Environmental Reviews · 2019. 2. 7. · Draft 1 1 Pharmaceuticals in the marine environment: A...

Draft

Pharmaceuticals in the marine environment: A review

Journal: Environmental Reviews

Manuscript ID er-2018-0054.R2

Manuscript Type: Review

Date Submitted by the Author: 20-Aug-2018

Complete List of Authors: Ojemaye, Cecilia Y.; University of the Western Cape Faculty of Natural Science, ChemistryPetrik, Leslie P.; University of the Western Cape Faculty of Natural Science, Chemistry

Is this manuscript invited for consideration in a Special

Issue?:Not applicable (regular submission)

Keyword: Persistent organic pollutants and contaminants, Seawater, Sediment, Marine organisms

https://mc06.manuscriptcentral.com/er-pubs

Environmental Reviews

Draft

1

1 Pharmaceuticals in the marine environment: A review

2 Cecilia Y. Ojemaye* and Leslie Petrik

3 Environmental and Nano Sciences Research Group, Department of Chemistry, University

4 of the Western Cape, Bellville, Republic of South Africa.

5 *Correspondence should be forwarded to: [email protected]

6 Abstract

7 Recently, despite the increasing presence of pharmaceuticals in marine environments and

8 their potential negative impacts, little research has been reported on the level and

9 occurrence of these contaminants in the marine ecosystem. This review provides

10 information on the occurrence (level/concentration) of pharmaceuticals in marine

11 environment including seawater, sediments and organisms within and/or around this

12 ecosystem. Also, the classification, sources, metabolism, and fate of these contaminants

13 in the marine environment were discussed in order to identify knowledge gaps. We

14 showed that antibiotics are the most commonly investigated and detected drugs in marine

15 environments. In addition, this review suggest that focused case studies should be a

16 priority for future research and highlighted the need for future assessments of the

17 potential risks of pharmaceuticals to marine species. We also suggested that it is

18 necessary to monitor the level of the most frequent and widespread pharmaceuticals like

19 antibiotics and NSAIDs in sewage and marine outfalls. Finally, we concluded that there is

20 a need for the development of effective treatment methods for the removal of these

21 pollutants from wastewater before their discharge into the receiving marine environment

22 or the main drinking water networks.

Page 1 of 59



Draft

2

23 Keywords

24 Persistent organic pollutants and contaminants, seawater, sediment, marine organisms

25 1.0 Introduction

26 Over the last decade, increasing attention has been directed towards understanding the

27 presence and impacts of pharmaceuticals entering or detected in freshwater ecosystems

28 (Hughes and Vincent 2012). Surprisingly, significantly little attention has been directed

29 towards understanding the release of pharmaceuticals from sewage and other pathways

30 into the coastal-marine environments and their potential negative impact on the marine

31 ecosystem. However, in order to minimize environmental exposure, there should be

32 global recognition and awareness of the problem while promoting human and animal

33 health.

34 Pharmaceuticals are synthesised or derived from natural inorganic or organic chemical

35 compounds and are used for the prevention and treatment of diseases. These compounds

36 are often used for diagnosis in humans and animals as well as improving their quality of

37 living. It can also be given to animals to speed up growth rate and improve their feeding

38 efficiency (Daghrir, R. & Drogui 2013; Maletz et al. 2013). Pharmaceuticals differ in

39 terms of their structure and behaviour, their applications, their metabolism in animals and

40 humans as well as their effect in the environment (Fawell and Ong 2012; Jiang et al.

41 2013). They are designed to accomplish particular biological effects identified with

42 human and animal health. In addition, these compounds are applied to domesticated

43 animal cultivation and aquaculture development. In spite of the fact that pharmaceuticals

44 are essentially intended to target people, there are worries about their negative impacts on

Page 2 of 59



Draft

3

45 non-target organisms in view of their active physicochemical and biological properties

46 (Seiler 2002). Over 100 pharmaceutical compounds, covering different therapeutic

47 classes, have been accounted for in drinking water, wastewater, ground water, marine

48 organisms, sewage, and surface water around the world (Heberer 2002; Choi et al. 2008).

49 Anti-infection agents are considered to have a high ecological hazard and need evaluation

50 on account of their broad use by people. Besides, these medications can conceivably

51 cause harm to the environment by influencing the distribution of key species and by

52 advancing the spread of resistant genes in the environment (Costanzo et al. 2005).

53 Although several studies have addressed the occurrence and fate of pharmaceuticals in

54 surface waters (Santos et al. 2010; Wang and Gardinali 2012; Gorga et al. 2013;

55 Klosterhaus et al. 2013; Miller et al. 2015), marine waters have long been neglected,

56 under the assumption that dilution would represent a safety factor. Thus, data determining

57 the potential ecosystem and health risks posed by pharmaceuticals in the ocean are

58 urgently needed. Indeed, there has been a rapid increase in investigations into marine

59 environments. This review aims to highlight that pharmaceuticals are present at low but

60 consistent concentrations anywhere they were assessed and are accumulating in

61 organisms present in the marine environment.

62 The first detection of pharmaceuticals as environmental contaminants was reported by

63 Richardson and Bowron (1985), although their negative ecological impact was not

64 recognised until the late 1990s when they were described as agents of subtle change

65 (Daughton and Ternes 1999). Van Doorslaer et al. (2014) reported that over 5000

66 pharmaceutical drugs manufactured for consumption by both humans and animals were

67 made accessible in the public market. Currently, the worldwide consumption of drugs

Page 3 of 59



Draft

4

68 annually is in the range of 100,000–200,000 tons with Russia, China, South Africa, India,

69 and Brazil having the larger proportion/percentage (Van Boeckel et al. 2015; Tijani et al.

70 2016).

71 Due to the increased utilisation of pharmaceuticals by humans and animals, together with

72 incomplete absorption in the body, parent drugs and their metabolites have been detected

73 in different marine environments. Since the early 2000s, there has been detailed research

74 focusing on the detection of pharmaceuticals and pharmaceutical residues in water

75 sources (Kanakaraju et al. 2014).

76 1.1 Classification

77 Pharmaceuticals are classified, based on their therapeutic uses, into the following groups:

78 anti-diabetics (e.g. alpha-glucosidase inhibitor), β-blockers (e.g. atenolol, metoprolol),

79 antibiotics (e.g. trimethoprim), lipid regulators (e.g. gemfibrozil), anti-epileptic (e.g.

80 acetazolamide), tranquilizers (e.g. diazepam), antimicrobials (e.g. penicillins), antiulcer

81 and antihistamine drugs (e.g. cimetidine and famotidine), antianxiety/hypnotic agents

82 (e.g. diazepam), anti-inflammatories and analgesics (e.g. ibuprofen, paracetamol,

83 diclofenac), antidepressants (e.g. benzodiazine-pines), anticancer drugs (e.g.

84 cyclophosphamide, ifosfamide), antipyretics and stimulants (e.g. dexamphetamine,

85 methylphenidate and modafinil), estrogens and hormonal compounds (estriol, estradiol,

86 and estrone) (Burger 2002; Ikehata et al. 2006; Esplugas et al. 2007; Bruce et al. 2010;

87 Canonica and Blaiss 2011; Alvin 2012; Bateman 2012; Rivera-Utrilla et al. 2013; Jiang et

88 al. 2013; Stringer and Snyder 2014; Kanakaraju et al. 2014; Linde et al. 2015). These

89 pharmaceuticals enter into the environment continuously which leads to their permanent

90 presence, which is referred to as “pseudo-persistent”.

Page 4 of 59



Draft

5

91 1.2 Sources of pharmaceuticals in the aquatic environment

92 The aquatic ecosystem has constantly been prone to human activities. Human activities

93 have negatively impacted the marine environment, with particularly deleterious effects

94 through human interference with nature. For example, physical pollution and destruction

95 are the types of deleterious environmental effects caused by human interference.

96 However, pollution is the most significant threat to the marine environment. With world

97 population increases, the utilisation of pharmaceuticals has escalated as a result of their

98 use to prevent as well as cure diseases through their incorporation in food products as

99 additives.

100 Municipal sewage treatment plants seem to play a large role in the release of

101 pharmaceuticals into the marine environment as observed for endocrine disruptors. This

102 is likely in light of the fact that wastewater treatment plants are not particularly designed

103 to decompose the vast majority of pharmaceutical compounds, because they are made to

104 be stable and robust, polar and non-volatile in nature, thus pass through the wastewater

105 treatment plants into the receiving marine water. These numerous compounds are

106 therefore consistently discharged into surface and marine waters in an extensive range of

107 concentrations (Heberer 2002; Boyd et al. 2003; Gros et al. 2010; Jelic et al. 2011;

108 Verlicchi et al. 2012; Baker and Kasprzyk-Hordern 2013; Kosma et al. 2014; Evgenidou

109 et al. 2015)

110 Be that as it may, most individuals are not aware of the hazards related to the introduction

111 of these compounds into the marine environment. Most individuals carelessly discard

112 unused or out of date drugs into sinks and toilets (Petrovic et al. 2004). Furthermore, a

113 large portion of medications that are ingested orally or by infusion are excreted through

Ground water

Leaching Percolation

Aquaculture

Soil Landfill

Run-off

Effluent

Direct dischargeDirect discharge

Fate of Pharmaceutical in the environmentDirect discharge

DomesticPharmaceuticals (Human and veterinary) Faeces and urine Unconsumed compounds

Sewerage system

Agricultural application

Sludge

Water treatment

plants

Drinking water

Industrial and commercial

Treated and untreated effluent from industries and hospital

Animal farming

Receiving water

(Marine water)

Sewage treatment

plants

Direct discharge

Page 5 of 59



Draft

6

114 urine or faeces due to their incomplete absorption (metabolism) in humans and animals,

115 and ultimately wind up in wastewater treatment plants. Other pathways for

116 pharmaceuticals to be delivered into the marine system are via landfill sites, septic tanks,

117 urban wastewater, showering and bathing, industrial effluent and agricultural practices

118 (Boxall et al. 2012; Rodil et al. 2012; Verlicchi et al. 2012; Lambropoulou and Nollet

119 2014). Because of the ever increasing use of pharmaceuticals by humans and animals,

120 coupled with incomplete metabolism in the body, parent compounds and their

121 metabolites or partially metabolised forms have been detected in the marine environment.

122 Ecological water samples such as surface, ground and wastewaters have been found to

123 contain these pharmaceutically active compounds in countries like Germany, China,

124 Holland, Canada, USA, Brazil, Spain and in South Africa (Garric and Ferrari 2005; Fent

125 et al. 2006; Chen et al. 2011; Rivera-Utrilla et al. 2013; Yan et al. 2014). The continuous

126 use of pharmaceuticals has led to concern over increasing levels of both human and

127 veterinary drug residues delivered into the environment, since many of these emerging

128 contaminants have been detected in significant concentrations in drinking water, surface

129 waters, sewage treatment plant effluents and ground waters (Kümmerer 2001; Schwaiger

130 et al. 2004; Martin-Diaz et al. 2009), which lead to their ubiquitous presence (Nunes et al.

131 2008), and systematic introduction in aquatic ecosystems. Figure 1 describes how

132 pharmaceuticals enter the environment through several pathways such as from hospitals,

133 industries, aquaculture, and runoff into soil through animal farming and manure

134 application (i.e. agricultural processes) and runoff from fields into surface waters. In all

135 of these routes or pathways, the marine environment is the ultimate recipient where

136 humans as well as marine species including fish and mussels are exposed and susceptible

137 to these contaminants.

Page 6 of 59



Draft

7

138 PLACE FIGURE 1 HERE

139 1.3 Metabolism of drugs

140 The fate of pharmaceuticals in the aquatic environment is dependent on various factors,

141 like the rate and level of transformation of the original drug, how the freshly formed

142 metabolites are structured and the amount of original drug and its metabolites that had

143 been excreted. The study of the processes by which a drug is absorbed, metabolised,

144 distributed, as well as the effect and routes of excretion by the body is called

145 ‘pharmacokinetics’ (Harris et al. 2014; Rosenbaum 2016). Pharmaceuticals are

146 formulated in a specific manner such that the active pharmaceuticals constituent can be

147 discharged at an intended site in the body to provide the necessary pharmacological

148 effect. In order for pharmaceuticals to arrive at a distinct site, they must have lipophilic

149 abilities to permeate the body’s cell membranes. According to Mittal et al. (2015)

150 metabolism is an enzymatic process required for the transformation of lipophilic chemical

151 compounds to a more polar by-product or hydrophilic metabolites that are suitable for

152 elimination. Metabolism influences the biological activity of a drug in many ways such

153 as deactivation, trans-activation, toxification and activation processes. Metabolism is

154 needed to discharge the active pharmaceutical compound and produce a pharmacological

155 effect in a relatively small number of drugs known as ‘prodrugs’ (Rautio et al. 2008). The

156 liver is mainly where drug metabolism occurs but other organs also have the

157 characteristics necessary to metabolise drugs including kidneys, lungs and the intestine

158 (Luscombe and Nicholls 1998). The metabolism of compounds in the body involves two

159 reaction processes namely: Phase I reactions involve exposing or adding of a reactive

160 functional group on the parent molecule and include oxidation, reduction hydration,

161 dethioacetylation, isomerisation and hydrolysis; and Phase II reactions, usually known as

Page 7 of 59



Draft

8

162 conjugation reaction (which include methylation, glycosidation, glutathione and fatty acid

163 conjugation, acetylation, sulfation, glucuronidation, condensation and amino acid), all of

164 which gets conjugated to the parent compound and its metabolites as well as with various

165 endogenous components into a highly polar moiety (Gibson and Paul Skett 1996;

166 Luscombe and Nicholls 1998; Taxak and Bharatam 2004).

167 The metabolites of pharmaceuticals cannot be considered inactive or safe. For example,

168 paracetamol and amitriptyline are mostly metabolised into highly reactive compounds

169 (Rudorfer and Potter 1997; Graham et al. 2013). When rainbow trout were water-exposed

170 under test conditions they were found to metabolise pharmaceuticals and the resulting

171 metabolites were detected in higher concentrations than the original compound in the fish

172 bile and plasma (Lahti et al. 2011). Other than the toxicological concerns, the likelihood

173 of take-up and digestion of pharmaceutical compounds in exposed marine/aquatic

174 organism requires more examination. Figure 2 below describes the metabolism of

175 acetaminophen. Pathways shown in and lead to non-toxic metabolites;

176 the pathway leads to N-acetyl-p-benzoquinone imine (NAPQI), which is toxic if

177 not conjugated to glutathione.

