Occurrence, fate and removal of pharmaceutically active compounds (PhACs) in water and wastewater treatment plants—A review

Journal of Water Process Engineering 32 (2019) 100927

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Occurrence, fate and removal of pharmaceutically active compounds (PhACs) in water and wastewater treatment plants—A review

T

Carolina F. Couto , Lisete C. Lange, Miriam C.S. Amaral ⁎

Department of Sanitary and Environmental Engineering, Federal University of Minas Gerais, P.O. Box 1294, 31.270-901, Belo Horizonte, MG, Brazil

ARTICLE INFO

ABSTRACT

Keywords: Pharmaceutically active compounds PhACs Water treatment Wastewater treatment Risk assessment Emerging pollutants

This paper reviews the occurrence of Pharmaceutically active compounds (PhACs) in water and wastewater worldwide as well as their fate, focusing on the removal by conventional water and wastewater treatment plants and the risk imposed to human health associated to the presence of PhACs in raw and drinking water. For this, it was assessed 23 drinking water treatment plants and 30 municipal wastewater treatment plants around the world of different capacities. Due to the high stability, intrinsic characteristics and low concentration, adsorption to the sludge and biodegradation are the most used path to remove of these compounds in wastewater treatment plants (WWTP). In water treatment plants (WTP), chlorination and application of activated granular carbon are the processes associated with the highest removal of pharmaceutical compounds, but, in general, conventional WTPs are able to reduce but not completely remove PhACs in potable water. Carbamazepine, gemfizobril and fenofibrate are found to be the PhACs that risks to human health could not be excluded. This indicates the necessity of investments in advanced techniques for the treatment of water and wastewater. The results also point to the need for more studies focusing on the determination of guideline values for drinking water of more PhACs.

1. Introduction Worldwide, pharmaceutical products, such as, analgesics, anti-inflammatory drugs, antibiotics, lipid regulators, beta-blockers and X-rays contrast media, have become more and more a part of the daily routine life, being used in human and animal for health treatment, to improve life quality and to increase their life span. In 2017, it was estimated that it was spent a total of US$1135 billion on prescription medications [1]. With the aging population combined with improvements in health standards specially in developing countries, the consumption of pharmaceutically active compounds (PhACs) is set to increase in future years [2]. In the year of 2013 alone, over 100 new formulations or chemical entities were approved by the US Food and Drug Administration (FDA) for clinical use [3]. These compounds reach water systems from different sources such as human excretion (sewage), wrongful disposal, landfill leachate, drain water, or from industries [4]. PhACs have been found in wastewater effluent, drinking water, rivers and dams in many different places such as Asia [5–7], America [8–11], Australia [9,11,12] and Europe [9,11,13–17] and Africa [18] at low concentration (ng/l to μg/l range) and the increase in the production, consumption and therefore discharge to the environment has been raising global attention and concern. ⁎

The presence of PhACs in the water cycle has been increasing the concern about the efficacy of water and wastewater treatment processes in removing these compounds. Several papers were published about the presence of PhACs in the environment, in drinking water and wastewater treatment plants. A research on Scopus was done in order to rise how many studies have been carried out in the last decade about the subject, using the keywords “pharmaceutically active compounds and drinking water” and “pharmaceutically active compounds and wastewater”. The majority of the studies are located in Europe, Asia and North America (Fig. 1). Thus, this paper reviews the occurrence of PhACs worldwide, their fate in the environment, focusing on the removal by the conventional water and wastewater plants and the risk imposed on human by the presence of these compounds in drinking water. For this, among more than 4000 papers, it was selected 99 papers on the subject using the key words “pharmaceutically active compounds and drinking water” and “pharmaceutically active compounds and wastewater” where it was possible to observe PhACs concentration before and after the treatment. It was assessed 23 drinking water treatment plants and 30 municipal wastewater treatment plants around the world of different sizes. It was selected the papers published no earlier than 2000.

Corresponding author. E-mail address: [email protected] (C.F. Couto).

https://doi.org/10.1016/j.jwpe.2019.100927 Received 23 April 2019; Received in revised form 19 August 2019; Accepted 22 August 2019 2214-7144/ © 2019 Elsevier Ltd. All rights reserved.

Journal of Water Process Engineering 32 (2019) 100927

C.F. Couto, et al.

Fig. 1. Global distribution of studies about occurrence of PhACs in drinking water and wastewater.

microbes to metabolize different carbon sources, thus affecting the metabolic diversity of the soil community [29]. Thus, this study suggests that the repeated amendment of agricultural soils with biosolids, sludges or even irrigation of wastewater rich in PhACs residuals may result in an increase of concentration of these compounds in the soil throughout the time and impact key ecological functions (i.e. the carbon cycle) [29]. When human health is concerned, many of these compounds may cause problems such as allergies, lung diseases, and cancers [30]. Another important source of concern is the increased resistance to antibiotics in humans, strongly related to the production of antibiotic resistant bacteria, which, in turn, have become ineffective for the prevention and treatment of various infectious diseases [30]. Because of this, in an attempt to ban or establish limits on the use or disposal of these PhACs in the environment, internationally recognized agencies have been struggling to develop lists of PhACs that either deserve special attention or need to be banned. As an example, the European Union [30] listed 45 priority compounds so that the established environmental quality standards (EQS) should be respected in aquatic environments and listed 8 others in the watch list of priority compounds in order address and verify the risk posed by these substances [30,31]. In this watch list it is possible to observe antibiotics such as trimethoprim, clarithromycin; anti-inflammatory drugs such as diclofenac, in addition to synthetic hormones Ethinyl estradiol (EE2) (Decision 2018/840, published on June 5, 2018). Similar regulations were also followed by Switzerland government when several ECs (endocrine compounds) are concerned. In the Drinking Water Contaminant Candidate List [32], it was also covered a large number of drugs and EDCs (endocrine disrupting compounds). Carbamazepine, naproxen, sulfamethoxazole, ibuprofen, genfibrozil, atenolol, diclofenac, erythromycin and bezafibrate are examples of PhACs, which have been classified as class I, i.e. high-priority pharmaceutical products according to the Global Water Research Coalition [32].

2. Environmental/health issues and regulations related to PhACs Over 200 different PhACs were observed in surface, ground water and sewage [19,20] and it is still unclear the levels and effects as well as the fate of these compounds on the human health and wildlife, however it has been found their potential to cause aquatic toxicity, development of resistance in pathogenic microbes; genotoxicity and endocrine disruption [20–22]. In addition, the release of PhACs in the environment is not regulated and covered by the existing water quality [23]. Verlicchi et al. [2] assessed the environmental risk posed by PhACs in secondary effluent. It was concluded that 14, out of 51 assessed compounds, pose a high environmental risk: 7 antibiotics (erythromycin, ofloxacin, sulfamethoxazole, clarithromycin, amoxicillin, tetracycline and azithromycin), 2 psychiatric drugs (fluoxetine and diazepam), 2 analgesics-anti/inflammatories (ibuprofen and mefenamic acid) and 3 lipid regulators (fenofibric acid, fenofibrate and gemfibrozil).. However, most of the toxicity data refer to acute rather than chronic effects, which limits the assessment. Long term effects are of hugely importance to understand of PhACs fate and effect on the environment and public health. Many studies have been carried out to assess the effects of the exposure to PhACs on the environment and on human health. Chen et al. [24] assessed the effects of hormones on sexual behaviours of O. melastigma. It was observed that sexual behaviour was induced in the fish groups submitted to hormones, increasing the duration of “dancing”. Also, estrogenic pharmaceutical compounds are found to cause an increase in the vitellogenin levels in male fish, as well as decreased levels of vitellogenin and estradiol in the plasma of female fish. These findings were associated with immature gonads and lower gonadosomatic index in G. brasiliensis adult females, as well as histological changes, such as degeneration of germ cells [25]. In addition, diclofenac was found to cause vitellogenin in male Japanese medaka fish [26], and ibuprofen, naproxen and diclofenac destabilize DMPS bilayers affecting their thermodynamic properties [27]. Diclofenac and the carbamazepine were found to decrease the emergence ratio and reduce the growth of the midges of Chironomus riparius, respectively [28]. PhACs were also associated to affect microbial communities by changing the ability of

