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Cite This: Chem. Rev. XXXX, XXX, XXX−XXX
Pharmaceuticals of Emerging Concern in Aquatic Systems: Chemistry, Occurrence, Effects, and Removal Methods Manvendra Patel,† Rahul Kumar,† Kamal Kishor,† Todd Mlsna,‡ Charles U. Pittman, Jr.,‡ and Dinesh Mohan*,† †
School of Environmental Sciences, Jawaharlal Nehru University, New Delhi 110067, India Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, United States
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‡
ABSTRACT: In the last few decades, pharmaceuticals, credited with saving millions of lives, have emerged as a new class of environmental contaminant. These compounds can have both chronic and acute harmful effects on natural flora and fauna. The presence of pharmaceutical contaminants in ground waters, surface waters (lakes, rivers, and streams), sea water, wastewater treatment plants (influents and effluents), soils, and sludges has been well doccumented. A range of methods including oxidation, photolysis, UVdegradation, nanofiltration, reverse osmosis, and adsorption has been used for their remediation from aqueous systems. Many methods have been commercially limited by toxic sludge generation, incomplete removal, high capital and operating costs, and the need for skilled operating and maintenance personnel. Adsorption technologies are a lowcost alternative, easily used in developing countries where there is a dearth of advanced technologies, skilled personnel, and available capital, and adsorption appears to be the most broadly feasible pharmaceutical removal method. Adsorption remediation methods are easily integrated with wastewater treatment plants (WWTPs). Herein, we have reviewed the literature (1990−2018) illustrating the rising environmental pharmaceutical contamination concerns as well as remediation efforts emphasizing adsorption.
CONTENTS 1. Introduction 2. Pharmaceuticals in the Environment 2.1. Pharmaceuticals versus Other Contaminants 2.2. Pharmaceutical Usage and Consumption Patterns and Their Relation with Environmental Occurrence 2.3. Pharmaceuticals Occurrence in the Environment 2.4. Sources and Pathways of Pharmaceuticals in the Environment 2.5. Fate and Transformation of Pharmaceuticals in the Environment 2.5.1. Effect of Pharmaceuticals’ Physicochemical Properties 2.5.2. Effect of Environmental Parameters 2.6. Risks and Toxic Effects of Pharmaceuticals in the Environment 2.6.1. Ecological and Environmental Risks 2.6.2. Toxicity and Human Health Risks 2.7. Standard Guidelines for Pharmaceutical Concentrations in the Environment 3. Analytical Techniques for the Estimation of Pharmaceuticals 3.1. Overview 3.2. Sample Collection and Preservation 3.3. Sample Preparation © XXXX American Chemical Society
B L L 4. M O W AP AQ AR 5.
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3.4. Solid Phase Microextraction and Molecularly Imprinted Extraction 3.5. Instrument Analysis 3.6. Detection 3.7. Data Analysis 3.8. Quality Control Pharmaceutical Removal Methods 4.1. Conventional Drinking Water Treatment 4.2. Conventional Wastewater Treatment 4.2.1. Biological Treatment Methods 4.2.2. Constructed Wetlands 4.3. Advanced Water Treatment 4.3.1. Removal Using Nanofiltration 4.3.2. Removal Using Reverse Osmosis 4.3.3. Advanced Oxidation Processes 4.3.4. Sorptive Removal 4.3.5. Pharmaceutical Removal Using Combined Processes Advantages and Disadvantages of Different Removal Methods Cost Evaluation Managing the Problem of Pharmaceuticals in the Environment Conclusions and Recommendations for Future Studies
BJ BJ BK BK BL BL BM BO BT CB CC CD CD CD CH EA EB EB EE EE