178 PLACE FIGURE TWO HERE

179 1.4 Occurrence of pharmaceuticals in the marine environment

180 The consequences of pharmaceuticals in the aquatic environment are of serious concern

181 because marine organisms are subjected to constant exposure with potential

182 consequences for future generations. These pharmaceuticals are present at low (trace)

183 concentrations (nanogram or microgram/L), depending on their source. The most serious

Page 8 of 59



Draft

9

184 problem is chronic exposure of organisms to pharmaceuticals due to their continuous

185 input into the environment (Petrović et al. 2005). However, although the presence of

186 many pharmaceuticals is confirmed in the freshwater, terrestrial and marine environments

187 as well as in biota, scientific information on the ecological and ecotoxicological

188 consequences remain sparse.

189 The presence of pharmaceuticals in the environment has continuously received attention

190 from scientific, government, public, and regulatory sectors (Daughton and Ternes 1999;

191 Ankley et al. 2007). International efforts are examining environmental occurrence, fate,

192 effects, ecological and human health risks, and risk management approaches for these

193 compounds. An increasing body of literature reveals that pharmaceuticals at nanogram

194 per gram (ng/g) concentrations accumulate in wild-caught fish populations (Brooks et al.

195 2005; Wen et al. 2006; Brown et al. 2007; Chu and Metcalfe 2007; Ramirez et al. 2007;

196 Nakamura et al. 2008; Mottaleb et al. 2009; Huerta et al. 2013). However, environmental

197 analytical chemistry efforts to examine pharmaceuticals in fish tissue have previously

198 focused on specific chemicals or chemical classes at single study sites.

199 Practically every single industrial process involved in the manufacture of

200 pharmaceuticals, results in discharging enormous amounts of emerging contaminants or

201 pollutants into the aquatic ecosystem. The most continuous occurrence is the growing

202 accumulation of pharmaceuticals and endocrine-disrupting compounds that have over-

203 burdened and polluted the different receiving water bodies.

204 One of the major issues resulting from the discharge of pharmaceutical into marine

205 waters is their capability to bioaccumulate in aquatic biota. The level of a chemical

206 compound in an organism by exposure to water only is known as bioconcentration, while

Page 9 of 59



Draft

10

207 the absorption or ingestion of chemical substances or compounds by an organism through

208 the contribution from air, food, water, and sediment, as it occurs in the natural aquatic

209 milieu is known as bioaccumulation (Arnot and Gobas 2006). Bioavailability in the

210 aquatic system, the physicochemical nature of pharmaceuticals, biotic factors relating to

211 the exposure aquatic organisms and the pH, temperature, flow and quality of its inhibiting

212 waters are a few of the components that can impact the bioaccumulation of

213 pharmaceuticals (Bremle et al. 1995; Nakamura et al. 2008; Rendal et al. 2011).

214 These persistent organic compounds have been detected in marine/seawater biota and

215 sediments of different coastal environments worldwide, with concentrations ranging from

216 0.21 ng/L to 5000 ng/L (seawater; Table 1) from 0.0402 ng/g dry weight to 208 ng/g wet

217 weight (biota; Table 2) and from 0. 2ng/g dry weight to 466 ng/g wet weight (sediments;

218 Table 3).

219 PLACE TABLE 1 HERE

220 1.5 Occurrence of pharmaceuticals in the marine biota

221 The publication of the presence of a contraceptive 17α-ethinyloestradiol in the bile of fish

222 from Sweden was amongst the first to report the bio-accumulation of human

223 pharmaceuticals in aquatic organisms (Larsson et al. 1999). A few reviews have

224 examined the presence of pharmaceuticals in wild aquatic organisms, concentrating

225 basically on accumulation in wild fish species. Similar work was undertaken by Brooks et

226 al. (2005) where various antidepressants were examined in the tissues of undomesticated

227 fish dwelling in two different effluent-influenced water bodies in north Texas, USA.

228 Fluoxetine and sertraline, two antidepressants, and their corresponding metabolites,

Page 10 of 59



Draft

11

229 norfluoxetine and desmethylsertraline, were observed at concentrations higher than 0.1

230 ng/g wet weight in all tissues, with the most elevated concentrations detected in the

231 cerebrum and liver. The corresponding values for trimethoprim ranged from 0.2 to 0.4

232 µg/kg and recovery rates between 51.9% and 52.8%. McEneff et al. (2014) also

233 determined over a period of 12 months, the spatial occurrence of five targeted

234 pharmaceuticals (trimethoprim, diclofenac, mefanamic acid, gemfibrozil and

235 carbamazepine) in the aquatic environment (marine surface water and in the mussel,

236 Mytilus spp). They observed the presence of all five pharmaceuticals at high

237 concentrations (ng/L) in exposed marine surface water and marine mussels. The limit of

238 quantification obtained was between 3 and 38 ng/L and between 4 and 29 ng/g dry

239 weights, respectively.

240 Fick et al. (2010) exposed cages of unpolluted rainbow trout at three different effluent

241 outfall sites for a duration of 14 days They reported that 16 of 25 pharmaceuticals

242 observed in the effluent were also detected in the plasma of the exposed fish. A similar

243 study was carried out, where rainbow trout were exposed for 14 days to a downstream

244 wastewater treatment plant in Canada and two antidepressants were found to be present at

245 high concentrations (in ng/L) in the bile of exposed rainbow trout (Togunde et al. 2012).

246 A recent pharmaceutical exposure study deployed five cages of blue mussels off the

247 Belgian coast for a period six months (Wille et al. 2011). They found that five

248 pharmaceuticals were present in the tissues of the mussels including the residues of

249 salicylic acid, with concentrations up to 490 ng/g dry weight.

250 In a study in North Carolina, fluoxetine, an antidepressant was detected in the tissues of

251 caged mussels at concentrations up to 79 ng/g wet weight after being exposed to a

Page 11 of 59



Draft

12

252 wastewater effluent channel for 14 days (Bringolf et al. 2010). In a recent study

253 conducted by McEneff et al. (2013), they determined different pharmaceutical residues

254 (gemfibrozil, diclofenac carbamazepine, trimethoprim and mefenamic acid) using an

255 optimised and validated method in blue mussels (Mytilus spp.). In addition, they

256 investigated the potential for human exposure through the effects of cooking (by

257 steaming). Limits of quantification obtained for extracted cooking water and artificial

258 seawater, artificial seawater in exposure tanks and for tissue of mussel was between 2 and

259 46 ng /L, between 2 and 64 μg /L and between 4 and 29 ng/g, respectively. They

260 observed that after cooking, the tissue of the contaminated mussels and the cooking water

261 showed an increase in pharmaceutical residues.

262 The presence of pharmaceuticals was investigated in the fillet and liver of fish from

263 effluent-influenced rivers around the United States (Ramirez et al. 2009). Norfluoxetine,

264 sertraline, diphenhydramine, diltiazem and carbamazepine was detected in all the tested

265 fish tissues, including the presence of gemfibrozil and fluoxetine in the liver. At one of

266 the exposure sites, the concentration of sertraline was up to 545 ng/g wet weight in the

267 liver of the wild white sucker fish species (Ramirez et al. 2009). The ingestion of

268 pharmaceuticals, such as antibiotics, has been previously detected in mussel species

269 collected from the Bohai Sea in China for a period of 48 months (Li et al. 2012). In a

270 recent study, low residues of sertraline and carbamazepine at concentrations of 0.3 ng/g

271 and 2.4 ng/g wet weight, respectively were detected in wild ribbed horse mussels

272 (Geukensia demissa) sampled from five near shore sites in San Francisco Bay

273 (Klosterhaus et al. 2013). The high concentration of chemical compounds in marine

274 organisms is evidence of bioaccumulation over time as the organisms have no way of

Page 12 of 59



Draft

13

275 escaping the pervasive presence of these chemicals in the seawater (Petrik et al. 2017).

276 Table 2 gives the concentration of various pharmaceuticals in marine organisms,

277 confirming that many of these substances are not effectively removed by effluent

278 treatment.

279 PLACE TABLE 2 HERE

280 1.6 Occurrence of pharmaceuticals in marine sediments

281 Given that pharmaceutical affinities for suspended solids are further enhanced at the typical pH

282 and salinity conditions of seawater, it is likely that marine sediments represent a sink for these

283 compounds (Gilroy et al. 2012). Sediment partitioning of pharmaceuticals in the marine

284 environment has been poorly investigated; however, these findings show the potential impacts of

285 sediment processes in defining the fate of pharmaceuticals in aquatic systems. Indeed, sediments

286 may act as a secondary pollution source from which pharmaceuticals can be released upon changes

287 in environmental salinity and pH (Liang et al. 2013), or during storm events or tidal changes. Table

288 3 gives the concentration of various pharmaceutical in sediment in different countries around the

289 world.

290 PLACE TABLE THREE HERE

291 1.7 Behaviour of pharmaceuticals in the environment

292 Aquatic movement and transformation processes in the environment involve sorption,

293 volatilisation, ionisation, oxidation-reduction, hydrolysis, photolysis, biological

294 transformation-degradation and precipitation-dissolution. These processes occur

295 continually in the environment and impact the existence and bioavailability of

296 pharmaceuticals in aquatic environments (Kümmerer et al. 2000; Boreen et al. 2003;

Page 13 of 59



Draft

14

297 Löffler et al. 2005; Wießner et al. 2005; Kümmerer 2008; Hijosa-Valsero et al. 2011).

298 The reaction of drugs to any of these processes for dissolution, debasement or

299 transformation in the environment could decrease their level of concentrations in the

300 environment or eliminate them completely, thereby reducing their potential to affect

301 human health and aquatic life. Pharmaceutical compounds that are available for sale in

302 large quantities, are capable of disintegration, or are impervious to degradation through

303 biological or chemical processes, have the greatest potential to reach persistent levels in

304 the environment and to be detected in different aquatic matrices.

305 Water pH, salt concentration, ionic strength, and conductivity could affect the behaviour

306 of pharmaceuticals in the marine environment. For instance, the pH and salt

307 concentrations of marine waters influence the electrostatic characteristics of

308 pharmaceuticals; this generates multiple ionisable functional groups with tangible values

309 of the acid dissociation constant (pKa). The change in pH determines the degree of

310 ionization and properties thereby affecting the environmental matrices and species.

311 Furthermore, the lipophilicity of pharmaceuticals have been reported to be enhanced in

312 marine waters with pH 8 (McEneff et al. 2014). Below pH 8.0, pharmaceuticals are not

313 completely ionized in marine waters but at pH 8.0, the un-ionized compounds are

314 bioaccumulated by marine bivalves owing to the greater likeness for lipophilic matter.

315 Similarly, salt concentration or salinity of marine waters influences the behaviour of

316 pharmaceuticals by acting as natural filters. The quantified amount of gemfibrozil and

317 mefanamic acids was below detectable levels when measured from marine surface waters

318 (Togola and Budzinski 2007). This was attributed to the high content of salts in the

Page 14 of 59



Draft

15

319 marine water causing the pharmaceuticals in these environments to be less soluble

320 (Bayen et al. 2013).

321 1.8 Fate of pharmaceuticals in the environment

322 Pharmaceuticals are manufactured to be stable and robust; most pharmaceuticals are polar

323 and non-volatile in nature, making their elimination in the aquatic environment difficult.

324 Information regarding the fate of pharmaceuticals is necessary when aiming to determine

325 the potential risk which these emerging micro-pollutants pose. Frequent usage and

326 regular presentation of pharmaceuticals into the terrestrial and aquatic surroundings cause

327 their pseudo-persistence (Hernando et al. 2006). The depletion of pharmaceutical

328 compounds in the aquatic environment is controlled or limited by various processes

329 (Baena-Nogueras et al. 2017). Aerobic and anaerobic bio-degradation and abiotic

330 transformation (dilution and movement within the aquatic milieu with possible uptake in

331 biological species) through degradation by UV-light (photochemical degradation),

332 sediment sorption and hydrolysis (sorption onto solid matrices) are the major processes

333 involved. To determine which of the above processes is most effective for their

334 transformation, the properties of the specific compounds in the drug and the

335 characteristics of the surrounding environment have to be considered i.e. the degradation

336 processes are heavily influenced by both the molecular structures of the xenobiotic

337 compounds and various environmental factors such as temperature, pH, bacterial

338 communities, salinity, and irradiance, among others (Baena-Nogueras et al. 2017).

339 Aerobic biodegradation usually involves bacteria using oxygen as electron acceptors.

340 Depending on the substance investigated, recent studies on the microbial degradation of

Page 15 of 59



Draft

16

341 some pharmaceuticals show very distinctive behaviour. For example, fluoxetine and

342 acetaminophen show high degradation speeds (t1/2 > 12 days), whereas carbamazepine,

343 sulfamethoxazole and trimethoprim show some persistence (t1/2 > 100 days) in marine

344 waters (Benotti and Brownawell 2009). The percentage biodegradation of triclosan in 5

345 days was reported to be 95%, producing metabolites such as catechol, phenol and 2, 4-

346 dichlorophenol (Veetil et al. 2012), whereas acetaminophen was biotransformed into 4-

347 aminophenol and hydroquinone (Zhang et al. 2013a). Moreover, the synergism between

348 both abiotic and biotic degradation processes can be expected in the environment, as it

349 has been recently reported for triclocarban when attacked by phototrophic bacteria (Lv et

350 al. 2014).

