Drugs of abuse in drinking water – a review of current detection methods, occurrence, elimination and health risks

Accepted Manuscript Title: Drugs of abuse in drinking water - a review of current detection methods, occurrence, elimination and health risks Author: Yan Peng, Sarah Hall, Lata Gautam PII: DOI: Reference:

S0165-9936(16)30147-9 http://dx.doi.org/doi: 10.1016/j.trac.2016.09.011 TRAC 14830

To appear in:

Trends in Analytical Chemistry

Please cite this article as: Yan Peng, Sarah Hall, Lata Gautam, Drugs of abuse in drinking water a review of current detection methods, occurrence, elimination and health risks, Trends in Analytical Chemistry (2016), http://dx.doi.org/doi: 10.1016/j.trac.2016.09.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

Drugs of abuse in drinking water - a review of current

2

detection methods, occurrence, elimination and health risks

3 4

Yan Peng, Sarah Hall * and Lata Gautam

5

Forensic and Investigative Sciences Research Group, Department of Biomedical and Forensic

6

Sciences, Faculty of Science and Technology, Anglia Ruskin University, Cambridge CB1 1PT, United

7

Kingdom

8

*Corresponding author. Tel.: 01223 363271 ext. 2170 E-mail address: [email protected]

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Highlights:

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

Drugs of abuse are reported at trace levels (ng/L) in raw and drinking waters globally

12



Current drinking water treatments cannot completely remove some drugs of abuse

13



Human health risks regarding the long term exposure of these contaminants in drinking

14

water cannot be ruled out

15



Studies regarding the analysis of new emerging drugs in drinking water are needed

16



A review of analytical methodologies for the determination of drugs of abuse in drinking

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water shows that SPE and LC-MS/MS is generally used

18 19

Abstract

20 21

This review focuses on the of drugs of abuse in drinking water, as their presence is of increasing

22

global concern, as trace levels of these compounds have previously been detected. Even though

23

these levels are not toxic, with long term exposure via drinking water, they have the potential to

24

bio accumulate and be in toxic to humans. In addition, transformation of these compounds

25

during water treatment processes and their effect need further investigation as there are recent

26

reports highlighting the increased toxicity to freshwater species. Currently there is limited

27

information available on the detection of emerging drugs, therefore high resolution mass

28

analyser could be a suitable alternative for non-target screening. Depending on the water

29

treatment method used, the level of drugs of abuse detected can vary. Therefore, water 1

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regulatory bodies need to enforce more effective treatment methods for safe and sustainable

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drinking water.

32 33

Keywords: drugs of abuse, novel psychoactive substances, drinking water, solid phase extraction,

34

chromatography-mass spectrometry, trace analysis, potential risk to human health.

35 36 37 38 39 40

1. Introduction

41

Since endocrine disrupting compounds, such as pesticides, have been detected in the aquatic

42

environment, the presence of water pollutants has led to growing public attention and scientific

43

interest, particularly with their adverse effects on human health [1, 2]. In the last few years,

44

research has turned to the study of new emerging water contaminants, such as drugs of abuse [3]

45

which may have an associated negative impact on the environment and health.

46 47

Drugs of abuse have been reported to be present in not only drinking water but other aquatic

48

systems including waste, surface and ground water [3, 4]. The major entry route of these

49

contaminants into waste water is via human waste as both parent compound and their

50

metabolites [5]. The waste water is processed at a treatment plant but some drugs of abuse still

51

remain as contaminants in the effluent, as they are not completely removed [3]. Subsequently

52

the treated effluents are then released into surface waters, such as rivers and lakes [5]. Once

53

present in the surface water, these compounds can further contaminate ground water via natural

54

seepage and leaking sewer systems [4].

55 56

Recent studies have reported the presence of drugs of abuse in drinking water at trace levels

57

(ng/L) and this raises concerns regarding their route of entry [5,6]. When using raw water

58

(abstracted from surface or ground water) for drinking water, they still contain such compounds

59

after treatment [5, 6]. This is owing to drinking water treatment plants (DWTPs) only removing 2

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contaminants included in and to the levels set out in the regulatory requirements [7, 8].

61 62

To date, most reviews focus on waste water [5, 9, 10, 11, 12], surface water [5, 9, 13] and ground

63

water [4, 5, 14] regarding the presence of drugs of abuse. However, with drinking water, there are

64

only a few reviews. [5]. The paper by Pal, et al [5] reviews the available literature regarding the

65

presence of drugs of abuse in drinking water including information on the presence of newer

66

emerging drugs.