3. The current panorama of PhACs on wastewater Municipal wastewater treatment plants (WWTPs) is the major 2

Analgesic

Ibuprofen

Anti-inflammatory drug

3

Acetaminophen

Ketoprofen

Diclofenac

Naproxen

PhACs

PhAC Classes

Primary treatment based on the partial removal of suspended solids and organic matter through coagulation, flocculation and sedimentation Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Conventional activated sludge. SRT 3–5 days

Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Urban wastewater, 450,000 PE; Secondary treated effluent, post-chlorination Urban wastewater, secondary treated effluent, post-chlorination Water treatment plant filter backwash water from plant to sludge tank after settling Urban wastewater, secondary treated effluent, no post-treatment Urban wastewater, 875,000 PE. Applies mechanical treatment with additional phosphate precipitation, followed by biological treatment with a denitrification/nitrification unit, equipped with a trickling filter. Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days NA

Treatment system

2000 300 820 2400

3.2 ± 0.4

– – – –

601

30 – 7

11600 357

5235 39

145250

146

1200

–

11245

8.1

131.61

NA

14.6 ± 1.9

268.0 ± 25.39

NA

196

1057

260

–

1983

2600

NA

Treated wastewater (ng/l)

NA

Raw Wastewater (ng/l)

Table 1 Concentrations and removal (%) of selected pharmaceuticals in WWTPs in different countries.

98

>99

23

96

98.7

46.8

–

–

–

–

–

94

0, 0, >71

90

94.6

96.4

>99

0, 0, >81

Overall removal (%)

2

67 - 21

–

0.1-1.5

21

2.5

5

5

5

5

5

7

5

14 - 1.2

2.5

3

12 - 7.6

10

Limit Detection (ng/l)

Turkey / ND

Mexico / 2016

United Arab Emirates / 2017 Colombia - 2016

Portugal / 2011

China / 2012-2013

Germany / 2015

Komesli et al., [46]

Rivera-Jaimes et al., [41]

Semerjian et al., [44] Botero-Coy et al., [45]

Salgado et al., [14]

Yan et al., [42]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Salgado et al., [14]

Inyang et al., [40]

Rivera-Jaimes et al., [41]

Yan et al., [42]

Salgado et al., [14]

Rivera-Jaimes et al., [41]

Inyang et al., [40]

Reference

(continued on next page)

Netherlands / 2015

South Africa / 2015

France / 2015

Australia / 2015

Portugal / 2011

USA / 2016

Mexico / 2016

China / 2012-2013

Portugal / 2011

Mexico / 2016

USA / 2016

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

Trimethoprim

Antibiotic

4

Sulfamethazine

Sulfadiazine

Sulfamethoxazale

Moxifloxacin

Azithromycin

Roxithromycin

Clarithromycin

Erythromycin

PhACs

PhAC Classes

Table 1 (continued)

Conventional activated sludge. SRT of approximately 10 days and HRT of 11.5 h. Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days

Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Primary treatment based on the partial removal of suspended solids and organic matter through coagulation, flocculation and sedimentation Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Primary clarifier, aerobic reactor a, secondary clarifier, and tertiary UV treatment Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. NA

Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. SRT 20 days and HRT 13-15 h Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days NA

Treatment system

186 52.6 ± 17.2

257 77.37 ± 22.72

150.2 ± 20.1

39.9 ± 6.5

155.0 ± 25.6

75

162

229.9 ± 22.5

730

1143

NA

800

2500

93

1147.9 ± 65.1

6.6 ± 0.9

81.5 ± 23.8

347.5 ± 35.4

0.31

153.0 ± 16.5

2935.4 ± 327.61

19.9 ± 7.4

362.5 ± 21.7

404.0 ± 34.2

0.32

254.24 ± 15.36

541

143

145

785

NA

Treated wastewater (ng/l)

NA

Raw Wastewater (ng/l)

73.4

32.6

73.8 ± 12.7

54

36

68

60.9

66.8

77.5

14

3

39.8

31

32

27.6

1

7, 17, 99

Overall removal (%)

7.5

15

1.7

0.1-1.5

33 - 13

36

3

12.2

1.5

1

1

2

0.1-1.5

4

2.1

7.8 - 1.3

2.5

Limit Detection (ng/l)

China / 2012-2013

China / 2012-2013

United Arab Emirates / 2017 Spain / 2009

Mexico / 2016

Yan et al., [42]

Semerjian et al., [44] Radjenovic et al., [13] Yan et al., [42]

Brown and Wong, [48] Rivera-Jaimes et al., [41]

Yan et al., [42]

Yan et al., [42]

Yan et al., [42]

Yan et al., [42]

Botero-Coy et al., [45]

Semerjian et al., [44] Yan et al., [42]

Inyang et al., [40]

Wang et al., [47]

Rivera-Jaimes et al., [41]

Inyang et al., [40]

Reference

(continued on next page)

Canada / 2016-2017

China / 2012-2013

China / 2012-2013

China / 2012-2013

China / 2012-2013

Colombia - 2016

United Arab Emirates / 2017 China / 2012-2013

China / 2012-2013

China / 2013

Mexico / 2016

USA / 2016

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

Cardiac

b-Blockers

PhAC Classes

Table 1 (continued)

5

Captopril

Amlodipine

Metoprolol

Atenolol

Ampicilin

Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days

4.9 ± 0.3 0

4676

64.7 ± 14.8


50.2 ± 5.3

62

<200

–

92

1000

–

126

940

–

122

720

–

NA

1300

–

5176

NA

0

30.4 ± 3.8

57.9 ± 18.4

510

Treated wastewater (ng/l)

NA

430

203.0 ± 16.1

345.9 ± 59.4

Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h Urban wastewater, 450,000 PE; Secondary treated effluent, post-chlorination Urban wastewater, secondary treated effluent, post-chlorination Water treatment plant filter backwash water from plant to sludge tank after settling Urban wastewater, secondary treated effluent, no post-treatment Urban wastewater, 875,000 PE. Applies mechanical treatment with additional phosphate precipitation, followed by biological treatment with a denitrification/nitrification unit, equipped with a trickling filter. Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. SRT 20 days and HRT 13-15 h NA

Norflaxacin

846

NA

Oflaxacin

Raw Wastewater (ng/l)

Treatment system

PhACs

100

–

33

100

–

–

–

–

–

48, 89, 99

100

85

82.8

40

Overall removal (%)

5

15

15

0.1-1.5

1.2

3

200

200

200

200

200

10

3

17.5

6.4

0.1-1.5

Limit Detection (ng/l)

Portugal / 2011

China / 2012-2013

United Arab Emirates / 2017 China / 2012-2013

China / 2013

Portugal / 2011

Germany / 2015

Salgado et al., [14]

Yan et al., [42]

Semerjian et al., [44] Yan et al., [42]

