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Chemosphere 82 (2011) 10621071

Contents lists available at ScienceDirect

Chemosphere
journal homepage: www.elsevier.com/locate/chemosphere

Analysis of the presence of cardiovascular and

analgesic/anti-inammatory/antipyretic pharmaceuticals
in river- and drinking-water of the Madrid Region in Spain
Y. Valcrcel a,, S. Gonzlez Alonso a, J.L. Rodrguez-Gil b, R. Romo Maroto a, A. Gil a, M. Catal c
a
Department of Preventive Medicine, Public Health, Immunology and Medical Microbiology, Faculty of Health Sciences, Rey Juan Carlos University, Avda Atenas s/n. E-28922
Alcorcn, Madrid, Spain
b
Centre for Toxicology, School of Environmental Sciences, University of Guelph, Bovey Building, Guelph, ON, Canada N1G2W1
c
Department of Biology and Geology, School of Experimental Science & Technology, Rey Juan Carlos University, Avda Tulipn s/n. E-28933 Mstoles, Madrid, Spain

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

Article history: Interest in the presence of pharmaceuticals in wastewater, in the water of our rivers and, to a lesser
Received 3 May 2010 extent, in our drinking water, has been growing in recent decades. Many of these substances, currently
Received in revised form 7 October 2010 classied as emerging pollutants, are biologically active compounds and continuously released in efu-
Accepted 11 October 2010
ents. As sewage treatment plants (STPs) are not adequately equipped to eliminate all of these substances
Available online 26 November 2010
completely, some are discharged directly into rivers. In Spain, as in most of its neighbouring countries,
there is an elevated use of pharmaceuticals for the treatment of cardiovascular diseases (which are extre-
Keywords:
mely prevalent among the older adult population) and anti-inammatory medications, which are obtain-
Pharmaceuticals
Surface water
able over the counter without a medical prescription.
Sewage treatment plant This study therefore sought to determine to what degree pharmaceuticals with the highest regional
Cardiovascular prescription and/or use rates, such as cardiovascular and analgesic/anti-inammatory/antipyretic medi-
Analgesic/anti-inammatory/antipyretic cations, were present in the principal rivers (Jarama, Manzanares, Guadarrama, Henares and Tagus) and
Spain tap-water samples of the Madrid Region (MR). Samples were taken downstream the discharge of 10 of
the most important regions STPs and the most frequently used drugs in the region were analysed for.
Of the 24 drugs analysed, 21 were detected at concentrations ranging from 2 ng L 1 to 18 lg L 1. The
highest drug concentrations corresponded to ibuprofen, diclofenac, naproxen, atenolol, frusemide (furo-
semide), gembrozil and hydrochlorthiazide, and in most cases exceeded the amounts reported in the
scientic literature. No traces of these groups of pharmaceuticals were detected in the drinking water
analysed.
On the basis of the high concentrations detected, we believe that an environmental surveillance system
should be implemented to assess the continuous discharge of these pharmaceuticals and their possible
ecotoxicological effects. At the same time, efforts to raise the awareness of the public about responsible
use and the proper disposal of such substances at purpose-designated collection points should be
increased. Furthermore sewage treatment processes should be suitably adapted to increase the rates of
removal of these drugs.
2010 Elsevier Ltd. All rights reserved.

1. Introduction
Since the 1980s, different studies conducted world-wide have
shown the presence in the environment of medications intended
Abbreviations: DSSTP, down-stream sewage treatment plant; DDT, dichloro
diphenyl trichloroethane; MR, Madrid Region; NSAIDs, non-steroidal anti-inam-
matory drugs; INE, National Statistics Institute (Instituto Nacional de Estadstica).
Corresponding author. Address: Edicio departamental I, Departamento de
Medicina Preventiva, Salud Pblica, Inmunologa y Microbiologa Mdicas, Facultad
de Ciencias de la Salud, Avda Atenas s/n. E-28922 Alcorcn, Madrid, Spain. Tel.: +34
914888891; fax: +34 914888955.
E-mail address: yolanda.valcarcel@urjc.es (Y. Valcrcel).
for human use and their metabolites (Richardson and Bowron,
1985). Medications can be released into water via a number of
routes, the most important being through excretion of pharmaceu-
ticals not wholly metabolised by the body or their pharmacologi-
cally active metabolites (Derksen et al., 2004). An alternative
route is through inappropriate elimination of pharmaceuticals by
citizens, frequently using drains for the purpose, instead of the
Integrated Medical Container & Drug Management and Collection
System (Sistema Integrado de Gestin y Recogida de Envases y
Medicmentos-SIGRE) purpose-designed by the Spanish pharmaceutical
industry for ensuring correct management of such waste matter
(http://www.sigre.es).