67 68 69 70

This review gives a comparative overview of the sample preparation and analytical

71

methodologies (Tables S1 and S2) used for determining drugs of abuse in drinking water. Solid

72

phase extraction (SPE) is the most commonly used sample preparation method to concentrate

73

the sample and to remove undesired interferences [15]. It is crucial to utilise an analytical

74

method which could offer both selectivity and sensitivity, when considering the determination of

75

trace levels of such contaminants. Liquid chromatography-tandem mass spectrometry

76

(LC-MS/MS),

77

electrophoresis-ultraviolet detector (CE-UV) have been previously used [16]. All of these

78

techniques are able to determine trace levels (ng/L), which can be used to assess the occurrence

79

and removal efficiencies of drugs of abuse during water treatment methods.

gas

chromatography-mass

spectrometry

(GC-MS)

and

capillary

80 81

2. Analytical methodology

82

Analytical methodologies for the detection and quantification of drugs of abuse in drinking water

83

normally include a sample preparation step followed by analysis using chromatography and mass

84

spectrometry based techniques for further separation and detection. These methods are

85

summarised in Table S1.

86 87

2.1 Sample collection

88

As shown in Table S1, drinking water is usually collected as grab samples. This sampling method

89

where the sample represents the water conditions at the time of collection (grab sampling) is 3

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better for detecting the changes of analyte concentrations during a short-term period, but not

91

suitable for obtaining the time-weighted average (TWA) [72]. By contrast, passive sampling can

92

accumulate the compounds of interest dissolved in the water into a receiving phase through

93

diffusion or permeation and thus provide TWA concentrations over a long-term period. This is

94

useful for assessing the overall impact of water contaminants on human health with long term

95

exposure [73]. The receiving phase of passive sampler is similar to SPE sorbent and its chemistry

96

is selected based on the target compounds as discussed later in Section 2.2. However, only a few

97

publications [17, 65] reported the use of passive samplers for the collection of drinking water.

98

This could be due to the relatively higher cost of equipment and extensive calibration studies that

99

are required to evaluate the sampling rates of analytes [11, 74, 75].

100

After sample collection, drinking water is mainly stored in glass bottles at low temperature (-20°C

101

to 8°C), except some authors reported the use of plastic bottles [19, 20, 21, 66, 68]. Baker and

102

Kasprzyk-Hordern [22] suggested all glassware used to store the sample should be silanised in

103

order to avoid the adsorption of drugs of abuse, which can result in the loss of compounds and

104

affect the recoveries, especially in trace analysis [23]. Aqueous solutions can deprotonate silanol

105

groups leaving a negative charge on the glassware surface resulting in cation exchange sites for

106

the interaction with basic compounds [76]. A study carried out on the analysis of drugs of abuse

107

from surface and waste water reported a higher recovery using silanised glassware [22]. This was

108

prominent for basic compounds such as amphetamines, ketamine and norketamine as they are

109

attracted to the negative charged surface [22]. For example, ketamine recovery was around 20%

110

when vials were unsilanised, compared to 84% when silanised vials were used. Thus, the use of

111

silanised glassware or the deactivation of glassware by rinsing with 5% dimethylchlorosilane in

112

toluene, followed by toluene and then methanol is recommended [30].

113 114

In order to accurately detect the concentrations of drugs of abuse in drinking water at the time of

115

collection, some authors add ascorbic acid and sodium thiosulfate to remove residual chlorine

116

[77] in order to prevent further degradation by chlorination [2, 6, 19, 24, 25, 26, 27, 66, 71].

117

Sodium azide has also been added to stop bacterial degradation [2, 24]. Then the sample is often

118

filtered through a glass fibre or membrane filter prior to SPE. At this point samples are either

119

extracted immediately or stored for 12hrs to 7 days, during which period analytes of interest may 4

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start degrading. Therefore, there is a need for further studies in relation to the stability of

121

analytes in the matrix itself.

122 123

2.2 Sample preparation

124

Solid phase extraction is used for the extraction of drugs of abuse from drinking water as shown

125

in Table S1. The majority of studies used reversed phase sorbents, including Oasis HLB, PLRP-s,

126

Strata-X polymeric reversed phase, Poly-Sery HLB and HySphere Resin GP, as they are developed

127

for the extraction of neutral, acidic and basic compounds from polar matrices. This is very

128

important for the simultaneous analysis of drugs of abuse from different classes including

129

amphetamines, benzodiazepines, cannabinoids, cocainics, dissociative anaesthetics, opioid

130

analgesics and synthetic cathinones. Authors reported moderate to high recoveries (50-132%),

131

indicating reversed phase sorbents can extract most of the target analytes from drinking water.

132

However, recoveries are variable between different classes of compounds (75-99% for

133

amphetamines, 50-114% for benzodiazepines, 85-116% for cocainics, 83-93% for dissociative

134

anaesthetics, 77-124% for hallucinogenic substances, 60-132% for opioid analgesics and 62-111%

135

cannabinoids). High recoveries were obtained (82-104%) using Oasis MCX, a mixed-mode

136

cation-exchange sorbent, for the extraction of basic compounds such as amphetamines,

137

benzodiazepines, cocainics, dissociative anaesthetics and opioid analgesics from drinking water

138

[31, 61, 65].