351 Photochemical degradation, sorption onto solid matrices and dilution and movement

352 within the aquatic milieu with possible uptake in biological species are some of the

353 processes which can occur to compounds in the aquatic environment. For abiotic

354 transformation of pharmaceutical compounds in the aquatic ecosystem, photochemical

355 degradation is the main pathway. Photolytic reactions can occur in two ways:1) direct

356 photolysis in which the compound absorbs light directly from sunlight, and 2) indirect

357 photolysis in which there is an interaction of a reactive intermediate of another species

358 brought about by light absorption (Andreozzi et al. 2003). These two reactions are not

359 stable in the compound making it split into many photoproducts.

360 As reported by Halling-Sorensen et al. (1998), drugs can be classified into three main

361 potential fates: (i) The mineralisation of compounds to water and carbon dioxide

362 (Richardson and Bowron 1985). (ii) Due to the lipophilic nature of the substance it is not

363 easily degradable so some of it will be held back in the sludge. (iii) The lipophilic parent

Page 16 of 59



Draft

17

364 substance is metabolised to a more hydrophilic form, which is still stable and persistent

365 thus passes through the wastewater treatment plant and winds up in any receiving water

366 bodies. If the metabolites are biologically active they can further impact the aquatic

367 organisms in the water (Richardson and Bowron 1985). Substances with latent qualities

368 may be retained in the sludge, sewage and, given that the sludge is dispersed on fields as

369 fertilizer, will be able to affect the micro-organisms and beneficial species of such micro-

370 organisms. Pharmaceutical compounds used for animals to enhance growth in stables will

371 possibly wind up in manure.

372 Currently, more than 80 pharmaceutical compounds have been identified at considerable

373 amounts in different environmental matrices like surface waters (Ashton et al. 2004;

374 Togola and Budzinski 2008; Klosterhaus et al. 2013), groundwater (Lapworth et al. 2012;

375 López-Serna et al. 2013), soils/sediment (Barron et al. 2008). Pharmaceutical compounds

376 have likewise been detected in biota from algae to fish in different concentrations all

377 around the world (Brooks et al. 2005; Ramirez et al. 2009; Huerta et al. 2013; Grabicova

378 et al. 2015; Liu et al. 2015). Some pharmaceuticals are recently being associated with

379 adverse developmental effects in aquatic organisms and with negative impacts on human

380 health. Nevertheless, there are a few drugs such as iopromide that are not likely to initiate

381 a risk, as they are present in low concentrations together with low toxicity (Steger-

382 Hartmann et al. 2002). In contrast, other pharmaceuticals such as either natural or

383 synthetic hormones are now well known to cause great risks for the aquatic ecosystem

384 (Nash et al. 2004) including the feminisation of male fish (i.e. whereby male fish become

385 female).

Page 17 of 59



Draft

18

386 The persistent discharge of pharmaceuticals in the environment and their potential

387 bioaccumulation is also a universal discussion. In addition, pharmaceuticals are

388 discharged into the environment as mixtures raising further concerns, as the synergetic

389 combined environmental effects of many different pharmaceutical compounds remain

390 unknown (Stackelberg et al. 2004). In addition to the potential ecological risks, human

391 health might also be at risk through prolonged intake of drinking water containing trace

392 levels of pharmaceuticals, as well as through the consumption of sea food. Even though

393 these medical compounds (drugs) in drinking water are at doses lower than the ones used

394 in therapy, a standard limit for pharmaceuticals in drinking water are yet to be

395 established.

396 1.9 Exposure

397 Aquatic organisms are exposed to pharmaceutical pollutants as a result of their discharge

398 into the aquatic environment. Exposure of humans to environmental concentrations of

399 pharmaceuticals is believed to be primarily through drinking water and through the

400 consumption and ingestion of meat and seafood where these compounds bioaccumulate.

401 Consumption of food is an important pathway for exposure of humans to persistent

402 organic pollutants (POP). The main route of exposure for POPs (pharmaceuticals) for the

403 general population is ingestion rather than through other exposure routes like inhalation

404 and dermal contact (Liem 1999; Sweetman et al. 2000; Falandysz et al. 2002).

405 Investigations have confirmed that more than 90% of human contaminants are derived

406 from food. Risk evaluation of POPs in food for human health is therefore of greatest

407 importance. Although sea food accounts for only about 10% nutrient of the human diet

408 globally, it is one of the main sources through which these chemical contaminants find

Page 18 of 59



Draft

19

409 their way into human tissues (Sjödin et al. 2000), which may be deleterious to human

410 health.

411 1.10 Effects

412 The level of human exposure to pharmaceuticals from the environment is complex and

413 can result be the result of a number of reasons including 1) the parent drug structurally

414 transforming into its metabolites, or through a process of natural degradation; 2) the

415 types, concentrations and dissemination of pharmaceutical compounds in the ecosystem;

416 3) the pharmacokinetics of every drug, and 4) the potential bioaccumulation of the drugs

417 (Daughton 2008; Daughton and Ruhoy 2008). Further studies are essential to determine

418 the chronic health effects of pharmaceuticals on human exposure over long periods at

419 nominal concentrations. Negative effects have been reported for marine organisms (Gaw

420 et al. 2014), including reports on the deleterious effect of analgesic such as a reduction in

421 feeding rates (Solé et al. 2010), biochemical markers (Gonzalez-Rey and Bebianno

422 2014), impacts on survival (Guler and Ford 2010), changes in immune response (Solé et

423 al. 2010), and mussel byssus strength reduction (Ericson et al. 2010). However, the broad

424 effects of exposure to many different pharmaceutical compounds at low concentrations

425 are unknown.

426 Globally, research has shown that pharmaceuticals are present in water bodies all over the

427 world. Moreover, the absence of empirical data cannot rule out the possibility of long-

428 term exposures to these substances. It is complex to determine the actual amount of

429 pharmaceuticals existing in environmental matrices chemically, because the amounts are

430 in parts per trillion (10−12) or parts per billion (10−9) (Daughton 2008). For example, if

Page 19 of 59



Draft

20

431 antibiotics in the environment are not debased proficiently, developing or maintaining

432 antibiotic resistant microbial populations is possible because of the persisting residues

433 (Witte 1998; Taylor et al. 2011; Gaw et al. 2014).

434 2.0 Conclusion

435 The presence and possible effects of biologically active forms of both veterinary and

436 human pharmaceutical compounds and their metabolites in the marine environment are

437 fairly new issues. However, a relatively large number of studies over the past few years

438 have reported the presence of many different pharmaceuticals in different marine

439 environmental matrices, and documented their effects on organisms. It has now been

440 recognised that pharmaceuticals in the marine environment is not just a matter for

441 developed and industrialised countries, but a subject of global importance. This review

442 article has re-affirmed that the parent pharmaceuticals compounds and their metabolites

443 (transformation products) are present in coastal and marine ecosystems due to the large

444 quantities of pharmaceuticals that are consumed daily by humans and partially excreted.

445 To date, occurrence statistics for marine ecosystems are only accessible for a small

446 portion of the enormous number of pharmaceutical compounds presently in use globally.

447 Scientists agree that pharmaceuticals are contaminants of concern in marine

448 environments (Gaw et al. 2014) and thus deserve more attention than that given to date. It

449 is clear from the literature that relatively few studies are available for the marine

450 environment and marine organisms. Therefore, it is necessary to monitor the level of the

451 most frequently used and widespread pharmaceuticals such as antibiotics and NSAIDs

452 found in sewage effluents and to develop efficient treatment methods that will remove

Page 20 of 59



Draft

21

453 these pollutants prior to being discharged into the receiving marine environment or the

454 main drinking water networks. It is also apparent that both field and laboratory

455 ecotoxicology data for the effect of pharmaceuticals on marine organisms are extremely

456 limited. Finally, data on human health risk assessment and ecotoxicological risk

457 assessment related to pharmaceuticals is lacking and must also be developed. These

458 strategies should be strengthened and used to inform policy. Management decisions

459 should be adjusted to minimise the quantity of pharmaceuticals entering the environment.

460 References

461 Alvarez-Muñoz, D., Huerta, B., Fernandez-Tejedor, M., Rodríguez-Mozaz, S., and

462 Barceló, D. 2015. Multi-residue method for the analysis of pharmaceuticals and

463 some of their metabolites in bivalves. Talanta 136: 174–182. Elsevier.

464 doi:10.1016/j.talanta.2014.12.035.

465 Álvarez-Muñoz, D., Rodríguez-Mozaz, S., Maulvault, A.L., Tediosi, A., Fernández-

466 Tejedor, M., Van den Heuvel, F., Kotterman, M., Marques, A., and Barceló, D.

467 2015. Occurrence of pharmaceuticals and endocrine disrupting compounds in

468 macroalgaes, bivalves, and fish from coastal areas in Europe. Environ. Res. 143: 56–

469 64. Elsevier. doi:10.1016/j.envres.2015.09.018.

470 Alvin, P.C. 2012. Mellitus. In Harrison’s text book of internal medicine, 18th edition.

471 McGraw Hill’s pub. p. 2968.

472 Andreozzi, R., Marotta, R., and Paxéus, N. 2003. Pharmaceuticals in STP effluents and

473 their solar photodegradation in aquatic environment. Chemosphere 50(10): 1319–

474 1330. doi:10.1016/S0045-6535(02)00769-5.

Page 21 of 59



Draft

22

475 Ankley, G.T., Brooks, B.W., Huggett, D.B., and Sumpter, J.P. 2007. Repeating history:

476 Pharmaceuticals in the environment. Environ. Sci. Technol. 41(24): 8211–8217.

477 doi:10.1021/es072658j.

478 Arnot, J.A., and Gobas, F.A. 2006. A review of bioconcentration factor (BCF) and

479 bioaccumulation factor (BAF) assessments for organic chemicals in aquatic

480 organisms. Environ. Rev. 14(4): 257–297. doi:10.1139/a06-005.

481 Ashton, D., Hilton, M., and Thomas, K. V. 2004. Investigating the environmental

482 transport of human pharmaceuticals to streams in the United Kingdom. Sci. Total

483 Environ. 333(1–3): 167–184. doi:10.1016/j.scitotenv.2004.04.062.

484 Baena-Nogueras, R.M., González-Mazo, E., and Lara-Martín, P.A. 2017. Degradation

485 kinetics of pharmaceuticals and personal care products in surface waters: photolysis

486 vs biodegradation. Sci. Total Environ. 590–591: 643–654. Elsevier B.V.

487 doi:10.1016/j.scitotenv.2017.03.015.

488 Baker, D.R., and Kasprzyk-Hordern, B. 2013. Spatial and temporal occurrence of

489 pharmaceuticals and illicit drugs in the aqueous environment and during wastewater

490 treatment: New developments. Sci. Total Environ. 454–455: 442–456. Elsevier B.V.

491 doi:10.1016/j.scitotenv.2013.03.043.

492 Barron, L., Tobin, J., and Brett Paull. 2008. Multi-residue determination of

493 pharmaceuticals in sludge and sludge enriched soils using pressurized liquid

494 extraction, solid phase extraction and liquid chromatography with tandem mass

495 spectrometry. J. Environ. Monit. 10(3): 353–361. doi:10.1039/B717453E.

Page 22 of 59



Draft

23

496 Bateman, D.N. 2012. Non-steroidal anti-inflammatory drugs. Medicine (Baltimore).

497 40(3): 140. Available from https://doi.org/10.1016/j.mpmed.2011.12.027.

498 Bayen, S., Zhang, H., Desai, M.M., Ooi, S.K., and Kelly, B.C. 2013. Occurrence and

499 distribution of pharmaceutically active and endocrine disrupting compounds in

500 Singapore’s marine environment: Influence of hydrodynamics and physical-

501 chemical properties. Environ. Pollut. 182: 1–8. Elsevier.

502 doi:10.1016/j.envpol.2013.06.028.

503 Benotti, M.J., and Brownawell, B.J. 2007. Distributions of pharmaceuticals in an urban

504 estuary during both dry- and wet-weather conditions. Environ. Sci. Technol. 41(16):

505 5795–5802. doi:10.1021/es0629965.

506 Benotti, M.J., and Brownawell, B.J. 2009. Microbial degradation of pharmaceuticals in

507 estuarine and coastal seawater. Environ. Pollut. 157(3): 994–1002. Elsevier Ltd.

508 doi:10.1016/j.envpol.2008.10.009.

509 Beretta, M., Britto, V., Tavares, T.M., da Silva, S.M.T., and Pletsch, A.L. 2014.

510 Occurrence of pharmaceutical and personal care products (PPCPs) in marine

511 sediments in the Todos os Santos Bay and the north coast of Salvador, Bahia, Brazil.

512 J. Soils Sediments 14(7): 1278–1286. doi:10.1007/s11368-014-0884-6.

513 Birch, G.F., Drage, D.S., Thompson, K., Eaglesham, G., and Mueller, J.F. 2015.

514 Emerging contaminants (pharmaceuticals, personal care products, a food additive

515 and pesticides) in waters of Sydney estuary, Australia. Mar. Pollut. Bull. 97(1–2):

516 56–66. Elsevier Ltd. doi:10.1016/j.marpolbul.2015.06.038.