Wang et al., [47]

Salgado et al., [14]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Inyang et al., [40]

Salgado et al., [14]

Yan et al., [42]

Semerjian et al., [44] Yan et al., [42]

Reference

(continued on next page)

Netherlands / 2015

South Africa / 2015

France / 2015

Australia / 2015

USA / 2016

Portugal / 2011

China / 2012-2013

United Arab Emirates / 2017 China / 2012-2013

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Urban wastewater, 450,000 PE; Secondary treated effluent, post-chlorination Urban wastewater, secondary treated effluent, post-chlorination Water treatment plant filter backwash water from plant to sludge tank after settling Urban wastewater, secondary treated effluent, no post-treatment Urban wastewater, 875,000 PE. Applies mechanical treatment with additional phosphate precipitation, followed by biological treatment with a denitrification/nitrification unit, equipped with a trickling filter. A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days

Mianserin Nordiazepam Amitriptyline Doxepin Clorazepate

6

Diazepam

Pipamperone

Fluoxetine

Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days screen, primary clarifier, anaerobic tank, anoxic tank, oxic tank, secondary clarifier and UV. SRT 20 days and HRT 13-15 h Secondary, biological nutrient removal, HRT 23 h and SRT 7.5 days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Conventional activated sludge. SRT 3–5 days Conventional activated sludge. SRT of approximately 10 days and HRT of 11.5 h. Biological nutrient removal (BNR) with an anaerobic configuration (Anaerobic, anoxic, aerobic). SRT of 8 days, and a HRT of 5.5 h A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days Screen, primary clarifier, anaerobic tank, anoxic tank, oxic tank, secondary clarifier and UV. HRT 0.9 ± 0.1 days Secondary, biological nutrient removal, HRT 23 h and SRT 7.5 days Conventional activated sludge treatment

Carbamazepine

Psychiatric

Treatment system

PhACs

PhAC Classes

Table 1 (continued)

138 4 NA

90 78 156

24 <10 <10 12 <10

5.1

– – – –

5.5

0.4 1 0.8 3.3 135

13.99

8.6

–

1.2 1 0.9 5.8 507

25

16

1.4 250

16.5 ± 3.3

14.5 ± 5.2

1.4 1310

723

1032

NA

27.5 18

68.2 17

NA

NA

Treated wastewater (ng/l)

NA

Raw Wastewater (ng/l)

7.3

–

–

–

–

–

66.7 0 11.1 43.1 73.2

44.04

47

0 80.9

95, 96, 95

94.9 <10

10

59.7

0, 0, 0

Overall removal (%)

6

10

10

10

10

10

10 4 1 6 17

0.05

0.7

10 17

5

1.5 15.8

5.5 - 0.7

0.2

0.2

2.5 2.1

5

Limit Detection (ng/l)

China / 2014

Germany / 2015

Wu et al., [49]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Lajeunesse et al., [50] Van De Steene et al., [51] Wu et al., [49] Wu et al., [49] Wu et al., [49] Wu et al., [49] Salgado et al., [14]

Wu et al., [49] Salgado et al., [14]

Komesli et al., [46] Radjenovic et al., [17] Inyang et al., [40]

Rivera-Jaimes et al., [41]

Lajeunesse et al., [50] Yan et al., [42]

Wu et al., [49] Wang et al., [47]

Inyang et al., [40]

Reference

(continued on next page)

Netherlands / 2015

South Africa / 2015

France / 2015

Australia / 2015

China / 2014 China / 2014 China / 2014 China / 2014 Portugal / 2011

Belgium / 2009

Canada / 2009-2010

China / 2014 Portugal / 2011

USA / 2016

Turkey / NA Spain / 2009

Mexico / 2016

China / 2012-2013

Canada / 2009-2010

China / 2014 China / 2013

USA / 2016

Location / Monitoring Period

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Journal of Water Process Engineering 32 (2019) 100927

7

NA – Not available.

antidopaminergic

Lipid regulator and metabolite

Hormones

PhAC Classes

Table 1 (continued)

A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days Screen, primary clarifier, anaerobic tank, anoxic tank, anoxic tank, secondary clarifier and UV. SRT 20 days and HRT 13-15 h A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days Secondary, biological nutrient removal, HRT 23 h and SRT 7.5 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days A2/O: Anaerobic-Anoxic-Oxic. SRT 12 days Conventional activated sludge. SRT 3–5 days Conventional activated sludge. SRT 3–5 days Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h Conventional activated sludge treatment after aerobic and anaerobic digestion. Finally, a tertiary treatment based on UV oxidation. Pre-treatment (settling in a primary clarifier), preliminary treatment, primary sedimentation. SRT 10 days and HRT 11.5 h unit and a secondary (biological) treatment. Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Screen, primary settling, cyclic activated sludge system, disinfection with chlorination. SRT 21.4 days and HRT 15.8 h days Conventional activated sludge treatment

Oxazepam Sulpiride

Domperidone

Atorvastatin

Sivastatin

Gemfibrozil

Temazepam Alprazolam Bromazepam Lorazepam Progesterone Estrone Bezafibrate

Estazolam Norfluoxitine

Treatment system

PhACs

2.9 ± 0.3 255

14.5 ± 2.5 178

37.9

1.5 ± 0.5

117.5 ± 16.0

15.7

0.5

19.8 ± 10.0

–

69.2 ± 20.0

125 ± 18.76

2000–5900

2.5 6 17.4 1.6 4 7 748

1.5 7.6

6.5 168

Treated wastewater (ng/l)

15 8.6 2.1 40.7 9 27 3105

2.9 10

10.8 143

Raw Wastewater (ng/l)

58.5751979

66.7

83.1

0

80

84

96.1 55.6 74.1 76

83.3 30.2

48.3 24

39.8

Overall removal (%)

<0.05

1.15

15

11.5

11 - 6.7

2

12.5

5 7 2 12 5 5 4.9 - 0.2

6 0.1

6 0.8

Limit Detection (ng/l)

Belgium / 2009

China / 2012-2013

China / 2012-2013

Spain / 2007

Mexico / 2016

China / 2012-2013

China / 2012-2013

China / 2014 China / 2014 China / 2014 China / 2014 Turkey / NA Turkey / NA Mexico / 2016

China / 2014 Canada / 2009-2010

China / 2014 China / 2013

Location / Monitoring Period

Van De Steene et al., [51]

Yan et al., [42]

Yan et al., [42]

Radjenovic et al., [17]

Rivera-Jaimes et al., [41]

Yan et al., [42]

Yan et al., [42]

Wu et al., [49] Lajeunesse et al., (2012) Wu et al., [49] Wu et al., [49] Wu et al., [49] Wu et al., [49] Komesli et al., [50] Komesli et al., [46] Rivera-Jaimes et al., [41]

Wu et al., [49] Wang et al. [47]

Reference

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

Journal of Water Process Engineering 32 (2019) 100927

C.F. Couto, et al.