0045-6535/$ - see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.chemosphere.2010.10.041
 Author's personal copy
Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071
The presence of these pharmaceuticals in the environment is
due to a great extent to their incomplete elimination at sewage
treatment plants (STPs) (Carballa et al., 2005; Petrovic et al.,
2005; Gros et al., 2009; Radjenovic et al., 2009). As a result, differ-
ent concentrations of pharmaceuticals have been detected in sur-
face waters (rivers, lakes and seas), groundwater and tap water
at concentrations ranging from ng L 1 to lg L 1, (Derksen et al.,
2004; Kmmerer, 2004; Zuccato et al., 2006; Mompelat et al.,
2009). The substances in question are characterised by being
potentially hazardous, as some are ubiquitous, persistent and bio-
logically active compounds.
Increasingly more information about the effects that such sub-
stances can have on ecosystems is being revealed. For instance,
apart from affecting the kidneys of mammals, the anti-inamma-
tory, diclofenac, has been associated (as a result of its use en veter-
inary practice) with the disappearance of the Oriental White-
backed Vulture in India and Pakistan, something that, according
to the authors of the study, Fent et al. (2006), may possibly amount
to an ecological disaster on a par with what happened in the case of
DDT. Evidence suggests that another medical drug, the beta block-
er, propranolol, detected by different studies conducted in north-
east Spain by Dr. Barcels team (Gros et al., 2007), has effects on
zooplankton and benthic organisms (Fent et al., 2006). Other ef-
fects that have been documented are the feminisation of male sh
caused by exposure to estrogens, the lack of mating among sh
(Huggett et al., 2002) and the appearance of antimicrobial resis-
tance (Kmmerer, 2004).
Notwithstanding this, most of these studies focus on individ-
ual compounds rather than on mixtures, which is how medica-
tions are really found in nature. Pomati et al. (2006) recently
examined the effects of a mixture of pharmaceuticals on human
embryonic cells in vitro. These results suggest that pharmaceuti-
cal residues at ng L 1 levels can inhibit cell proliferation by affect-
ing their physiology and morphology. Indeed, the effects of this
cocktail of human pharmaceuticals has not yet been adequately
evaluated.
In 2008, expenditure on pharmaceuticals in Spain totalled
10 607.39 million euros (http://www.msc.es), approximately 4.5
million of which was accounted for by prescriptions in the Madrid
Region (MR) (Antoanzas et al., 2005). The therapeutic groups
most widely administered under medical prescription by primary
care practices are those targeting the nervous, cardiovascular, and
digestive systems (Sans et al., 2002; Farmaindustria, 2010). Never-
theless, both analgesics and non-steroidal anti-inammatory
drugs (NSAIDs) rank among the most used pharmaceuticals
world-wide. This is due to the fact that they are used for diseases
and symptoms which are highly prevalent among the general
population and can be bought over the counter without a medical
prescription. In Spain, paracetamol (acetaminophen), ibuprofen
and acetylsalicylic acid account for most of the analgesics and
anti-inammatories used by the general population (Fortuny
et al., 2005). Similarly, owing to changes in dietary habits and to
sedentary lifestyles, hypercholesterolaemia and hypertension are
two frequent health problems in developed countries. The rise
in their prevalence has entailed a considerable increase in the
use of pharmaceuticals which are designed to combat such
diseases and which already represent over 12% of all medications
annually used in Spain. Indeed, close on 977 million euros is
spent on hypolipidaemic agents and hypotensors in Spain
(http://www.msc.es).
Accordingly, this study sought to determine to what degree
pharmaceutical drugs having the highest regional prescription
and/or use rates, such as cardiovascular and analgesic/anti-
inammatory/antipyretic drugs, were present in the regions main
rivers and in tap-water samples from the Madrid metropolitan
area.
1063
2. Materials and methods
2.1. Description of sampling sites and method of sampling
With an area of only 8028 square kilometres, 1.6% of Spanish
territory, the Madrid Region (MR) has an estimated population of
6 million (13.45% of the countrys population). This therefore
makes it the Autonomous Region with the greatest population den-
sity (676 inhabitants per square kilometre), and ranks it among the
most densely populated regions in Europe. As much as 89.3% of the
population is concentrated within a conurbation formed by the city
and its suburbs (54.2%), and towns lying in the Greater Madrid
metropolitan area (35.1%), with the remaining population spread
over the rest of the region.
Ten out of the 145 sewage treatment plants in the MR were se-
lected, according to the population served. Sampling was per-
formed approximately 100 m downstream from STP outfall
points. Fig. 1 includes downstream STP (DSSTP) sample codes,
the name of the STP, population equivalent, receiving water and
treatment. Efuent is discharged by STPs directly into the ve main
rivers of the MR (Jarama, Manzanares, Henares, Tagus (Tajo), and
Guadarrama), except in the case of the Arroyo del Bodonal (arroyo;
stream) and Arroyo del Soto, where it is discharged into water-
courses feeding into the Jarama and Guadarrama Rivers respec-
tively (Fig. 1). Grab samples of river water were collected in a
single campaign in October 2007. One litre of water was collected
in pre-rinsed amber glass bottles, chilled and sent to the laboratory
of analysis within the next 24 h.
The ve main drinking water supply areas for Metropolitan Ma-
drid were selected for our study (Table 1). Grab tap-water samples
were taken in pre-rinsed amber glass bottles from both public
places and private residences during the period, 25th30th Octo-
ber 2007.
Procedural blanks and spiked samples were analysed. None of
the target compounds were detected in the procedural blanks.
Spiked samples were determined with good precision and recover-
ies. All samples were spiked with the internal surrogate standard
13C-phenacetin to compensate for losses involved in the sample
extraction. The limit of detection, mean recovery and relative stan-
dard deviation of the method have been reported elsewhere (Mar-
tinez Bueno et al., 2010).
2.2. Pharmaceuticals selected
In line with a previous study which exclusively analysed medi-
cations of the central nervous system (Gonzlez Alonso et al.,
2010), we analysed 24 medications for human use belonging to
the two most frequently prescribed and/or used therapeutic
groups in Spain in general and in the MR in particular, namely, car-
diovascular and analgesic/anti-inammatory/antipyretic drugs
(Table 2).
2.3. Sample preparation
Preconcentration of the samples prior to chromatographic anal-
ysis was performed by solid phase extraction (SPE), using commer-
cial Oasis HLB cartridges (200 mg, 6 cc) from Waters (Mildford,
MA, USA) and an automated ASPEC XL sample processor from
Gilson (Villiers-le-Bel, France) for the purpose. The operational
procedure has been described in detail elsewhere (Martinez Bueno
et al., 2010). Briey, the cartridges were preconditioned with
MeOH (6 mL) and HPLC-grade deionised water (5 mL, pH adjusted
to 8 with 20% NH4OH) at a ow rate of 1 mL min 1. Aliquots of
200 mL of sample (pH adjusted to 8) were then loaded into the car-
tridge at a ow rate of 10 mL min 1, rinsed with 5 mL of deionised
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1064 Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071

Fig. 1. Map of the study area and sample site localizations (DSSTP) in the Community of Madrid and codes of the sampling points and characteristics of the monitored sewage
treatment plants (STPs).

Table 1
Characteristics of the drinking water samples.

Water supply area Population served Town District Sampling site Sample code
Colmenar 1724 029 Madrid Chamartn Bus station tap water P-CHAM
Getafe 594 744 Titulcia Private residence tap water P-TIT
Islas Filipinas 739 708 Madrid Usera Private residence tap water P-USE
Retamares 433 627 Legans Private residence tap water P-LEG
Valmayor 846 406 Alcorcn University tap water P-ALC

water and nally eluted with 2  4 mL of MeOH at 1 mL min 1. The
extracts so obtained were nally evaporated until almost dryness,
reconstituted with 1 mL of MeOH:water, 10:90 (v/v), ltered, and
diluted 1:1 with MeOH:water (10:90) prior to analysis.
2.4. Liquid chromatography-Q-TRAP-mass spectrometry
phase A) and HPLC-grade water (mobile phase B) at a ow rate
of 0.3 mL min 1. LC gradient progressed from 30% A to 100% A in
7 min, and was maintained at 100% A for 8 min. The re-equilibra-
tion time was 10 min. The injection volume was 20 lL in both
modes. Specic operational conditions were optimised and have
been described elsewhere (Martinez Bueno et al., 2010).