Page 23 of 59



Draft

24

517 Van Boeckel, T.P., Brower, C., Gilbert, M., Grenfell, B.T., Levin, S.A., Robinson, T.P.,

518 Teillant, A., and Laxminarayan, R. 2015. Global trends in antimicrobial use in food

519 animals. Proc. Natl. Acad. Sci. 112(18): 5649–5654. doi:10.1073/pnas.1503141112.

520 Boreen, A.L., Arnold, W.A., and McNeill, K. 2003. Photodegradation of pharmaceuticals

521 in the aquatic environment: A review. Aquat. Sci. 65(4): 320–341.

522 doi:10.1007/s00027-003-0672-7.

523 Boxall, A.B.A., Rudd, M.A., Brooks, B.W., Caldwell, D.J., Choi, K., Hickmann, S.,

524 Innes, E., Ostapyk, K., Staveley, J.P., Verslycke, T., Ankley, G.T., Beazley, K.F.,

525 Belanger, S.E., Berninger, J.P., Carriquiriborde, P., Coors, A., DeLeo, P.C., Dyer,

526 S.D., Ericson, J.F., Gagné, F., Giesy, J.P., Gouin, T., Hallstrom, L., Karlsson, M. V,

527 Larsson, D.G.J., Lazorchak, J.M., Mastrocco, F., McLaughlin, A., McMaster, M.E.,

528 Meyerhoff, R.D., Moore, R., Parrott, J.L., Snape, J.R., Murray-Smith, R., Servos,

529 M.R., Sibley, P.K., Straub, J.O., Szabo, N.D., Topp, E., Tetreault, G.R., Trudeau,

530 V.L., and Van Der Kraak, G. 2012. Pharmaceuticals and personal care products in

531 the environment: what are the big questions? Environ. Heal. Perspect. 120(9): 1221–

532 1229. doi:http://dx.doi.org/10.1016/j.envint.2013.06.012.

533 Boyd, G.R., Reemtsma, H., Grimm, D.A., and Mitra, S. 2003. Pharmaceuticals and

534 personal care products (PPCPs) in surface and treated waters of Louisiana, USA and

535 Ontario, Canada. Sci. Total Environ. 311(1–3): 135–149. doi:10.1016/S0048-

536 9697(03)00138-4.

537 Bremle, G., Okla, L., and Larsson, P. 1995. Uptake of PCBs in Fish in a Contaminated

538 River System: Bioconcentration Factors Measured in the Field. Environ. Sci.

Page 24 of 59



Draft

25

539 Technol. 29(8): 2010–2015. doi:10.1021/es00008a020.

540 Bringolf, R.B., Heltsley, R.M., Newton, T.J., Eads, C.B., Fraley, S.J., Shea, D., and

541 Cope, W.G. 2010. Environmental occurrence and reproductive effects of the

542 pharmaceutical fluoxetine in native freshwater mussels. Environ. Toxicol. Chem.

543 29(6): 1311–1318. doi:10.1002/etc.157.

544 Brooks, B.W., Chambliss, C.K., Stanley, J.K., Ramirez, A., Banks, K.E., Johnson, R.D.,

545 and Lewis, R.J. 2005. Determination of select antidepressants in sh from an ef uent-

546 dominated stream. Environ. Toxicol. Chem. 24(2): 464–469.

547 Brown, J.N., Paxéus, N., Förlin, L., and Larsson, D.G.J. 2007. Variations in

548 bioconcentration of human pharmaceuticals from sewage effluents into fish blood

549 plasma. Environ. Toxicol. Pharmacol. 24(3): 267–274.

550 doi:10.1016/j.etap.2007.06.005.

551 Bruce, G., Pleus, R., and Snyder, S. 2010. Toxicological Relevance of Pharmaceuticals

552 and EDCs in Drinking Water. Environ. Sci. Technol. 44(14): 5619–5626.

553 Burger, H.G. 2002. Androgen production in women. Fertil. Steril. 77(4): S3–S5.

554 doi:10.1016/S0015-0282(02)02985-0.

555 Canonica, W., and Blaiss, M. 2011. Antihistaminic, anti-inflammatory, and antiallergic

556 properties of the nonsedating second-generation antihistamine desloratadine: A

557 review of the evidence. World Allergy Organ. J. 4(2): 47–53.

558 doi:10.1097/WOX.0b013e3182093e19.

559 Chen, F., Ying, G.G., Kong, L.X., Wang, L., Zhao, J.L., Zhou, L.J., and Zhang, L.J.

Page 25 of 59



Draft

26

560 2011. Distribution and accumulation of endocrine-disrupting chemicals and

561 pharmaceuticals in wastewater irrigated soils in Hebei, China. Environ. Pollut.

562 159(6): 1490–1498. Elsevier Ltd. doi:10.1016/j.envpol.2011.03.016.

563 Choi, K., Kim, Y., Jung, J., Kim, M.H., Kim, C.S., Kim, N.H., and Park, J. 2008.

564 Occurrences and ecological risks of roxithromycin, trimethoprim, and

565 chloramphenicol in the Han River, Korea. Environ. Toxicol. Chem. 27(3): 711–719.

566 doi:10.1897/07-143.1.

567 Chu, S., and Metcalfe, C.D. 2007. Analysis of paroxetine, fluoxetine and norfluoxetine in

568 fish tissues using pressurized liquid extraction, mixed mode solid phase extraction

569 cleanup and liquid chromatography-tandem mass spectrometry. J. Chromatogr. A

570 1163(1–2): 112–118. doi:10.1016/j.chroma.2007.06.014.

571 Costanzo, S.D., Murby, J., and Bates, J. 2005. Ecosystem response to antibiotics entering

572 the aquatic environment. Mar. Pollut. Bull. 51(1–4): 218–223.

573 doi:10.1016/j.marpolbul.2004.10.038.

574 Daghrir, R. & Drogui, P. 2013. Tetracycline antibiotics in the environment: a review. In

575 Environmental Chemistry Letters. Springer Berlin Heidelberg. pp. 209–227.

576 Daughton, C.G. 2008. Pharmaceuticals as environmental pollutants: The ramifications for

577 human exposure. In International Encyclopedia of Public Health. doi:10.1016/B978-

578 012373960-5.00403-2.

579 Daughton, C.G., and Ruhoy, I.S. 2008. The afterlife of drugs and the role of

580 pharmEcovigilance. Drug Saf. 31(12): 1069–1082. doi:10.2165/0002018-

Page 26 of 59



Draft

27

581 200831120-00004.

582 Daughton, C.G., and Ternes, T.A. 1999. Pharmaceuticals and personal care products in

583 the environment: agents of subtle change? Environ. Health Perspect. 107(6): 907.

584 Dodder, N.G., Maruya, K.A., Lee Ferguson, P., Grace, R., Klosterhaus, S., La Guardia,

585 M.J., Lauenstein, G.G., and Ramirez, J. 2014. Occurrence of contaminants of

586 emerging concern in mussels (Mytilus spp.) along the California coast and the

587 influence of land use, storm water discharge, and treated wastewater effluent. Mar.

588 Pollut. Bull. 81(2): 340–346. Elsevier Ltd. doi:10.1016/j.marpolbul.2013.06.041.

589 Van Doorslaer, X., Dewulf, J., Van Langenhove, H., and Demeestere, K. 2014.

590 Fluoroquinolone antibiotics: An emerging class of environmental micropollutants.

591 Sci. Total Environ. 500–501: 250–269. Elsevier B.V.

592 doi:10.1016/j.scitotenv.2014.08.075.

593 Du, J., Zhao, H., Liu, S., Xie, H., Wang, Y., and Chen, J. 2017. Antibiotics in the coastal

594 water of the South Yellow Sea in China: Occurrence, distribution and ecological

595 risks. Sci. Total Environ. 595: 521–527. doi:10.1016/j.scitotenv.2017.03.281.

596 Ericson, H., Thorsén, G., and Kumblad, L. 2010. Physiological effects of diclofenac,

597 ibuprofen and propranolol on Baltic Sea blue mussels. Aquat. Toxicol. 99(2): 223–

598 231. doi:10.1016/j.aquatox.2010.04.017.

599 Esplugas, S., Bila, D.M., Krause, L.G.T., and Dezotti, M. 2007. Ozonation and advanced

600 oxidation technologies to remove endocrine disrupting chemicals (EDCs) and

601 pharmaceuticals and personal care products (PPCPs) in water effluents. J. Hazard.

Page 27 of 59



Draft

28

602 Mater. 149(3): 631–642. doi:10.1016/j.jhazmat.2007.07.073.

603 Evgenidou, E.N., Konstantinou, I.K., and Lambropoulou, D.A. 2015. Occurrence and

604 removal of transformation products of PPCPs and illicit drugs in wastewaters: A

605 review. Sci. Total Environ. 505: 905–926. Elsevier B.V.

606 doi:10.1016/j.scitotenv.2014.10.021.

607 Falandysz, J., Wyrzykowska, B., Puzyn, T., Strandberg, L., and Rappe, C. 2002.

608 Polychlorinated biphenyls ( PCBs ) and their congener- specific accumulation in

609 edible fish from the Gulf of Gdańsk, Baltic Sea. 19(8): 779–795.

610 doi:10.1080/0265203021014501.

611 Fang, T.H., Nan, F.H., Chin, T.S., and Feng, H.M. 2012. The occurrence and distribution

612 of pharmaceutical compounds in the effluents of a major sewage treatment plant in

613 Northern Taiwan and the receiving coastal waters. Mar. Pollut. Bull. 64(7): 1435–

614 1444. Elsevier Ltd. doi:10.1016/j.marpolbul.2012.04.008.

615 Fawell, J., and Ong, C.N. 2012. Emerging Contaminants and the Implications for

616 Drinking Water. Int. J. Water Resour. Dev. 28(2): 247–263.

617 doi:10.1080/07900627.2012.672394.

618 Fent, K., Weston, A.A., and Caminada, D. 2006. Ecotoxicology of human

619 pharmaceuticals. Aquat. Toxicol. 76(2): 122–159.

620 doi:10.1016/j.aquatox.2005.09.009.

621 Ferreira, A.P., De Lourdes, C., and Da Cunha, N. 2005. Anthropic pollution in aquatic

622 environment: Development of a caffeine indicator. Int. J. Environ. Health Res.

Page 28 of 59



Draft

29

623 15(4): 303–311. doi:10.1080/09603120500155898.

624 Fick, J., Lindberg, R.H., Parkkonen, J., Arvidsson, B., Tysklind, M., and Joakim Larsson,

625 D.G. 2010. Therapeutic levels of levonorgestrel detected in blood plasma of fish:

626 results from screening rainbow trout exposed to treated sewage effluents. Environ.

627 Sci. Technol. 44(7): 2661–2666. doi:10.1021/es903440m.

628 Franzellitti, S., Buratti, S., Capolupo, M., Du, B., Haddad, S.P., Chambliss, C.K., Brooks,

629 B.W., and Fabbri, E. 2014. An exploratory investigation of various modes of action

630 and potential adverse outcomes of fluoxetine in marine mussels. Aquat. Toxicol.

631 151: 14–26. Elsevier B.V. doi:10.1016/j.aquatox.2013.11.016.

632 Garric, J., and Ferrari, B. 2005. Pharmaceuticals in aquatic ecosystems. Levels of

633 exposure and biological effects: A review. Rev. des Sci. l’Eau/Journal Water Sci.

634 18(3): 307–330.

635 Gaw, S., Thomas, K. V., and Hutchinson, T.H. 2014. Sources, impacts and trends of

636 pharmaceuticals in the marine and coastal environment. Philos. Trans. R. Soc. B

637 Biol. Sci. 369(1656): 20130572–20130572. doi:10.1098/rstb.2013.0572.

638 Gibson, G.G., and Paul Skett. 1996. Pathways of drug metabolism. In Introduction to

639 Drug Metabolism. Springer, Boston, MA, Boston. pp. 1–31. doi:10.1007/978-1-

640 4899-3188-7.

641 Gilroy, È.A.M., Balakrishnan, V.K., Solomon, K.R., Sverko, E., and Sibley, P.K. 2012.

642 Behaviour of pharmaceuticals in spiked lake sediments – Effects and interactions

643 with benthic invertebrates. Chemosphere 86(6): 578–584. Pergamon.

Page 29 of 59



Draft

30

644 doi:10.1016/J.CHEMOSPHERE.2011.10.022.

645 Gonzalez-Rey, M., and Bebianno, M.J. 2014. Effects of non-steroidal anti-inflammatory

646 drug (NSAID) diclofenac exposure in mussel Mytilus galloprovincialis. Aquat.

647 Toxicol. 148: 818–831. Elsevier B.V. doi:10.1016/j.aquatox.2014.01.011.

648 Gorga, M., Petrovic, M., and Barceló, D. 2013. Multi-residue analytical method for the

649 determination of endocrine disruptors and related compounds in river and waste

650 water using dual column liquid chromatography switching system coupled to mass

651 spectrometry. J. Chromatogr. A 1295: 57–66. Elsevier B.V.

652 doi:10.1016/j.chroma.2013.04.028.

653 Grabicova, K., Grabic, R., Blaha, M., Kumar, V., Cerveny, D., Fedorova, G., and

654 Randak, T. 2015. Presence of pharmaceuticals in benthic fauna living in a small

655 stream affected by effluent from a municipal sewage treatment plant. Water Res. 72:

656 145–153. Elsevier Ltd. doi:10.1016/j.watres.2014.09.018.

657 Graham, G.G., Davies, M.J., Day, R.O., Mohamudally, A., and Scott, K.F. 2013. The

658 modern pharmacology of paracetamol: Therapeutic actions, mechanism of action,

659 metabolism, toxicity and recent pharmacological findings. Inflammopharmacology

660 21(3): 201–232. doi:10.1007/s10787-013-0172-x.