139 140

SPE centres more on the removal of undesired interferences from waste and surface waters in

141

order to reduce matrix effects, as matrix components are responsible for adverse effect on

142

analyte during injection in GC-MS or ion suppression/enrichment during ionisation process in

143

LC-MS. This can consequently impact on accuracy, precision and reproducibility [78, 79]. For

144

drinking water analysis, it is less of an issue because the matrix is cleaner than waste and surface

145

water, but removing matrix components is still of importance. In addition, internal standards

146

should be added into water samples before extraction to compensate for matrix effect [60].

147

Some authors recommend using a matrix matched standard addition method for quantification

148

[83, 84] and Cimetiere, et al. [84] reported improvements in the determination of

149

pharmaceuticals in drinking water using this method. 5

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The use of SPE can also concentrate the water samples in order to increase method sensitivity.

152

Boleda, et al. [19] and Sun, et al. [28] both used Oasis HLB sorbent to extract codeine from

153

drinking water. They reported similar recoveries (96 and 99.7%) but their quantification limit

154

(LOQ) was lowered to 0.03 ng/L [28] due to 2000-fold enrichment factor as opposed to 0.5 ng/L

155

with enrichment factor of 400. Thus, acquiring a high enrichment factor is more important as

156

drugs of abuse are present in drinking water at trace levels (sub ng/L) and this is possible by the

157

use of SPE as shown in Table 1.

158 159 160 161

2.3 Analytical techniques

162

LC-MS/MS has been widely reported for detecting and quantifying drugs of abuse in drinking

163

water (Table S2), with some exceptions [31]. In this case the authors used GC-MS to detect

164

diazepam and its metabolite nordiazepam from drinking water. The advantages of GC-MS are (i)

165

this technique is less expensive than LC-MS/MS and thus more widely available in laboratories

166

and (ii) the mass spectra can be compared between different instruments and to reference

167

databases for identification [37]. However, the drawback of GC-MS is the need of chemical

168

derivatisation [37] as most drugs of abuse are polar compounds [39] and are less volatile [40, 41].

169

The analysis of drugs of abuse by LC-MS/MS does not need derivatisation and hence why

170

LC-MS/MS is the preferred method.

171 172

Botello, et al. [69] reported an alternative analytical method for the analysis of four drugs of

173

abuse in drinking water using in-line SPE in combination with CE-UV. This method was reported

174

to be environmentally friendly due to the low volume of organic solvent used for analysis.

175

However, it is not suitable for compounds without chromophores and this method suffers from

176

low

177

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

178

6-acetylmorphine ranged between 70 and 260 ng/L, which are significantly higher than those

179

reported using LC-MS/MS (0.02-17 ng/L) (Table S2).

sensitivity.

The

lower

limit

of (EDDP),

detection cocaine,

(LOD)

of

codeine

and

6

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LC-MS/MS methods as reported in Table S2 used reversed-phase chromatography. Electrospray

182

ionisation is often used as it is more efficient for polar and ionisable compounds than

183

atmospheric pressure chemical ionisation and more sensitive for alkaloids when using selected

184

reaction monitoring (SRM) [80, 81]. Flow rates below 1mL/min and pH values ranging from

185

3.2-4.7 are applied to improve the ionisation of drugs of abuse [32]. The choice of ionisation

186

mode (i.e. positive and negative) is decided by the chemical properties of target analytes. The

187

analysis of drugs of abuse is commonly carried out in positive mode. As an exception,

188

cannabinoids have been analysed in both positive and negative mode. The LOQs were reported in

189

the range of 0.1 and 6.81 ng/L in negative mode [20, 21] as compared to the significantly higher

190

values in positive mode (7-50 ng/L) [19, 25].

191 192

Tandem mass spectrometry is dominantly used as this kind of analyser combines two or more

193

mass-to-charge ratio separation devices of the same or different types. This results in faster

194

acquisition time and higher resolving power when compared to a single mass analyser [34]. Triple

195

quadrupole (QqQ) and hybrid triple quadrupole-linear ion trap (QqQ-LIT) have also been used for

196

the analysis of drugs of abuse in drinking water. Although selected ion monitoring (SIM) was

197

reported in one study [35], SRM is most commonly utilised as acquisition mode, as it can

198

fragment the precursor ion of target compound and then monitor the unique product ions and

199

therefore is reported to increase selectivity [36]. Two SRM transitions (precursor ion/product ion)

200

are normally monitored for each analyte in order for reliable quantification and confirmation.

201

The precursor ions are their protonated molecular ions in positive ionisation and deprotonated

202

molecular ions in negative ionisation (Table S2). Two most abundant product ions are then

203

selected for each analyte. However, the selected ions are variable between different methods as

204

shown in Table S2, as collision energy and gas pressures used may not be the same from

205

instrument to instrument [82]. This causes difficulty in building a LC-MS library/database.

206 207

Recently, the hybrid linear ion trap/orbitrap mass spectrometer (LIT-Orbitrap), a high resolution

208

mass analyser type, has been utilised to analyse drugs of abuse in drinking water. Rodayan, et al.

