000 m3/day DOC: 7.3 mg/L COD: 24.4 mg/L BOD5: 11.2 mg/L pH: 7.2


70

Common Compounds

Removal (%)

Atenolol

88 ± 9

Carbamazepine

90 ± 9

Ciprofloxacin

63 ± 32

Iopromide

47 ± 30

Irbesartan

98

Ofloxacin

83 ± 24

Trimethoprim

94 ± 4

Venlafaxine

46

17 β Stradiol

>61

10,11-Dihydro10,11-dihydroxy carbamazepine

52

Ref

(273)




46

CarboPlus Pilot/DaCarb PB-170 (PAC)


240,000 m3/day DOC: 6.9 mg/L COD: 27 mg/L BOD5: 3.8 mg/L


113

Common Compounds

Removal (%)

Atenolol

90*

Carbamazepine

93*

Ciprofloxacin

84*

ofloxacin

66*

Trimethoprim

92

Atrazine

54

Diuron

87*

Bisphenol A

66

Triclosan

23

Indeno[123]pyrene

12*


Ref

(272, 278)


Ozonation -> Biological filter -> Activated carbon/Filtrasorb 400 (GAC)


DOC: 23.7 mg/L COD: 61.5 mg/L BOD5: 5.6 mg/L pH: 6.9


11

Common Compounds

Removal (%)

47

Atenolol

90

Carbamazepine

86

Clarithromycin

70

Diazepam

48

Gemfibrozil

92

Ketoprofen

39

Lorazepam

83

Naproxen

91

Sulfamethoxazole

12

Trimethoprim

35

Ref

(267)




48

Pilot scale biofilters -> Activated Carbon and O3 + Activated carbon/Acticarb BAC GA1000N (GAC)


DOC: 4.2–8.1 mg/L pH: 6.8


21

Common Compounds

Removal (%)

Atenolol

92

Carbamazepine

98

Diclofenac

90

Frusemide

99

Paracetamol

98

Ranitidine

93

Sulfamethoxazole

90

Tramadol

98

Trimethoprim

93

Venlafaxine

99


Ref

(274, 275)


49

Mobile pilot plant (previous studies 8 activated carbons 3 PAC, 5 GAC)/Pulsorb C/Aquasorb MP20 /Aquasorb 5000P/Aquacarb 207C/Aquasorb 5000/Filtrasorb 400/D Gpp-20/Carbsorb 30


149,000 m3/day 50,000 m3/day 48,000 m3/day


22

Common Compounds

Removal (%)

Atenolol

97

Carbamazepine

96

Diclofenac

94

Irbesartan

92

Memantine

70

Oxazepam

94

Sotalol

96

Tramadol

94

Trimethoprim

95

Venlafaxine

84

Ref

(268, 269)




50

WWTP -> O3 + GAC or BAC/Epibon A, Donau Carbon GmbH

*


50,000 habitants equivalent DOC: 11–252 mg/L COD: 5.3–68.3 mg/L


30

Common Compounds

Removal (%)

Carbamazepine

Conventional and Advanced Processes for the Removal of

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