Analysis of the selected pharmaceuticals was performed by a 3. Results and discussion

3200 QTRAP (quadrupole-ion trap) MS/MS system (Applied Biosys-
tems, Ontario, Canada) using a turbo ionspray source in positive
and negative modes. Separation was performed in an Agilent Tech-
nologies HPLC series 1100, equipped with a reversed-phase C-18
analytical column (ZORBAX SB, 250 mm  3.0 mm I.D.; 5 lm).
For analysis in positive mode, the compounds were separated
using acetonitrile (mobile phase A) and HPLC-grade water with
0.1% formic acid (mobile phase B) at a ow rate of 0.2 mL min 1.
A linear gradient progressed from 10% A to 100% A in 40 min, after
which the mobile phase composition was maintained at 100% A for
10 min. The re-equilibration time was 15 min. Compounds ana-
lysed in negative mode were separated using acetonitrile (mobile
Of the 24 pharmaceuticals analysed, 21 were detected at con-
centrations ranging from 2 ng L 1 to 18 lg L 1 (Table 3). On total-
ling the concentrations of all the pharmaceuticals analysed at the
respective sampling points, the highest concentrations were ob-
tained at DSSTP sampling point 8, corresponding to the Arroyo
del Soto STP, with a total concentration of 44 lg L 1. This sewage
plant collects wastewater from Mstoles, the MRs second largest
town after the capital, Madrid, in terms of number of inhabitants
(population 206 478) (INEbase, 2007), and from other towns in
the Greater Madrid area, and discharges into the waste-dominated
stream, Arroyo del Soto.
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Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071 1065

Table 2 Fig. 2 compares the total concentrations found at the respective

Characteristics of analyzed pharmaceuticals. sampling points for the two therapeutic groups analysed. Although
Therapeutic Pharmaceutical active CAS no. MQLa total concentrations by sampling point and type of drug showed a
groups compounds (ng L 1) higher overall concentration of cardiovascular drugs, 16 lg L 1
Analgesics, anti-inammatory drugs and antipyretics versus 12 lg L 1 (Table 3), this was not the case for all the individ-
Anhydrous codeinea 76-57-3 125 ual sampling points.
Diclofenac 15307- 1 At sampling points DSSTP 5 and DSSTP 6, which correspond to
86-5
Ibuprofen 15687- 7
the city of Madrid (River Manzanares), concentrations of analge-
27-1 sics/anti-inammatories/antipyretics were higher than those of
Indomethacin 53-86-1 1 cardiovascular drugs, namely, 22 lg L 1 versus 15 lg L 1 at DSSTP
Ketoprofen 22071- 2 sampling point 5, and 22 lg L 1 versus 13 lg L 1 at DSSTP sam-
15-4
pling point 6. The greater contributions to these concentrations
Mefenamic acid 61-68-7 2
Naproxen 22204- 14 were due to the elevated presence of ibuprofen at these points. A
53-1 higher concentration of analgesics/anti-inammatories/antipyret-
Paracetamol 103-90-2 4 ics, 7.8 lg L 1 versus 4.1 lg L 1, was likewise found at DSSTP sam-
(acetaminophen) pling point 10, corresponding to the River Tagus passage through
Phenazone (antipyrine) 60-80-0 2
the MR. The only town of importance traversed by the River Tagus
Propyphenazone 479-92-5 1
Salicylic acid 69-72-7 1 on its route through the MR is Aranjuez with 54 055 inhabitants
(INEbase, 2007). At DSSTP sampling point 1, the concentration of
Cardiovascular drugs analgesic/anti-inammatory/antipyretic group exceeded that of
b-blockers
cardiovascular drugs, though these differences were minimal, i.e.,
Atenolol 29122- 1
68-7
21.8 lg L 1 versus 21.6 lg L 1.
Metoprolol tartrate 56392- 1
17-7 3.1. Cardiovascular drugs
Nadolol 42200- 1
33-9
Chronic cardiovascular disease accounts for a huge proportion
Propranolol 525-66-6 1
Sotalol hydrochloride 959-24-0 2 of human illness and is responsible for 30% of deaths world-wide.
It has given rise to the worlds largest therapeutic drug sector, with
Lipid regulators
Bezabrate 41859- 1 annual sales of around 70 billion dollars (IMS Health, 2006; http://
67-0 www.imshealth.com).
Clobric acid 882-09-7 3 In Spain, cardiovascular disease is the leading cause of hospital
Fenobrate 49562- 2
admission and death (Spanish Society of Cardiology, 2009), and it is
28-9
Frusemide (furosemide) 54-31-9 2
estimated that, of all the cardiovascular risk factors, hypertension
Gembrozil 25812- 7 is the main or secondary cause in 50% of cardiovascular diseases
30-0 around the world (World Health Organization, 2002). In Spain, 1
Hydrochlorothiazide 58-93-5 7 out of every 4 all-cause deaths and 1 out of every 2.5 deaths due
Mevastatin 73573- 3
to cardiovascular disease are related to hypertension (Garca del
88-3
Pravastatin sodium 81131- 6 Pozo et al., 2004).
70-6 According to Spanish National Health System data for 2001,
Simvastatin 79902- 8 pharmaceuticals for cardiovascular disease and specically those
63-9 for hypertension represented 15% of total pharmaceutical expendi-
a
MQL: method quantication limit. ture. Of all the cardiovascular drugs, diuretics were the most
widely accepted in Spain, appearing in arterial hypertension clini-
cal practice guidelines as the pharmaceuticals of rst choice, with
their use accounting for 21.2% of the total. Beta blockers, on the
The points with second highest concentrations were DSSTP other hand, only represented 8.4% of total use in 2001. Despite
sampling point 1, which corresponds to the waste-dominated being in constant use, as compared to other countries, these phar-
stream, Arroyo del Bodonal (River Jarama), and DSSTP sampling maceuticals continue to enjoy little acceptance in Spain (Garca del
point 3, which belongs to the River Jarama, where the concentra- Pozo et al., 2004).
tions were 44 lg L 1 and 41 lg L 1 respectively. DSSTP sampling For control of hyperlipidaemia, statins are the pharmaceuticals
point 1 receives wastewater discharged by the town of Tres Cantos. of choice in hypercholesterolaemias and brates in hypertriglycer-
Despite its being relatively small (population 41 064) (INEbase, idaemias. Both groups are widely used, safe and well-tolerated
2007), this town is home to a leading university campus (Autono- (Alonso et al., 2006).
mous University of Madrid), a technological industrial estate with
pharmaceutical plants, a hospital and a large old age home. 3.2. Cardiovascular drugs (b-blockers)
Ranking immediately below these two were DSSTP sampling
points 5 and 6, with total concentrations of 37 lg L 1 and 35 lg L 1 Beta blockers are one of the most widely prescribed groups of
respectively, corresponding in both cases to discharges released by therapeutic drugs. These pharmaceuticals work on the heart and
the Sur and Butarque sewage plants into the River Manzanares, the circulatory system to lower hypertension, relieve angina (chest
only river that ows through the city of Madrid (population pain), correct arrhythmias and, in heart-attack patients, help pre-
3255 944) (INEbase, 2007). vent additional heart attacks.
The remaining sampling points registered total concentra- Within this group of pharmaceuticals, the highest concentra-
tions ranging from 6.4 lg L 1 to 23 lg L 1. DSSTP 9, corresponding tions detected corresponded to atenolol, 6.2 lg L 1, and the lowest
to the River Henares downstream from the Alcal Este STP to propranolol, 15 ng L 1 (Table 3 and Fig. 3). Both propranolol and
outfall, was the sampling point that displayed the lowest atenolol were found in 100%, metoprolol tartrate in 80%, and sota-
concentrations. lol and nadolol in only 50% and 20% of samples respectively (Fig. 4).
 1066