209

[65] reported similar or higher LOD and LOQs when using QqQ and QqQ-LIT (Table S2) for the 7

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determination of amphetamines, cocainics, opioids and one dissociative anaesthetic in drinking

211

water. Owing to this, LIT-Orbitrap might not be the best choice for quantification but would

212

certainly add value to elucidate the molecular formulae and structures of the suspected or

213

unknown molecules, which is more suitable for suspect screening and non-target screening. This

214

is because the hybrid system is able to measure the masses of molecules accurately to several

215

decimal places and allows the differentiation between two compounds which would be identical

216

if a low resolution instrument, such as QqQ was used. LIT-Orbitrap has been used by Kiwa Water

217

Research Institute [64] for the screening of surface, ground and drinking waters in search of

218

accurate masses corresponding to target pharmaceuticals, benzotriazoles and drugs of abuse as

219

well as unknown compounds. This method can sensitively and reliably propose tentative

220

elemental composition of an unknown compound which is of importance when screening for

221

emerging drugs of abuse such as NPSs.

222

3. Occurrence of drugs of abuse in drinking water

223

Drinking water refers to water that has undergone drinking water treatment and is ready for

224

human consumption. Samples are normally taken from the outlets of DWTPs via passive or grab

225

sampling or directly from the taps in public places or private residences. Recent literature

226

indicates that drugs of abuse (amphetamines, benzodiazepines, cannabinoids, cocainics,

227

dissociative anaesthetics and opioid analgesics) have been determined in drinking water at

228

concentrations in the ng/L range in Europe, America and Asia. Results from these studies are

229

summarised in Table 1, including the frequency of determination, which is calculated by dividing

230

the number of quantified samples (>LOQ) by the number of total samples.

231 232 233

The frequency of determination of drugs of abuse in drinking water is limited, only 20 drugs of

234

abuse and eight metabolites (Table 1) have been detected at concentration ranges of 0.1-562

235

ng/L in Europe, America and Asia. Boleda, et al. [19] analysed drinking water from around the

236

world, more than half the samples were from Spain and the others from seven European

237

countries (Austria, France, Germany, Iceland, Slovakia, Switzerland and the UK), seven Latin

238

American countries (Argentina, Brazil, Chile, Colombia, Panama, Peru and Uruguay) and Japan.

239

This is the only study, where drinking water samples from different countries have been analysed. 8

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240 241

Five amphetamines [amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA),

242

methylenedioxyethylamphetamine (MDEA) and 3.4-methylenedioxymethamphetamine (MDMA)]

243

were quantified in a few samples from Spain and Latin American countries at trace levels

244

(0.2-3.13 ng/L) (Table 1). These low concentrations could be due to the high removal efficiency as

245

a result of using ultraviolet (UV) disinfection, reverse osmosis and ozonation (O3) at DWTPs

246

(96-100%) [6, 42]. Only a higher concentration of MDA (6.7 ng/L) was reported in the drinking

247

water of Canada, which could be associated to less efficient water treatment methods

248

(clarification and post-chlorination) [65]. Compared to amphetamines, benzodiazepines were

249

present in drinking water at higher concentrations (0.1-562 ng/L) in China, Italy, Spain, the UK

250

and the USA. Alprazolam, diazepam and temazepam were frequently determined in most

251

samples as shown in Table 1. These results are probably due to their extensive, daily medical use

252

as anti-anxiety pharmaceuticals [38, 48]. Lorazepam was reported at 562 ng/L in Spain [47],

253

which is much higher concentration than other benzodiazepines (0.1-23.5 ng/L). The mean

254

concentration in drinking water (562 ng/L) was higher as compared to surface water (167 ng/L)

255

collected from the same cities [47]. This could be associated with the conversion of the

256

glucuronide metabolite of lorazepam to the parent compound during water treatment [47, 85].

257 258

The presence of cannabinoids, Δ9-tetrahydrocannabinol (THC) and two metabolites

259

11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol

260

(THC-COOH), in drinking water was only reported in Spain (0.49 to 5.53 ng/L). The low

261

concentration of cannabinoids do not correlate with their high consumption rate [86].

262

Cannabinoids being less soluble in water could have resulted in the partition to solids depending

263

on their physiochemical properties (log Kow >5) [48]. This is evidenced by the detection of THC

264

metabolites (THC-COOH and OH-THC) in suspended solids in raw wastewater and activated

265

sludge [87]. On the contrary, cocaine and its two metabolites (benzoylecgonine and cocaethylene)

266

were present in drinking water from different countries, including Canada, European and Latin

267

American countries. The concentration of benzoylecgonine (0.11-9.9 ng/L) was higher than

268

cocaine (0.1-4.3 ng/L) and this can be explained by its metabolism. Cocaine is mainly excreted as

269

benzoylecgonine (20-60%) and only 1-15% is eliminated in the urine unchanged [16]. 9