Received: May 17, 2018
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Canada,71 as were salicylic acid (1.83−95.62 μg/L) and clofibric acid (2.54−9.74 μg/L) in U.S.72 and clofibric acid (165 ng/L) in Germany.73,74 Other early examples include meprobamate, pentobarbital, phensuximide and sulfonamides in the U.S.,75 sulfonamides (up to 6470 μg/L) and barbiturates (205 μg/L) in groundwater in the vicinity of a landfill site in Denmark,76 lipid regulating agents (up to 5 μg/L) and NSAIDs in Germany,65,66 and both β-blockers and antibiotics (up to 6 μg/L) in Germany.77,78 Pharmaceuticals are still unregulated.49,82,83 Their residues in the environment are considered to be “compounds of emerging concern” because they have the potential to cause considerable impact on human health and ecosystems.2 The hazardous potential of pharmaceutical compounds on ecosystems was recently established.3,9,38,49,84 Advanced analytical techniques (such as GC-MS/MS, LC-MS/MS, UPLC/MS) have permitted the determination that some environmental effects of pharmaceuticals can be established in the μg/L and ng/L concentration ranges.2,83,85−93 These techniques enabled the determination and quantification of almost 3000 biologically active compounds in the environment.94,95 These pharmaceutically active compounds are pseudopersistent because of their continuous influx into environmental matrices despite their continuous degradation and removal by various processes.2 This causes the development of “a complex pharmaceutical pool” in many natural matrices.96−98 Once pharmaceutical residues enter water and soil, they also become incorporated into plants grown in these soils or waters. Example uptakes have been reported in cabbages, cucumbers, corn, carrots, lettuces, and green onions.99−104 Wastewater treatment plants (WWTPs) were never designed for and do not completely remove pharmaceuticals. Remediation efficiencies can be less than 10% in the case of such pharmaceuticals as carbamazepine, atenolol, acetylsalicylic acid, diclofenac, mefenamic acid, propranolol, atenolol, clofibric acid, and lincomycin.96,105−107 WWTPs are unable to fully degrade pharmaceuticals because they are generally designed to handle easily and moderately degradable organics in the mg/L range. However, pharmaceutical solubilities, absorbabilities, volatilities, biodegradabilities, polarities, and stabilities vary over a wide range, and they are present and can be active at very low (ng/L−μg/L) concentrations.8,108,109 Several reviews were published covering small or special sections of environmental pollution by pharmaceuticals.3,6,7,9,32,51,83,105,107,110−125 None cover the broad spectrum including occurrence, chemistry, health, and remediation aspects. Thus, a comprehensive review is justified which treats environmental concerns broadly, including location, chemical degradation, analysis, toxic effects, and removal. Data was reviewed from almost 1006 research publications to summarize pharmaceutical occurrence and associated risks. Wastewater treatment plant efficiencies and other advanced pharmaceutical removal techniques are examined with a special focus on adsorption. Efforts have been made to include data for preventive, therapeutic, and diagnostic active pharmaceutical substances. This study does not include the data for illicit drugs, natural hormones, and estrogens and their derivatives, specifically, but the overlapping nature leads to instances where these compounds are mentioned. Nutraceuticals, health supplements, and homeopathic and Ayurveda medicines are less studied and not included.