661 Gros, M., Petrović, M., Ginebreda, A., and Barceló, D. 2010. Removal of

662 pharmaceuticals during wastewater treatment and environmental risk assessment

663 using hazard indexes. Environ. Int. 36(1): 15–26. doi:10.1016/j.envint.2009.09.002.

664 Guler, Y., and Ford, A.T. 2010. Anti-depressants make amphipods see the light. Aquat.

Page 30 of 59



Draft

31

665 Toxicol. 99(3): 397–404. Elsevier B.V. doi:10.1016/j.aquatox.2010.05.019.

666 Halling-Sorensen, B., Halling-Sorensen, B., Nielsen, S.N., Nielsen, S.N., Lanzky, P.F.,

667 Lanzky, P.F., Ingerslev, F., Ingerslev, F., Holten Lutzhoft, H.C., Holten Lutzhoft,

668 H.C., S.E., J., and S.E., J. 1998. Occurence, fate and effects of pharmaceuticals

669 substance in the environment - A review. Chemosphere 36(2): 357–393.

670 doi:http://dx.doi.org/10.1016/S0045-6535(97)00354-8.

671 Harris, P., Nagy, S., and Vardaxis, N. 2014. Mosby’s Dictionary of Medicine, Nursing

672 and Health Professions-Australian & New Zealand Edition-eBook. Edited ByN.

673 Harris, P., Nagy, S. and Vardaxis. Elsevier Health Sciences., Australia.

674 Heberer, T. 2002. Occurrence , fate , and removal of pharmaceutical residues in the

675 aquatic environment : a review of recent research data. 131: 5–17.

676 doi:10.1016/S0378-4274(02)00041-3.

677 Hernando, M.D., Mezcua, M., Fernández-Alba, A.R., and Barceló, D. 2006.

678 Environmental risk assessment of pharmaceutical residues in wastewater effluents,

679 surface waters and sediments. Talanta 69(2 SPEC. ISS.): 334–342.

680 doi:10.1016/j.talanta.2005.09.037.

681 Hijosa-Valsero, M., Sidrach-Cardona, R., Martín-Villacorta, J., Cruz Valsero-Blanco, M.,

682 Bayona, J.M., and Bécares, E. 2011. Statistical modelling of organic matter and

683 emerging pollutants removal in constructed wetlands. Bioresour. Technol. 102(8):

684 4981–4988. doi:10.1016/j.biortech.2011.01.063.

685 Huerta, B., Jakimska, A., Gros, M., Rodríguez-Mozaz, S., and Barceló, D. 2013. Analysis

Page 31 of 59



Draft

32

686 of multi-class pharmaceuticals in fish tissues by ultra-high-performance liquid

687 chromatography tandem mass spectrometry. J. Chromatogr. A 1288: 63–72. Elsevier

688 B.V. doi:10.1016/j.chroma.2013.03.001.

689 Hughes, S., and Vincent, M. 2012. Managing gout and hyperuricaemia. Clin. Pharm.

690 4(3): 79–83. Elsevier Ltd. doi:10.1016/j.mpmed.2011.12.027.

691 Ikehata, K., Jodeiri Naghashkar, N., and Gamal El-Din, M. 2006. Degradation of aqueous

692 pharmaceuticals by ozonation and advanced oxidation processes: A review. Ozone

693 Sci. Eng. 28(6): 353–414. doi:10.1080/01919510600985937.

694 Jelic, A., Gros, M., Ginebreda, A., Cespedes-Sánchez, R., Ventura, F., Petrovic, M., and

695 Barcelo, D. 2011. Occurrence, partition and removal of pharmaceuticals in sewage

696 water and sludge during wastewater treatment. Water Res. 45(3): 1165–1176.

697 Pergamon. doi:10.1016/j.watres.2010.11.010.

698 Jiang, J.J., Lee, C.L., and Fang, M. Der. 2014. Emerging organic contaminants in coastal

699 waters: Anthropogenic impact, environmental release and ecological risk. Mar.

700 Pollut. Bull. 85(2): 391–399. Elsevier Ltd. doi:10.1016/j.marpolbul.2013.12.045.

701 Jiang, J.Q., Zhou, Z., and Sharma, V.K. 2013. Occurrence, transportation, monitoring and

702 treatment of emerging micro-pollutants in waste water - A review from global

703 views. Microchem. J. 110: 292–300. Elsevier B.V.

704 doi:10.1016/j.microc.2013.04.014.

705 Kanakaraju, D., Glass, B.D., and Oelgemöller, M. 2014. Titanium dioxide photocatalysis

706 for pharmaceutical wastewater treatment. Environ. Chem. Lett. 12(1): 27–47.

Page 32 of 59



Draft

33

707 doi:10.1007/s10311-013-0428-0.

708 Kim, H.Y., Lee, I.S., and Oh, J.E. 2017. Human and veterinary pharmaceuticals in the

709 marine environment including fish farms in Korea. Sci. Total Environ. 579: 940–

710 949. Elsevier B.V. doi:10.1016/j.scitotenv.2016.10.039.

711 Klosterhaus, S.L., Grace, R., Hamilton, M.C., and Yee, D. 2013. Method validation and

712 reconnaissance of pharmaceuticals, personal care products, and alkylphenols in

713 surface waters, sediments, and mussels in an urban estuary. Environ. Int. 54: 92–99.

714 Elsevier Ltd. doi:10.1016/j.envint.2013.01.009.

715 Knee, K.L., Gossett, R., Boehm, A.B., and Paytan, A. 2010. Caffeine and agricultural

716 pesticide concentrations in surface water and groundwater on the north shore of

717 Kauai (Hawaii, USA). Mar. Pollut. Bull. 60(8): 1376–1382. Elsevier Ltd.

718 doi:10.1016/j.marpolbul.2010.04.019.

719 Kosma, C.I., Lambropoulou, D.A., and Albanis, T.A. 2014. Investigation of PPCPs in

720 wastewater treatment plants in Greece: Occurrence, removal and environmental risk

721 assessment. Sci. Total Environ. 466–467: 421–438. Elsevier B.V.

722 doi:10.1016/j.scitotenv.2013.07.044.

723 Kümmerer, K. 2001. Drugs in the environment: Emission of drugs, diagnostic aids and

724 disinfectants into wastewater by hospitals in relation to other sources - A review.

725 Chemosphere 45(6–7): 957–969. doi:10.1016/S0045-6535(01)00144-8.

726 Kümmerer, K. 2008. Pharmaceuticals in the environment- A Brief Summary. In

727 Pharmaceuticals in the environment: sources, fate, effects and risks., 3rd edition.

Page 33 of 59



Draft

34

728 Springer Science & Business Media. pp. 3–21.

729 Kümmerer, K., Al-Ahmad, A., and Mersch-Sundermann, V. 2000. Biodegradability of

730 some antibiotics, elimination of the genotoxicity and affection of wastewater

731 bacteria in a simple test. Chemosphere 40(7): 701–710. doi:10.1016/S0045-

732 6535(99)00439-7.

733 Lahti, M., Brozinski, J.M., Jylhä, A., Kronberg, L., and Oikari, A. 2011. Uptake from

734 water, biotransformation, and biliary excretion of pharmaceuticals by rainbow trout.

735 Environ. Toxicol. Chem. 30(6): 1403–1411. doi:10.1002/etc.501.

736 Lambropoulou, D.A., and Nollet, M.L. 2014. Transformation products of emerging

737 contaminants in the environment: analysis, processes, occurrence, effects and risks.

738 In 1st edition. John Wiley & Sons.

739 Lapworth, D.J., Baran, N., Stuart, M.E., and Ward, R.S. 2012. Emerging organic

740 contaminants in groundwater: A review of sources, fate and occurrence. Environ.

741 Pollut. 163: 287–303. Elsevier Ltd. doi:10.1016/j.envpol.2011.12.034.

742 Larsson, D.G.J., Adolfsson-Erici, M., Parkkonen, J., Pettersson, M., Berg, A.H., Olsson,

743 P.E., and Förlin, L. 1999. Ethinyloestradiol - An undesired fish contraceptive?

744 Aquat. Toxicol. 45(2–3): 91–97. doi:10.1016/S0166-445X(98)00112-X.

745 Li, W., Shi, Y., Gao, L., Liu, J., and Cai, Y. 2012. Investigation of antibiotics in mollusks

746 from coastal waters in the Bohai Sea of China. Environ. Pollut. 162: 56–62. Elsevier

747 Ltd. doi:10.1016/j.envpol.2011.10.022.

748 Liang, X., Chen, B., Nie, X., Shi, Z., Huang, X., and Li, X. 2013. The distribution and

Page 34 of 59



Draft

35

749 partitioning of common antibiotics in water and sediment of the Pearl River Estuary,

750 South China. Chemosphere 92(11): 1410–1416. Elsevier Ltd.

751 doi:10.1016/j.chemosphere.2013.03.044.

752 Liem, A.K.D. 1999. Dioxins and dioxin-like PCBs in foodstuffs. Levels and trends.

753 Organohalogen Compd. 44: 1–4.

754 Linde, K., Kriston, L., Rücker, G., Jamil, S., Schumann, I., Meissner, K., Sigterman, K.,

755 and Schneider, A. 2015. Efficacy and Acceptability of Pharmacological Treatments

756 for Depressive Disorders in Primary Care: Systematic Review and Network Meta-

757 Analysis. Ann. Fam. Med. 13(1): 69–79. doi:10.1370/afm.1687.INTRODUCTION.

758 Liu, J., Lu, G., Xie, Z., Zhang, Z., Li, S., and Yan, Z. 2015. Occurrence, bioaccumulation

759 and risk assessment of lipophilic pharmaceutically active compounds in the

760 downstream rivers of sewage treatment plants. Sci. Total Environ. 511: 54–62.

761 Elsevier B.V. doi:10.1016/j.scitotenv.2014.12.033.

762 Löffler, D., Römbke, J., Meller, M., and Ternes, T.A. 2005. Environmental fate of

763 pharmaceuticals in water/sediment systems. Environ. Sci. Technol. 39(14): 5209–

764 5218. doi:10.1021/es0484146.

765 López-Serna, R., Jurado, A., Vázquez-Suñé, E., Carrera, J., Petrović, M., and Barceló, D.

766 2013. Occurrence of 95 pharmaceuticals and transformation products in urban

767 groundwaters underlying the metropolis of Barcelona, Spain. Environ. Pollut. 174:

768 305–315. doi:10.1016/j.envpol.2012.11.022.

769 Luscombe, D., and Nicholls, P.J. 1998. Processes of drug handling by the body. In Smith

Page 35 of 59



Draft

36

770 and Williams’ Introduction to the Principles of Drug Design and Action, 3rd edition.

771 Edited by H.J. Smith. Overseas Publishers Association. pp. 1–31.

772 Lv, M., Sun, Q., Xu, H., Lin, L., Chen, M., and Yu, C.P. 2014. Occurrence and fate of

773 triclosan and triclocarban in a subtropical river and its estuary. Mar. Pollut. Bull.

774 88(1–2): 383–388. Elsevier Ltd. doi:10.1016/j.marpolbul.2014.07.065.

775 Maletz, S., Floehr, T., Beier, S., Klümper, C., Brouwer, A., Behnisch, P., Higley, E.,

776 Giesy, J.P., Hecker, M., Gebhardt, W., Linnemann, V., Pinnekamp, J., and Hollert,

777 H. 2013. In vitro characterization of the effectiveness of enhanced sewage treatment

778 processes to eliminate endocrine activity of hospital effluents. Water Res. 47(4):

779 1545–1557. doi:10.1016/j.watres.2012.12.008.

780 Martin-Diaz, L., Franzellitti, S., Buratti, S., Valbonesi, P., Capuzzo, A., and Fabbri, E.

781 2009. Effects of environmental concentrations of the antiepilectic drug

782 carbamazepine on biomarkers and cAMP-mediated cell signaling in the mussel

783 Mytilus galloprovincialis. Aquat. Toxicol. 94(3): 177–185.

784 doi:10.1016/j.aquatox.2009.06.015.

785 McEneff, G., Barron, L., Kelleher, B., Paull, B., and Quinn, B. 2013. The determination

786 of pharmaceutical residues in cooked and uncooked marine bivalves using

787 pressurised liquid extraction, solid-phase extraction and liquid chromatography-

788 tandem mass spectrometry. Anal. Bioanal. Chem. 405(29): 9509–9521.

789 doi:10.1007/s00216-013-7371-6.

790 McEneff, G., Barron, L., Kelleher, B., Paull, B., and Quinn, B. 2014. A year-long study

791 of the spatial occurrence and relative distribution of pharmaceutical residues in

Page 36 of 59



Draft

37

792 sewage effluent, receiving marine waters and marine bivalves. Sci. Total Environ.

793 476–477: 317–326. Elsevier B.V. doi:10.1016/j.scitotenv.2013.12.123.

794 Miller, T.H., McEneff, G.L., Brown, R.J., Owen, S.F., Bury, N.R., and Barron, L.P. 2015.

795 Pharmaceuticals in the freshwater invertebrate, Gammarus pulex, determined using

796 pulverised liquid extraction, solid phase extraction and liquid chromatography-

797 tandem mass spectrometry. Sci. Total Environ. 511: 153–160. Elsevier B.V.

798 doi:10.1016/j.scitotenv.2014.12.034.

799 Minh, T.B., Leung, H.W., Loi, I.H., Chan, W.H., So, M.K., Mao, J.Q., Choi, D., Lam,

800 J.C.W., Zheng, G., Martin, M., Lee, J.H.W., Lam, P.K.S., and Richardson, B.J.

801 2009. Antibiotics in the Hong Kong metropolitan area: Ubiquitous distribution and

802 fate in Victoria Harbour. Mar. Pollut. Bull. 58(7): 1052–1062. Elsevier Ltd.