Table 3
Concentration of PhACs in different sampling points of the rivers of Madrid downstream the main STPs (bold: maximum, underlined: minimum concentrations detected in this study).
1
Therapeutic groups Pharmaceutical active compound Concentration (ng L )
Jarama river Manzanares river Guadarrama river Henares river Tagus river Median
DSSTP 1 DSSTP 2 DSSTP 3 DSSTP 4 DSSTP 5 DSSTP 6 DSSTP 7 DSSTP 8 DSSTP 9 DSSTP 10
Cardiovascular drugs
b-blockers
Atenolol 6042 1121 2000 1504 4667 5042 2450 6167 318 679 2225
Metoprolol tartrate 52 25 76 51 60 71 28 41 52
Nadolol 16 62 39
Propranolol 46 25 117 46 35 63 109 178 15 18 46
Sotalol hydrochloride 864 428 123 399 455 428
Lipid regulators
Bezabrate 472 415 854 730 1294 1648 634 2315 367 234 682
Clobric acid 27 185 57 70 26 40 44 28 24 40
Fenobrate
Frusemide (Furosemide) 1015 388 3228 793 1077 609 1020 1961 262 1015
Gembrozil 5141 4096 3678 4508 5192 4164 1113 4915 1288 1610 4130
Hydrochlorothiazide 7866 5573 17 589 6561 2399 1664 9802 13 399 1261 1296 6067
Mevastatin
Pravastatin Sodium 88 378 64 43 42 106 76
Simvastatin
1
Total concentrations (ng L ) 21 613 11 828 28 405 14 450 15 192 13 343 15 216 29 627 3273 4099 15 624

Analgesics anti-inammatory drugs and antipyretics

Anhydrous Codeine 693 253 542 194 501 470 377 751 50 25 424
Diclofenac 1982 1036 3274 2098 2735 2586 1750 3363 313 2040
Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071

Ibuprofen 14 671 3569 4467 4425 16 587 16 886 4461 2234 4174 4461
Author's personal copy

Indomethacin 169 66 267 69 116 151 86 240 134

Ketoprofen 902 223 1057 399 677 556 514 1567 47 43 535
Mefenamic Acid 35 35 104 57 45 47 26 61 29 45
Naproxen 3140 1091 1891 1190 768 686 1016 2522 544 387 1054
Paracetamol (acetaminophen) 188 710 2813 710
Phenazone (Antipyrine) 268 153 752 208 269 255 194 268 53 53 232
Propyphenazone 2 13 22 7 25 24 56 27 2 3 18
Salicylic Acid 27 39 40 53 53 83 35 79 55 53
1
Total concentrations (ng L ) 21 889 6478 12 416 8700 21 776 21 744 4242 14 049 3226 7811 12 081
Total 43 502 18 306 40 821 23 150 36 968 35 087 19 458 43 676 6499 11 910 27 705
 Author's personal copy
Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071
Fig. 2. Total cumulative concentration of pharmaceuticals (ng L
Atenolol was the sole b-blocker found in concentrations at lg L 1
levels (median 2.2 lg L 1). Sotalol was found in concentrations at
a median level of 428 ng L 1 (minimum 123 ng L 1 and maximum
864 ng L 1), though only in 50% of samples.
The remaining pharmaceuticals in this subgroup were found at
far lower concentrations, and in all cases at ng L 1 levels. Owing to
their high volume of use, particularly outside Spain, concentrations
of beta blockers have been detected in surface water in both Eur-
ope and North America, at concentrations ranging from ng L 1 to
2.2 lg L 1 (Alder et al., 2010), with the latter measure correspond-
ing to the study undertaken by Ternes (2001) in 40 German rivers.
In our study, the highest concentrations of atenolol were found
at DSSTP sampling point 8 (Arroyo del Soto) with values of
6.2 lg L 1, at DSSTP sampling point 1 (Arroyo del Bodonal),
6.0 lg L 1, and also at DSSTP sampling points 6 and 5 (River Man-
zanares, city of Madrid) with values de 5.0 lg L 1 and 4.6 lg L 1
respectively.
In Barcel et al.s study of the River Ebro (north-east Spain)
(Gros et al., 2007), atenolol and sotalol were likewise the two beta
blockers most frequently found in this river, albeit at concentra-
tions far lower than those detected by us. Similarly, Martinez Bue-
no et al. (2010) detected atenolol, propanol, sotalol and metoprolol
in their study of different rivers in the MR but the highest reported
concentrations were in the order of 600 ng L 1 for atenolol and
39 ng L 1 for sotalol.
Furthermore, beta blockers were also detected at higher or low-
er concentrations by Vieno et al. (2007) in the River Vantaa in Fin-
land and Roberts and Thomas (2006) in the River Tyne in the
United Kingdom (UK).
Our results conrm that some beta blockers, such as atenolol
(Garner et al., 1994) and propranolol (Alder et al., 2010), belong
to the most ubiquitous group of pharmaceuticals in the aquatic
environment, with higher concentrations being obtained by us
than by Kasprzyk-Hordern et al. (2008) in south Wales (UK), Gros
et al. (2007) in north-east Spain Zuccato et al. (2000) in Italy, Cal-
amari et al. (2003) also in Italy, and Martinez Bueno et al. (2010) in
the Madrid Region (Spain).
1067
1
) by therapeutic group.
3.3. Cardiovascular drugs (lipid regulators)
Lipid abnormalities rank among the key risk factors for cardio-
vascular disease. It has been shown that interventions which de-
crease concentrations of low-density lipoprotein cholesterol can
signicantly reduce the incidence of coronary heart disease and
other major vascular events among a wide range of individuals.
In this therapeutic group, the highest concentration corre-
sponded to the diuretic, hydrochlorothiazide, with a maximum
concentration of 18 lg L 1, and the lowest to clobric acid, with
24 ng L 1 (Table 3). Hydrochlorothiazide, bezabrate and gem-
brozil were detected in 100%, furosemide and clobric acid in
90%, metoprolol in 80%, and pravastatin sodium in only 60% of
samples. Fenobrate and the statins, mevastatin and simvastatin,
were not detected (Fig. 4).
Hydrochlorothiazide was the drug found in greatest quantities,
with a minimum concentration of 1.3 lg L 1, a maximum of
18 lg L 1, and a median of 6.0 lg L 1 (Table 3 and Fig. 3). The high-
est concentrations were found at DSSTP sampling points 3 (River
Jarama) with 18 lg L 1, and 8 (Arroyo del Bodonal) with 13 lg L 1,
though concentrations were at lg L 1 levels at all sampling points.
Another diuretic, frusemide (furosemide), was also detected in
elevated quantities, with a median value of 1.0 lg L 1 (minimum
263 ng L 1; maximum 3.2 lg L 1). The antilipidaemic agent, gem-
brozil, registered a median value of 4.1 lg L 1, (1.1 lg L 1;
5.2 lg L 1). The highest concentrations were found at DSSTP sam-
pling points 5 (River Manzanares) with 5.2 lg L 1, and 1 (Arroyo
del Bodonal) with 5.1 lg L 1, though high concentrations at
lg L 1 levels were found at all points.
Concentrations of hydrochlorothiazide were greater than those
reported in the literature, whether in surface waters or even in
sewage plant efuent. In the MR study conducted by Martinez Bue-
no et al. (2010), the highest concentration of this drug in surface
water was 1 lg L 1, a value similar to those obtained by Castiglioni
et al. (2006) in sewage plant efuent.
The antilipidaemic agent, gembrozil, was detected in the sec-
ond highest concentration. Kolpin et al. (2002) reported 790 ng L 1
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1
Fig. 3. Medians (ng L ) for cardiovascular and analgesic/anti-inammatory/antipyretics drugs in decreasing order.