EF EF EF EF EF EG EG
1. INTRODUCTION Pharmaceuticals, a milestone in human scientific development, have lengthened life spans, cured millions from deadly diseases, and improved the quality of life. This very success has now led to their emergence as rapidly growing environmental contaminants.1−15 In the past three decades, pharmaceutical residues have been discovered in almost all environmental matrices on every continent. This includes surface water (lakes, rivers, streams, estuaries, and seawater),16−28 groundwater,29,30 wastewater treatment plant (WWTP) effluent and influents, and sludge.1,3,7,31,32 They now appear broadly in the geosphere33,34,6,35−39 and biosphere.39−44 Polar regions, the earth’s most pristine environment, are now reported to harbor pharmaceutical contaminants.45,46 Several endocrine disruptors along with antimicrobials and synthetic estrogens have been found in Northern Antarctica.47 Recently, a team of scientists at the German environmental agency, Umweltbundesamt, extensively compiled and reviewed the pharmaceutical occurrence data in 71 countries.48 Pharmaceutical contaminates and their concentrations span wide ranges. Variable degradation rates lead from almost complete degradation to limited degradation in both the natural environment and the wastewater treatment plants. Most pharmaceuticals are not highly persistent. However, their continuous addition to the environment in small but significant amounts from several sources renders many to be “pseudo-persistent”.2,49−52 Little is known about how pharmaceutical contaminants effect flora and fauna and even less about their potential longterm effects at environmental concentrations on humans.7,43,53 There is a dearth of specific guidelines and regulations worldwide on this topic.2,54 To the best of our knowledge, Australia is the only country that has formulated guidelines for pharmaceuticals in drinking water.55 Pharmaceuticals include an enormous group of compounds. More than 3000 frequently used pharmaceuticals are registered just in the European Union market.56 Their numbers are increasing everyday around the world. Thus, determining regulations, maintaining guidelines for all these compounds, and following their dispersion throughout the environment is a daunting task, and even more so considering the thousands of additional compounds that are registered but not in frequent use. Recently, a German research group reported more than 600 different pharmaceuticals are now known contaminants worldwide.48 A list of commonly used major 100 pharmaceuticals with their classes, therapeutic applications, and important physicochemical properties is given in Table 1. Early evidence of pharmaceuticals in aquatic systems was reported in the 1970−90s. For example, caffeine was found in both waste and surface waters in the U.S.;57−59 estrogens were detected in aquatic environments in ng/L concentrations in Germany.60−66 Theophylline and tetracycline were detected in ∼1 μg/L concentrations in U.K. river waters.67−69 The analgesic phenacetin was found in Spain.70 Two NSAIDs, ibuprofen and naproxen, were discovered in sewage in B
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Table 1. Commonly Used (top 100) Pharmaceuticals, Their Classes, Therapeutic Applications, Physicochemical Properties, and Structuresb
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a
CEC values have been adopted from ref 81. bData adopted from Pubchem79 and ref 80.
2. PHARMACEUTICALS IN THE ENVIRONMENT
characteristics, including their complex chemical structures, multiple ionization sites, and polymorphism.127 According to Rivera-Utrilla et al.,9 pharmaceutical contaminants differ from most other contaminants based on: (a) having molecular masses 1.5 is desirable during the environmental samples analysis, for the enantiomers to be efficiently baseline separated. The relative enantiomeric composition of a chiral drug in the analysis is expressed using enantiomeric fraction (EF) (eq 1).
biologically active. For example, naproxen, sulfamethoxazole, and erythromycin can persist for almost one year while clofibric acid can remain unchanged for multiple years. Finally, (g) these molecules tend to adsorb and be distributed in a living body, which metabolically modifies their chemical structure.5,9,124,126 Molecules with one or more stereogenic centers are chiral compounds. Nonsuperimposable mirror image molecule pairs are enantiomers while diastereomers are stereoisomers which are superimposable on their mirror images (Figure 1). Enantiomers have the same structures (except for the atomic arrangement around the stereogenic center) and identical physicochemical properties except for their interaction with chiral molecules and the direction they rotate plane polarized light.129 Enantiomers have different biological