Page 9 of 26

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Cocaethylene, which is a cocaine metabolite excreting as 0.7% in the presence of ethanol [16],

271

was quantified from Spain and Latin American countries with the concentration of 0.9 ng/L. This

272

has also been positively identified in other European countries (<0.1 ng/L), indicating a high level

273

of alcohol consumption [48]. Significantly higher concentrations of cocaine and benzoylecgonine

274

(85.67 and 52.73 ng/L, respectively) were reported from the Aranjuez of Spain [66] with the

275

concentration ratio of 1.62, which is considered as an abnormal ratio (>0.75), suggesting the

276

measured value may not result from human consumption only [88]. Therefore, this could be due

277

to the disposal of cocaine at/near the sampling site as trace amounts of cocaine (0.12-1.21 ng/L)

278

and benzoylecgonine (1.13-1.55 ng/L) were determined in a water sample treated by the same

279

DWTP (Tajo, Spain) but was collected from a different sampling site (Titulcia, Spain) [66]. In

280

addition to this, the highest concentration of benzoylecgonine (130 ng/L) was determined in

281

drinking water in the northeastern region of Spain [6] despite high removal efficiency of the

282

DWTP (89%). This could be explained by highly contaminated raw water (770 ng/L) that was used

283

for drinking water production.

284 285

Among eight opioids and two metabolites, the highest concentration in drinking water was

286

reported for codeine at the concentrations of 30 and 44 ng/L in the USA and Canada. This is not

287

surprising as codeine is a prescription medication that is also contained in nonsteroidal

288

anti-inflammatory drugs such as aspirin and ibuprofen [89]. The presence of methadone in

289

drinking water from European and Latin American countries ranged between 0.1-2.7 ng/L while

290

its metabolite EDDP was also reported from Japan. Rodayan, et al. [65] reported heroin (<4.6

291

ng/L) and acetylcodeine (5.7 ng/L) in the drinking water from Ontario, Canada. The presence of

292

acetylcodeine indicates the illicit use of heroin in the province of Ontario. This is because

293

acetylcodeine is an impurity of manufacturing process [90]. Oxycodone was also found in

294

drinking water (5.1 ng/L), even after its ban in Ontario in 2012. This could be owing to the easy

295

access of oxycodone via online stores. Subsequent to this ban, the increase use of fentanyl and

296

ketamine was evident from drinking water analysis (11.7 and 15 ng/L, respectively).

297 298

4. Removal efficiencies of drugs of abuse from drinking water treatment plants

299

Even though after treatment, low concentrations of drugs of abuse are still being detected in 10

Page 10 of 26

300

drinking water (Table 1). Therefore, there are concerns that current drinking water treatment

301

methods do not completely remove such contaminants. The removal efficiencies of drugs of

302

abuse in DWTPs have been reported in some studies [2, 6, 25, 26, 42, 65] and are summarised in

303

Table 2.

304 305 306 307 308 309 310 311 312 313

Generally, raw water undergoes several processes to produce drinking water. Chlorine gas,

314

chloramines, ultraviolet light are applied to water for the disinfection of microorganisms [49].

315

Clarification, normally including coagulation, flocculation, sedimentation and sand filtration, are

316

used to remove suspended sediments and dissolved organic carbon [44, 50]. Some advanced

317

drinking water treatment processes, such as O3, ultrafiltration, reverse osmosis and granular

318

activated carbon (GAC), also remove organic and inorganic contaminants from water [49]. The

319

removal efficiency of drugs of abuse depends on the applied water treatment methods. As shown

320

in Table 2, advanced water treatments proved to be an efficient way to remove drugs of abuse

321

from drinking water. For example, O3 and GAC treatments resulted in much better removal

322

efficiencies for MDA, diazepam, cocaine, benzoylecgonine, ketamine, codeine, fentanyl and

323

morphine (89-100%) [6, 25, 26, 42], compared to the range of -18% and 49% when using

324

disinfection and clarification processes [2, 65]. Ultrafiltration and reverse osmosis were able to

325

remove MDMA, cocaine, benzoylecgonine, norbenzoylecgonine, ketamine, codeine, norcodeine,

326

methadone and EDDP with the efficiencies between 97% and 99% [42]. In contrast, using

327

disinfection and clarification, low removal efficiencies (-39% to 49%) have been reported for MDA,

328

cocaine, benzoylecgonine, ketamine, codeine, dihydrocodeine, fentanyl, morphine, oxycodone

329

and tramadol [2, 65]. This indicates that the treatment method may influence the level of drugs 11

Page 11 of 26

330

of abuse present in drinking water.

331 332

In general, some drugs of abuse can still remain even after advanced water treatments, resulting

333

in their presence in drinking water at trace levels as shown in Table 2. For instance, Boleda,

334

Galceran and Ventura [25] have evaluated the removal efficiencies of methadone and EDDP from

335

a Spanish DWTP which used pre-chlorination, clarification, O3, GAC and post-chlorination. Both of

336

these compounds were partiality removed (91% for methadone and 88% for EDDP) and therefore

337

were detected in drinking water at trace levels. This is a cause of concern knowing the amount of

338

water consumed by an individual on daily basis and the bioaccumulation of lipophilic

339

compounds.

