Emerging Contaminants xxx (2016) 1e16

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Emerging Contaminants
journal homepage: http://www.keaipublishing.com/en/journals/
emerging-contaminants/

Pharmaceuticals and personal care products (PPCPs) in the freshwater

aquatic environment
Anekwe Jennifer Ebele a, Mohamed Abou-Elwafa Abdallah a, b, *, Stuart Harrad a
a
School of Geography, Earth, and Environmental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom
b
Department of Analytical Chemistry, Faculty of Pharmacy, Assiut University, 71526 Assiut, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Pharmaceuticals and personal care products (PPCPs) are a unique group of emerging environmental
Received 7 October 2016 contaminants, due to their inherent ability to induce physiological effects in human at low doses. An
Received in revised form increasing number of studies has confirmed the presence of various PPCPs in different environmental
5 December 2016
compartments, which raises concerns about the potential adverse effects to humans and wildlife.
Accepted 6 December 2016
Available online xxx
Therefore, this article reviews the current state-of-knowledge on PPCPs in the freshwater aquatic
environment. The environmental risk posed by these contaminants is evaluated in light of the persis-
tence, bioaccumulation and toxicity criteria. Available literature on the sources, transport and degra-
Keywords:
Pharmaceuticals and personal care products
dation of PPCPs in the aquatic environment are evaluated, followed by a comprehensive review of the
Aquatic environment reported concentrations of different PPCP groups in the freshwater aquatic environment (water, sedi-
WWTPs ment and biota) of the five continents. Finally, future perspectives for research on PPCPs in the fresh-
Sediment water aquatic environment are discussed in light of the identified research gaps in current knowledge.
Persistence Copyright © 2017, KeAi Communications Co., Ltd. Production and hosting by Elsevier B.V. on behalf of
Biaccumulation KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://
Fate and behaviour creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction of 33 priority substances was also identified under the EU Water

Framework Directive (WFD) 2000/60/EC to be used as a control
Pharmaceuticals are defined as prescription, over the counter measure for the next 20 years. In 2007, PPCPs such as diclofenac,
and veterinary therapeutic drugs used to prevent or treat human iopamidol, musks and carbamazepine were identified as future
and animal diseases, while personal care products (PCPs) are used emerging priority candidates. Ibuprofen, clofibric acid, triclosan,
mainly to improve the quality of daily life [16]. Over the past few phthalates and bisphenol A are proposed additions to this list [45].
years, there has been increasing awareness of the unintentional Due to their large number and diverse chemical nature of PPCPs,
presence of PPCPs in various compartments of the aquatic envi- the Environment Agency (EA) of England and Wales proposed a
ronment (e.g. water, sediments and biota) at concentrations ranking system for these chemicals according to their perceived
capable of causing detrimental effects to the aquatic organisms. relative risk, with the aim of identifying substances with great
This has become a major concern because PPCPs are extensively potential to pose a risk to the aquatic environment. This ranking
and increasingly used in human and veterinary medicine, resulting system used a combination of traditional risk assessment proced-
in their continuous release to the environment [119]. Priority ures, persistence, bioaccumulation and toxicity (PBT) criteria,
pollutant lists have been developed both by the European Union occurrence data from various countries, availability of suitable
(EU) and the United States Environmental Protection Agency analytical methods, and aimed to include compounds representa-
(USEPA) identifying a wide variety of chemicals present in waste- tive of different therapeutic classes. Based on this procedure, the
waters and storm water runoff that may pose a threat to receiving top 10 compounds were: Lofepramine, Dextropropoxyphene, Pro-
water bodies including surface water. In the year 2000, an initial list cyclidine, Tramadol, Paracetamol, Clotrimazole, Thioridazine,
Mebeverine, Aminophylline, and Tamoxifen [6]. In a similar exer-
cise, using the OSPAR selection and prioritisation mechanism for
* Corresponding author. School of Geography, Earth, and Environmental Sciences, hazardous substances (DYNAMEC), an alternative list of priority
University of Birmingham, Birmingham, B15 2TT, United Kingdom. substances was identified, including: Lofepramine, Dextro-
E-mail address: [email protected] (M. Abou-Elwafa Abdallah). propoxyphene, Procyclidine, Tramadol, Paracetamol, Clotrimazole,
Peer review under responsibility of KeAi Communications Co., Ltd.

http://dx.doi.org/10.1016/j.emcon.2016.12.004
2405-6650/Copyright © 2017, KeAi Communications Co., Ltd. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: A.J. Ebele, et al., Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment,
Emerging Contaminants (2016), http://dx.doi.org/10.1016/j.emcon.2016.12.004
2 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

Thioridazine, Mebeverine, Aminophylline, Tamoxifen, Fluoxetine, relevant concentration over 14 days resulted in a plasma bio-
Trimethoprim, Sulfamethoxazole, Fenofibrate1, and Diclofenac concentration factor of 113 [114]. Another study by Ref. [160],
(OSPAR Commission, 2002 [188]). revealed bioaccumulation of the antiepileptic drug carbamazapine
Since then, several studies have investigated concentrations of (CBZ) by algae - Pseudokirchneriella subcapitata and the crustacean -
these priority and related PPCPs in the fresh water aquatic envi- Thamnocephalus platyurus with bioaccumulation factors of 2.2 and
ronment. This paper aims to: (a) provide an overview of the envi- 12.6 respectively. Furthermore [161], reported the uptake and
ronmental risk associated with PPCPs; (b) discuss the depuration of pharmaceuticals in reclaimed water by mosquito fish
environmental fate and behaviour of PPCPs in the aquatic system; (Gambusia holbrooki). The bioaccumulation factors measured for
(c) review the current state-of-knowledge on the levels and trends caffeine, diphenhydramine, diltrazem, carbamazepine and
of PPCPs in various compartments of the fresh water environment; ibuprofen were 2.0, 16, 16, 1.4, and 28 respectively. Oxazepam was
and (d) discuss the current research gaps and provide recommen- detected at high concentrations in Eurasian perch fish with a bio-
dations for future research. accumulation factor of 12 [19]. Also [43] revealed the accumulation
of fluoxetine in snails with the bioaccumulation factor of 3000 [42].
1.1. Environmental risk of PPCPs monitored 145 PPCPs in wild and caged mussels from the Grand
River, Ontario. Forty-three pharmaceuticals from different classes
The detection of chemical compounds in any environmental were detected in mussel tissues, with bioaccumulation factors
matrix does not necessarily mean that it is of concern or may cause ranging from 0.66 for metformin to 32 022 for sertraline.
harm. However, major concerns arise from the detection of chem- As distinct from pharmaceuticals, PCPs have been detected in
icals for which there is evidence that they may adversely affect algae which comprise the greatest abundance of plant biomass in
aquatic life [164]. The following sections summarise some of the the aquatic environment. The lipid content of algae provides an
major concerns about the presence of PPCPs in the freshwater entry point for trophic transfer of lipophilic organic contaminants.
aquatic environment. A study conducted by Ref. [38] detected the presence of two widely
used antimicrobial agents e triclocarban (TCC), triclosan (TCS) as
1.1.1. Persistence well as its metabolite methyl-triclosan (M-TCS) in algae samples
The physicochemical properties of many PPCPs, means that collected around a wastewater treatment plant (WWTP) in Texas.
many are not easily removed by conventional water treatment Concentrations of target PCPs in water samples were low ranging
processes, as demonstrated by their presence in drinking water from 50 to 200 ng/L, while higher levels of 50e400 ng/g fresh
[147]. The inability to effect complete removal of PPCPs from waste weight were detected in algae. The resulting bioaccumulation fac-
treatment plant poses a potential risk to aquatic organisms and tors ranged from (700e1500), (900e2100) and (1600e2700) for M-
public health. The overwhelming evidence from monitoring studies TCS, TCS and TCC respectively.
is that PPCPs have found their way into the aquatic environment
and are ubiquitous [21]. The extensive nature of global PPCPs use, 1.1.3. Toxicity
coupled with the escalating introduction of new pharmaceuticals The major concern about the toxic implications of pharmaceu-
to the market is contributing substantially to the environmental ticals (c.f. persistent organic pollutants such as PCBs (poly-
presence of these chemicals and their active metabolites in the chlorinated biphenyls), PFASs (perfluoroalkyl substances) and
aquatic environment [40]. Moreover, while not all PPCPs are PBDEs (polybrominated diphenyl ethers)) is that they were
persistent, their continuous use and release to the environment designed specifically to maximise their biological activity at low
means many are considered “pseudo-persistent”. Pseudo- doses and to target certain metabolic, enzymatic, or cell-signalling
persistent pharmaceuticals are suggested to have greater poten- mechanisms. The evolutionary conservation of these molecular
tial for environmental persistence than other organic contaminants targets in a given species potentially increases the possibility that
like pesticides, because their source continually replenishes even these pharmaceuticals will be pharmacologically active in non-
when acted on by environmental processes such as biodegradation, target organisms. This mode of action (MoA) concept can be
photodegradation and particulate sorption. Hence, pharmaceuti- applied to all aquatic biota, which are unintentionally exposed to
cals that may degrade would eventually and effectively behave as pharmaceuticals in their natural environment, thus raising the risk
persistent compounds because of their constant release into the of ecotoxicological effects [46]. The MoA conceptual frame work
environment [76]. Loffler et al. categorised 10 pharmaceuticals and was tested using the anti-depressant agent Fluoxetine, which tar-
pharmaceutical metabolites into low, moderate and high persis- gets the serotonin (5-HT) signaling pathway. Because 5-HT is a
tence compounds according to their dissipation time (DT50) in high-tier physiological controller in aquatic organisms, alterations
water/sediment samples. Paracetamol, Ibuprofen, 2- of the 5-HT pathway by fluoxetine had many adverse outcomes on
hyroxyibuprofen and CBZ-diol were classed as showing low key physiological functions, including reproduction, metabolism
persistent (DT50 ¼ 3.1-7 days), Oxazepam, Iopromide and Iver- and locomotion in mussels at concentrations approaching or even
mectin were deemed moderately persistent (DT50 ¼ 15-54 days) below environmental levels [60,61]. A major concern raised by the
while Clofibric acid, Diazepam, Carbamazepine were rated highly presence of PPCPs in the aquatic environment is their ability to
persistent (DT50 ¼ 119-328 days) [101]. A more recent study interfere with the endocrine system to produce undesired effects/
demonstrated the anxiolytic drug (Oxazepam) to display extended disruption of homeostasis. The World Health Organization (WHO)
persistence in freshwater lakes due to past input and growing ur- defined endocrine disruptors (ED) as ‘exogenous substance or
ban population [89]. mixture that alters function(s) of the endocrine system and
consequently causes adverse health effects in an organism, its
1.1.2. Bioaccumulation progeny or sub-population’. EDs include a vast group of chemicals
Although PPCPs are detected in the freshwater environment at from natural (e.g. mycotoxins and phytoestrogens) and synthetic
relatively low concentrations, many of them and their metabolites origin (e.g. diethylstilbesterol (DES) and Bisphenol A) in varieties of
are biologically active and can impact non-target aquatic organ- consumer products (e.g. PPCPs, cleaning products, antimicrobials,
isms. Several studies have examined the effect of PPCPs on non- food preservatives and phthalates) [166]. Endocrine disrupting
target organisms especially fish. The exposure of goldfish (Car- pharmaceuticals include sex hormones, glucocorticoids, veterinary
assius auratus) to waterborne gemfibrozil at an environmentally growth hormones and few non-steroidal pharmaceutical