properties because biological molecules (enzymes) are dissymmetric (have chirality).130 Enantiomers are identified as (+) if they rotate the polarized light clockwise or (−) if they rotate the polarized light counterclockwise.131 An equimolar racemate of both enantiomers (±) does not rotate polarized light. The absolute configuration at a stereogenic center is specified as (R) or (S) (see Cahn, Ingold, and Prelog).132 This identifies unequivocally the three-dimensional arrangement of the groups attached to the stereogenic center.132 Carbohydrates, enzymes, and proteins are chiral, so pharmaceutical enantiomers can influence metabolism differently. Almost half of the drugs in the market today are single enantiomers.133 Some pharmaceuticals are prepared both as racemates and single enantiomers, so the enantiomer distribution released to the environment varies.113 Enantiomers interact enantioselectively in biological systems.131 Hence, their (R)/(S)enantiomeric ratios can change with time in the environment. Enantiomer-specific catalytic reactions, bindings, and interactions can produce different therapeutic effects, human health consequences, and environmental fates.134,135 Thus, based on their biological specificity, enantiomers are classified as (i) eutomers, having high affinity for the receptors, or (ii) diastomers, having less affinity.136 Chiral drugs can be classified into three main classes: (i) drugs having one major bioactive form, (ii) drugs having
EF =
[E1] [E1] + [E2]
(1)
Here, E1 and E2 are the molecule’s enantiomers. When the value of EF = 0.5, then the mixture is a racemate, and EF = 1 for a single enantiomer.138 2.2. Pharmaceutical Usage and Consumption Patterns and Their Relation with Environmental Occurrence
Although pharmaceutical consumption data in many countries is available, the present data is still inadequate to establish the country-specific data for pharmaceutical consumption.48 Pharmaceutical consumption and record keeping at the global level varies greatly from country to country, resulting in a paucity of total worldwide consumption data.139−142 In many countries, pharmaceuticals are also sold as unregulated “over the counter drugs”. Thus, these sales cause more uncertainty for consumption estimates and usage patterns.5,124 In the UK, approximately 3000 registered pharmaceuticals and more than 5000 over the counter drugs are sold.143 About 5000 drugs in M
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Figure 2. Consumption pattern of different pharmaceuticals around the world. Figure prepared using data from ref 147.
were detected in wastewater for antipsychotics, benzodiazepines, antihypertensives, and antidepressants, respectively. The usage of the illicit drugs methadone, ecstasy, and methamphetamine also underwent striking 7, 5, and 2-fold increases, respectively.152 The pharmaceutical consumption patterns also vary with seasonal change.153 The influent loads of antibiotics (such as macrolides) surges during the winter and can be directly correlated to increased consumption patterns. This increase is also supported by monthly sales data and the greater prevalence of respiratory infection rates during the winter.16 Pharmaceutical consumption patterns also differ on the basis of location/region/country.154 The median per capita pharmaceutical consumption in nonhospitalized sectors in upper income countries (1042 by volume) is much higher than upper middle (515 by volume), lower middle (215 by volume), and low-income countries (134 by volume).155 This large disparity in pharmaceuticals consumption patterns significantly affects their environmental occurrence patterns. A wide range of pharmaceuticals are used in agricultural practice156 and animal husbandry122 on a large scale. These are provided to the animals through both oral (through water or feed) and topical (by injection, implant, drench, paste) routes101,122 for the prevention and treatment of various infectious and noninfectious diseases. Antibiotics (β-lactams, sulfonamides, tetracycline), steroidal and nonsteroidal antiinflammatories, and nutrient supplements are widely used. Management of animal reproductive systems employs hormones and estrogens such as oxytocin, steroids, ergonovine, HCG, GnRH, progesterone, prostaglandins, and FSH. Recently, antibiotics and hormones use for growth promotion have decreased in Europe and North America. Enhanced milk and meat production involves using hormonal growth implants, subtherapeutic antibiotics, bovine somatotropin, and ionophores. Parasites have been controlled using insecticides and dewormers.157 Animal antibiotic consumption far exceeds human consumption.122 Environmental loading of pharmaceuticals from animal husbandry can be more problematic because often human waste is treated while animal waste is not.