803 doi:10.1016/j.marpolbul.2009.02.004.

804 Mittal, B., Tulsyan, S., Kumar, S., Mittal, R.D., and Agarwal, G. 2015. Chapter Four:

805 Cytochrome P450 in Cancer Susceptibility and Treatment. Adv. Clin. Chem. 71: 77–

806 139. Available from https://doi.org/10.1016/bs.acc.2015.06.003.

807 Moreno-González, R., Rodriguez-Mozaz, S., Gros, M., Barceló, D., and León, V.M.

808 2015. Seasonal distribution of pharmaceuticals in marine water and sediment from a

809 mediterranean coastal lagoon (SE Spain). Environ. Res. 138: 326–344. Elsevier.

810 doi:10.1016/j.envres.2015.02.016.

811 Moreno-González, R., Rodríguez-Mozaz, S., Huerta, B., Barceló, D., and León, V.M.

812 2016. Do pharmaceuticals bioaccumulate in marine molluscs and fish from a coastal

813 lagoon? Environ. Res. 146: 282–298. Elsevier. doi:10.1016/j.envres.2016.01.001.

Page 37 of 59



Draft

38

814 Mottaleb, M.A., Usenko, S., O’Donnell, J.G., Ramirez, A.J., Brooks, B.W., and

815 Chambliss, C.K. 2009. Gas chromatography-mass spectrometry screening methods

816 for select UV filters, synthetic musks, alkylphenols, an antimicrobial agent, and an

817 insect repellent in fish. J. Chromatogr. A 1216(5): 815–823.

818 doi:10.1016/j.chroma.2008.11.072.

819 Munaron, D., Tapie, N., Budzinski, H., Andral, B., and Gonzalez, J.L. 2012.

820 Pharmaceuticals, alkylphenols and pesticides in Mediterranean coastal waters:

821 Results from a pilot survey using passive samplers. Estuar. Coast. Shelf Sci. 114:

822 82–92. Elsevier Ltd. doi:10.1016/j.ecss.2011.09.009.

823 Murkin, A. 2014. Metabolism of acetaminophen (paracetamol). Available from

824 https://commons.wikimedia.org/wiki/File:Acetaminophen_metabolism.png

825 [accessed 12 July 2017].

826 Na, G., Fang, X., Cai, Y., Ge, L., Zong, H., Yuan, X., Yao, Z., and Zhang, Z. 2013.

827 Occurrence, distribution, and bioaccumulation of antibiotics in coastal environment

828 of Dalian, China. Mar. Pollut. Bull. 69(1–2): 233–237. Elsevier Ltd.

829 doi:10.1016/j.marpolbul.2012.12.028.

830 Nakamura, Y., Yamamoto, H., Sekizawa, J., Kondo, T., Hirai, N., and Tatarazako, N.

831 2008. The effects of pH on fluoxetine in Japanese medaka (Oryzias latipes): Acute

832 toxicity in fish larvae and bioaccumulation in juvenile fish. Chemosphere 70(5):

833 865–873. doi:10.1016/j.chemosphere.2007.06.089.

834 Nash, J.P., Kime, D.E., Van der Ven, L.T.M., Wester, P.W., Brion, F., Maack, G.,

835 Stahlschmidt-Allner, P., and Tyler, C.R. 2004. Long-term exposure to

Page 38 of 59



Draft

39

836 environmental concentrations of the pharmaceutical ethynylestradiol causes

837 reproductive failure in fish. Environ. Health Perspect. 112(17): 1725–1733.

838 doi:10.1289/ehp.7209.

839 Nunes, B., Gaio, A.R., Carvalho, F., and Guilhermino, L. 2008. Behaviour and

840 biomarkers of oxidative stress in Gambusia holbrooki after acute exposure to widely

841 used pharmaceuticals and a detergent. Ecotoxicol. Environ. Saf. 71(2): 341–354.

842 doi:10.1016/j.ecoenv.2007.12.006.

843 Petrik, L., Green, L., Zackon, M., Sanusi, C.Y., and Green, L. 2017. Desalination and

844 seawater quality at Green Point , Cape Town : A study on the effects of marine

845 sewage outfalls. 113(11): 1–10. doi:10.17159/sajs.2017/a0244.

846 Petrovic, M., Eljarrat, E., Lopez De Alda, M.J., and Barceló, D. 2004. Endocrine

847 disrupting compounds and other emerging contaminants in the environment: A

848 survey on new monitoring strategies and occurrence data. Anal. Bioanal. Chem.

849 378(3): 549–562. doi:10.1007/s00216-003-2184-7.

850 Petrović, M., Hernando, M.D., Díaz-Cruz, M.S., and Barceló, D. 2005, March 4. Liquid

851 chromatography-tandem mass spectrometry for the analysis of pharmaceutical

852 residues in environmental samples: A review. Elsevier.

853 doi:10.1016/j.chroma.2004.10.110.

854 Ramirez, a, Brain, R., Usenko, S., Mottaleb, M., O’Donnell, J., Stahl, L., Wathen, J.,

855 Snyder, B., Pitt, J., Perez-Hurtado, P., Dobbins, L., Brooks, B., and Chambliss, C.

856 2009. Occurrence of pharmaceuticals and personal care products in fish: results of a

857 national pilot study in the United States. Environ. Toxicol. Chem. 28(12): 2587–

Page 39 of 59



Draft

40

858 2597. doi:10.1897/08-561.1.

859 Ramirez, A.J., Mottaleb, M.A., Brooks, B.W., and Chambliss, C.K. 2007. Analysis of

860 pharmaceuticals in fish using liquid chromatography-tandem mass spectrometry.

861 Anal. Chem. 79(8): 3155–63. doi:10.1021/ac062215i.

862 Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., J??rvinen, T., and

863 Savolainen, J. 2008. Prodrugs: Design and clinical applications. Nat. Rev. Drug

864 Discov. 7(3): 255–270. doi:10.1038/nrd2468.

865 Rendal, C., Kusk, K.O., and Trapp, S. 2011. Optimal choice of pH for toxicity and

866 bioaccumulation studies of ionizing organic chemicals. Environ. Toxicol. Chem.

867 30(11): 2395–2406. doi:10.1002/etc.641.

868 del Rey, R.Z., Granek, E.F., and Sylvester, S. 2012. Occurrence and concentration of

869 caffeine in Oregon coastal waters. Mar. Pollut. Bull. 64(7): 1417–1424. Elsevier Ltd.

870 doi:10.1016/j.marpolbul.2012.04.015.

871 Richardson, M.L., and Bowron, J.M. 1985. The fate of pharmaceutical chemicals in the

872 aquatic environment. J. Pharm. Pharmacol. 37(1): 1–12. doi:10.1111/j.2042-

873 7158.1985.tb04922.x.

874 Rivera-Utrilla, J., Sánchez-Polo, M., Ferro-García, M.Á., Prados-Joya, G., and Ocampo-

875 Pérez, R. 2013. Pharmaceuticals as emerging contaminants and their removal from

876 water. A review. Chemosphere 93(7): 1268–1287. Elsevier Ltd.


878 Rodil, R., Quintana, J.B., Concha-Graña, E., López-Mahía, P., Muniategui-Lorenzo, S.,

Page 40 of 59



Draft

41

879 and Prada-Rodríguez, D. 2012. Emerging pollutants in sewage, surface and drinking

880 water in Galicia (NW Spain). Chemosphere 86(10): 1040–1049. Elsevier Ltd.


882 Rodríguez-Navas, C., Björklund, E., Bak, S.A., Hansen, M., Krogh, K.A., Maya, F.,

883 Forteza, R., and Cerdà, V. 2013. Pollution pathways of pharmaceutical residues in

884 the aquatic environment on the island of Mallorca, Spain. Arch. Environ. Contam.

885 Toxicol. 65(1): 56–66. doi:10.1007/s00244-013-9880-x.

886 Rosenbaum, S.E. 2016. Basic Pharmacokinetics and Pharmacodynamics: An Integrated

887 Textbook and Computer Simulations. In 2nd edition. John Wiley & Sons., New

888 jersey.

889 Rudorfer, M. V., and Potter, W.Z. 1997. The role of metabolites of antidepressants in the

890 treatment of depression. CNS Drugs 7(4): 273–312. doi:10.2165/00023210-

891 199707040-00003.

892 Santos, L.H.M.L.M., Araújo, A.N., Fachini, A., Pena, A., Delerue-Matos, C., and

893 Montenegro, M.C.B.S.M. 2010. Ecotoxicological aspects related to the presence of

894 pharmaceuticals in the aquatic environment. J. Hazard. Mater. 175(1–3): 45–95.

895 doi:10.1016/j.jhazmat.2009.10.100.

896 Schwaiger, J., Ferling, H., Mallow, U., Wintermayr, H., and Negele, R.D. 2004. Toxic

897 effects of the non-steroidal anti-inflammatory drug diclofenac. Part I:

898 Histopathological alterations and bioaccumulation in rainbow trout. Aquat. Toxicol.

899 68(2): 141–150. doi:10.1016/j.aquatox.2004.03.014.

Page 41 of 59



Draft

42

900 Seiler, J.P. 2002. Pharmacodynamic activity of drugs and ecotoxicology - Can the two be

901 connected? Toxicol. Lett. 131(1–2): 105–115. doi:10.1016/S0378-4274(02)00045-0.

902 Siegener, R., and Chen, R.F. 2002. Caffeine in Boston Harbor seawater. Mar. Pollut.

903 Bull. 44(5): 383–387. doi:10.1016/S0025-326X(00)00176-4.

904 Sjödin, A., Hagmar, L., Klasson-Wehler, E., Björk, J., and Bergman, Å. 2000. Influence

905 of the consumption of fatty Baltic Sea fish on plasma levels of halogenated

906 environmental contaminants in Latvian and Swedish men. Environ. Health Perspect.

907 108(11): 1035–1041. doi:10.1289/ehp.001081035.

908 Solé, M., Shaw, J.P., Frickers, P.E., Readman, J.W., and Hutchinson, T.H. 2010. Effects

909 on feeding rate and biomarker responses of marine mussels experimentally exposed

910 to propranolol and acetaminophen. Anal. Bioanal. Chem. 396(2): 649–656.

911 doi:10.1007/s00216-009-3182-1.

912 Stackelberg, P.E., Furlong, E.T., Meyer, M.T., Zaugg, S.D., Henderson, A.K., and

913 Reissman, D.B. 2004. Persistence of pharmaceutical compounds and other organic

914 wastewater contaminants in a conventional drinking-water-treatment plant. Sci.

915 Total Environ. 329(1–3): 99–113. doi:10.1016/j.scitotenv.2004.03.015.

916 Steger-Hartmann, T., Länge, R., Schweinfurth, H., Tschampel, M., and Rehmann, I.

917 2002. Investigations into the environmental fate and effects of iopromide (ultravist),

918 a widely used iodinated X-ray contrast medium. Water Res. 36(1): 266–274.

919 doi:10.1016/S0043-1354(01)00241-X.

920 Stringer, L.J., and Snyder, S.I. 2014. Anticancer drug. Encyclopædia Britannica, inc.

Page 42 of 59



Draft

43

921 Available from https://www.britannica.com/science/anticancer-drug.

922 Sweetman, A.J., Alcock, R.E., Wittsiepe, J., and Jones, K.C. 2000. Human exposure to

923 PCDD/FS in the UK: The development of a modelling approach to give historical

924 and future perspectives. Environ. Int. 26(1–2): 37–47. doi:10.1016/S0160-

925 4120(00)00076-3.

926 Taxak, N., and Bharatam, P. V. 2004. Drug Metabolism. J. Clin. Pharmacol. (January):

927 259–282.

928 Taylor, N.G.H., Verner-Jeffreys, D.W., and Baker-Austin, C. 2011. Aquatic systems:

929 Maintaining, mixing and mobilising antimicrobial resistance? Trends Ecol. Evol.

930 26(6): 278–284. doi:10.1016/j.tree.2011.03.004.

931 Tijani, J.O., Fatoba, O.O., Babajide, O.O., and Petrik, L.F. 2016. Pharmaceuticals,

932 endocrine disruptors, personal care products, nanomaterials and perfluorinated

933 pollutants: a review. Environ. Chem. Lett. 14(1): 27–49. Springer International

934 Publishing. doi:10.1007/s10311-015-0537-z.

935 Togola, A., and Budzinski, H. 2007. Development of polar organic integrative samplers

936 for analysis of pharmaceuticals in aquatic systems. Anal. Chem. 79(17): 6734–6741.

937 doi:10.1021/ac070559i.

938 Togola, A., and Budzinski, H. 2008. Multi-residue analysis of pharmaceutical compounds

939 in aqueous samples. J. Chromatogr. A 1177(1): 150–158.

940 doi:10.1016/j.chroma.2007.10.105.

941 Togunde, O.P., Oakes, K.D., Servos, M.R., and Pawliszyn, J. 2012. Optimization of solid

Page 43 of 59



Draft

44

942 phase microextraction for non-lethal in vivo determination of selected

943 pharmaceuticals in fish muscle using liquid chromatography-mass spectrometry. J.

944 Chromatogr. A 1261: 99–106. Elsevier B.V. doi:10.1016/j.chroma.2012.07.053.

945 Veetil, G.P.P., Vijaya. Nadaraja, A., Bhasi, A., Khan, S., and Bhaskaran, K. 2012.

946 Degradation of triclosan under aerobic, anoxic, and anaerobic conditions. Appl.

947 Biochem. Biotechnol. 167(6): 1603–1612. doi:10.1007/s12010-012-9573-3.

948 Verlicchi, P., Al Aukidy, M., and Zambello, E. 2012, July 1. Occurrence of

949 pharmaceutical compounds in urban wastewater: Removal, mass load and

950 environmental risk after a secondary treatment-A review. Elsevier.