Fig. 4. Frequency of detection of cardiovascular and analgesic/anti-inammatory/antipyretics drugs.

as being the highest concentration found in surface water. In Mar- Bezabrate, with a median value of 682 ng L 1 (234 ng L 1;
tinez Buenos (2010) study, gembrozil was the second most fre- 2.3 lg L 1) was the fourth leading medical drug in this group in
quently detected lipid regulator yet its highest concentration was terms of concentration. This nding was in line with other studies
nevertheless in the order of 1.1 lg L 1. undertaken in European rivers, in which bezabrate is one of the
 Author's personal copy
Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071
pharmaceuticals usually found (Bendz et al., 2005). Castiglioni
et al. (2006) also detected furosemide and bezabrate in their
study conducted in Italy, albeit at far lower concentrations. Simi-
larly, these pharmaceuticals were detected by Gros et al. (2007)
in the River Ebro (north-east Spain) and by Glassmeyer et al.
(2009) in the USA. Indeed, STPs have been reported as showing a
very low percentage elimination of bezabrate, ranging from 34%
to 51% (Ternes, 1998).
In the case of statins, the only one detected was pravastatin so-
dium, with minimum and maximum values of 42 ng L 1 and
378 ng L 1 respectively. Neither mevastatin nor simvastatin was
detected.
Fenobrate, mevastatin and simvastatin were below the quan-
tication limit. Furthermore, no traces of pharmaceuticals were de-
tected in the study that targeted the Rivers Taff and Ely in south
Wales (Kasprzyk-Hordern et al., 2008). In general, few studies have
addressed the study of the statins, pravastatin and simvastatin.
Clofbric acid, the active metabolite in a number of blood lipid
regulators (clobrate, etofylline clobrate and etobrate), was de-
tected in almost all samples, though at low concentrations ng L 1
levels with a median value of 40 ng L 1 (24 ng L 1; 185 ng L 1).
Different studies (reviewed by Khetan and Collins (2007)),
including that conducted by Gros et al. (2007) in Spain, have shown
clobric acid to be one of the most widely detected antilipidaemic
agents. It is regarded as one of the most persistent drug residues
with an estimated persistence in the environment of 21 years in
soil/sediment (Zuccato et al., 2000) and a reported sewage-plant
percentage elimination of 5083%. This latter fact might explain
the low concentrations of this medical drug obtained by Ternes
study (1998) in spite of its having been found at all sampling
points, thus conrming its ubiquity in the aquatic environment.
3.4. Analgesics/anti-inammatories/antipyretics
Analgesics, non-steroidal anti-inammatories and antipyretics
rank among the most consumed pharmaceuticals world-wide.
They are used for very common conditions and diseases in the gen-
eral population (pain, viriasis, etc.) and may be sold without med-
ical prescription in Spain.
We examined the presence of 11 analgesics/anti-inammato-
ries/antipyretics, all found at higher or lower concentrations at
the various sampling points. The highest concentration was
17 lg L 1, corresponding to ibuprofen, and the lowest was
2 ng L 1, corresponding to propyphenazone (Table 3).
Most of the pharmaceuticals analysed were detected in 90
100% of samples, except for indomethacin which was found in
80% and paracetamol (acetaminophen) which was found in only
30% (Fig. 4). In other studies, this is the drug group with the highest
concentrations in surface waters, ranging from 0.4 ng to 15 lg L 1,
with diclofenac, paracetamol (acetaminophen) and ibuprofen
being the pharmaceuticals detected in the highest quantities
(Heberer, 2002).
Ibuprofen, an NSAID, is one of the most frequently prescribed
pharmaceuticals in Europe and has been previously reported as
being one of the most common drug residues in surface water. In
2003, close on 276.1 tons of ibuprofen were used in Spain (Carballa
et al., 2008), making it the most consumed pharmaceutical. In this
drug group, ibuprofen accounted for the highest concentrations,
with a median value of 4.4 lg L 1 (2.2 lg L 1; 16.8 lg L 1)
(Fig. 3). High concentrations at lg L 1 levels were obtained at
all sampling points. The greatest single contributions to these lev-
els of ibuprofen came from the waters of the city of Madrid at
DTSSP sampling points 6 and 5, with concentrations of 16.8 lg L 1
and 16.5 lg L 1 respectively.
In the study conducted by Farre et al. (2001) in the principal riv-
ers of Catalonia (north-east Spain), considerably high concentra-
1069
tions of ibuprofen, in the order of 2.7 lg L 1, were reported in
surface water. The highest concentration obtained in Martinez
Buenos study was 1.4 lg L 1 (2010). In most European studies,
ibuprofen has been detected in surface water, albeit at lower con-
centrations, (Vanderford et al., 2003; Roberts and Thomas, 2006),
and even in the USA the highest concentration obtained by Kolpin
et al. (2002) was 200 ng L 1. Recently, Pailler et al. (2009) under-
took a study in Luxembourg, in which the mean concentrations
were similar to ours, i.e., 4 lg L 1.
The most recent studies indicate that 14% of all ibuprofen con-
sumed is eliminated as an unchanged drug. Reported sewage-plant
percentage elimination of ibuprofen was relatively high, ranging
from 65% to 90% (Ternes, 1998). Nonetheless, we feel that the ele-
vated concentrations obtained as a result of this substances mass
consumption by the population are attributable to the fact that
ibuprofen can be bought without prescription in Spain and is used
for a wide spectrum of diseases.
The second most detected medical drug was the anti-inamma-
tory, diclofenac, with a minimum concentration of 212 ng L 1, a
maximum of 3.4 lg L 1, and a median of 2.0 lg L 1. The highest
concentration of diclofenac was found at DSSTP sampling points