Germany were registered in 2001, but 2700 of them resulted in >90% of the overall consumption, corresponding to approximately 38,000 tons of active pharmaceutical compounds.144 In 2001, the United States alone consumed approximately 22,700 tons of antibiotics.5 Worldwide consumption of antibiotics was 100,000− 200,000 tons per annum in 2002,145 and this quantity is considerably higher today. Beek et al.48 reported the production of paracetamol was 5790 tons in USA in 2002 and 3303 tons in France in 2005 while 2763 tons of chlortetracycline was consumed in South Korea for veterinary purposes only.48 According to the IMS,146 total consumption of the 50 most used pharmaceuticals in the UK alone is more than 6000 tons and the consumption of paracetamol alone is more than 3500 tons. The consumption pattern of important pharmaceuticals around the world is represented in Figure 2.147 According to one estimate, global medicine use will reach 4.5 trillion doses by 2020.148 Worldwide, antibiotics consumption alone in 2015 reached 34.8 billion defined daily doses (these are the average maintenance doses per day for a drug as used for its major applications in adults), with an unprecedented increase of 65% from the year 2000 (21.1 billion defined daily doses or DDD).149 More than 50% of the world’s population will be consuming >1 dose/person/day of medicines by 2020. This rapid consumption growth is driven by India, China, Brazil, and Indonesia pertaining to their high populations.148 Medicine usage in Africa and Middle-Eastern countries will also reach 500 billion doses by 2020.148 More than 3000 pharmaceuticals are present in the European market alone.56 Currently, ∼4000 active pharmaceutical ingredients are available in the global market with annual global consumption of ∼100,000 tons/y approximately.150,151 The consumption of pharmaceuticals can be influenced by socioeconomic conditions. The economic crisis in Greece (between 2010 and 2014) caused striking changes in pharmaceutical consumption patterns, particularly in the psychoactive drugs usage. Surges of 35, 19, 13, and 11-fold N
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Figure 3. Regional patterns of the detection of pharmaceutical substance groups in each United Nations region. WEOG = Western Europe and Others group, EEG = Eastern Europe group, GRULAC = Latin American and Caribbean states, and MEC = measured environmental concentration. Reproduced with permission from ref 48. Copyright 2016, Wiley-VCH Verlag GmbH & Co. KGaA.
estimates the population normalized PPCPs consumption using eq 4.
The European Medicines Evaluation Agency (EMEA) proposed a model (eq 2) for the prediction of pharmaceuticals in drinking water based on its usage, population of the area, and wastewater production.158 PECdw =
ij jj mg Consumption of PPCPjjj 1000inh jjj k day
A × (100 − R ) × (100 − M ) × (100 − W ) 365 × P × V × D × 100 × 100 × 100
yz MWpar zz Ci × F zz = × zz MWmet P × Ei zz {
(2)
(4)
Here, PECdw is the predicted drinking water concentration (mg/L), A is the amount of pharmaceutical used in the catchment area in a year (mg/yr), R is the sewage treatment plant rate of removal, M is the percentage of pharmaceutical metabolized in the human body, W is the rate of removal by drinking water treatment plants, P is the area’s population, and V is the wastewater volume produced per capita per day. Finally, D is the environmental dilution factor.143,158 Pharmaceutical use can be estimated by back calculations using concentrations present in the influent wastewater. A methodology developed in 2001 by Daughton is the first approach.159 This method is also used for the back estimation of licit and illicit drug consumption patterns. The back estimation can be calculated using eq 3.
In eq 4, Ci (mg/L) is the concentration of compound (i) in the sample, F (L) is the total day’s flow when sampled, P (1000 inhabitants) is the population size in the WWTP’s catchment area, and Ei (%) is excretion factor of the biomarker PPCPs selected for analysis. MWpar and MWmet are the parent compound and metabolite molecular weights, respectively.