340 341

5. Human health impacts

342

Although drugs of abuse have been detected in drinking water at ng/L range, these trace levels

343

are not sufficient to induce acute toxic effects to humans as their concentrations are many orders

344

of magnitude lower than those known to cause toxicological and pharmaceutical effects. The

345

lethal and therapeutic doses are included in Table 2. As an example, cocaine has been measured

346

at the maximum concentration of 85.67 x 10-9 g/L (i.e. 85.67 ng/L) in drinking water [66].

347

Assuming that an individual drinks two litres of water per day, they would ingest an amount of

348

cocaine equivalent to 171.34 x 10-9 g and over a year 62.54 x 10-6 g, whereas the minimal lethal

349

dose of cocaine is 1.2 g [51]. Our major concern is the long-term exposure of drugs of abuse via

350

drinking water as some of these compounds are lipophilic and therefore can bio accumulate (e.g.

351

cocaine and diazepam) [52, 53, 54]. Thus, their presence in drinking water can still be a potential

352

threat to human health due to long-term exposure. Another consideration would be the possible

353

reaction with other compounds which might cause synergistic or antagonistic effects. For

354

instance, the combination of cocaine and heroin has been reported to amplify the effect of both

355

drugs, therefore these compounds on their own (at a specific dose) may not be lethal but in

356

combination could be toxic/lethal [55]. Therefore, it is impossible to rule out the potential toxicity

357

or adverse effect of these compounds on human health via exposure to drinking water.

358 359

It has been already demonstrated that some drugs of abuse and their metabolites can also 12

Page 12 of 26

360

undergo different transformation during treatment processes resulting in products that may have

361

higher toxicity compared to the parent compounds [71, 91, 92, 93]. Such transformation products

362

have been reported from the oxidation of EDDP via chlorination [93]. Although the human health

363

impact of such transformation products and drugs of abuse in drinking water has not been

364

reported, ecotoxicological impact of EDDP and its transformation products have already been

365

reported in freshwater organisms [93]. This highlights the need for further research in assessing

366

the human health impact due to the drugs of abuse in drinking water.

367 368

6. Summary and conclusion

369

This review includes an overview of sample preparation and analytical techniques used for the

370

analysis of drugs of abuse in drinking water. SPE seems to be the most commonly used extraction

371

method followed by LC-MS/MS analysis for the simultaneous detection of drugs of abuse.

372

However, other mass spectrometers such as single quadrupole are much less used, but could be a

373

good alternative as they are less expensive and their instrumental sensitivities are in general

374

comparable to tandem mass spectrometers [34, 57].

375 376

This review also summarises the occurrence and concentrations of drugs of abuse in drinking

377

water from Europe, America and Asia, showing a global problem. These water contaminants are

378

often found in drinking water at concentrations in ng/L range. This review reveals that studies

379

regarding the analysis of such compounds in drinking water are scarce. Most of these studies

380

have been focussed in Spain, whereas relatively few studies are from other European, American

381

and Asian countries. Currently there is no information available from Africa and Oceania.

382

Therefore, there is a need to carry out more comprehensive and complementary studies to

383

enable better comparison of data, prevalence and removal efficiencies of drugs of abuse from the

384

DWTPs worldwide.

385

This review reveals that most research focuses on the detection of traditional drugs of abuse in

386

drinking water, with a gap in knowledge on the detection of novel psychoactive substances (NPSs).

387

NPSs such as cathinones, piperazines and synthetic cannabinoids are designed to mimic the

388

pharmacological effects of known specific controlled drugs, such as amphetamines and cannabis,

389

thus they have gained popularity among drug users and their consumption has grown [58]. 13

Page 13 of 26

390

Consequently, NPSs have been detected in waste water and surface water. For example, butylone,

391

mephedrone, methcathinone, benzylpiperazine (BZP), 4-methoxyphenylpiperazine (4-MeOPP),

392

3-trifluoromethylphenylpiperazine (3-TFMPP) and ketamine have been detected in the waste and

393

river water from the UK. [59, 30]. However only ketamine has been detected in drinking water so

394

far [65]. Therefore, other NPSs needs to be investigated further, owing to their highly dynamic

395

market, with newly identified NPSs reported globally (in 2013, 202 new NPSs were described and

396

in 2014 a further 69 was recorded) [86]. This is not surprising as manufacturers continually carry

397

out minor changes to their structures to evade legislation. High resolution mass spectrometry (as

398

mentioned in Section 2.3) can be used to screen the drinking water samples, which could aid in

399

the identification of new NPSs.