8 (Arroyo del Bodonal) with 3.4 lg L 1, and 3 (River Jarama) with
3.3 lg L 1. Our results are in line with those reported by other
studies in the literature, in which diclofenac was obtained at high-
er concentrations, i.e., in lg L 1 (reviewed by Heberer (2002) and
by Zhang et al. (2008)). In Spain, 32.3 tons of diclofenac were con-
sumed in 2003 (Carballa et al., 2008).
Many of the studies conducted by Heberer et al. in Berlin high-
light diclofenac as being the most important medical drug in the
water cycle, and indeed the highest concentrations of diclofenac
obtained in river water were 1.0 lg L 1 in Germany (Heberer,
2002). Sewage plants eliminate anywhere from 0% to 80% of dic-
lofenac, with most eliminating in the region of 2140% (Zhang
et al., 2008). Different ecotoxicological studies are assessing the
acute toxicity of diclofenac, something that is considered unlikely,
though its long-term effects on aquatic ecosystems or its synergic
effects with other types of pharmaceuticals cannot yet be ruled out
(Zhang et al., 2008).
In this group, naproxene was the third most detected pharma-
ceutical with a minimum concentration of 387 ng L 1, a maximum
of 3.1 lg L 1, and a median of 1.1 lg L 1. The greatest proportion
was found at the DSSTP 1 sampling point (Arroyo del Bodonal, Riv-
er Jarama). In Martinez Buenos study (2010) undertaken in the
MR, naproxene was also found, albeit at lower concentrations, with
the highest value obtained being 444 ng L 1, on a par with that re-
ported by Farre et al. (2001).
Ketoprofen, phenazone, indomethacin, mefanamic acid and
propyphenazone were detected at concentrations ranging from
18 ng L 1 to 535 ng L 1 (median value). These analgesics were also
detected in various studies that reported on surface waters (Farre
et al., 2001; Ternes, 2001; Heberer, 2002; Kolpin et al., 2002).
Paracetamol (acetaminophen) is another of the pharmaceuticals
most widely dispensed at pharmacies, with the fact that it can be
administered without prescription in Spain (Fortuny et al., 2005)
making it one of the countrys most popular analgesics. In our
study, it was detected at only three sampling points but with con-
centrations of 188 ng L 12.8 lg L 1 and a median level of
710 ng L 1. In the USA, Kolpin et al. (2002) detected a median level
of 110 ng L 1 and a maximum of 10 lg L 1, while in Korea, Yoon
et al. (2010) detected levels of 1261 ng L 1 in the River Han. Given
paracetamol is easily degraded and eliminated at sewage plants
(Kolpin et al., 2002; Roberts and Thomas, 2006), the elevated levels
found, especially in DSSTP sampling point 10 (Aranjuez) could be
attributed to the contribution of the non-treated efuents of dis-
persed small populations discharging into the rivers analysed. A
breakdown in STPs cannot either ruled out.
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1070 Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071
Codeine is an opioid analgesic often detected in surface waters
(Heberer, 2002). In our study, it was detected at all sampling
points with a median value de 424 ng L 1, and concentrations
of 25751 ng L 1, amounts comparable to those reported by
Kasprzyk-Horden in the UK (Kasprzyk-Hordern et al., 2008),
Humme in Germany (Hummel et al., 2006) and Glassmeyer in
the USA (Glassmeyer et al., 2009).
Salicylic acid was obtained at very low concentrations, with a
maximum of 83 ng L 1, a minimum of 27 ng L 1, and a median of
53 ng L 1. Although it is a very frequently used drug at a global le-
vel, it is not found in very high concentrations in river water.
Ternes (1998) obtained a concentration of 340 ng L 1 in surface
water. Sewage-plant percentage elimination of salicylic acid is rel-
atively high, approaching 80%.
The especially elevated pharmaceutical concentrations in the
rivers obtained in our study might be due to different causes. In
most European countries, STPs perform tertiary treatments aimed
at rendering the water subsequently reusable, whereas in Spain
most of these plants undertake only primary and secondary treat-
ments (Gros et al., 2010). Mediterranean rivers have low ow rates
which together with the high population density of Madrid Region
could also account for higher pharmaceutical concentrations in our
rivers. On the other hand, the election of sampling points may ac-
count in part for the divergences with the work of Martinez Bueno
et al. (2010) also carried out in Madrid rivers. Our strategy con-
sisted in sampling in the dilution area of the efuents of the most
important STPs, where the highest levels of pharmaceuticals may
be expected. Seasonality could also be involved.
3.5. Drinking water/tap water
Despite the elevated river concentrations of many of the phar-
maceuticals analysed, none of them was detected in drinking
water. This may be due to the fact that the drinking water supply
for MR comes from reservoirs located at the headwaters of rivers
where there are no important inputs of pollutants.
Most of the European studies which have focused on tap-water
analysis of pharmaceuticals for human use have been undertaken
in Germany, Italy, France and Finland. In the cardiovascular drug
group, clobric acid, a lipid-regulating metabolite, was found in
tap water at concentrations of 50270 ng L 1 in Berlin. Zuccato
et al. (2000) also detected low concentrations of clobric acid,
5.3 ng L 1, in the drinking water of Milan (Italy) (reviewed by
Mompelat et al. (2009)).
In addition, diclofenac was also detected at concentrations of
635 ng L 1 in a drinking water sample from a private water tap in
Berlin, along with very low concentrations of ibuprofen, 3 ng L 1,
and phenazone. Stumpf et al. (1999) again in Germany, detected
bezabrate at a concentration of 27 ng L 1. Togola and Budzinski