U (g d−1) =
Cinfluent × Q × 10−6 P × T R abs × R excreted − R abs PS
2.3. Pharmaceuticals Occurrence in the Environment
Many pharmaceutically active compounds have been detected in water since the first discovery of such contaminants in aquatic systems in the 1980s. Bush162 grouped these therapeutic compounds as (i) anti-inf lammatories and analgesics (ibuprofen, paracetamol, diclofenac); (ii) antibiotics (sulfonamides, tetracyclines, penicillins, β-lactams, macrolides, fluoroquinolones, imidazoles); (iii) antiepileptics (carbamazepine); (iv) antidepressants (benzodiazepines); (v) lipid lowering agents (fibrates); (vi) antihistamines (famotidine, ranitidine); (vii) β-blockers (metoprolol, atenolol, propranolol); and (viii) other substances (barbiturates, narcotics, antiseptics, and contrast media).9,162 Antibiotics are the most frequently detected compounds followed by analgesics. However, results vary depending upon the country, region, area consumption pattern, and manufacturing industry locations (Figure 3).48,163 Most environmental pharmaceutical detections have located pollutant classes in specific environmental compartments including hospital effluents, effluents, and influents of sewage treatment plants, groundwater, surface water, and drinking water.13,14,48,164,165 Seasonal, spatial, and temporal variations have also been evaluated often.163,166−172 The frequency of pharmaceutical occurrence varies from sample to sample. From one to many pharmaceuticals have been reported in samples collected from the same location. Thus, contamination of a sample from a particular location can contain from “1” to “n” number of pharmaceuticals. Here n can be up to the known number of pharmaceuticals manufactured or used in that area. Available literature shows pharmaceutical concentrations
(3) −1
In eq 3, U is the back-estimated target drug use (g d ), Cinfluent is the measured influent concentration, Q (m3 d−1) is the measured daily flow rate of wastewater, and Rabs and Rexcreted are the percentages of the drug adsorbed (bioavailability) and excreted as its parent compound, respectively. PT and PS refer to the total population and population served by the WWTP being studied, respectively. Assumptions needed before performing these calculations include (i) no sewage loss in the sewer system, (ii) no significant transformation or adsorption of target compounds with particulate matter, (iii) negligible direct drug disposal into sewer systems, and (iv) no substantial population change during the study period.152 Additional models have been developed since 2014. Some were even used for back calculating the population served by WWTPs. A model developed by O’Brien et al.160 estimates the de facto area population using Bayesian inferences based on the daily pharmaceuticals and personal care products (PPCPs) mass loads against the population’s size.161 This model O
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Figure 4. Global Detection of pharmaceutical substances in drinking/tap waters, groundwater, and surface waters. Reproduced with permission from ref 48. Copyright 2016, Wiley-VCH Verlag GmbH & Co. KGaA.
Kingdom, Switzerland, Portugal, and the USA. Asian studies were mainly conducted in China, Japan, and South Korea. In the rest of the world, studies are limited or missing. Only 6 of 176 provinces of Asian countries contributed more than 50% of the existing data.163 Most countries (71%), including some large countries (such as Pakistan, Brazil, and Australia), have published only 3 or fewer studies detailing pharmaceuticals in the environment. The data that is available is incomplete. In the USA, 28 states have completed only 1 or no studies.163 Pharmaceutical pollution studies in China are mainly concentrated to a small area of the country located near densely populated areas containing the main industrial and coastal Chinese cities.183 This raises many questions regarding the actual overall gravity of this problem globally. Pharmaceuticals have been widely reported in groundwater, drinking water, and drinking water treatment plants,30,164,184−187 raising human health effect concerns. Concentrations in drinking water are far lower, reported in ng/L ranges, which are much less than their therapeutic doses. Thus, daily doses at these levels are considered to be inconsequential, but long-term effects of such doses are still unknown.188 The relative frequency of finding different pharmaceuticals varies with location. For example, painkillers are the most frequently found pharmaceutical class globally but in Asia antibiotics have this distinction. Based on concentration, antibiotics were highest in Asia, while painkillers were reported in highest concentrations in Europe.163 The frequency of finding