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Emerging Contaminants (2016), http://dx.doi.org/10.1016/j.emcon.2016.12.004
 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16 3

substances (Fig. 1). Furthermore, toxicity arising from complex days [114].
mixtures of PPCPs at low concentrations could lead to synergistic Another important concern related to the presence of PPCPs in
interactions. This means that while individual PPCPs may be pre- the environment is the potential creation of antibiotic resistant
sent at low concentrations that do not elicit significant toxic effects strains in natural bacterial populations. Extensive use of antibiotics
when acting singly; PPCP mixtures can still exert considerable in human medicine and animal husbandry is the major cause for
ecotoxicity. This was demonstrated by Ref. [35]; whereby the the emergence and spread of antibiotic resistant bacteria, which
antiepileptic drug e carbamazepine and the lipid lowering agent has become a threat to the effective prevention and treatment of
clofibric acid (both belonging to different therapeutic classes) various infectious diseases caused by antibiotic-resistant patho-
exhibited much stronger effects to Daphnia magna than single genic bacteria [164]. Six antibiotics (ciprofloxacin, tetracycline,
compounds at the same concentration [154]. also revealed that the ampicillin, trimethoprim, erythromycin and trimethoprim/sulpha-
mixture effect of estradiol (E2) and 4-tert-nonylphenol (NP) can methoxazole) detected in the effluent of a WWTP in Australia
give an additive/synergistic reaction, and consequently induce increased the resistance of 2 natural bacterial strains found in the
vitellogenin production in juvenile rainbow trout. A study on the receiving waters [39]. Positive correlations have been found be-
brown trout, a salmonid species native to German rivers, investi- tween antibiotic-resistant microorganisms and trace concentra-
gated the effect of diclofenac, one of the most prevalent pharma- tions of aquatic antibiotic contaminants [120]. Furthermore, the
ceuticals in surface water. Results revealed that water-borne presence of antibiotics could have a detrimental effect on naturally
diclofenac at levels of 5e50 mg/L affects kidney and gill integrity occurring bacteria present in the environment. Specifically [41],
and selected immune parameters in the fish [75]. A laboratory and showed that even at sub-inhibitory concentrations, antibiotics may
field study conducted in France revealed that exposure to 17b- still exert their biological impact on natural microbial communities
estradiol on a freshwater fish; chub (Leuciscus cephalus) resulted in by influencing transcription in microbes. Some studies have re-
a significant and rapid increase in plasma vitellogenin (Vtg) in both ported adverse effects on aquatic organisms including: toxicity of
male and female chub [58]. Mimeault et al. also demonstrated that ciprofloxacin to green algae [68], toxicity of oxolinic acid (a
exposure to waterborne gemfibrozil on goldfish (Carssius auratus) commonly used feed additive in fish farms) to Daphnia magna, as
resulted in reduction on plasma testosterone by over 50% after 14 well as the toxicity of fluoroquinolone antibiotics (ciprofloxacin,

Fig. 1. Summary of endocrine disrupting PPCPs.

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4 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

lomefloxacin, ofloxacin, levofloxacin, enrofloxacin and flumequine) 1.2. Environmental fate and behaviour of PPCPs
on five aquatic organisms, the cynobacterium; Microcystis aerugi-
nosa, duckweed; Lemna minor, the green alga; Pseudokirchneriella 1.2.1. Sources
subcapitata, the crustacean; Daphnia magna and fathead minnow; Post-use, many PPCPs find their way into the environment
Pimephales promelas [139]. through different routes (Fig. 2). The major sources of PPCPs to the
Overall, the toxicity of PPCPs in the aquatic environment ex- environment are via sewage treatment plants (STPs) [40], WWTPs,
tends beyond the acute effects observed when therapeutic levels and landfill leaching. PPCPs are often not completely and consis-
are reached or exceeded. Recent studies have shown PPCP toxicity tently removed during conventional wastewater treatment pro-
to vary depending on the exposed organism, duration of exposure, cesses, and thus are frequently detectable in reclaimed surface
contaminant concentration, and developmental window at which water at concentrations ranging from ng/L to mg/L [30]. The
exposure occurs. Moreover, the effects of chronic trace-level contamination of the freshwater environment with pharmaceuti-
exposure, especially at certain sensitive stages of development, cals can occur in various ways e an important pathway is absorp-
are more likely to explain observed abnormalities within exposed tion of PPCPs by the body following therapeutic use, followed by
non-target organisms than acute high dose exposure [167]. As excretion and release into the sewage system or septic tank. After
many pharmaceutical contaminants are environmentally intro- treatment of sewage, the wastewater may be used for irrigation
duced after human or veterinary use, metabolite concentrations with the biosolids (treated sludge) potentially applied as fertilizer
may be more significant than that of parent compounds. For to agricultural land [178]. Another source of PPCPs to the envi-
instance, some acetylated metabolites of antibiotics (such as N4- ronment is via their manufacture as the wastewater from the
acetylsulfapyridine) were found to be more toxic than the parent production facility goes directly into STPs [57]. After treatment, the
compound (sulfapyridine) in algae [62]. In addition, the presence of sludge is deposited on the soil as fertilizer, with the liquid effluent
active pharmaceutical agents under undesirable conditions in the discharged directly into the freshwater environment. In addition,
aquatic environment may alter their toxicological properties. To PPCPs can reach the groundwater through leaching from the soil
illustrate, the photodegradation products of naproxen were re- and this could pose a threat to drinking water. Not only that,
ported to have more toxic effects than the parent compound on pharmaceuticals can also reach freshwater through run-off from
algae, rotifers, and microcrustaceans [82]. Acidic pharmaceutical land treated with digested sludge for agricultural purposes [119].
compounds may elicit different toxicological responses at different Veterinary drugs are released into the environment when animal
pH levels in exposed non-target organisms [50] and metals shown wastes either in solid or liquid states are sprayed on agricultural
to accumulate in river biofilms have been shown to increase the field as fertilizers. These veterinary drugs together with their me-
toxicity of certain antibiotic contaminants (fluoroquinolones and tabolites pollute the soil and could enter the food chain. Conse-
tetracyclines) in an additive manner [182]. quently, agricultural run-off can enter freshwater systems and
leach to groundwater [49]. Furthermore, externally applied PCPs
are mostly discharged through shower waste, bathing, swimming
and washing sinks. They can pass through WWTPs, and reach the

Fig. 2. Illustration of sources of environmental contamination with PPCPs.