barriers that can prevent contaminants in wastewater from entering the receiving environment. However, WWTPs are designed aiming the removal of easily or moderately biodegradable carbon, nitrogen and phosphorus compounds and microbiological organisms, which regularly arrive at the WWTP in concentrations to the order of mg L−1 and at least 106 MPN/100 mL, respectively, WWTPs are not equipped to deal with complex compounds in low concentrations, such as, pharmaceuticals [2,33]. Since PhACs are not removed in the conventional treatment process applied to the urban wastewater, they are continuously discharged into aquatic ecosystems, which makes WWTP effluents the main source of human pharmaceuticals in the environment [34]. Generally, municipal wastewater treatment plants include screening, degritting, primary sedimentation, secondary treatment, and final sedimentation show low efficiency in removing PhACs. The capabilities of primary treatment processes (i.e., sedimentation) in removing PhACs are very limited [35], since adsorption is one of the main mechanisms of PhACs removal in these processes and most PhACs have hydrophilic nature. Secondary treatment involves biological process. Biological processes removal of PhACs can occur through partition, adsorption, biotransformation, and biodegradation [36]. Biodegradation is the breakdown of complex molecules, which can or cannot confer the property of toxicity into simples, less toxic products by the activity of microorganisms using these compounds as a donator of electrons in order to produce energy. This mechanism is the key processes of a biological treatment system. It is possible to highlight two main mechanisms which are associated with the biodegradation of PhACs in the WWTP, co-metabolism and degradation of the substrate sludge. In the first, the compound is degraded through the enzymes secreted by the microorganisms present in the biological sludge; In the second mechanism, PhACs represent the carbon and energy source of the active microbiological mass [36]. Studies by Jiang et al. [37] point out that the Trametes Versicolor fungus was efficient in removing carbamazepine by being able to secrete laccase and peroxidase enzymes. According to Jiang et al. [37] several strains of Pseudomonas use the antibiotic sulfamethoxazole as the only source of carbon and energy for its development. A comparison was performed between the cometabolic and single substrate degradation processes to determine the main mechanism of removal of PhACs. It was found that for ibuprofen, bezafibrate and naproxen, the co-metabolic biodegradation process was the main mechanism involved in the removal process, meanwhile, it was observed that the total amount of ketoprofen was only partially degraded as a single substrate [38]. It is possible to observe that even for the drugs belonging to the same therapeutic group, the removal mechanisms can differ considerably, as well as the rate of degradation and removal efficiency of each compound can vary greatly and be directly dependent on the type of digestion developed in the reactor, be it aerobic or anaerobic digestion; it may also be dependent on the molecular structure and functional group of the compounds (Table 1). Studies conducted by Schwarzenbach et al. [39] point out that a greater speed in the efficiency of the degradation of chlorinated compounds in aerobic digestion processes; however, slower degradation of the polyhalogenated compounds is observed in the same type of digestion. Long chain aliphatic compounds are more easily degraded by biological treatments than the aromatic compounds of the sulphate or halogen group due to their complex ring structure [39]. The biodegradation of PhACs, following first-order kinetics, depends directly on their structure and bioavailability. Their potential for biodegradation is also closely linked to the characteristics of the medium, the pH redox potential, its own stereochemical structure as well as the chemical properties of adsorbent and sorbent molecules, since these molecules favour intercalation [52]. Thus, it can be stated that biodegradability is governed by the sum of several factors associated with the complexity and stability of the compounds as well as the way in which the medium interacts with the compound [39]. According

to Tiwari et al. [52], compounds having short and unsaturated aliphatic side chains are more readily biodegradable than aromatic or highly branched side chain compounds. In addition, the removal of these compounds in the WWTP is also associated with the presence of electron withdrawal/donation groups in their structure [53]. In addition, an increase in the concentration of some PhACs after treatment (Table 1) is possible to observed, which can be associated both to deficiencies in sample collection and to the transformation of human metabolites and the conversion of metabolites formed into parent compounds [52]. Table 1 summarizes the occurrence of PhACs as influents and effluents of WWTPs worldwide. The removal efficiency also changes as a function of the solids retention time (SRT) and hydraulic retention time (HRT), and the tertiary treatment process. The increase of some compounds in the WWTPs effluents can be associated either to analytical deviations and/or cleavage of conjugates (glucuronides, sulfates) of target compounds [54]. Diversity and size of the microbial community in WWTP are controlled by the sludge retention time. It was observed an increase of PhACs removal with a longer SRT (26d), whereas decreased removal with shorter SRT of 8 d [55]. Hydrophobic compounds can be removed using a high sludge retention time (SRT), it has been reported that with an SRT of at least 10 days there is effective removal [56] as well as the transformation of ibuprofen, sulfamethoxazole, acetylsalicylic acid and bezafibrate are achieved which require an SRT of d [57]. Long SRT promotes the growth of specialized microorganisms, which, although they naturally have a slower growth, are effective in the removal of nitrogen and, therefore, can increase the removal of PhACs. However, in general, WWTPs are not planned to operate with a long enough SRT to satisfy this requirement. Besides that, some pharmaceuticals, for example, carbamazepine, are highly persistent and have been shown to be inert to the biological treatment process [56,58]. Properties such as acidity and alkalinity of influent of wastewater treatment plants may affect the nature of the pharmaceutical compound in addition to being able to influence the structure and composition of the microbial community acting in the medium and may increase or decrease the activity of the microbial enzymes released in the medium, and therefore the PhACs biodegradation. It has been found that the removal of ionizable compounds such as ibuprofen and sulfamethoxazole is highly dependent on the pH for degradation [52]. In acidic media, these compounds are in a hydrophobic form which turns in greater elimination and therefore a higher efficiency of the process. However, compounds, such as, carbamazepine, that are non-ionizable compounds, the removal is independent of pH [59]. In the biological treatment stage of WWTP, the removal of PhACs are also related to sorption to suspended solids [60]. Adsorption is the main mechanism in the removal of micropollutants during primary treatment [47] and it is generally in agreement with their hydrophobicity (expressed by the octanol–water partition coefficient Kow). Compounds with low logKow values (< 3.0), such as carbamazepine, metoprolol (1.88), trimethoprim (0.91), sulpiride (1.10), and atenolol (0.16), are not expected to adsorb greatly to the particles, but to dissociate in the aqueous phase [14]. Trimethoprim is neither biodegraded nor adsorbed and carbamazepine could be hardly removed regardless of secondary treatment process applied [47]. Inyang et al. [40] in their research found that trimethoprim was removed under both anoxic and aerobic conditions and atenolol could be removed in anaerobic, anoxic and aerobic regimes. The EAWAG Biodegradation Biocatalysis Database Prediction Pathway System (EAWAG-BBD PPS) predicts that under aerobic conditions, atenolol can degrade by microbial hydrolysis of its primary amide into carboxylic acid [13] proving its high removal in all studied cases (Table 1). PhACs with logKow that varies from 3.0 to 5.9, such as diclofenac (4.51) and naproxen (3.18) corresponded to high and medium adsorption observed and, therefore, more expressive removal rates. This effect could be due to the high biodegradation rates observed for these two compounds. Ibuprofen, however, can be observed to be an 8

Journal of Water Process Engineering 32 (2019) 100927

C.F. Couto, et al.