951 doi:10.1016/j.scitotenv.2012.04.028.

952 Vidal-Dorsch, D.E., Bay, S.M., Maruya, K., Snyder, S.A., Trenholm, R.A., and

953 Vanderford, B.J. 2012. Contaminants of emerging concern in municipal wastewater

954 effluents and marine receiving water. Environ. Toxicol. Chem. 31(12): 2674–2682.

955 doi:10.1002/etc.2004.

956 Wang, J., and Gardinali, P.R. 2012. Analysis of selected pharmaceuticals in fish and the

957 fresh water bodies directly affected by reclaimed water using liquid

958 chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 404(9): 2711–

959 2720. doi:10.1007/s00216-012-6139-8.

960 Weigel, S., Kuhlmann, J., and Hühnerfuss, H. 2002. Drugs and personal care products as

961 ubiquitous pollutants: Occurrence and distribution of clofibric acid, caffeine and

962 DEET in the North Sea. Sci. Total Environ. 295(1–3): 131–141. doi:10.1016/S0048-

963 9697(02)00064-5.

Page 44 of 59



Draft

45

964 Wen, Y., Wang, Y., and Feng, Y.Q. 2006. Simultaneous residue monitoring of four

965 tetracycline antibiotics in fish muscle by in-tube solid-phase microextraction

966 coupled with high-performance liquid chromatography. Talanta 70(1 SPEC. ISS.):

967 153–159. doi:10.1016/j.talanta.2005.11.049.

968 Wießner, A., Kappelmeyer, U., Kuschk, P., and Kästner, M. 2005. Influence of the redox

969 condition dynamics on the removal efficiency of a laboratory-scale constructed

970 wetland. Water Res. 39(1): 248–256. doi:10.1016/j.watres.2004.08.032.

971 Wille, K., Kiebooms, J.A.L., Claessens, M., Rappé, K., Vanden Bussche, J., Noppe, H.,

972 Van Praet, N., De Wulf, E., Van Caeter, P., Janssen, C.R., De Brabander, H.F., and

973 Vanhaecke, L. 2011. Development of analytical strategies using U-HPLC-MS/MS

974 and LC-ToF-MS for the quantification of micropollutants in marine organisms.

975 Anal. Bioanal. Chem. 400(5): 1459–1472. doi:10.1007/s00216-011-4878-6.

976 Witte, W. 1998. Medical consequences of antibiotic use in agriculture. Science (80-. ).

977 279(5353): 996–997. doi:10.1126/science.279.5353.996.

978 Xie, Z., Lu, G., Yan, Z., Liu, J., Wang, P., and Wang, Y. 2017. Bioaccumulation and

979 trophic transfer of pharmaceuticals in food webs from a large freshwater lake.

980 Environ. Pollut. 222: 356–366. Elsevier Ltd. doi:10.1016/j.envpol.2016.12.026.

981 Yan, Q., Gao, X., Huang, L., Gan, X.M., Zhang, Y.X., Chen, Y.P., Peng, X.Y., and Guo,

982 J.S. 2014. Occurrence and fate of pharmaceutically active compounds in the largest

983 municipal wastewater treatment plant in Southwest China: Mass balance analysis

984 and consumption back-calculated model. Chemosphere 99: 160–170. Elsevier Ltd.


Page 45 of 59



Draft

46

986 Yang, Y., Ok, Y.S., Kim, K.-H., Kwon, E.E., and Tsang, Y.F. 2017. Occurrences and

987 removal of pharmaceuticals and personal care products (PPCPs) in drinking water

988 and water/sewage treatment plants: A review. Sci. Total Environ. 596–597: 303–


990 Zhang, L., Hu, J., Zhu, R., Zhou, Q., and Chen, J. 2013a. Degradation of paracetamol by

991 pure bacterial cultures and their microbial consortium. Appl. Microbiol. Biotechnol.

992 97(8): 3687–3698. doi:10.1007/s00253-012-4170-5.

993 Zhang, R., Tang, J., Li, J., Cheng, Z., Chaemfa, C., Liu, D., Zheng, Q., Song, M., Luo,

994 C., and Zhang, G. 2013b. Occurrence and risks of antibiotics in the coastal aquatic

995 environment of the Yellow Sea, North China. Sci. Total Environ. 450–451: 197–


997 LEGEND

998 Figure 1

999

1000 Figure 1: Sources and pathway of human and veterinary pharmaceuticals in the marine

1001 environment (modified from Yang et al., 2017)

1002 Figure 2

1003 Pathways and lead to non-toxic metabolites; the pathway

1004 leads to N-acetyl-p-benzoquinone imine (NAPQI), which is toxic if not conjugated to

1005 glutathione

Fate of Pharmaceutical in the environmentDirect discharge

Page 46 of 59



Draft

47

1006 Figure 2: Metabolism of acetaminophen (modified from Murkin 2014)

1007

Page 47 of 59



DraftGround water

Leaching Percolation

Aquaculture

Soil Landfill

Run-off

Effluent

Direct dischargeDirect discharge

DomesticPharmaceuticals (Human and veterinary) Faeces and urine Unconsumed compounds

Sewerage system

Agricultural application

Sludge

Water treatment

plants

Drinking water

Industrial and commercial

Treated and untreated effluent from industries and hospital

Animal farming

Receiving water

(Marine water)

Sewage treatment

plants

Direct discharge

Figure 1: Sources and pathway of human and veterinary pharmaceuticals in the marine environment (modified from Yang et al., 2017)

Page 48 of 59



Draft

OH

HN CH3

O

HN CH3HO

O

OH

acetaminophenN-hydroxylation

by cyochrome

P-450

N CH3

O

ONAPQI

toxicityconjugation with protein, nuclei acids

OH

HN

S-glutathione

CH3

O

O

HN CH3

O

S OO OH

HN

O

CH3

O

O

HO

OH

OH

CO2H

glucuronidationsulfation

glutathione conjugation

dehydration

Figure 2: Metabolism of acetaminophen (modified from Murkin 2014)

Page 49 of 59



Draft

Table 1: The occurrence of pharmaceuticals in marine/sea water

Pharmaceutical compound / residue

Therapeutic use

Concentration ng/L

Matrix Country Reference

Aspirin Analgesic 2.1 ng/L Marine water South coast of France (Togola and Budzinski 2008)Caffeine Stimulants 32 ng/L Coastal water Gulf of Lions, France (Munaron et al. 2012)

16.92 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)16 ng/L Seawater North Sea (Weigel et al. 2002)8.5 - 152.2 ng/L Seawater/Coastal water Oregon coast U.S. (del Rey et al. 2012)370 - 6700 ng/L Seawater Boston Harbor USA (Siegener and Chen 2002)2 - 10 ng/L Coastal water Kauai (Hawaii, USA) (Knee et al. 2010)134–147 ng/L Coastal water Southeast Brazil (Ferreira et al. 2005)ND - 5000 ng/L Estuary Jamaica Bay, New York,

USA(Benotti and Brownawell 2007)

55.1 - 778 ng/L Seawater Southern Sea of Korea (Kim et al. 2017)Clofibrate Clofibric acid Lipid lowering 1.3 ng/L Seawater North Sea (Weigel et al. 2002)

1.40 - 55.10 ng/L Seawater Northern Taiwan (Fang et al. 2012)Diazepam Anxiolytic 1.9 ng/L Marine water South coast of France (Togola and Budzinski 2008)

19 ng/L Marine water Mallorca, Spain (Rodríguez-Navas et al. 2013)Diclofenac Analgesic 22 ng/L Marine surface water Ireland (McEneff et al. 2014)

2.6 ng/L Marine water South coast of France (Togola and Budzinski 2008) 2.50 - 53.60 ng/L Seawater Northern Taiwan (Fang et al. 2012)

Ibuprofen Analgesic 1.7 ng/L Marine water South coast of France (Togola and Budzinski 2008)12.1 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014) 2.50 - 57.10 ng/L Seawater Northern Taiwan (Fang et al. 2012)

Ketoprofen Analgesic 1.8 ng/L Marine water South coast of France (Togola and Budzinski 2008)23.3 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)<1.70 - 6.59 ng/L Seawater Northern Taiwan (Fang et al. 2012)

Naproxen Analgesic 2.1 ng/L Marine water South coast of France (Togola and Budzinski 2008)0.7 ng/L Seawater Southern California (Vidal-Dorsch et al. 2012)

Sulfamethoxazole Antibiotic <0.23–50.4 ng/L Seawater North China (Zhang et al. 2013b)0.6 – 47.5 ng/L Seawater Hong Kong (Minh et al. 2009)2.23 ng/L Seawater Dalian, China (Na et al. 2013)48.1 ng/L Seawater Yellow Sea in China (Du et al. 2017)

Page 50 of 59



Draft

Erythromycin Antibiotic 26.6 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)<0.23–50.4 ng/L Seawater North China (Zhang et al. 2013b)0.665 - 1.02 ng/L Seawater Southern sea of Korea (Kim et al. 2017)1.7 ng/L Seawater Yellow Sea in China (Du et al. 2017)12 – 1974 ng/L Seawater Hong Kong (Minh et al. 2009)

Tetracycline Antibiotics 6.9 – 86 ng/L Seawater Hong Kong (Minh et al. 2009)Mefenamic acid NSAID 29 ng/L Marine surface water Ireland (McEneff et al. 2014)Trimethoprim Antibiotic <0.23–50.4 ng/L Seawater North China (Zhang et al. 2013b)

3 ng/L Marine surface water Ireland (McEneff et al. 2014)1.37 - 13.3 ng/L Seawater Southern sea of Korea (Kim et al. 2017)1.4 - 95.8 ng/L Seawater Yellow Sea in China (Du et al. 2017)0.6 – 47.5 ng/L Seawater Hong Kong (Minh et al. 2009)

Fluoxetine Antidepressant 0.9 - 36.0 ng/L Marine water Australia (Birch et al. 2015)Carbamazepine Antiepileptic 4 ng/L Marine surface water Ireland (McEneff et al. 2014)

2.2 ng/L Marine water South coast of France (Togola and Budzinski 2008)12 ng/L Coastal water Gulf of Lions, France (Munaron et al. 2012) 3.83 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)3.96 - 4.13 ng/L Seawater Southern sea of Korea (Kim et al. 2017)1.9 - 2.7 ng/L Marine water Australia (Birch et al. 2015)

Gemfibrozil Lipid regulator 38 ng/L Marine surface water Ireland (McEneff et al. 2014)1.2ng/L Marine water South coast of France (Togola and Budzinski 2008)3.67 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)0.9 ng/L Seawater Southern California (Vidal-Dorsch et al. 2012)

Imipramine Antidepressant 1.6 ng/L Marine water South coast of France (Togola and Budzinski 2008)Metropolol β- blockers 8 ng/L Seawater Mallorca, Spain (Rodríguez-Navas et al. 2013)Chloramphenicol Antibiotics 1.14 ng/L Seawater Dalian, China (Na et al. 2013)

73.2 ng/L Seawater Yellow Sea in China (Du et al. 2017)Acetaminophen Analgesic 16.7 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)

5.0 - 67.1 ng/L Marine water Australia (Birch et al. 2015)Amoxycillin Antibiotics 2.7 – 128 ng/L Seawater Hong Kong (Minh et al. 2009)Tramadol Analgesic 1.3 - 5.8 ng/L Marine water Australia (Birch et al. 2015)Codeine NSAIDS 63.6 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)

1.9 - 9.5 ng/L Marine water Australia (Birch et al. 2015)Propranolol β- blockers 7.02 - 7.58 ng/L Seawater Southern sea of Korea (Kim et al. 2017)

1.5 - 8.9 ng/L Marine water Australia (Birch et al. 2015)

Page 51 of 59



Draft

Sulfadiazine Antibiotics 0.207 - 5.69 ng/L Seawater Southern sea of Korea (Kim et al. 2017)2.05 ng/L Seawater Dalian, China (Na et al. 2013)

Sulfamethazine Antibiotics 2.81 ng/L Seawater Bohai Sea of China (Na et al. 2013)6.9 – 86 ng/L Seawater Hong Kong (Minh et al. 2009)

Clarithromycin Antibiotics 89.0 ng/L Seawater Yellow Sea in China (Du et al. 2017)Lincomycin Antibiotics 47.8 ng/L Seawater San Francisco, USA (Kim et al. 2017)Diltiazem Antianginal 11 ng/L Marine water Mallorca, Spain (Rodríguez-Navas et al. 2013)Sulfadimethoxine Antibiotics 2.00 ng/L Seawater Dalian, China (Na et al. 2013)

9.3 ng/L Seawater Yellow Sea in China (Du et al. 2017)Sulfamethoxypyridazine Antibiotics 1.95 ng/L Seawater Dalian, China (Na et al. 2013)Sulfamethizole Antibiotics 1.34 ng/L Seawater Dalian, China (Na et al. 2013)Atenolol β- blockers 8 - 38 ng/L Marine water Mallorca, Spain (Rodríguez-Navas et al. 2013)Sulfathiazole Antibiotics 1.89 ng/g Seawater Dalian, China (Na et al. 2013)Venlafaxine Antidepressant 0.8 - 44.7 ng/L Marine water Australia (Birch et al. 2015)Ampicillin Antibiotics 88.7 ng/L Seawater Southwestern Taiwan (Jiang et al. 2014)Ciprofloxacin Antibiotics 0.798 - 1.52 ng/L Seawater San Francisco, USA (Kim et al. 2017)Azithromycin Antibiotics 138.9 ng/L Seawater Yellow Sea in China (Du et al. 2017)

Page 52 of 59



Draft

Table 1: The occurrence of pharmaceuticals in marine biota

Pharmaceutical compound

Therapeutic use

Concentration Matrix Country Reference

Caffeine Stimulants 0.81 ng /g Fish (Gambusia holbrooki ) Miami, USA (Wang and Gardinali 2012)140 ng/g Mussels (Mytilus spp.) California U.S. (Dodder et al. 2014)1.00 - 1.36 ng/g Fish (Sebastes schlegelii) (Mugil

cephalus) and (Pagrus major) Southern sea of Korea

(Kim et al. 2017)

<20 ng/g

<20 ng/g

<20 ng/g<30 ng/g

Mussels (Mytilus galloprovincialis, Mytilus spp.) Striped venus clam(Chamalea gallina)Pacific oyster (Crassostrea gigas)Fish (Liza aurata and Platichthys flesus)

Europe (Italy, Spain, Portugal, Netherlands and Norway)Europe (Italy, Spain, Portugal, Netherlands and Norway

(Álvarez-Muñoz et al. 2015)


(Álvarez-Muñoz et al. 2015)(Álvarez-Muñoz et al. 2015)

Clofibrate Clofibric acid Lipid lowering 1 ng/g Mussels (Mytilus edulis) Belgium (Wille et al. 2011)Diazepam Anxiolytic < 20 ng/g Macroalgae (Saccharina

latissima and Laminaria digitate)Europe (Italy, Spain, Portugal, Norway and Netherlands)


Diclofenac Analgesic 29 ng/g Mussels (Mytilus spp.) Ireland (McEneff et al. 2014)1.2 - 2.2 ng/g Fish (Liza aurata) Murcia, Spain, (Moreno-González et al.