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 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16 5

environment [128] (Fig. 2). widely for animal husbandry, cannot be photodegraded because of
its adsorption onto sediment [155]. However, the analgesic diclo-
1.2.2. Transport fenac could be easily and rapidly degraded through direct photol-
Once released into the environment, there is possibility of long ysis with a (pseudo) first-order elimination rate and a short half-life
range transport of some PPCPs depending on the physicochemical of <1 h [23] [140]. reported 11e68% of propranolol was removed by
properties of the compound and the characteristics of the receiving photodegradation in US rivers and predicted removal of up to 27%
environment. PPCPs generally have low volatility and are highly in the River Aire, UK, during the summer. Similar results were re-
polar and hydrophilic in nature; therefore their distribution ported for Ibuprofen, Metronidazole, Acetaminophen and several
through the environment will primarily occur through aqueous other PPCPs, suggesting photolysis as one of the major degradation
transport and food chain dispersal [26]. Transport of PPCPs be- pathways of PPCPs in surface waters [15,27].
tween different environmental media depends on the sorption Biodegradation stems from the reaction with natural microbial
behaviour of the compound in treatment plants, soil, and the water- flora in the environment. Many PPCPs undergo microbial mediated
sediment system [17]. Several groups of PPCPs can be found in reactions during WWT processes [72] and in the environment,
sludge samples of STPs through adsorption. This creates a potential resulting in the formation of transformation products. Oenesois
pathway for PPCPs into the environment by direct release or et al. provided a comprehensive review on biodegradation and
application of sludge to agricultural land as fertilizer [156]. A study removal of PPCPs in treatment systems. They concluded that
observed that PPCPs were transported into groundwater when accurately predicting biodegradability based on a PPCP's intended
biosolids were applied onto agricultural land [70] as well as fields function may not be possible. Since biodegradation involves
irrigated with treated wastewater [129]. This resulted in the uptake enzymatic reactions specific to chemical structures, the biode-
of PPCPs by crops, which may constitute a potential pathway of gradability of PPCPs with different structures grouped in the same
human exposure to PPCPs through dietary intake [170,171]. Runoff therapeutic class is expected to vary, thwarting efforts to observe
from biosolids containing PPCPs either from landfills or applied on general trends [125]. Microorganisms that utilize PPCP substrates
agricultural land may be transported into the surrounding surface at certain concentration either as a carbon or energy source would
water or leach into the groundwater [90], thereby posing a risk to be expected to increase in microbial growth and thereby resulting
aquatic life and public health. Sorption in sediment is another in further degradation of PPCPs. However, the increase in PPCP
mechanism through which PPCPs are transported to the aquatic concentrations could inhibit biodegradation, therefore becoming
environment. The sediment acts as a sink and accumulates these toxic to the natural occurring microorganisms. Despite an initial
environmental contaminants which may be released back to the increasing trend of degradation up to concentrations of 100 mg/L;
aquatic environment [183]. Several studies have shown some PPCPs none of the studied PPCPs including 4-isopropyl-3-methylphenol
(e.g. sulfamethoxazole, carbamazepine, triclosan and ciprofloxacin) (biosol), p-chloro-m-xylenol, gemfibrozil, ketoprofen, and
to be more persistent in sediment than water [31,36]. Osenbruck phenytoin achieved their highest degradation at the highest
et al. identified local river water infiltration, sewer exfiltration, and respective concentration of 1000 mg/L, thereby suggesting enzyme
urban stormwater recharge as the major sources of carbamazepine, saturation at such high concentrations [124].
galaxolide, and bisphenol A in groundwater underlying the city of During waste water treatment (WWT), transformation of PPCPs
Halle (Saale), Germany [126]. may occur depending on the physicochemical properties of the
Nevertheless, the fact that adsorption to sediment or suspended compound and the conditions of the WWT. During the process,
solids may influence concentrations of PPCPs in receiving water PPCPs may be completely destroyed, or partially transformed to
does not necessarily result in a reduction of their bioavailability or metabolites or in some instances left unchanged [172]. It is
toxicity. Several studies have reported accumulation of PPCPs in important to bear in mind that the breakdown or removal of the
different environmental compartments including sediments parent compounds during WWT does not necessarily mean the
[8,29,145]. Therefore, there exists the possibility of continuous removal of toxicity, it is expected that a great number of trans-
release of these chemical compounds from sediments to overlying formation products with unknown toxicity and persistence may
water. This may have adverse effects on benthic organisms that are still be present in the final effluent as well as in receiving water
continuously exposed to these chemicals within the sediments, bodies [80]. Typical examples of the transformation of pharma-
interstitial water and in overlying water [66]. Tamura et al. esti- ceuticals are presented below for the anti-inflammatory/analgesic
mated the combined contribution of triclosan, triclocarban and ibuprofen, the X-ray contrast media diatrizole and an antihyper-
galaxolide to total river sediment toxicity to be as high as 8.2% using tensive drug (valsartan).
the benthic organism, Chironomus yoshimatsui [151]. Further un- [187] used a biofilm reactor (BFR) and batch experiment with
derstanding of the toxicological impacts of PPCPs in freshwater activated sludge (BAS) to study the transformation of ibuprofen.
sediments appears imperative as sediment acts as a sink for these The result revealed hydroxyibuprofen (OH-Ibu) to be the major
chemicals. metabolite of ibuprofen under oxic conditions and carboxyhyra-
tropic acid (CA-HA) under anoxic conditions. Moreover, carbox-
1.3. Environmental degradation and transformation yibuprofen (CA-Ibu) was identified as a major metabolite under
both oxic and anoxic conditions. These transformation products
Biodegradation, photodegradation and other abiotic trans- either generated by human metabolism or by microorganisms
formation processes such as hydrolysis [14], may reduce concen- present in the WWTPs and in the natural environment may in-
trations of PPCPs in the environment and result in partial loss and crease the probability of their environmental presence [51].
mineralization of these compounds [3]. In contrast to ibuprofen, diatrizole does not metabolize and is
The extent of photodegradation depends on the intensity of excreted unchanged. In WWTPs, it has been shown to be persistent
solar irradiation, water depth, organic matter composition, eutro- under aerobic conditions. Therefore, diatrizole has been detected at
phic conditions, latitude and seasonality. A study conducted by elevated concentrations in the effluents of WWTPs, surface water,
Ref. [32]; revealed that under artificial estuarine water condition, a groundwater and even in finished drinking water [136].
photodegradation product of carbamazepine is acridine. This [72] reported on the transformation of valsartan. The trans-
metabolite has shown to be toxic, mutagenic and carcinogenic. formation products formed followed a sequence of transformation
Another study suggested that tetracycline, an antibiotic used steps. The first reaction was an N-dealkyation reaction, yielding

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6 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

dealkylated valsartan. This transformation product further trans- sulphamethoxazole, tetracyclin and theophylline up to 1 mg/L [137].
formed to amino-valsartan by an amide hydrolysis reaction and Subsequently, a study in German municipal STPs and rivers,
subsequently another transformation product was formed [2'-(1H- investigated 32 pharmaceuticals from different classes including
tetrazol-5-yl)biphenyl-4-yl]acetaldehyde (otherwise referred to as antiphlogistics, lipid regulators, psychiatric drugs, antiepileptic
valsartan acid), through the hydrolysis and oxidation of amino- drugs, betablockers and b2-sympathomimetics in discharged ef-
valsartan. These transformation products were suggested to pro- fluents, stream and river waters. More than 80% of the selected
vide the rationale for the environmental persistence of valsartan. drugs were detectable in at least one municipal STP effluent with
concentrations of carbamazepine up to 6.3 mg/L with resultant
1.4. PPCPs in the freshwater aquatic environment contamination of the receiving waters. The lipid regulator “beza-
fibrate” showed the highest concentration of 3.5 mg/L in the
The environmental occurrence of pharmaceuticals was first re- sampled river waters [152]. Concentrations of ibuprofen detected in
ported in Kansas City, US in 1976, where clofibric acid was detected influent and effluent samples from various German WWTPs dis-
in treated wastewater at concentrations ranging from 0.8 to 2 mg/L played a maximum of 3.5 and 0.3 mg/L respectively [81]. Hirsch et al.
[50]. Subsequently [137], investigated the presence of 25 pharma- investigated STP effluents and random river water samples
ceuticals in the river Lee (a source of potable water for North collected in Germany for the presence of antibiotic residues. The
London) with concentrations up to 1 mg/L in 1981. Since then, results showed frequent detection of erythromycin, roxithromycin
several studies have detected PPCPs in different environmental and sulfamethoxazole at concentrations up to 6 mg/L [74]. Another
compartments across the globe [74,92,134]. Despite the fact that German study [52] reported detection of 6 pharmaceuticals: car-
reported concentrations of these PPCPs are low; many of them have bamazaepine, clofibric acid, diclofenac, propranolol and sulfa-
the potential to persist in the natural environment for months to methoxazole at concentrations 6.3, 1.6, 2.1, 0.29 and 2 mg/L in
years [16]. The detection of pharmaceuticals in the environment effluent and 1.1, 0.55, 1.2, 0.59, and 0.48 mg/L in surface water,
varies not only between countries but also between different re- respectively. In addition, carbamazepine, diclofenac, ibuprofen, as
gions of the same country. That is to say, detectable pharmaceuti- well as a variety of antibiotics and lipid regulators were detected in
cals in one country or region may not appear in other countries/ water samples collected from the River Elbe in 1998 at concentra-
regions where they are not highly prescribed [83]. This precludes tions ranging between 20 and 140 mg/L [165]. Moreover, a study
meaningful global comparison of PPCPs levels due to variations of examined the fate of triclosan and its active transformation prod-
the targeted compounds and detected chemicals in each reported uct, triclosan-methyl in STPs and surface water (River Ruhr) in
study. For instance, we compared the reported concentrations of Northern Germany. Concentrations of both compounds ranged
NSAIDs in surface water from different countries (Fig. 3). While this between <3 and 10 ng/L for triclosan and between 0.3 and 10 ng/L
figure may provide indicative information on the global contami- for triclosan-methyl [13].
nation levels, it should be studied carefully because studies from In the UK, Hilton et al. detected mefenamic acid, diclofenac,
different countries have targeted and/or detected different mem- propranolol, erythromycin, trimethoprim and acetyl-
bers of the NSAIDs group. Therefore, concentrations of different sulfamethozole in both effluent samples and surface water
classes of PPCPs reported in the freshwater aquatic environment sampled downstream of effluent discharge [73]. Ashton et al.
from each continent will be reviewed separately in the next section. investigated effluent and surface water samples from Corby, Great
Billing, East Hyde, Harpenden and Ryemeads STPs in the UK. Ten
pharmaceuticals were detected in the STP effluent samples: pro-
1.5. Europe pranolol (detection frequency ¼ 100%, median ¼ 76 ng/L), diclo-
fenac (86%, 424 ng/L), ibuprofen (84%, 3086 ng/L), mefenamic acid
1.5.1. Wastewater and surface water (81%, 133 ng/L), dextropropoxyphene (74%, 195 ng/L), trimethoprim
Richardson and Bowron reported the presence of 25 pharma- (65%, 70 ng/L), erythromycin (44%, <10 ng/L), acetyl-
ceuticals in water samples taken in 1981 from the river Lee, UK with sulfamethoxazole (33%, <50 ng/L), sulfamethoxazole (9%, <50 ng/
concentrations of dextropropoxyphene, erythromycin,