exception, that although presents a medium logKow value (3.97), low adsorption is observed [14]. Under aerobic condition, the metabolization of ibuprofen yields hydroxyibuprofen and carboxy-ibuprofen metabolites [61], whereas biotransformation of naproxen can yield 2-(6hyd roxynaphthalen-2-yl) propanoic acid and 1-(6-methoxynaphtha len-2-yl) ethanon as intermediates [62]. Increasing HRT of these compounds by sludge adsorption provides more time for microbial degradation, i.e., micro-pollutant gets degraded either by catabolic microbial enzymes or utilized by microorganisms as a carbon source. On the other hand, hydrophilic micro-pollutants escape from WWTP without biodegradation along with effluent and evades the biodegradation process. Another feature related to the PhACs removal is associated to volatilization of the compound, which is defined by the Henry law constant (kH). To achieve significant volatilization, it is required kH value > 3 × 103 mol/(m3.Pa), however in the case of pharmaceuticals, this value is normally around of kH < 10-5 [63]. Thus, volatilization of PhACs in a wastewater treatment plant can be negligible. Photo-degradation of these compounds is also considered insignificant due to the high sludge concentration, which increases the wastewater turbidity and, therefore, blocks the penetration of sunlight in the top layer [52]. Since WWTPs are not designed to remove PhACs, especially antibiotic, they are known to be the main source of antibiotics and antibiotic-resistance genes for surface waters [64]. Thus, more attention has to be paid to the adverse ecological effect caused by their persistence, especially throughout the WWTPs, and potential long-term effects toward the non-target aquatic organisms even at low concentrations. It is possible to note that, in general, individual concentrations of many PhACs are higher in effluents of WWTPs than concentrations found in surface water. It is attributed to dilution as well as partial remediation by natural pathways like hydrolysis, sorption onto colloids, biodegradation natural attenuation and photolysis [65,66]. Due to the majority PhACs’ characteristics of being biorefractory, partial transformation by abiotic reactions is more likely to happen [67]. pH, natural organic matter (NOM) and ionic strength of the receiving media may influence the speciation and concentration level of each PhAC in the environment. Once in the water body, PhACs can take many different pathways. Some PhACs, at different pH, become charged and can easily absorb onto colloids, trapped by NOM or associated with cations in the water and transferred to sediments [65]. In general, the levels of the studied pharmaceutical compounds were also water source dependent, which, in turn, depends on the location, popular habits, wastewater treatment type, PhACs consumption patterns, physicochemical properties and stability as well as the season [68]. Rainfall or lack of therefore, might be one of the causes associated with the PhACs fluctuation concentration [24,69]. Increased flow caused by rainfall might have two different effects on the PhACs concentration influent to WTP. Firstly, they might dilute the PhACs concentrations on rivers bed, resulting in lower removal efficiency by WTP. Secondly it could suspend settled sediments in which pharmaceutical compounds are adsorbed and releasing them into the water stream [23]. Additionally, after rainfall incidents, surface water could be polluted by WWTP overflows which might increase the PhACs concentration on water sources to WTP [23]. Some compounds have higher usage rates during winter months, for example antipyretics such as diclofenac, ibuprofen and naproxen, which are less efficiently removed during wastewater treatment in winter weather. The same can be stated to warmer seasons, where it is possible to note a pick in the consumption of antihistamines, for example, gemfibrozil, salicylic acid and acetaminophen [68,70]. Also, on warmer seasons, the microbiological active is higher due to the increase in the temperature [50,71]. Other pharmaceuticals, such as antibiotics, antiepileptic or b-blockers are similarly consumed during both seasons, thus it is not observed seasonal pattern [68]. Nelson et al. [71] assessed the distribution of PhACs concentration during the days. It was found

that some compounds have broad increase/decrease in concentration over such as erythromycin, azithromycin, atenolol, propranolol and gemfibrozil. The highest concentrations generally occur between 4 and 7 pm and lowest concentrations seem to occur between 8 and 11 a.m. Gemfibrozil seems to have a bimodal cycle similar to naproxen. Other compounds such as carbamazepine, primidone, fluoxetine, metoprolol, triclocarban, and phenytoin don’t show any variation in their concentration along the day. Some compounds appear to have daily minima during 10-11:30 a.m. This behaviour is possible to be explained by taking into consideration that both consumption and excretion patterns of the studied population. PhACs are usually administered every 8 or 12 h, and the last intake of the day is usually at night. During the night, these compounds are accumulated in urine and faeces and are released along with the first toilet flush of the morning [72]. Also, from Table 1, it is possible to observe that some compounds found all around the world are also listed on the watch list of EU [30], for instance, macrolide antibiotics such as erythromycin, clarithromycin and estrone, also carbamazepine, atenolol, ibuprofen, bezafibrate, gemfizobril, sulfamethoxazole, and naproxen are classified as Class I (high priority) in Global Water Research Coalition (GWRC) [32]. This rise attention to the possibility of consumption increase and, therefore, the release in the environment of these compounds as well as their potential threat to the environment and public health. More toxicity data should be raised in order to determine the effects of these PhACs, not only in target organisms but also in non-target populations, as well as their effects as a mixture. 4. The current panorama of PhACs on drinking water When public health is concern, drinking water treatment plants (WTP) may impose another barrier that can prevent the return of these PhACs to human body. Many studies have been carried out in order to detect PhACs in conventional WTP (Table 2). However, the conventional treatment plants that consist in coagulation, flocculation and filtration followed by a kind of disinfection, such as chlorination and ozonation, have poor removal efficiencies, especially the steps of coagulation, flocculation and sand filtration [74,74]. Prechlorinaton is found to be very efficient in removal some PhACs due to the high reactivity of chlorine with primary and secondary amines [75,76]. According to Huerta-Fontela et al. [73] the efficiency of the prechlorination is pH dependent, achieving higher removal at lower pHs when applied for carbamazepine, also, the same study suggests that the absence of the imidazole moiety contributed to the deactivation of the aromatic ring to the chlorine reaction when analysing the angiotensin agents’ behaviour. The presence of a bromide instead of chlorine in one of the aromatic rings and the substitution of a benzene ring by a pyridine one block the reactivity of this compound through chlorine attack [77]. However, the application of chlorine has no efficiency in the removal of β-blockers [73]. According to Stackelberg et al. [78] the process of clarification (which consists of coagulation, flocculation, sedimentation and filtration) is generally not a primary route by which PhACs in filtered-water samples are degraded or removed mostly due to the intrinsic characteristics of the compounds. The application of ferric chloride coagulation may result in base or acid hydrolysis, however the low concentration of PhACs in superficial water and the hydrophobic behaviour of some PhACs with log Kow > 3.0, may explain the lower removal of PhACs through this process which could indicate removal by partitioning. Some, such as sulfamethoxazole or acetaminophen compounds can occur hydrolysis during coagulation step [78]. Sand filtration is based on the sieving and, in less proportion, adsorption processes, and since PhACs have a molecular weight ranging from 100 to 800 KDa, these processes is not efficient in removing the target compounds. Gemfibrozil, diclofenac, naproxen, propranolol, atenolol, carbamazepine, iopamidol and fenofibrate were the major compounds detected 9

ND

6.6 0.06

Analgesic

1.3

314 (257–357)

Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media, disinfection with sodium hypochlorite Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration Filtration followed by disinfection

10

Acethaminophen

Nimesulide Naproxen

Diclofenac

0.5 (0.4–0.6)

830

49 15.49

NA -

Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration

Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media, disinfection with sodium hypochlorite Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media disinfection with sodium hypochlorite -

NA Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media, disinfection with sodium hypochlorite Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration NA Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration NA

-

50.6

ND

-

21.9 71

< 0.03

ND

3.1 75 (55–110)

< 0.06

11

278 164 (71–321)

ND

ND

1.8 12 99-152

< 0.10

259 (210–316)

-

18

8.8 ND

16.6 175-292

Disinfection Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration -

39

4

3

NA

-

36

Ibuprofen

ND

2.5

Conventional chemical coagulation, sedimentation, and rapid sand filtration Preoxidation with chlorine followed by coagulation/flocculation, sedimentation, filtration and post-chlorination NA

Treated Water (ng/l)

Indomethacin

Raw Water (ng/l)

Anti-inflammatory drug

Treatment system

PhACs

PhAC Classes

Table 2 Concentrations and removal (%) of selected pharmaceuticals in conventional WTPs in different countries.