400 401

Although not included in current drinking water regulatory framework, it is important that

402

drinking water companies and water regulatory bodies should be aware of the presence of drugs

403

of abuse in drinking water. Further research on these contaminants needs to be carried out in

404

order to gain valuable information on their occurrence and fate, as there is currently limited

405

understanding of the human health impact with regards to their exposure via drinking water. In

406

addition, incomplete removal of these compounds highlights the importance of future

407

investment in more effective treatment processes and monitoring of drinking water with respect

408

to these newer contaminants.

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714

Table 1 Concentrations of drugs of abuse and their metabolites in drinking water

Compound

Country

Study Period

Sample Number

Concentration (ng/L)

Determination Frequency (%)

Refs

Spain Canada Latin America d Spain Latin America d Spain Latin America d Spain Spain Latin America d Spain Spain

2008-2009 2012 2008-2009 2008-2009 2008-2009 2008-2009 2008-2009 2010 2013 2008-2009 2008-2009 2013

50 3k 9 50 9 50 9 3 28 9 50 28

<1 j; 1.7 h 6.7±1.1 g <0.8 j; 1.3 h <0.8 j; 0.9 h <0.2 j; 0.4 h <0.2 j; 0.6 h <0.2 j; 0.4 h 1.51 1.47 <0.5 j; 0.6 h <0.5 j; 1.4 h 3.13

2.0 n.r. 44.4 2.0 22.2 4.0 44.4 33.3 3.6 11.1 4.0 3.6

[19] [65] [19] [19] [19] [19] [19] [20] [66] [19] [19] [66]

Lorazepam Temazepam

China Spain China China Italy UK USA Spain China

2014 2008-2009 2014 2014 n.r. n.r. 2006-2007 2008-2009 2014

5 75 5 5 4 n.r. 19 75 5

2.30-2.60 i; 2.42±0.13 g 11 0.4 0.60-3.20 i; 1.94±1.17 g 0.2-23.5 i; 14.43±12.48 g 10 h <0.25-0.33 i; 0.33 h 562 g <0.1-0.6 i; 0.24±0.23 g

100.0 1.3 20.0 100.0 75.0 n.r. 5.3 2.7 80.0

[38] [47] [38] [38] [46] [70] [2] [47] [38]

Cannabinoids THC OH-THC a THC-COOH a

Spain Spain Spain

2010 2010 2012

3 3 8

5.53 0.49 1g

33.3 33.3 12.5

[20] [20] [21]

Canada Europe e Japan Latin America d Spain Spain Spain Canada Canada Europe e

2012 2008-2009 2008-2009 2008-2009 2008-2009 2012 2013 2012 2012 2008-2009

3k 15 3 9 50 6 28 3k 2l 15

4.30±0.73 g 0.1 g <0.1 j 0.6 g 0.4 g; 2.3 h 1.61 0.11-85.67 i 10.0±2.8 g 9.85 g; 9.0-10.7 i 0.2 g

n.r. n.r. n.r. n.r. 66.0 16.7 25.0 n.r. 100.0 n.r.

[65] [19] [19] [19] [19] [48] [66] [65] [65] [19]

Amphetamines Amphetamine MDA

MDEA MDMA

Methamphetamine

Benzodiazepines Alprazolam Bromazepam Diazepam

Cocainics Cocaine

Benzoylecgonine b

23

Page 23 of 26

Cocaethylene b

Latin America d Spain Spain Spain Spain UK Europe e Latin America d Spain

Dissociative Anaesthetics Ketamine Canada Canada Opioid Analgesics Acetylcodeine Codeine

Dihydrocodeine Fentanyl

Methadone

EDDP c

Canada Canada Canada USA Canada Canada Canada Spain Europe e Latin America d Spain Spain Spain Spain Europe e Japan Latin America d Spain Spain Spain Canada Canada Canada Canada

2008-2009 2007 2008-2009 2009 2013 2010 2008-2009 2008-2009 2008-2009

9 24 50 n.r. 28 94 15 9 50

4.5 g 3-130 i 0.4 g; 3.1 h 1.5 h 0.11-52.73 i 1.12-3.51 i; 2.53±0.85 g <0.1 j <0.1 j; 0.4 h 0.2 g; 0.9 h

n.r. 91.7 34.0 n.r. 50.0 9.6 n.r. n.r. 28.0

[19] [6] [19] [42] [66] [17] [19] [19] [19]

2012 2012

3k 2l

15.0±3.1 g 15 g; 14-16 i

n.r. 100.0

[65] [65]

2012 2012 2012 2003 2012 2012 2012 2008-2009 2008-2009 2008-2009 2007-2008 2008-2009 2010 2013 2008-2009 2008-2009 2008-2009 2007-2008 2008-2009 2013 2012 2012 2012 2012

2l 3k 2l 12 3k 3k 2l 50 15 9 18 50 3 28 15 3 9 18 50 28 3k 2l 3k 3k

5.7 g; 5.3-6.1 i 44.0±3.5 g <2.3 j 30 h 5.7±1.5 g 12.0±1.7 g 11.5 g; 11-12 i <1 j; 1.4 h 0.1 g 0.2 g 0.1 - 1.7 i 0.2 g; 2.7 h 0.99 0.11-0.31 i; 0.18±0.09 g 0.4 g 0.1 g 0.4 g 0.2-2.9 i 0.4 g; 3.5 h 0.20-1.41 i; 0.81±0.86 g 6.4±4.1 g 6.7 g; 5.7-7.7 i 5.10±0.75 g 5.4±1.4 g

100.0 n.r. 0.0 8.3 n.r. n.r. 100.0 2.0 n.r. n.r. 61.1 18.0 33.3 14.3 n.r. n.r. n.r. 77.8 86.0 7.1 n.r. 100.0 n.r. n.r.