Fig. 3. Concentrations (ng/L) of non-steroidal anti-inflammatory drugs (NSAIDs)* reported in surface water samples from different countries**.
* NSAIDs include Ibuprofen, Naproxen, Diclofenac, Ketoprofen and Acetaminophen.
** Data from [116], [86], [85], [87], [144], [18], [111], [112], [177], [122], [52], [165], [23], [24], [67], [33], [7].

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 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16 7

L), tamoxifen (4%, <10 ng/L). In the corresponding receiving and meclofenamic acid (28e176 ng/L). The highest concentration of
streams, fewer compounds and lower concentrations were found all studied compounds was for diclofenac in the effluent discharge
[6]. Another study conducted in the UK by Ref. [153] detected clo- site (543 ng/L). Apart from the water samples analysed, high con-
fibric acid, clotrimazole, dextropropoxyphene, diclofenac, centrations of pharmaceuticals were also detected in all solid res-
ibuprofen, mefenamic acid, propranolol, tamoxifen, and trimetho- idue samples in the month of June 2010 with the highest
prim at measurable concentrations in water samples collected from concentrations being: diclofenac (58.7 ng/g), carbamazepine
the lower reaches of the rivers Tyne, Tees, Mersey, and Thames as (46.5 ng/g), indomethacine (42.6 ng/g), and meclofenamic acid
well as Belfast Lough in the UK. Clotrimazole appeared to be the (37.3 ng/g).
most frequently detected in 59% of all the samples collected at a Buser et al. identified clofibric acid concentrations found in
maximum concentration of 22 ng/L and a mean concentration of various Swiss lakes (the Zurichsee, the Sempachersee and the
7 ng/L [138]. surveyed wastewater effluent and surface waters of Greifensee) fell in the range of 1e9 ng/L [22]. Buser et al. also
the lower River Tyne, UK. Out of 9 compounds analyzed in the raw studied the occurrence and fate of diclofenac in Swiss lakes and
effluent samples, sulfamethoxazole and acetyl-sulfamethoxazole rivers. The concentrations in the lakes ranged from <1 to 12 ng/L,
were detected at concentrations ranging from 11 to 69 570 ng/L. while the highest concentration (11e310 ng/L) were observed in
In surface water samples, clotrimazole, dextropropoxyphene, the river Aabach, one of the major inflows of Lake Greifensee [23].
erythromycin, ibuprofen, propranolol, tamoxifen and trimethoprim In 1999, the same research group investigated the presence and
were detected at concentrations ranging from 4 to 2370 ng/L. behaviour of ibuprofen in surface and wastewater samples. Surface
In the South Wales, UK [86], reported the contamination of the water samples were collected from lakes and rivers in Switzerland
River Taff and the River Ely with PPCPs, illicit drugs and other and from the North Sea, with wastewater samples collected from
endocrine disruptors, which was attributed mainly to the extensive the Swiss WWTPs of Gossau, Pfaffikon and Uster. The concentration
discharge of treated wastewater effluent into the rivers. The of ibuprofen in the influents of the WWTPs was up to 3 mg/L while
investigation suggested that the most frequently detected PPCPs in the river and lakes, ibuprofen was detected at concentrations up
represent the compounds that are highly dispensed in the Welsh to 8 ng/L [24].
community. These include: anti-inflammatories/analgesics (tra- Carbamazepine, atenolol, metoprolol, sulfametoxazole, gemfi-
madol, codeine, paracetamol, naproxen, ibuprofen and diclofenac), brozil and propanolol were detected and demonstrated a high
antibacterial drugs (erythromycin, trimethoprim and amoxicillin) degree of persistence in the Hoje River in Sweden, at concentra-
and antiepileptic drugs (gabapentin and carbamazepine). Some of tions ranging from 0.16 to 1.18 mg/L [12]. In a wide survey of more
these PPCPs (e.g. codeine, erythromycin, valsartan, gabapentin and than 100 individual water samples from over 100 European rivers
carbamazepine) were found to be ubiquitous and persistent in the from 27 European countries, Loos et al. identified persistent phar-
aqueous environment. Illicit drugs were also detected in both rivers maceuticals as benzotriazole, caffeine and carbamazepine to be the
at low concentrations. The average daily loads of amphetamine, most frequently detected and at the highest concentration levels
cocaine and its main metabolite benzoylecgonine were reported at [103]. A study in Catalonia, Spain also determined the presence of
8, 1 and 39 g/day respectively. 11 PPCPs in both surface water (Ebro and Llobregat River) and
[185] also reported PPCPs such as: propranolol, sulfamethoxa- wastewaters with benzophenone-3 having the highest concentra-
zole, carbamazepine, indomethacine and diclofenac were tion (7 ng/L) [130]. Another study reported the occurrence and
frequently detected in wastewater and river water sampled from distribution of multi-class pharmaceuticals, their active metabo-
three WWTPs in England and the River Ouse. Carbamazepine lites and transformation products in the Ebro River basin in Spain.
showed the highest concentrations (up to 2336 ng/L) in WWTP Out of 77 target analytes, the compounds found to be ubiquitous
influent samples. Interestingly [93], reported as the presence of were carbamazepine, clarithromycin, sulfadiazine, propranolol,
glucocorticoids (GCs) in the river Thames, in the UK. The total tamoxifen and salicylic acid. The highest concentration of 1667 ng/L
concentrations of 28 GCs ranged between 30 ng/L and 850 ng/L. was detected for the carbamazepine metabolite (10,11 epoxi-
These concentrations were much higher than those of more carbamazepine) in a small tributary, the Zadorra river [104].
extensively studied estrogens especially ethinylestradiol and other Calamari et al. reported the detection of therapeutic agents such
steroid hormones. At such concentrations, adverse effects on as atenolol, lincomycin, erythromycin, clarithromycin, bezafibrate
aquatic organisms are possible. However, Baker and Kasprzyk- and furosemide in the River Po and Lambro, Northern Italy at
Hordern went further to report occurrence of a comprehensive concentration ranging from 0.1 to 250 ng/L [25]. A study in Portugal
set of drugs of abuse in river water, untreated and treated waste- revealed the presence of pharmaceutical active compounds (mostly
water in England, UK. They identified the top ten pharmaceuticals nonsteroidal anti-inflammatory drugs) ranging from 0.050 to
with the highest median concentration detected from the WWTPs 100 mg/L in the influent and up to 50 mg/L in the effluent of 5
influent and effluent to be: caffeine (23 778.4 ng/Le1744.2 ng/L), 1,7 WWTPs. Musks were also detected at concentrations of 11.5 mg/L,
dimethylxanthine (20 400.4 ng/Le1219.8 ng/L), nicotine 0.9 mg/L and 22.6 mg/L in the influent, effluent and sludge respec-
(3919.3 ng/Le85.7 ng/L), codeine (1255.9 ng/Le372.2 ng/L), tra- tively [141]. Furthermore [110], monitored seasonal variation of 15
madol (1122.6 ng/Le738.7 ng/L), ephedrine (476.2 ng/Le35.0 ng/L), pharmaceuticals during four seasons (February, May, July and
nortramadol (397.0 ng/Le144.8 ng/L), morphine (371.2 ng/ November 2010) along a wastewater polluted watercourse, River
Le59.1 ng/L), dihydrocodeine (226.6 ng/Le118.2 ng/L), and Rakkolanjoki and Lake Haapajarvi in Eastern Finland. The concen-
amitriptyline (206.3 ng/Le66.3 ng/L) respectively. Similar high trations ranged from 0 to 556 ng/L. Out of the 15 studied com-
median concentrations of these pharmaceutical compounds were pounds, carbamazepine had the highest concentrations and was
observed in river water samples collected both upstream and not eliminated during any of the seasons.
downstream of the WWTPs [10].
Furthermore [184], reported the occurrence of pharmaceuticals 1.5.2. Sediment and sewage sludge
in samples collected from the River Medway, UK in February 2010. Several studies have shown that pharmaceuticals consumed in
Concentrations in water sampled for upstream sewage effluent and large quantities have been detected in the aqueous environment
effluent discharge sites were: propranolol (8e35 ng/L), meso-bili- particularly in sediment. Loffler and Ternes reported the detection
verdin (3e11 ng/L), thioridazine (6e22 ng/L), carbamazepine of acidic pharmaceuticals and their metabolites (clofibric acid,
(53e265 ng/L), tamoxifen (2e8 ng/L), indomethacine (6e28 ng/L), diclofenac, fenoprofen, gemfibrozil, ibuprofen, 2-hydroxy-