> 99

-

> 99

> 99

> 99

96

> 99 > 99

> 99

> 99

-

63.3

-

47 > 99

-

80.3

90.2

95.3

> 99

> 99

> 99

Overall removal (%)

2

0.28

0.01

4

0.02

0.5

4 6

1

8 0.02

25

1

0.29

1 3

0.5

7

0.01

5

1.3

10

1.7

Limit Detection (ng/l)

Wilkinson et al., [96] Vulliet et al., [81]

Azzouz and Ballestero, [69]

Vulliet et al., [81]

Carmona et al., [94] Azzouz and Ballestero, [69]

Caldas et al., [98] Boleda et al., [79]

Wilkinson et al., [96] Carmona et al., [94] Praveena et al., [97] Caldas et al., [98] Azzouz and Ballestero, [69] Vulliet et al., [81]

Kleywegt et al., [80] Wang et al., [95] Boleda et al., [79]

Simazaki et al., [74] Gaffiney et al., [93] Carmona et al., [94] Carmona et al., [94] Azzouz and Ballestero, [69] Vulliet et al., [81]

Reference

(continued on next page)

France / 2007-2008

England / '-

Spain / 2012

France / 2007-2008

Spain / 2012

Spain / 2012

Brazil / 2010-2011 Spain / 2010

France / 2007-2008

Brazil / 2010-2011 Spain / 2012

Malaysia / -

Spain / 2012

England / '-

US / NA Spain / 2010

Canada / NA

France / 2007-2008

Spain / 2012

Spain / 2012

Spain / 2012

Portugal / 2013

Japan / 2006-2019

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

b-Blockers

Sulfamethoxazole

Antibiotic

11

Sotalol

Propanolol

Atenolol

Acebutolol

Trimethoprim

Erythromycin

Clarithromycin

Sulfadimethoxine

PhACs

PhAC Classes

Table 2 (continued)

Disinfection Preozonation, coagulation, sedimentation, sand filtration, ozonation and GAC filtration Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration Filter treatment system Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration

Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration Filtration followed by disinfection

Filter treatment system Preozonation, coagulation, sedimentation, sand filtration, ozonation and GAC filtration Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration Preozonation, coagulation, sedimentation, sand filtration, ozonation and GAC filtration Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration Preoxidation with chlorine followed by coagulation/flocculation, sedimentation, filtration and post-chlorination Filtration followed by disinfection

Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration Filtration followed by disinfection

Conventional chemical coagulation, sedimentation, and rapid sand filtration -

Treatment system

0.33

0.98

3.6 26

6.7 54

53

0.4

10.9

100

380

36 470

44

ND 3.7-ND

ND

0.4 4.6 17-4.1

ND

0.03

0.4 9.5-22.8

200

3200

0.8-1.4

ND-1.8

ND-1.5 21-33

ND

ND

40.1–54.4

ND-8.3

0.37 5.4-ND

ND

4

0.87 87-35.4

ND

-

114.24 57–149

ND

Treated Water (ng/l)

4.4

Raw Water (ng/l)

47

46.3 51.9

96.3

19.1

18.2

> 99 > 78.2

-

> 99

92.5

99.4

95

> 90

> 99

> 99

57.5 > 93.8

66.3

> 99

> 99

-

> 99

Overall removal (%)

0.1

0.4 1.1

1

5

0.01

0.3 0.6

1

0.9

10

150

0.2

0.3

0.2

0.8

0.32 1.1

2

0.5

1

25

0.9

Limit Detection (ng/l)

Spain / 2008-2009

US / 2012 Spain / 2008-2009

Subedi et al., [99] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73]

Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Vulliet et al., [81]

Kleywegt et al., [80] Wang et al., [95] Lin et al., [100]

Gaffiney et al., [93] Kleywegt et al., [80] Boleda et al., [79]

Boleda et al., [79]

Lin et al., [100]

Boleda et al., [79]

Boleda et al., [79]

Kleywegt et al., [80] Subedi et al., [99] Lin et al., [100]

Vulliet et al., [81]

Simazaki et al., [74] Praveena et al., [97] Boleda et al., [79]

Reference

(continued on next page)

France / 2007-2008

Spain / 2008-2009

Spain / 2008-2009

US / NA China / NA

Canada / NA

Spain / 2010

Canada / NA

Portugal / 2013

Spain / 2010

China / NA

Spain / 2010

Spain / 2010

US / 2012 China / NA

Canada / NA

France / 2007-2008

Spain / 2010

Malaysia / -

Japan / 2006-2002

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

Psychiatric

Amlodipine

Cardiac

12

Oxazepam Diazepam

Desmethylvenlafaxine

Chlorpromazine

Chlordiazepoxide

Carbamaz epoxide

Carbamazepine

Bromazepam

Warfarin

Hydrochlorthiazide

Furosemide

Diltiazem

Clopidogrel

PhACs

PhAC Classes

Table 2 (continued)

followed by coagulation, flocculation and sand

followed by coagulation, flocculation and sand

followed by coagulation, flocculation and sand

followed by coagulation, flocculation and sand

followed by coagulation, flocculation and sand

followed by coagulation, flocculation and sand

Disinfection Filter treatment system Preozonation, coagulation, sedimentation, sand filtration, ozonation and GAC filtration Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration NA Prechlorination followed by coagulation, flocculation and sand filtration

Prechlorination followed by coagulation, flocculation and sand filtration Conventional chemical coagulation, sedimentation, and rapid sand filtration NA Prechlorination followed by coagulation, flocculation and sand filtration Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media, disinfection with sodium hypochlorite Chlorinated drinking water, sourced from a protected surface water catchment 10 DW France Chlorinated drinking water, sourced from a protected surface water catchment November 2015 Dam water treated by dosing with lime and flocculant, flocculation, air floatation & sand filtration simultaneously, granular activated carbon, chlorination 18 DW Netherlands Non-chlorinated drinking water, sourced from open surface water November 2015 Groundwater treated by aeration for iron and manganese removal Preoxidation with chlorine followed by coagulation/flocculation, sedimentation, filtration and post-chlorination Filtration followed by disinfection

Prechlorination filtration Prechlorination filtration Prechlorination filtration Prechlorination filtration Prechlorination filtration Prechlorination filtration NA

Treatment system

40.4 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 13 0.21

186 (144–215) 20 3

< LQO 4 < 0.5

-

4 < 40 12

5

1

35

54 5

7

54

2.2 ND ND-0.65

ND ND

25.3 13

8.4 0.1 0.5-1.01

ND

1.8

ND

ND

1 7

0.2

74

ND

2

ND

ND

Treated Water (ng/l)

1

670

22

4

2

1

Raw Water (ng/l)

-

> 99 66.7

20

80

35.2

87

73.8 > 99 > 35.6

93

65

-

-

-

-

75.5

> 99 > 99

> 99

> 99

> 99

80

89

> 99

50

> 99

> 99

Overall removal (%)

0.25

40 0.4

0.02

1.1

1.2

0.01

0.5 0.03 0.2

1

0.25 8

0.25

0.25

0.25

0.25

0.01

2.3 1.1

0.4

5

0.3

0.1

1

9

0.8

0.15

0.01

Limit Detection (ng/l)

Australia / 2015

Germany / 2011 Spain / 2008-2009

Spain / 2008-2009 Spain / 2008-2009 Spain / 2007-2008

Spain / 2008-2009

Spain / 2008-2009

US / NA US / 2012 China / NA

Canada / NA

Germany / 2015 Portugal / 2013

Netherlands / 2015

Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Hass et al., [101] Huerta-Fontela et al., [73] Leusch et al., [43]