[65] [65] [65] [44] [65] [65] [65] [19] [19] [19] [25] [19] [20] [66] [19] [19] [19] [25] [19] [66] [65] [65] [65] [65]

Morphine 6-Acetylmorphine f Oxycodone Tramadol 715 n.r., not reported; EDDP, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; MDA, 3,4-methylenedioxyamphetamine; MDEA, 9 716 methylenedioxyethylamphetamine; MDMA, 3.4-methylenedioxymethamphetamine; THC, Δ -tetrahydrocannabinol; THC-COOH, 9 717 11-nor-9-carboxy-Δ -tetrahydrocannnabinol; OH-THC, 11-hydroxy-Δ9-tetrahydrocannabinol a b c d 718 Metabolite of THC; Metabolite of cocaine; Metabolite of methadone; Includes Argentina, Brazil, Chile, Colombia, Panama, e f g 719 Peru and Uruguay; Includes Austria, France, Germany, Iceland, Slovakia, Switzerland and the UK; Metabolite of morphine; 24

Page 24 of 26

720 721

Mean concentration;

h

i

Maximum concentration; Concentration range (min - max);

j

Mean concentration LOD;

k

l

Sample numbers of passive sampling; Sample numbers of grab sampling

722 723 724 725

Table 2 Removal efficiencies of drugs of abuse and their metabolites during drinking water

726

treatment Compounds

DWTP Routes e

Removal Efficiency (%)

Lethal Dose f (g)

Therapeutic Dose f (g)

Refs

100 100 7 100 96 99 100

0.2 0.5

0.02-0.1 -

0.3

0.08-0.2

Methamphetamine

1 1 5 1 1 2 1

1

0.0025-0.025

[6] [6] [65] [6] [42] [42] [6]

Benzodiazepines Bromazepam Diazepam Oxazepam

1 1 1

>99 >99 97

-

0.003-0.018 -

[26] [26] [26]

Cannabinoids THC THC-COOH a

4 4

>99 >99

-

-

[25] [25]

1 1 2 5 1 1 2 5 1 2

100 99 >99 -18 89 96 99 14 96 99

1.2

-

-

-

-

-

[6] [42] [42] [65] [6] [42] [42] [65] [42] [42]

1 2

92 98

-

-

Amphetamines Amphetamine MDA MDMA

Cocainics Cocaine

Benzoylecgonine b

Norbenzoylecgonine b

Dissociative Anaesthetics Ketamine

[42] [42] 25

Page 25 of 26

Opioid Analgesics Codeine

Norcodeine c

Dihydrocodeine Fentanyl Methadone

EDDP d

Morphine Oxycodone Tramadol 727 728 729 730 731 732 733 734 735 736

5

49

1 2 4 5 1 2 4 5 4 5 1 2 4 1 2 4 4 5 5 5

>99 >99 >99 25 89 97 >99 -10 >99 0 99 >99 91 >99 >99 88 >99 -2 -3 -39

[65]

0.8

0.03-0.06

-

-

0.5 0.002

0.03-0.06 -

0.05

0.0025-0.01

-

-

0.2

0.005-0.02

0.5 -

0.05-0.1

[42] [42] [25] [65] [42] [42] [25] [65] [25] [65] [42] [42] [25] [42] [42] [25] [25] [65] [65] [65]

Cl2, chlorine; C, coagulation; F, flocculation; sed., sedimentation; filt., filtration; NH 2Cl, chloramines; O3, ozonation; GAC, granular activated carbon; ultra-filt., ultrafiltration; UV, ultraviolet disinfection; RO, reverse osmosis; re-mine., remineralisation. a

Metabolite of THC; Metabolite of cocaine; Metabolite of codeine; Metabolite of methadone

e

1 = Cl2 → C → F → sed. → filt. → O3 → GAC → Cl2

e

2 = Cl2 → C → F → sed. → filt. → ultra-filt. → UV → RO → re-mine. → Cl2

e

3 = Cl2 → C → F → sed. → Cl2 → filt. → NH2Cl

e

4 = Cl2 → C → F → filt. → O3 → GAC → Cl2

e

5 = C → F → filt. → Cl2

f

b

c

d

Moffat, et al., 2011 [56]

737

26

Page 26 of 26