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8 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

ibuprofen, indomethacin, ketoprofen, and naproxen), antibiotics 1.6. North and South America
(clarithromycin, erythromycin, roxithromycin, sulfadiazine, sulfa-
methazine, sulfamethoxazole and trimethoprim) and parasiticide 1.6.1. Wastewater and surface water
ivermectin in sediment from the Wickerbach creek, close to In a seminal study, concentrations of pharmaceuticals were re-
Frankfurt, Germany [102]. Martin et al. investigated pharmaceuti- ported in Kansas City, US in 1976 in treated wastewater, with clo-
cals in sewage sludge, compost as well as sediment samples fibric acid present at concentrations ranging from 0.8 to 2 mg/L [50].
collected from the surface water of Guadiamar River in Seville, In South America, Stumpf et al. detected polar drugs residues in
Southern Spain. The pharmaceuticals detected in the sediment sewage and natural waters in the state of Rio de Janeiro, Brazil. In
were naproxen, salicylic acid, propranolol, caffeine and 17a-ethi- surface water, clofibric acid, diclofenac and naproxen were
nylestradiol at concentrations of 11.2, 9.49, 3.37, 7.21, and 48.1 mg/kg frequently detected at low concentrations (0.01e0.06 mg/L) in the
respectively [108]. A more recent study examined sediment sam- major river used for drinking water production [149].
ples collected along four representative Iberian River basins; Llo- [79] reported estrogenic hormones in effluent from four
bregat, Ebro, Jucar and Guadalquivir, Spain. The most widely spread municipal WWTPs effluent in California, USA, as well as in surface
and highly concentrated pharmaceuticals were hydrochlorothia- water from a wetland receiving such effluent, namely the Colorado
zide (3 ng/g), gemfibrozil (6 ng/g), tetracyclines (6 ng/g), codeine River and the Sacramento River delta. Median concentrations in the
(12 ng/g) azithromycin (24 ng/g), and ibuprofen (13 ng/g) [127]. wastewater effluents were 1.9 ng/L and - 0.6 ng/L for 17b-estradiol
Varga et al. investigated selected acidic pharmaceuticals: (E2) and 17a-ethinylestradiol (EE2), respectively. Median concen-
ibuprofen, naproxen, ketoprofen and diclofenac in the Danube river trations in surface water were 0.08 ng/L and > 0.05 ng/L for E2 and
water and sediment in Budapest, Hungary. In the river water, EE2.
ketoprofen was always below the LOQ, while ibuprofen, naproxen [92] detected various pharmaceuticals in samples from a
and diclofenac were quantified in the range of 8e50, 2e30, network of 139 streams susceptible to contamination (i.e. down-
7e90 ng/L. In sediments, only naproxen and diclofenac were found stream of urban areas and livestock production) across 30 states
in the range of 2e20 and 5e38 ng/g, respectively [157]. Concen- during 1999 and 2000. The most frequently detected compounds
trations of human pharmaceuticals, illicit drugs, and bactericides were coprostanol (fecal steroid), cholesterol (plant and animal
were reported in Scottish sediments and sludge samples. None of steroid), N,N-diethyltoluamide (insect repellent), caffeine (stimu-
the illicit drugs and metabolites were detected but triclosan (up to lant), triclosan (antimicrobial disinfectant), tri (2-chloroethyl)
5940 ng/g) and triclocarban (up to 2829 ng/g) were [94]. The study phosphate (flame retardant), and 4-nonylphenol (nonionic deter-
concluded that the drug content of sediment depended on its gent metabolite). Measured concentrations for this study were
concentration in the aqueous phase and the total organic carbon generally low and rarely exceeded drinking water guidelines,
content of the sediment. drinking water health advisories, or aquatic life criteria. Boyd et al.
investigated the presence of PPCPs in surface water and treated
waters of Louisiana, USA and Ontario, Canada. The study revealed
that naproxen was detected in Louisiana STP effluent at 81e106 ng/
1.5.3. Biota L and in Louisiana (Mississippi River) and Ontario (Detroit River)
Globally, studies have shown that exposure to WWTP effluents surface waters at 22e107 ng/L [18]. Another study in Montana, USA,
containing PPCPs is associated with a range of deleterious effects on reported detection of sulfamethoxazole, atrazine, carbamazepine,
the reproduction in aquatic organisms [65]. revealed bio- dilantin and diclofenac with maximum concentrations of 490 ng/L,
accumulation of a mixture of estrogenic contaminants in fish tis- 130 ng/L, 420 ng/L, 22 ng/L and 46 ng/L respectively in ground
sues, thereby resulting in the induction of vitellogenin and possibly water [113]. Batt et al. reported the presence of some antibiotics in
contributing to feminization of wild fish residing in UK rivers. receiving streams impacted by wastewater discharge in East Aurora
Pojana et al. examined natural and synthetic endocrine-disrupting and Holland, New York. Ciprofloxacin, sulfamethoxazole and clin-
chemicals (EDCs) in water, sediment and biota of a coastal lagoon in damycin (0.043e0.076 mg/L) were detected 100 m from the
Venice. The result of their study showed that most of the selected discharge point [11].
compounds were found in water and sediment at concentration A study of the Mississippi in New Orleans, Louisiana, USA,
ranging from 2.8 to 211 ng/L and 3.1e289 mg/kg dry weight revealed contamination by PPCPs including: clofibric acid
respectively. The compounds detected in the Mediterranean mussel (3e27 ng/L), ibuprofen (<1e34 ng/L), acetaminophen (25e65 ng/L),
(Mytilis galloprovincialis) were 17a-ethinylestradiol and non- caffeine (<1e38 ng/L), naproxen (<1e135 ng/L), triclosan (9e26 ng/
ylphenol at concentration range 7.2e240 ng/g in dry weight [132]. L), bisphenol A (<1e147 ng/L), carbamazepine (43e114 ng/L),
In another study by Ref. [56]; in which rainbow trout were exposed estrone (<1e5 ng/L) and 17b-estradiol (<!-5 ng/L) at the following
to pharmaceutical sewage effluents, levonorgestrel was accumu- concentrations [181]. A study of a major receiving river, the Chop-
lated in fish blood at concentrations of 8.5e12 ng/ml. tank in Maryland, USA, revealed the presence of various antibiotics
Subedi et al. measured galaxolide and tonalide in tilapia and and hormones at different concentrations in a major agricultural
bream fish samples collected from Rhine River, Germany at con- watershed. The most frequently detected antibiotic in the river
centrations of 81 and 5.5 ng/g wet weight respectively [150]. were sulfamethoxazole and sulfadimethoxine at concentrations
Alvarez-Munoz et al. investigated the presence of pharmaceuticals ranging from 0.005 to 0.007 mg/L [5].
in oyster, clam and mussel samples collected from the Ebro delta, Wu et al. reported the occurrence of selected pharmaceuticals in
Spain. The results revealed the most ubiquitous compounds an agricultural landscape, western Lake Erie basin in northern Ohio.
detected were the psychiatric drug venlanfaxine and the antibiotic The results showed that the most frequently detected compounds
azithromycin, with the highest concentrations found in mussels were caffeine, carbamazepine, ibuprofen and paraxanthine at
(2.7 ng/g) and oysters (3.0 ng/g) [4]. Another Spanish study maximum concentrations of 4.2, 1.2, 2.8 and 1.8 mg/L [169]. Another
examined residual pharmaceuticals in pork, veal, lamb and chicken study examined the distribution and temporal trends of 19 PPCPs
muscle, liver and kidney as well as salmon, sea bass and sole flesh including 11 hormones in two WWTPs from Charleston, SC, USA
purchased at a local supermarket. The study revealed the most over a period of one year. Acetaminophen, caffeine and ibuprofen
frequently detected analytes were the hormones estrone and 17b- showed the highest concentrations in both WWTPs samples, fol-
estradiol and the antibacterials florfenicol and pyrimethamine [9]. lowed by triclosan and triclocarban. In Charleston Harbour surface