Leusch et al., [43] Gaffiney et al., [93] Kleywegt et al., [80] Wang et al., [95] Subedi et al., [99] Lin et al., [100]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Carmona et al., [94] Huerta-Fontela et al., [73] Simazaki et al., [74] Wu et al., [49] Huerta-Fontela et al., [73] Azzouz and Ballestero, [69]

Reference

(continued on next page)

South Africa / 2015

France / 2015

Australia / 2015

Spain / 2012

China / 2014 Spain / 2008-2009

Japan / 2006-2009

Spain / 2008-2009

Spain / 2012

Spain / 2008-2009

Spain / 2008-2009

Spain / 2008-2009

Spain / 2008-2009

Spain / 2008-2009

Spain / 2008-2009

Location / Monitoring Period

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

13

Bezafibrate

Gemfibrozil

Fenofibrate

Tamoxifen

Testosterone

Progesterone

Ethinyl estradiol

NA – Not available. ND – Not detected by the analytical method.

Lipid regulator and metabolite

Estrone

Hormones

Estriol

PhACs

PhAC Classes

Table 2 (continued)

< 0.5 < 0.5 1.9 ND

24.3 0.3

2

77 0.2

Filtration followed by disinfection Coagulation, flocculation, sedimentation, filtration in sand, ozonation and chloration Filtration followed by disinfection

ND

ND 0.5

1.9 0.7

ND

21

NA

5.9

2.4

187-326

23

0.1

2.8

1.7

< 0.20

-

0.23 44 (10–97)

NA

2.5

ND

< 0.5

-

26

< 0.5

Treated Water (ng/l)

-

Raw Water (ng/l)

Preoxidation, coagulation, sedimentation, filtration in anthracite–sand media, disinfection with sodium hypochlorite Coagulation, floculation, sedimentation, filtration in sand, ozonation and chloration Coagulation, floculation, sedimentation, filtration in sand, ozonation and chloration Prechlorination followed by coagulation, flocculation and sand filtration Conventional chemical coagulation, sedimentation, and rapid sand filtration Dioxychlorination, coagulation, flocculation, settling, sand filtration and groundwater dilution to improve raw water quality. Ozonation and granular activated carbon (GAC) filtration NA

Chlorinated drinking water, sourced from a protected surface water catchment 10 DW France Chlorinated drinking water, sourced from a protected surface water catchment November 2015 Dam water treated by dosing with lime and flocculant, flocculation, air floatation & sand filtration simultaneously, granular activated carbon, chlorination 18 DW Netherlands Non-chlorinated drinking water, sourced from open surface water November 2015 Groundwater treated by aeration for iron and manganese removal NA Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration Prechlorination followed by coagulation, flocculation and sand filtration -

Treatment system

28.6

> 99

-

97.4

> 99

8.7

> 99

−110.7

−41.2

> 99

-

> 99

> 99

92.2 > 99

-

-

-

Overall removal (%)

0.5

1

1

0.3

2

0.2

0.01

0.02

0.02

0.06

0.98

0.2

4.7

0.25 0.1 0.2

0.25

0.25

0.25

Limit Detection (ng/l)

Canda / NA

France / 2007-2008

Canda / NA

Spain / 2012

Spain / 2010

Japan / 2006-2009

Spain / 2008-2009

France / 2007-2009

France 2007-2008

Spain / 2012

England / '-

Spain / 2008-2009

Spain / 2008-2009

Germany / 2015 China / 2014 Spain / 2008-2009

Netherlands / 2015

South Africa / 2015

France / 2015

Location / Monitoring Period

Kleywegt et al., [80]

Carmona et al., [94] Kleywegt et al., [80] Vulliet et al., [81]

Huerta-Fontela et al., [73] Simazaki et al., [74] Boleda et al., [79]

Vulliet et al., [81]

Leusch et al., [43] Wu et al., [49] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Huerta-Fontela et al., [73] Wilkinson et al., [95] Azzouz and Ballestero, [67] Vulliet et al., [81]

Leusch et al., [43]

Leusch et al., [43]

Leusch et al., [43]

Reference

C.F. Couto, et al.

Journal of Water Process Engineering 32 (2019) 100927

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C.F. Couto, et al.

in WTP effluents [74,79–81]. These compounds are characterized by low Kow and carbamazepine is also found to be persistent throughout physic-chemical treatment. This compound is considered to be a trace of human presence [58,60,47]. In general, most of the PhACs removal would be dependent on chemical oxidation by chlorination and/or ozonation, adsorptive process by granular activated carbon (GAC), and membrane filtration employed at each WTP. The removal ratios of several pharmaceuticals (i.e., ibuprofen, and fenofibrate) ranged from 10% and 80%. Ibuprofen could also be removed moderately by ozonation and activated carbon adsorption. According to Huber et al. [82], ibuprofen was considered slow-reacting pharmaceutical during conventional ozonation and, in contrast, carbamazepine and sulfamethoxazole were considered fastreacting pharmaceuticals, being in accordance with the results found in survey realised by Huerta-Fontela et al. [73]. Fenofibrate, that has high hydrophobic property (log Kow 5.28) and exists as neutral molecular at pH 7.0, is expected to be efficiently removed by activated carbon filtration, however, it was observed a removal of approximately 9% (Table 2); this may be due to the competition of adsorption on activated sites of GAC [74]. It is possible to observe a negative removal efficiency when progesterone and testosterone are concerned (Table 2). It may be due to a gap in the actual hydraulic retention time (HRT) at each WTP and estimated HRT to set sampling schedule of its source water and finished water. Advanced treatment technologies, such as ozonation, activated carbon adsorption, and reverse osmosis (RO), are applicable to PhACs removal in WTPs [74,83–86]. Ozonation is able to remove a large spectrum of contaminants found in raw waters. Although studies have demonstrated that the primary attack by ozone is sufficient to reduce specific effects, such as endocrine disruption [82], antibacterial [87] and antiviral activity [83], during ozonation, a mineralization of PhACs is typically not achieved and compounds are only transformed [88]. Despite the general removal of specific effects by ozonation there is a concern about the unspecific toxicity of the mostly unknown transformation products, which rises up possible problems with the application of ozone and the consequences to human health. Granular active carbon (GAC) filtration is also efficient to remove compounds with high hydrophobic properties [73]. Reverse osmosis is recognized as an effective and reliable form of being applied, mainly, in the treatment of supply water either as a polishing step or in raw water purification [89,90]. Studies indicate that electrostatic exclusion is the predominant phenomenon in the rejection process of these membranes and, therefore, effective rejections of negative pharmaceutical compounds were observed, exceeding 95% by RO membranes [84–86]. The results of a study on the removal of hormones and pharmaceuticals in treated wastewater indicated that treatments using ozonation, microfiltration and nanofiltration were partially effective, while the treatment with RO was the most successful in the removal of target compounds [91]. Ozaki and Li [92] investigated the rejection of various products, among them the PhACs by polyamide NF and RO membranes, and observed that the rejection of organic compounds by ultra low pressure RO (ULPRO) increased linearly with molecular weight and molecular weight of the evaluated compound. From Table 2, it is possible to note that, as well as for the wastewater panorama, many compounds that are listed in the watch list of EU [30] are found in the water surface, as well as in drinking water, for instance, macrolide antibiotics such as erythromycin and clarithromycin, estrone and ethinylestradiol, which confirms the necessity of increasing the efforts in order to monitor water sources and drinking water all around the world. Also, since the consumption of PhAC tends to increase throughout the time, more emphasis should be paid to nondetected or not studied PhACs as well as to developing countries, in order to fill the gaps about occurrence of PhACs in the environment,