(2008) also detected 210 ng L 1 of paracetamol (acetaminophen),
2.5 ng L 1 of diclofenac, 3 ng L 1 of ketoprofen and 0.6 ng L 1 of
ibuprofen. Vieno et al. (2007) detected ibuprofen, 8.5 ng L 1, and
ketoprofen, 8 ng L 1. In the USA, Loraine and Pettigrove detected
1.4 lg L 1 of ibuprofen in tap water (reviewed by Mompelat
et al. (2009)).
4. Conclusions
Our study detected the presence of a number of frequently used
pharmaceuticals in the surface water of the Madrid Regions main
rivers, thus furnishing evidence of insufcient elimination of these
substances at the local STPs.
The main pharmaceuticals detected can be classied into three
groups, based on the concentrations (median values) obtained:
Group 1: concentrations of 1 lg L 1 or higher: ibuprofen, dic-
lofenac, naproxene, atenolol, frusemide (furosemide), gembrozil
and hydrochlorothiazide.
Group 2: concentrations lower than 1 lg L 1 and down to
100 ng L 1: anhydrous codeine, indomethacin, ketoprofen, para-
cetamol (acetaminophen), phenazone (antipyrine), sotalol hydro-
chloride and bezabrate.
Group 3: concentrations below 100 ng L 1: mefenamic acid, pro-
pyphenazone, salicylic acid, metoprolol tartrate, nadolol, propran-
olol, clobric acid and pravastatin sodium.
None of the pharmaceuticals studied was detected in the drink-
ing water of the ve main supply areas of the city of Madrid, prob-
ably due to the high quality of the drinking water origin, at the
headwaters of the rivers in the mountains of the Madrid Region.
Currently, there are few studies addressing the effect of these
substances on aquatic organisms. Hence, in-depth ecotoxicological
studies are called for, particularly during critical biological stages,
using organisms of ecological relevance. Preliminary studies
(unpublished) conducted by our team indicate that environmental
concentrations of these pharmaceuticals exceed the experimental
lowest observed adverse effect concentration in animal and plant
development and could thus have a negative impact on wildlife.
The effects of chronic exposure and the toxicity of mixtures of
these substances are also of special relevance.
We recommend that the Madrid Regional Authorities imple-
ment an environmental surveillance system to evaluate the contin-
uous discharge of these pharmaceuticals into our rivers by sewage
plants. Equally necessary is the study and development of new
waste treatment technologies capable of completely eliminating
these substances, thereby serving to maintain the balance of the
Madrid Regions aquatic ecosystems.
Furthermore, a complete life cycle assessment of pharmaceuti-
cals would furnish invaluable information, so that the health
authorities, acting in co-ordination with the pharmaceutical indus-
try, could issue guidelines for the replacement of the environmen-
tally most problematic medications by others having similar
pharmacological efcacy and safety.
Lastly, stress must be laid on educating the population as regards
responsible use of pharmaceuticals and raising public awareness
as to the need for pharmaceuticals to be deposited at purpose-
designated recycling points.
Acknowledgements
This study was made possible thanks to solid all-round team-
work, in that the idea for the project came from Dr. Valcrcel, the
study itself was supervised by Dr. Gil, the bibliographic review
was mainly undertaken by Drs. Valcrcel and Catal, and the eld
work was co-directed by Drs. Valcrcel and Gonzlez and con-
ducted by Dr. Gonzlez Alonso, Ral Maroto and Jose Lus Rodr-
guez. In addition, the map and tables were drawn up by Jose Luis
Rodrguez Gil, Dr. Gonzlez Alonso. Dr. Valcrcel drafted the man-
uscript in collaboration with Dr. Catal. All named authors have re-
viewed the nal paper.
We should like to thank Dr. Fernandz-Alba and his team at the
Department of Hydrogeology & Analytical Chemistry at the Univer-
sity of Almera, and Dr. Agera in particular, for having carried out
the drug analysis. Lastly, a word of thanks must also go to Michael
Benedict for revising the English version of this paper.
References
Alder, A.C., Schaffner, C., Majewsky, M., Klasmeier, J., Fenner, K., 2010. Fate of beta-
blocker human pharmaceuticals in surface water: comparison of measured and
simulated concentrations in the Glatt Valley Watershed, Switzerland. Water
Res. 44, 936948.
 Author's personal copy
Y. Valcrcel et al. / Chemosphere 82 (2011) 10621071
Alonso, R., Mata, N., Mata, P., 2006. Control de las hiperelipemias en la prctica
clnica. Revista Espaola de Cardiologa 6, 2435.
Antoanzas, F., Rodrguez, R., Sacristn, J., Illa, R., 2005. Los medicamentos en la
Unin Europea: el tndem comercio-salud. Gaceta Sanitaria 19, 116.
Bendz, D., Paxeus, N.A., Ginn, T.R., Loge, F.J., 2005. Occurrence and fate of
pharmaceutically active compounds in the environment, a case study: Hoje
River in Sweden. J. Hazard. Mater. 122, 195204.
Calamari, D., Zuccato, E., Castiglioni, S., Bagnati, R., Fanelli, R., 2003. Strategic survey
of therapeutic drugs in the rives Po and Lambro in northern Italy. Environ. Sci.
Technol. 37, 12411248.
Carballa, M., Omil, F., Lema, J.M., Llompart, M., Garcia, C., Rodriguez, I., Gomez, M.,
Ternes, T., 2005. Behaviour of pharmaceuticals and personal care products in a
sewage treatment plant of northwest Spain. Water Sci. Technol. 52, 2935.
Carballa, M., Omil, F., Lema, J.M., 2008. Comparison of predicted and measured
concentrations of selected pharmaceuticals, fragrances and hormones in
Spanish sewage. Chemosphere 72, 11181123.
Castiglioni, S., Bagnati, R., Fanelli, R., Pomati, F., Calamari, D., Zuccato, E., 2006.
Removal of pharmaceuticals in sewage treatment plants in Italy. Environ. Sci.
Technol. 40, 357363.
Derksen, J.G., Rijs, G.B., Jongbloed, R.H., 2004. Diffuse pollution of surface water by
pharmaceutical products. Water Sci. Technol. 49, 213221.