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 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16 9

water, caffeine, cotinine and acetaminophen were detected in upstream [55]. Elsewhere [44], reported caffeine to be present in
98.6%, 33.3%, and 22.2% of samples respectively [71] [14]. also re- surface water in Barbados at concentrations ranging from 0.1 to
ported detection of 32 pharmaceuticals in Lake Michigan water, 6.9 mg/L.
with 30 detected in the sediment. Among those most frequently
detected were: metformin, caffeine, sulfamethoxazole and 1.6.2. Sediment and sewage sludge
triclosan. The occurrence of PPCPs in freshwater sediment has been
A study in Cape Cod, Massachusetts, USA, reported most documented by several authors. Sediment samples collected from
frequently-detected pharmaceuticals including sulfamethoxazole, rivers (Mississippi, Sauk, South Fork of the Crow and Grindstone),
the anticonvulsant phenytoin, and carbamazepine at maximum creeks (Center, Okabena) and lakes (Pepin, Superior, Shagawa) in
concentrations of 113 ng/L, 66 ng/L and 72 ng/L, respectively in well Minnesota, US, revealed a high level of triclocarban in freshwater
water [142]. Fairbairn et al., also reported the detection of PPCPs sediments at concentration up to 822 ng/g [158]. A study conducted
(detection frequencies and median concentration in parentheses) such by Yang et al. investigated pharmaceuticals and organochlorine
as atrazine (99%, 29 ng/L), caffeine (97%, 17 ng/L), metolachlor (88%, pesticides in sediments from the Alafia River in Florida, USA. The
10 ng/L), acetaminophen (88%, 3.3 ng/L), DEET (87%, 16 ng/L) and most frequently detected compounds were carbamazepine, acet-
trimethoprim (72%, 5.9 ng/L) in 68 grab water samples from the aminophen, diphenhydramine, trimethoprim, caffeine, nicotine,
Zumbro River watershed, Minnesota, USA at concentrations over a lidocaine and ephedrine at concentrations ranging from 0 to 33 ng/
period of one year [47]. g [177]. Analysis of surface water, sediment and mussel samples
Metcalfe et al. reported the occurrence of neutral and acidic collected from San Francisco Bay, California, an urban estuary that
drugs in the effluents of Canadian STPs. The study showed that lipid receives direct discharge from 40 municipal and industrial waste-
regulators such as bezafibrate and gemfibrate were detected in water outfalls, revealed the predominant compounds to be: tri-
some influent and effluent samples as well as carbamazepine at clocarban in sediment, valsartan in surface water and DEET in
concentrations as high as 2.3 mg/L [111]. To determine the distri- mussels at concentrations of 33 ng/g, 92 ng/L and 14 ng/g respec-
bution of acidic and neutral drugs in surface waters near STPs in the tively [91].
lower Great Lake, Metcalfe and colleagues examined surface water
collected from Lake Ontario and Lake Erie and STPs effluents. The 1.6.3. Biota
result shows detection of all the acidic drug analytes except keto- A national pilot study in the US, assessed accumulation of PPCPs
profen in the effluents. However, ibuprofen and gemfibrozil were in fish sampled from five effluent-dominated rivers receiving direct
detected in STP effluents at concentrations >1 mg/L [112]. Verenitch discharge from wastewater treatment in Illinois, Texas, Florida,
et al. also reported the presence of acidic drugs and caffeine in Arizona, and Pennsylvania. The study revealed the presence of
municipal wastewaters and receiving water on the west coast of galaxolide and tonalide in fish fillets at every effluent-dominated
Vancouver Island, British Columbia, Canada. Ibuprofen, naproxen as site with maximum concentrations ranging from 300 to 2100 ng/
well as salicylic acid were detected in the samples of STP waste- L and 21e290 ng/L respectively. The pharmaceuticals detected both
water and also in surface water samples collected near STP outfalls in liver and fillets include: diphenhydramine, norfluoxetine, ser-
[159]. Concentrations of pharmaceuticals and s-triazine herbicides traline, diltiazem, carbamazepine, fluoxetine, gemfibrozil, with
were determined in wastewater effluent and surface water sampled sertraline the most abundant at a maximum concentration in fillet
from the upper Detroit River, Canada. 15 pharmaceuticals including and liver tissue of 19 and 545 ng/L respectively [134]. The same
carbamazepine, cotinine, caffeine, trimethoprim, fluoxetine were research group also reported concentrations of diphenhydramine,
detected in the WWTP effluent at concentrations ranging from 1.7 diltiazem, carbamazepine and norfluoxetine detected in muscle
to 1244 ng/L [78]. tissues from fish collected in Pecan Creek, Denton County Texas,
Gibson et al. investigated reuse of wastewater for irrigation from USA. The concentrations ranged from 0.66 to 1.32, 0.11e0.27,
the Tula Valley in Mexico. The study revealed wastewater used for 0.83e1.44, 3.49e5.14 ng/g respectively [135]. Mottaleb et al. used
irrigation to contain pharmaceuticals and potential endocrine dis- two screening methods to determine 10 extensively used PCPs and
ruptors. Ibuprofen (742e1406 ng/L), naproxen (7267e13589 ng/L), 2 alkylphenol surfactants in fish fillets collected from a regional
and diclofenac (2052e4824 ng/L) were consistently present while effluent-dominated stream in Texas, USA. Benzophenone, galax-
other pharmaceuticals such as gemfibrozil, clofibric acid and olide, tonalide and triclosan were detected in all environmental
ketoprofen were below LOD [64]. samples at concentrations ranging from 37 to 90, 234e970, 26e97
[53] revealed the presence of ibuprofen in both influent and and 17e31 ng/g respectively [117].
effluent from WWTPs at Penha and Ilha do Governador, Rio de Foltz et al. quantified selected nitromusks, antimicrobial agents
Janeiro, Brazil. Ibuprofen was detected in all samples analyzed, and antihistamines in edible frozen retail fresh and salt water fish
confirming low removal efficiency of conventional treatment fillets in Maryville, Missouri, USA. The compounds consistently
plants. Another study by same author [54] investigated psychiatric detected were galaxolide, tonalide, triclosan and diphenhydramine
pharmaceuticals in Guandu River, Rio de Janeiro, Southern Brazil. at concentrations ranging from 0.163 to 0.892, 0.068e0.904,
The study revealed the presence of benzodiazepines such as bro- 0.189e1.182 and 0.942e7.472 ng/g respectively. Musk ketone was
mazepam, clonazepam and diazepam in all samples of surface not detected in any of the fish studied [59]. A report by Brooks et al.
water at maximum concentrations of 42 ng/L, 198 ng/L, and 335 ng/ revealed pharmaceutical accumulation in fish of effluent-
L respectively. In a comparative study conducted by the Minnesota dominated streams in North Texas, USA. The study showed the
Pollution Control Agency, DEET, cotinine, lopamidol, bisphenol A, selective serotonin reuptake inhibitors (SSRI) fluoxetine and ser-
metformin and the steroidal hormone androstenedione were traline, in addition to their metabolites norfluoxetine and desme-
frequently detected in lake water at maximum concentrations of thylsertraline to be detected at concentrations > 0.1 ng/g in all fish
103, 42, 510, 36, 18 and 5 ng/L. Overall, in surface water, sixteen tissues examined [20]. Schultz et al. investigated the occurrence
chemicals including some antidepressants, antibiotics and antihy- and fate of antidepressant pharmaceuticals in surface water, sedi-
pertensive pharmaceuticals were detected downstream of the ment, and native white sucker (Catostomus commersoni) samples
WWTPs, while six out of 56 target PPCPs such as Bisphenol A (BPA), collected from Boulder Creek, (Colorado) and Fourmile Creek
carbadox, fluoxetine, sulfamethozine, virginiamycin, methylpred- (Iowa). Fluoxetine, sertraline, and their degradates were the prin-
nisolone, moxifloxacin and triclosan were detected frequently cipal antidepressants observed in fish brain tissue, typically at low

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10 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