Fig. 2. Comparison of reported concentrations in drinking water (a) and raw water (b) to drinking water guideline values (Drinking Water Equivalent Levels – DWEL). A BQ ≤ 0.1 or ≤0.2 for drinking water and wastewater respectively (indicating no potential risk to human health at lifetime consumption) is calculated for PhACs above the continuous line (green area), and a value 0.1 or 0.2 for drinking water and wastewater respectively < BQ ≥ 1 (warranting further investigation – yellow area). BQ ≥ 1 (indicating potential human health risk – red area). 1 - indomethacin; 2 - ibuprofen; 3 - diclofenac; 4 - nimesulide; 5 Naproxen; 6 - acetaminophen; 7 - sulfamethoxazole; 8 - clarithromycin; 9 trimethoprim; 10 - atenolol; 11 - propranolol; 12 - sotalol;14 - hydrochlorothiazide; 15 - carbamazepine; 16 - diazepam; 17 - Ethinylestradiol; 18 fenofibrate; 19 - gemfibrozil; 20 – bezafibrate.

drinking water and wastewater. A risk assessment was conducted with the concentration values of PhACs in the raw and treated water observed in Table 2. For this purpose, the Benchmark Quotient (BQ) was calculated as the ratio between the mean or maximum drinking water concentration and the drinking water guidelines values (Drinking water equivalent level - DWEL) for the compounds for which the values were available in the literature. The DWEL values were calculated by using Eq. (1).

DWEL =

TDI x M x f V

(1)

Where TDI, M, F and V are Tolerable Daily Intake (μg/kg bw/day) (values available in Supplementary Material), body weight (considered to be 60 kg), drinking water allocation (adopted value of 0.2) and personal drinking water consumption (2 L/day). A BQ value of 1 corresponds to a (potable) water concentration equal to the reference value (DWEL). Thus, when a value of BQ ≥ 1 is observed in the drinking water, a potential human health risk may be associated if this consumption is prolonged over a period of life [102]. BQ values ≥0.1 in drinking water need an in-depth investigation of the risk imposed associated with the presence of PhACs. It is worth mentioning that, for compounds that have been found in 14

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raw water, be it surface or underground water, conventional drinking water treatment can dampen the risks and provide additional safety. For these compounds, it was assumed that a BQ of ≤0.2 presents no significant risk to human health [102]. In Fig. 2, the concentrations reported for drinking water (Fig. 2a) and raw water (Fig. 2b) are compared with DWEL. Fig. 2 shows that, for most substances, BQ values are ≤0.1 or ≤0.2 for drinking raw water, respectively, representing no significant risk to human health. In the range that needs further investigation, it is possible to observe carbamazepine, diazepam, hydrochlorothiazide, clarithromycin, sotalol and gemfizobril, raising attention to the presence of these compounds in the drinking water. Also, of these compounds only clarithromycin is listed in the watch list of EU [30] and carbamazepine and gemfizobril are listed in the GWRC [32] as class I (high priority) bringing special attention to explore the human exposure to these PhACs. In drinking water, three compounds were detected with a BQ ≥ 1: fenofibrate, carbamazepine and atenolol. All of the three compounds are listed as Class I in the GWRC [32], also, their high concentration in drinking water and the inefficiency of WTP in reducing their concentrations and, therefore, risks in different parts of the globe, draws attention to the necessity of removing these PhACs and produce safer drinking water. Also, it is possible to observe the presence of these compounds in the wastewater effluent in high concentration (Table 2), specially carbamazepine which is not considered as a highly persistent compounds and have been shown to be inert to the biological treatment process [56,58]. Studies from Turkey, Mexico, Canada and 2 from China have found either carbamazepine or carbamazepine and gemfizobril in the WWTP effluent, as well as diazepam, atenolol, sulfamethoxazole, clarithromycin and erythromycin. This also brings attention to the necessity of an application of an advanced treatment for wastewater in order to reduce the possible risks associated to the higher concentrations in raw surface water. For 18 of the 38 PhACs evaluated in this study, the health risk assessment for drinking water could not be performed because either toxicity data or their concentrations in drinking water were missing. Most of these PhACs are classified as psychiatric, cardiac or hormonal, highlighting the need for further studies focusing on determining the guideline values of these compounds in drinking water.

produce good quality water reaching the drinking water standards due to their higher removal rate of low molecular weight organic pollutants, minimizing the risk associated to the source and its contaminants as well as its modularity and ability to integrate with other systems. To increase its efficiency and to reduce problems with fouling, it is possible to integrate membrane systems using low pressure driven membranes such as ultrafiltration (UF) and microfiltration (MF) with NF/RO membranes. 6. Conclusion Pharmaceutically active compounds are a real threat around the world and the increasing tendency in the consumption and, therefore, the realise of these compounds in the environment, raises a global warning, since the acute and chronical effects are still not clear. The chemical stability associated with a low concentration of PhACs, makes conventional water and wastewater treatment not efficient processes in removing these kinds of micropollutants, what turns out to be released in the environment. Biodegradation, adsorption and chlorination are the processes associated with the highest removal of PhACs. The existence of these compounds in the domestic wastewater as well as in the superficial and ground water are linked to the location, season and populational habits. More attention should be paid to developing countries in order to assess the real risks due to PhACs in the environment, especially due to lack of sanitation and trends of consumption increase of these compounds. Also, more efforts should be given in order to determine all the range of PhACs in the environment as well as their respective drinking water guideline value. Although conventional drinking water treatment were able to reduce the risks associated to the PhACs in the water, carbamazepine, diazepam and genfizobril were still found with high risks associated to human health, which brings attention to the development of safer techniques for drinking water production. More studies are still needed on the detection toxicities, especially on non-target organisms, persistence and priorities of other compounds especially in order to give background and subsidize decision making, as well as to evaluate the environmental impact of mixtures of different PhACs and to evaluate the best end-of-pipe technology to guarantee better removal of the most persistence and toxic compounds.

5. Future perspectives There are thousands of pharmaceuticals in the market that can go to the environment, but less than 2% of them have been detected and investigated for treatment [74]. Therefore, more efforts are needed to work on detection, toxicities, persistence and priorities of other compounds. Furthermore, close attention has to be paid to the sensitive/ vulnerable subpopulations (e.g., pregnant women), since these groups are not contemplated in the researches found in the literature. Also, it should be noted that the majority of the surveys are realised with target pharmaceuticals alone, which may not represent the real hazard to human health, since there is a mixture of many different PhACs in the drinking water supplies. Effects of chronic, low-level exposure to pharmaceutical, including exposure of sensitive subpopulations in a life time of consumption, should also be assessed. Considering the difficulty in predicting the real and the full effects and risks of those trace organic substances impose either to human health or to wild life, as well as their consumption increasing trend and therefore release in the environment, the removal of these compounds of the wastewater and drinking water is paramount. Thus, due to the failure of the current WWTP and WTP in removing PhACs mainly due to the low concentration, many studies have focused on the application of advanced water treatment processes such as membrane separation processes [33,86,88,90,103] in order to produce water with enough quality to protect human health and wild life. Membrane separation processes (MSP) including nanofiltration (NF) and reverse osmosis (RO) have become an important alternative to

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