pharmaceuticals along with regional contamination patterns by pharmaceutical types is given in Figure 3.163 A pharmaceutical’s ecological footprint is determined by six factors, including (i) human population size and distribution along with age distribution (demography), (ii) accessibility of health facilities (usage and consumption patterns and price regulations), (iii) the manufacturing sector’s presence and size, (iv) sewage treatment systems and their connectivity, (v) the environment in which effluents are received, and (vi) availability and effectiveness of regulation guidelines.189 The pharmaceutical contamination scenario in developing countries is far less explored. However, their presence has been reported in India, China, Pakistan, Ghana, and others. Segura et al.190 reviewed data from 62 peer-reviewed papers, concluding that fewer studies were conducted in low income
follow the general order: Industrial effluents > hospital effluents > wastewater treatment plant effluents > surface water > groundwater > drinking water. Pharmaceutical releases can be traced to every continent on the planet, owing to human activities. Even the pristine Arctic and Antarctica environments have been contaminated with pharmaceutically active compounds along with other trace organic contaminants.46,173 Pharmaceuticals have also been detected in the northern Scandinavian aquatic environment.45 Germany’s Ministry for the Environment commissioned a review of pharmaceuticals in the environment that reported 631 pharmaceuticals were present above analytical detection limits out of the 713 compounds tested. These pharmaceuticals were found in 71 countries (Figure 4).48 A total of 203 pharmaceuticals in 41 different countries were reported in a global critical evaluation.163 Nationwide studies have evaluated emerging organic compounds of concern, including pharmaceutically active compounds in the USA, Japan, and Germany. A nationwide Japanese study of 12 different antibiotics was conducted in 37 rivers, and their combined concentrations reached a high of 626 ng/L.174 A comprehensive study of 81 pharmaceuticals in different water types including waste (industrial and municipal), surface, underground, and drinking water from Serbia was carried out.175 Forty seven of 81 pharmaceuticals in the ng L−1 to >1 μg L−1 were present in analyzed water samples.175 The first nationwide USA study detected 95 pharmaceuticals in 139 streams across 30 states during 1999−2000.49 Also, a nationwide reconnaissance of organic wastewater contaminants in 18 states, detected 35 different pharmaceuticals in groundwater. Sulfamethoxazole, present in 23% of the sampling sites, had the highest occurrence frequency while ibuprofen exhibited the highest average concentration of ∼3 μg/L. 176 Tables 2, 3, and 4 include some of the pharmaceuticals and their concentrations found in the literature since 2013 worldwide in various types of waters. Another review by Beek et al. covered pharmaceutical distributions published prior to 2013.48 These previous reviews49,163,183 reveal many biases in pharmaceutical occurrence data. Monitoring has been confined to only certain areas, regions, and countries of the world. Most studies were conducted in the western European countries including Germany (the largest contributor), Spain, United P
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Table 2. Pharmaceutical Contamination Reported after 2013 in Treated Waters (drinking and tap water) and Groundwater (directly used for drinking) Worldwide (after 2013)a Country
Water type (Environmental matrix)
China (Shanghai)
Drinking water987
China (Beijing)
Drinking water988
China (Beijing)
Tap Water988
Serbia (Novi Sad, Zrenjanin, Bečej, Vrbas and Obrenovac)
Drinking water175
Serbia (Novi Sad, Zrenjanin, Bečej, Vrbas and Obrenovac)
Underground water175
Spain (Madrid)
Tap water for drinking purpose177
Taiwan (Taipei and Hsinchu)
Groundwater336
Q
Pharmaceutical
Conc range (ng/L)
Alprazolam Diazepam Temazepam Bezafibrate Antipyrine Aminopyrine Carbamazepine Ibuprofen Naproxen Diclofenac Bezafibrate Sulfamethoxazole Carbamazepine Clofibric acid Ketoprofen Salicylic acid Carbamazepine 10,11-Epoxycarbamazepine Sotalol Propranolol Metoprolol Hydrochlorothiazide (HCTZ) Irbesartan Salbutamol Iopromide Levamisole Phenazone Propyphenazone Carbamazepine Propranolol Carazolol Albendazole Naproxen Ibuprofen Salicylic acid Caffeine Diatrizoate Iohexol Iomeprol Iopromide Sulfadiazine Sulfamethoxazole Sulfathiazole Sulfamethazine Sulfamonomethoxine Sulfadimethoxine Erythromycin-H2O Clarithromycin Nalidixic acid Flumequine Pipemidic acid Norfloxacin Ofloxacin Dimetridazole Metronidazole Atenolol Acebutolol Metoprolol Acetaminophen Ibuprofen
2.4 1.9 0.2 0.31−0.85 0.15−0.22 0.17−0.64 0.37−1.15