(0.1e6) ng/g concentrations [143]. Another study investigated the ranging from 11 to 67 ng/L and 66e460 ng/L, respectively [174].
uptake of human pharmaceuticals in bull sharks (Carcharhinus Another study conducted in the urban riverine water of the
leucas) inhabiting the wastewater impacted Caloosahatchee River. Pearl River Delta at Guangzhou, South China, revealed the presence
Compounds detected in the plasma of Caloosahatchee River sharks of the estrogenic hormone, estrone, at a maximum concentration of
were: 17a-ethyinestradiol, citalopram, fluoxetine, fluvoxamine, 65 ng/L, while acidic pharmaceuticals such as salicylic acid, clofibric
paroxetine, sertraline and venlafaxine at concentrations ranging acid and ibuprofen were detected in most of the water samples
from 0.10 to 6.25 [63]. with maximum concentrations of 2098, 248, and 1417 ng/L
respectively [131]. In a study of the uptake of antibiotics in irriga-
1.7. Asia tion water by plants in Tianjin, China, most of the target analytes
including sulfamethoxazole, sulfadoxine, sulfachloropyridazine,
1.7.1. Wastewater and surface water choramphenicol, tetracycline, lincomycin, chlortetracycline, oflox-
Yamagishi et al., detected musk xylene and musk ketone (syn- acin, and pefloxacin were detected in vegetables between 0.1 and
thetic musks) in 100% and 80% respectively of 74 samples from 532 mg/kg [77]. Luo et al. reported the occurrence and transport of
Tama River and Tokyo Bay in Japan [175]. Elsewhere, the levels and tetracycline, sulfaonamide, quinolone and macrolide antibiotics in
distribution of 12 antimicrobials were investigated in water from the Haihe River Basin, China. The sources of the 12 antibiotics
the Mekong Delta, Vietnam and compared with those in the Tam- studied were assessed as likely originating from veterinary appli-
agawa River, Japan. While a few compounds such as sulfamethox- cation in swine farms and fish ponds at concentrations ranging
azole, sulfamethazine, trimethoprim and erythromycin-H2O were from 0.12 to 47 mg/L [105]. A more recent study in Taihu Lake, China
detected in Vietnam at concentrations between 7 and 360 ng/L, detected eight pharmaceutically active compounds, namely: roxi-
while more antimicrobials were found in the Japanese urban river thromycin, erythromycin, ibuprofen, diclofenac, propranolol, car-
including: sulfamethoxazole, sulfapyridine, trimethoprim, eryth- bamazepine, E2, and EE2 in surface water and sediment samples
romycin-H2O, azithromycin, clarithromycin, and roxithromycin at with maximum concentrations in the range of 8.74e118 ng/L and
concentrations ranging from 4 to 448 ng/L [107]. A study by 0.78e42.5 ng/L dry weight respectively [173]. Ma et al. also
Ref. [95] investigated the effluent from a WWTP impacted by drug examined some pharmaceutically active drugs in Dongting Lake,
manufacturing in Patancheru, near Hyderabad, India. Extremely China. The most frequently detected compound was caffeine fol-
high concentrations of pharmaceuticals, such as ciprofloxacin up to lowed by diclofenac, DEET, mefenamic acid, fluoxetine, ibuprofen,
31 mg/L were measured in the effluent. Moreover [57], reported a and carbamazepine with mean concentrations between 2.0 and
severe case of contamination of surface, ground and drinking water 80.8 ng/L [106].
with pharmaceuticals in the Patancheru industrial area in India. In Northern Taiwan [48], reported 4 pharmaceutical residues in
Compounds detected included: 1.2 mg/L of cetrizine and 6.5 mg/L wastewater STP and in seawater around the effluent discharge area.
of ciprofloxacin, in addition to several other pharmaceuticals The pharmaceutical concentrations measured in influent were:
detected at mg/L levels. clofibric acid (104e109 ng/L), diclofenac (152e185 ng/L), ibuprofen
Choi et al. examined the concentrations of several pharmaceu- (724e2200 ng/L), and ketoprofen (128e184 ng/L). Corresponding
tical residues in surface water of the Han River, Korea. The con- concentrations in effluent were: 95e102 ng/L, 100e131 ng/L,
centrations of the target compounds such as cimetidine, caffeine, 552e1600 ng/L, and 68e128 ng/L respectively.
acetaminophen, and sulfamethoxazole detected in the surface
water were 281, 268.7, 34.8 and 26.9 ng/L respectively [34]. Another 1.7.2. Sediment and sewage sludge
study [87]; detected several pharmaceuticals including: ibuprofen Lei et al. studied concentrations of six estrogens including:
(nd to 414 ng/L), carbamazepine (nde595 ng/L), atenolo (nd- diethylstilbestrol (DES), estrone (E1), b-estradiol (E2), estriol (E3),
690 ng/L), clarithromycin (nd-443 ng/L), mefenamic acid 17a-ethynylestradiol (EE2), and b-estradiol 17-valerate (EV) in
(nde326 ng/L), erythromycin (nde137 ng/L), propranolol surface water and sediment sampled from three rivers in Tianjin
(nde40.1 ng/L), indomethacin (nde33.5 ng/L), fluconazole (nd- area, northern China. The concentrations of all six estrogens ranged
111 ng/L), levofloxacin (nd-87.4 ng/L) and ifenprodil (nd-35.4 ng/L) from 0.98 to 51.6 ng/g in sediment and varied for each river [96].
in surface water from the Mankyung River, South Korea. The same Yang et al. measured four classes of antibiotics, namely: sulpho-
research group documented the frequent detection of many phar- namides, macrolides, fluoroquinolones and tetracyclines in sedi-
maceuticals, hormones, and antibiotics in three major rivers, the ment of the Pearl River in China. Ofloxacin was detected at the
Han River, the Nakdong River and the Youngsan River in South highest concentration of 1560 mg/kg [176]. In another study con-
Korea [88]. Another study by Sim et al. investigated the occurrence ducted by Liu and co-workers, high concentrations of chloram-
and distribution of pharmaceuticals in influents of WWTPs located phenicol (5.8e47.4 mg/L), oxytetracycline (0.2e5.7 mg/L), and
near major river basins in Korea. Results showed that non-steroidal tetracycline (0.7e65.2 mg/L) were observed in the sediment of the
anti-inflammatory drugs, caffeine, and carbamazepine were Nanming River, Guiyang city, China during summer [99].
dominant in the influents and the distribution of pharmaceuticals Ramaswany et al. studied antiepileptic, antimicrobial and pre-
varied with sampling sites and periods [146]. servative compounds in surface water and sediment from the
Lin et al. quantified some pharmaceutical residues such as clo- Kaveri, Tamiraparani, and Vellar rivers in India. The maximum
fibric acid, ibuprofen, carbamazepine, naproxen, ketoprofen, and concentrations reported for the antimicrobial triclosan in sediment
diclofenac in tap water, groundwater, WWTPs and river water from in the three rivers were 85.3, 46.9 and 32.1 ng/g respectively [133].
the Fu-Hsing River in China. None of the target compounds were A study by Zhou et al. reported the occurrence of 4 classes of
detected in tap water and groundwater. However, 30 ng/L of nap- commonly used antibiotics including sulphonamides, fluo-
roxen was measured in the river water, while concentrations of roquinolones, tetracycline, and macrolides in the sediments of the
ibuprofen, carbamazepine and naproxen reached 30 ng/L, 420 ng/L, Yellow River, Hai River and Liao River in Northern China. Higher
and 170 ng/L respectively in WWTP effluent [98]. Xu et al. exam- concentrations were detected for most antibiotics in the Hai River
ined several antibiotics in Victoria Harbour, Hong Kong and the sediment compared to the other rivers. The most frequently
Pearl River in South China. Concentrations were below the limit of detected antibiotics were norfloxacin, ofloxacin, ciprofloxacin and
quantification in seawater but all of the target compounds except oxytetracycline at concentrations up to 5770, 1290, 653 and 652 ng/
amoxicillin were detected in the Pearl River at concentrations g respectively [186]. Another study examined the occurrence of

Please cite this article in press as: A.J. Ebele, et al., Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment,
Emerging Contaminants (2016), http://dx.doi.org/10.1016/j.emcon.2016.12.004
 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16 11