2016)< 30 ng/g Fish (Liza aurata and Platichthys

flesus)Europe (Italy, Spain, Portugal, Norway and Netherlands)


34.4*105 ng/L Fish plasma (Juvenile rainbow trout) Sweden (Brown et al. 2007)Ibuprofen Analgesic 46.8*105 ng/L Fish plasma (Juvenile rainbow trout) Sweden (Brown et al. 2007)Ketoprofen Analgesic 5 ng/g Mussels (Mytilus edulis) Belgium, Western

Europe(Wille et al. 2011)

6.0*104 ng/L Fish plasma (Juvenile rainbow trout) Sweden (Brown et al. 2007)Naproxen Analgesic 36.4*105 ng/L Fish plasma (Juvenile rainbow trout) Sweden (Brown et al. 2007)lndometacin Hypnotics 0.84 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)

Page 53 of 59



Draft

Sulfamethoxazole Antibiotic 20.1 ng/g Mollusks Bohai Sea of China (Li et al. 2012)< 20 ng/g Mussels (Mytilus

galloprovincialis, Mytilus spp.)Europe (Italy, Spain, Portugal, Norway and Netherlands)


2.27 ng/g Molluscs Dalian, China (Na et al. 2013)Erythromycin Antibiotic 0.51 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)

0.1 ng/g Mussels(Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)0.69 - 4.02 ng/g Fish (Sebastes schlegelii, Mugil

cephalus, and Pagrus major)Southern sea of Korea

(Kim et al. 2017)

2 ng/g Mussels (Mytilus spp.) California, US (Dodder et al. 2014)31.3 ng/g Mollusks Bohai Sea of China (Li et al. 2012)

Mefenamic acid NSAID 23 ng/g Mussels (Mytilus spp.) Ireland (McEneff et al. 2014)Trimethoprim Antibiotic 4 ng/g Mussels (Mytilus spp.) Ireland (McEneff et al. 2014)

1.03 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)1 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)0.040 - 7.5 ng/g Fish (Sebastes schlegelii, Mugil


(Kim et al. 2017)

Fluoxetine Antidepressant 1.19 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)0.64 - 4.0 ng/g Fish (Oncorhynchus mykiss and

Pimephales promelas)Canada (Togunde et al. 2012)

8.4 - 192.9 ng/g Mussels (Mytilus galloprovincialis) Cesenatico, Italy (Franzellitti et al. 2014)Sertraline Antidepressant 0.26 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)

1.4 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)0.24 - 2.09 ng/g Fish (Oncorhynchus mykiss and


5.5 ng/g Mussels (Mytilus spp.) California, US (Dodder et al. 2014)Carbamazepine Antiepileptic 5.3 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)

1.5 ng/g0.2 ng/g2.3 ng/g0.4 - 6.4 ng/g

Cockle (Cerastoderma glaucum) Noble pen shell (Pinna nobilis) Sea snail (Murex trunculus) Fish (Liza aurata and Gobius niger )

Murcia, Spain (Moreno-González et al. 2016)Moreno-González et al. 2016)

Page 54 of 59



Draft

Carbamazepine Antiepileptic 11 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)6 ng/g Mussels (Mytilus spp) Ireland (McEneff et al. 2014)0.1 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)2.1 ng/g Pacific oyster (Crassostrea gigas) Spain (Alvarez-Muñoz et al. 2015)< 20 ng/g

< 40 ng/g

Mussels (Mytilus galloprovincialis, Mytilus spp.) Fish (Liza aurata and Platichthys flesus)

Europe (Italy, Spain, Portugal, Netherlands and Norway)



Gemfibrozil Lipid regulator 18 ng/g Mussels (Mytilus spp.) Ireland (McEneff et al. 2014)320.7*105 ng/L Fish plasma (Juvenile rainbow trout) Sweden (Brown et al. 2007)

Norfluoxetine Antidepressant 0.41 ng/g Fish (Gambusia holbrooki) Florida USA (Wang and Gardinali 2012)< 0.64 ng/g Fish (Oncorhynchus mykiss and


Metropolol β- blockers 0.7 ng/g Fish (Liza aurata and Gobius niger ) Murcia, Spain (Moreno-González et al. 2016)

< 20 ng/g

< 20 ng/g

Macroalgae (Saccharina latissima and Laminaria digitate)Fish (Liza aurata and Platichthys flesus)



Chloramphenicol Antibiotics 3.23 ng/g Mollusks Dalian, China (Na et al. 2013)2.5 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)

Cocaine Stimulant 0.3 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)Acetaminophen Analgesic 2.5 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)Codeine NSAIDS 1.7 ng/g Mussels (Mytilus spp.) California, US (Dodder et al. 2014)Propranolol β- blockers 52 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)

0.5 ng/g Fish (Liza aurata and Gobius niger ) Murcia, Spain (Moreno-González et al. 2016)

< 20 ng/g

< 20 ng/g

Macroalgae (Saccharina latissima and Laminaria digitate)Fish (Liza aurata and Platichthys flesus)




0.1 - 0.4 ng/g Fish (Carassius auratus and Hemiculter leucisculus)

Nanjing, China (Liu et al. 2015)

Sulfadiazine Antibiotics 2.72 ng/g Mollusks Bohai Sea of China (Li et al. 2012)0.052 - 0.4 ng/g Fish (Sebastes schlegelii, Mugil


(Kim et al. 2017)

Page 55 of 59



Draft

5.21 ng/g Molluscs Dalian, China (Na et al. 2013)Sulfamethazine Antibiotics 5.98 ng/g Mollusk Bohai Sea of China (Li et al. 2012)

3.93 ng/g Mollusks Bohai Sea of China (Na et al. 2013)430 ng/g Mussels (Mytilus spp.) California, USA (Dodder et al. 2014)

Lincomycin Antibiotics 1.05 ng/g Fish (Gambusia holbrooki) Florida USA (Wang and Gardinali 2012)Diphenhydramine Antihistamines 0.08 ng/g Fish (Gambusia holbrooki) Florida USA (Wang and Gardinali 2012)

0.3 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)Diltiazem Antianginal 0.11 ng/g Fish (Gambusia holbrooki) Florida US (Wang and Gardinali 2012)

0.1 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)1.5 ng/g Pacific oyster (Crassostrea gigas) Spain (Alvarez-Muñoz et al. 2015)

Sulfadimethoxine Antibiotics 1.75 ng/g Mollusk Bohai Sea of China (Li et al. 2012)Sulfamethoxypyridazine Antibiotics 6.11 ng/g Mollusks Dalian, China (Na et al. 2013)Sulfamethizole Antibiotics 0.2 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)

2.05 ng/g Mollusks Dalian, China (Na et al. 2013)Amphetamine Stimulants 4.2 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)

20 ng/g Mussels (Mytilus spp.) California, US (Dodder et al. 2014)Atenolol β- blockers 0.3 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)

1 ng/g Mussels (Mytilus edulis) Belgium, Europe (Wille et al. 2011)13 ng/g Mussels (Mytilus spp.) California, US (Dodder et al. 2014)

Sulfathiazole Antibiotics 35.2 ng/g Mollusk Bohai Sea of China (Li et al. 2012)2.16 ng/g Mollusks Dalian, China (Na et al. 2013)

Hydrochlorothiazide Diuretic 1.6 ng/g3.2 ng/g1.8 ng/g3.9 - 10.5 ng/g


Murcia, Spain

Murcia, Spain

(Moreno-González et al. 2016)

< 20 ng/g

< 40 ng/g




Paroxetine Antidepressant 0.14 - 0.40 ng/g Fish (Oncorhynchus mykiss and Pimephales promelas)

Canada (Togunde et al. 2012)

Triamterene Diuretics 0.6 ng/g Mussels (Geukensia demissa) San Francisco USA (Klosterhaus et al. 2013)Ciprofloxacin Antibiotics 208 ng/g Mollusk Bohai Sea of China (Li et al. 2012)Sulfamerazine Antibiotics 5.98 ng/g Mollusk Bohai Sea of China (Li et al. 2012)

16.69 ng/g Mollusks Dalian, China (Na et al. 2013)

Page 56 of 59



http://www.sciencedirect.com/science/article/pii/S0025326X12006297



Draft

Venlafaxine Antidepressant 0.09 - 17 ng/g Fish (Oncorhynchus mykiss and Pimephales promelas)

Canada (Togunde et al. 2012)

0.3 - 1.1 ng/g2.7 ng/g0.4 ng/g3.1 ng/g


Murcia, Spain

Murcia, Spain

(Moreno-González et al. 2016)(Moreno-González et al. 2016)

2.7 ng/g2.7 ng/g2.3 ng/g

Pacific oyster (Crassostrea gigas)Mussel (Mytilus galloprovincialis)Striped venus clam (Chamelea gallina)

Spain

Spain

(Alvarez-Muñoz et al. 2015)


< 20 ng/g

< 40 ng/g




Azithromycin Antibiotics < 20 ng/g

< 40 ng/g

Mussels (Mytilus galloprovincialis, Mytilus spp.) Macroalgae (Saccharina latissima and Laminaria digitate)




3.0 ng/g1.3 ng/g3.0 ng/g

Pacific oyster (Crassostrea gigas)Mussel (Mytilus galloprovincialis)Striped venus clam (Chamelea gallina)

Spain

Spain



Page 57 of 59



Draft

Table 1: The occurrence of pharmaceuticals in marine sediment

Pharmaceutical compound

Therapeutic use Concentration Matrix Country Reference

Caffeine Stimulants 29.7 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)23.4 ng/g Sediment Bahia, Brazil (Beretta et al. 2014)17.2 - 466 ng/g Sediment Southern sea of Korea (Kim et al. 2017)

Clofibrate Clofibric acid Lipid lowering agent 8.6 ng /g Sediment Wuxi, China (Xie et al. 2017)Diazepam Anxiolytic 0.71 ng/g Sediment Bahia, Brazil (Beretta et al. 2014)Diclofenac Analgesic 1.06 ng/g Sediment Bahia, Brazil (Beretta et al. 2014)Ibuprofen Analgesic 14.3 ng/g Sediment Bahia, Brazil (Beretta et al. 2014)lndometacin Hypnotics 15.8 - 19.2 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Sulfamethoxazole Antibiotic 0.7 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)Erythromycin Antibiotic 3.4 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)

20.4 - 48.1 ng/g Sediment Southern sea of Korea (Kim et al. 2017)2 - 2.37 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)2.29 ng/g Sediment Bahia, Brazil (Beretta et al. 2014)

Trimethoprim Antibiotic 18.2 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)ND - 10.6 ng/g Sediment Southern sea of Korea (Kim et al. 2017)

Bezafibrate Lipid-lowering agent 0.37 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Chloramphenicol Antibiotics 2.31 ng/g Sediment Dalian, China (Na et al. 2013)Pravastatin Lipid-lowering agent 2.48 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Valsartan Diuretics 1.27 - 1.72 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Cocaine CNS stimulant and

local anesthetic0.2 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)

Sulfadiazine Antibiotics 1.22 - 3.13 ng/g Sediment Southern sea of Korea (Kim et al. 2017)1.39 ng/g Sediment Dalian, China (Na et al. 2013)

Sulfamethazine Antibiotics 1.76 ng/g Sediment Bohai Sea of China (Na et al. 2013)Clarithromycin Antibiotics 3 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Sulfamethoxypyridazine Antibiotics 7.67 ng/g Sediment Dalian, China (Na et al. 2013)Amphetamine CNS stimulants 3.3 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)Sulfathiazole Antibiotics 1.24 ng/L Sediment Dalian, China (Na et al. 2013)Hydrochlorothiazide Diuretic 1.8 ng/g Sediment Murcia, Spain (Moreno-González et al. 2015)Triamterene Diuretics 10.8 ng/g Sediment San Francisco, USA (Klosterhaus et al. 2013)Sulfamerazine Antibiotics 3.67 ng/g Sediment Dalian, China (Na et al. 2013)

Page 58 of 59



Draft

Page 59 of 59



Date post:	03-Mar-2021
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

Environmental Reviews · 2019. 2. 7. · Draft 1 1 Pharmaceuticals in the marine environment: A...

Documents