antibiotics in water, sediments, aquatic plants and animals from antibiotics entering local waterways of South East Queensland.
Baiyangdian Lake in North China. While sulphonamides were the Among the antibiotics investigated, cephalexin had the highest
dominant antibiotics in lake water, quinolones were prominent in concentration of 2000 ng/L being the second most prescribed
sediments at concentrations of 0.86e1563 ng/L and 65.5e1166 mg/ antibiotic in Australia [39].
kg respectively [97].
1.9. Sediment and sewage sludge
1.7.3. Biota
The catastrophic decline in the vulture population in Pakistan Few studies have been conducted in Australia in terms of
has been partially attributed to dietary exposure of vultures to monitoring pharmaceuticals in sediments [168]. investigated iso-
diclofenac-treated livestock. Specifically, the diclofenac concen- topic exchangeability to measure the available fraction of carba-
trations of 0.051e0.643 mg/g were found in the kidneys of all 25 mazepine in river sediment collected from Mackreath Creek and
vultures that died of renal failure [121]. Li et al. also detected 13 Scott Creek in South Australia. The study demonstrated isotopic
antibiotics in most of the studied hydrophyte samples (aquatic exchangeability as a relatively quick and simple alternative to batch
plants) such as: Salvinia natans (Sal), Hydrocharis dubia (Hyd) and desorption techniques for the assessment of the available fraction
Ceratophyllum demersum (Cer) and four crustacean species of the carbamazepine in sediments following their release into
including: crab (Eriocheir sinensis), river snail (Viva parus), shrimps aquatic ecosystems [168]. Another study reported the detection of
(Macrobrachium nipponense) and lobster (Palinuridae), 7 fish spe- emerging contaminants including pharmaceuticals in the
cies: topmouth gudgeon (Pseudorasbora parva), loach (Misgurnus estuarine-receiving environment around Auckland, New Zealand.
anguillicaudatus), yellow catfish (Pelteobagrus fluvidraco), to 21 out of 46 targeted pharmaceuticals were quantified in one or
mention but a few from Baiyangdian Lake, China. The concentra- more estuarine sediments with concentrations ranging from 0.2 to
tions of antibiotics in Sal, Cer and Hyd were 1769 mg/kg, 253 mg/kg 7.7 ng/g. The highest concentrations were detected for acetamin-
and 129 mg/kg respectively [97]. Other studies have also reported ophen (7.7 ng/g) and naproxen (5.5 ng/g) [148].
concentrations of ciprofloxacin in the aquatic plant (Echinodorus
amazonicus) as high as 795 mg/kg [28,180]. 1.10. Africa
Liu et al. also reported steroid estrogens at concentrations up to
11.3 ng/g dry weight in wild fish species such as crucian carp, carp, 1.10.1. Wastewater and surface water
and silvery minnow from Dianchi Lake in Southern China. Liver Currently, very little is known about the occurrence, fate and
displayed highest estrogen accumulation, followed by gills and behaviour of PPCPs in the African freshwater aquatic environment.
muscle [100]. Following a study of fluoroquinolones in the aqua- In most developing countries in Africa, where the waste disposal
culture environment of the Pearl River Delta, South China, He et al. system is basically through landfill, it is important to monitor the
reported the accumulation of fluoroquinolones in Siganus fusces- presence of PPCPs, since some of these PPCPs are not easily
cens from Hailing island, Sparus microcephalus from Dapeng'ao and degradable either through biodegradation or photodegradation.
Lutianus argentimaculatus from Hailing island, at concentrations of Moreover, they can contaminate groundwater which constitutes a
255, 133 and 5 ng/g wet weight respectively, with concentrations major water supply for a large proportion of the population in arid
higher in liver than in muscle tissue. ~Concentrations of norfloxacin regions of Africa.
were higher than those of ciprofloxacin and enrofloxacinin in both Antimalarial drugs such as artemether and lumefantrine, that
tissues [69]. are widely used in Africa for the treatment of the malaria parasite,
as well as amoxicillin were detected at concentrations ranging from
1.8. Australia 3 to 32 mg/L in Tanzania [115]. A study in South Africa reported the
presence of pharmaceuticals such as erythromycin, chloramphen-
1.8.1. Wastewater and surface water icol, nalidixic acid, tetracycline, sulfamethoxazole, acetaminophen,
Data exists demonstrating the presence of numerous pharma- atenolol, diclofenac, ibuprofen, caffeine and others in Umgeni sur-
ceuticals in effluents, river systems, marine sediments and sewage face water and in a dam along the Umgeni River used for water
sludge in Australia as well as New Zealand. During a national survey supply in KwaZulu-Natal South Africa. There was 100% occurrence
of trace organic contaminants in Australian rivers, the most of the analytes studied in wastewater, with caffeine displaying the
commonly detected contaminants were pharmaceuticals such as: highest average concentration at 61 ± 5 mg/L and nalidixic acid
salicylic acid, paracetamol, carbamazepine, and caffeine at being the most abundant antibiotic at 31 ± 3 mg/L. The waste
maximum concentrations of 1530 ng/L, 7150 ng/L, 682 ng/L and treatment process reduced the influent concentrations by 43e94%
3770 ng/L respectively [144]. A study by Ref. [162] reported the before discharge except for atenolol removal (for which reduction
occurrence of antibiotics in three hospital effluents, five WWTPs, was only 15%). Analyte concentrations were generally much lower
six rivers and a drinking water catchment within watersheds of in the surface water (<10 mg/L), except acetaminophen (16 mg/L)
South-East Queensland, Australia. The results of the study showed and atenolol (39 mg/L) [1]. A more recent study reported residues of
high concentrations of antibiotics in the hospital effluent (up to pharmaceuticals in wastewater from Msunduzi River, KwaZulu-
14.5 mg/L). Concentrations of target antibiotics in the studied Natal, South Africa. Results revealed ibuprofen to display the
WWTP influent and effluent were up to 64 mg/L and 3.4 mg/L highest concentrations at 117 mg/L and 85 mg/L in wastewater and
respectively, while river water samples contained up to 2 mg/L of surface water respectively. Concentrations of antibiotics in surface
target analytes. Interestingly, none of the studied antibiotics were water were generally lower (>10 mg/L) but up to 34.5 mg/L in
detected in drinking water. wastewater [109]. In Kenya [84], investigated 10 classes of phar-
[179] detected the antimicrobial triclosan in wastewaters and maceutically active ingredients (PAIs) in Nairobi River. Analgesics,
biosolids from Australia WWTPs. Concentrations of triclosan anti-inflammatory and antiepileptic agents were the most preva-
ranged from 23 to 434 ng/L and 0.09e16.79 mg/kg for the WWTP lent PAIs at about 30e35 mg/L, followed by antibiotics/antimalarial
effluents and biosolids respectively. Triclosan at concentrations up drugs at up to 25e30 mg/L, while antivirals were detected at up to
to 75 ng/L was detected in surface waters (outfall, upstream, and 10e15 mg/L. Another study reported the occurrence of antibiotics
downstream) from five rivers receiving effluent discharge from the and antivirals in the Nairobi River Basin, Kenya. The maximum
investigated WWTPs. Costanzo et al. reported detection of six concentrations in river water for sulfamethoxazole, trimethoprim,

Please cite this article in press as: A.J. Ebele, et al., Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment,
Emerging Contaminants (2016), http://dx.doi.org/10.1016/j.emcon.2016.12.004
12 A.J. Ebele et al. / Emerging Contaminants xxx (2016) 1e16

ciprofloxacin, lamivudine, nevirapine, and zidovudine were 13.8, PPCPs for bottom-feeding aquatic biota.
2.6, 0.5, 5.4, 4.8, and 7.7 mg/L respectively [118]. Currently, very little is known about the levels of PPCPs in biota
Olaitan et al. reported the detection of pharmaceutical com- in general. Few studies have investigated PPCP residues in fish,
pounds in surface and groundwater samples collected from an birds and mammals. There is also a lack of information on the po-
irrigation canal and several wells in a pharmaceutical industrial tential trophic magnification of these compounds or the influence
area of Sango Ota, Ogun State, Nigeria. The average concentrations of prenatal exposure on the possible transfer of PPCPs to birds' eggs
of the targeted pharmaceuticals such as diclofenac, chloroquine, and other nascent wildlife.
paracetamol and ciprofloxacin were 17 mg/L, 5 mg/L, 3 mg/L and 1 mg/ It is also imperative to further the current understanding of the
L, respectively [122]. To augment the limited database on the toxicological implications of chronic exposure to complex mixtures
occurrence of pharmaceutical compounds in the Nigerian envi- of PPCPs at sub-therapeutic levels in both target and non-target
ronment, a monitoring campaign was conducted in Lagos. Phar- organisms. More research is also needed to characterise the influ-
maceutical residues in wastewater impacted surface waters and ence of such exposure on the status of public health in contami-
sewage sludge were quantified using LC-MS/MS. For the surface nated areas (e.g. impacts on malarial resistance in Africa or fertility/
water, ibuprofen showed the highest concentrations up to 8.8 mg/L, fecundability in areas contaminated with estrogenic hormones).
while diclofenac was more abundant in sewage sludge with con- Although data exist about the presence of PPCPs in the fresh-
centrations up to 1100 mg/kg dry weight [123]. water aquatic environment, there appear gaps in knowledge about
the seasonal variability in concentrations of commonly and
1.10.2. Sediment and sewage sludge consistently detected PPCPs in the aquatic environment [184].
Aspirin, diclofenac, ketoprofen and ibuprofen were measured in highlighted seasonal variations in concentrations of some phar-
sediment samples collected from Msunduzi River, kwazulu-Natal, maceuticals in water samples collected between December 2009
South Africa. The highest concentrations in sediment were and 2010 from the river Medway, Kent, UK, with the highest con-
observed for aspirin (212e427 ng/g). The concentrations of diclo- centrations detected in June. Further investigation is needed to
fenac, ketoprofen, and ibuprofen detected in sediment were be- provide more detailed definition of seasonal variations of PPCPs in
tween 57 and 309, 7e57 and 5e11 ng/g respectively [2]. Matongo various environmental compartments. Another important area that
et al. also detected ibuprofen in sediment from the Msunduzi River, has to be properly addressed is the bioaccumulation of PPCPs in
KwaZulu-Natal, South Africa at concentrations as high as 659 ng/g aquatic organisms such as: algae, crustaceans, and fish. Initial in-
[109]. vestigations of this issue [37,163,166] highlight its importance and
further study of the potential bioaccumulation by aquatic biota is
2. Summary, research gaps and future perspectives warranted, including its implications for human exposure via
consumption of contaminated fish/shellfish.
PPCPs are a group of emerging contaminants with physico- Finally, future research on PPCPs should not focus only on the
chemical characteristics that distinguish them from other con- parent (intact) compounds but also on their potential degradation
taminants (e.g. persistent organic pollutants). Pharmaceuticals are products/metabolites in various matrices. This is of importance
structurally designed to maximise their biological activity at low because such degradation products/metabolites formed under
concentrations and developed to produce a prolonged action. These various environmental conditions (temperature, pressure, UV light
properties highlight the risks associated with the inadvertent … etc) or by non-target organisms may differ from those formed
presence of PPCPs in the environment. This review highlights that under human physiological conditions. Consequently, this may
aquatic organisms are continuously exposed to PPCPs throughout produce more toxic/bioaccumulative compounds than the parent
their life cycle and there is mounting evidence that the unintended PPCPs.
presence of these contaminants in the aquatic environment may
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