Farmaindustria. La industria farmacutica en cifras. <http://www.farmaindustria.
es/idc/groups/public/documents/publicaciones/farma_002843.pdf> (accessed
February 2010).
Farre, M.L., Ferrer, I., Ginebreda, A., Figueras, M., Olivella, L., Tirapu, L., Vilanova, M.,
Barcelo, D., 2001. Determination of drugs in surface water and wastewater
samples by liquid chromatographymass spectrometry: methods and
preliminary results including toxicity studies with Vibrio scheri. J.
Chromatogr. A 938, 187197.
Fent, K., Weston, A.A., Caminada, D., 2006. Ecotoxicology of human
pharmaceuticals. Aquat. Toxicol. 76, 122159.
Fortuny, J., Silverman, D., Malats, N., Tardn, A., Garca, R., Serra, C., Carrato, A.,
Rothman, N., Dosemeci, M., Kogevinas, M., 2005. Uso de analgsicos y cido
acetilsaliclico en un estudio multicntrico en Espaa. Gaceta Sanitaria 19, 316
320.
Garca del Pozo, J., Ramos Sevilano, E., De Abajo, F., Mateos Campos, R., 2004.
Utilizacin de los antihipertensivos en Espaa (19952001). Revista Espaola
de Cardiologa 57, 241249.
Garner, S.S., Wiest, D.B., Reynolds Jr., E.R., 1994. Stability of atenolol in an
extemporaneously compounded oral liquid. Am. J. Hosp. Pharm. 51, 508
511.
Glassmeyer, S.T., Hinchey, E.K., Boehme, S.E., Daughton, C.G., Ruhoy, I.S., Conerly, O.,
Daniels, R.L., Lauer, L., McCarthy, M., Nettesheim, T.G., Sykes, K., Thompson, V.G.,
2009. Disposal practices for unwanted residential medications in the United
States. Environ. Int. 35, 566572.
Gonzlez Alonso, S., Catal, M., Romo, R., Rodrguez, J., Gil, A., Valcrcel, Y., 2010.
Pollution by psychoactive pharmaceuticals in the Rivers of Madrid metropolitan
Area (Spain). Environ. Int. 36, 195210.
Gros, M., Petrovic, M., Barcelo, D., 2007. Wastewater treatment plants as a pathway
for aquatic contamination by pharmaceuticals in the Ebro river basin (northeast
Spain). Environ. Toxicol. Chem. 26, 15531562.
Gros, M., Petrovic, M., Barcelo, D., 2009. Tracing pharmaceutical residues of different
therapeutic classes in environmental waters by using liquid chromatography/
quadrupole-linear ion trap mass spectrometry and automated library searching.
Anal. Chem. 81, 898912.
Gros, M., Petrovic, M., Ginebreda, A., Barcelo, D., 2010. Removal of pharmaceuticals
during wastewater treatment and environmental risk assessment using hazard
indexes. Environ. Int. 36, 1526.
Heberer, T., 2002. Occurrence, fate, and removal of pharmaceutical residues in the
aquatic environment: a review of recent research data. Toxicol. Lett. 131, 5
17.
Huggett, D.B., Brooks, B.W., Peterson, B., Foran, C.M., Schlenk, D., 2002. Toxicity of
select beta adrenergic receptor-blocking pharmaceuticals (B-blockers) on
aquatic organisms. Arch. Environ. Contam. Toxicol. 43, 229235.
Hummel, D., Lofer, D., Fink, G., Ternes, T.A., 2006. Simultaneous determination of
psychoactive drugs and their metabolites in aqueous matrices by liquid
chromatography mass spectrometry. Environ. Sci. Technol. 40, 73217328.
IMS Health, 2006. IMS Health Service Team. Available from: <http://www.
imshealth.com> (accessed February 2010).
INEbase, 2007. National Statistics Institute on-line database. <http://www.ine.es/
inebmenu/indice.htm> (accessed February 2010).
1071
Kasprzyk-Hordern, B., Dinsdale, R.M., Guwy, A.J., 2008. The occurrence of
pharmaceuticals, personal care products, endocrine disruptors and illicit
drugs in surface water in South Wales, UK. Water Res. 42, 34983518.
Khetan, S.K., Collins, T.J., 2007. Human pharmaceuticals in the aquatic environment:
a challenge to Green Chemistry. Chem. Rev. 107, 23192364.
Kolpin, D.W., Furlong, E.T., Meyer, M.T., Thurman, E.M., Zaugg, S.D., Barber, L.B.,
Buxton, H.T., 2002. Pharmaceuticals, hormones, and other organic wastewater
contaminants in US streams, 19992000: a national reconnaissance. Environ.
Sci. Technol. 36, 12021211.
Kmmerer, K., 2004. Pharmaceuticals in the environment: scope of the vook and
introduction. In: Pharmaceuticals in the Environment: Sources, Fate, Effects and
Risks. Springer, Heidelberg, Germany, pp. 312.
Martinez Bueno, M., Hernando, M., Herrera, S., Gmez, M., Fernndez-Alba, A.,
Bustamante, I., Garca-Calvo, E., 2010. Pilot survey of chemical contaminants
from industrial and human activities in river waters in Spain. Int. J. Environ.
Anal. Chem. 90, 321343.
Mompelat, S., Le, B.B., Thomas, O., 2009. Occurrence and fate of pharmaceutical
products and by-products, from resource to drinking water. Environ. Int. 35,
803814.
Pailler, J.Y., Krein, A., Pster, L., Hoffmann, L., Guignard, C., 2009. Solid phase
extraction coupled to liquid chromatographytandem mass spectrometry
analysis of sulfonamides, tetracyclines, analgesics and hormones in surface
water and wastewater in Luxembourg. Sci. Total Environ. 407, 47364743.
Petrovic, M., Hernando, M.D., Daz-Cruz, M.S., Barcelo, D., 2005. Liquid
chromatographytandem mass spectrometry for the analysis of
pharmaceutical residues in environmental samples: a review. J. Chromatogr.
A 1067, 114.
Pomati, F., Castiglioni, S., Zuccato, E., Fanelli, R., Vigetti, D., Rossetti, C., Calamari, D.,
2006. Effects of a complex mixture of therapeutic drugs at environmental levels
on human embryonic cells. Environ. Sci. Technol. 40, 24422447.
Radjenovic, J., Petrovic, M., Barcelo, D., 2009. Fate and distribution of
pharmaceuticals in wastewater and sewage sludge of the conventional
activated sludge (CAS) and advanced membrane bioreactor (MBR) treatment.
Water Res. 43, 831841.
Richardson, M.L., Bowron, J.M., 1985. The fate of pharmaceutical chemicals in the
aquatic environment. J. Pharm. Pharmacol. 37, 112.
Roberts, P.H., Thomas, K.V., 2006. The occurrence of selected pharmaceuticals in
wastewater efuent and surface waters of the lower Tyne catchment. Sci. Total
Environ. 356, 143153.
Sans, S., Paluzie, G., Puig, T., Balaa, L., Balaguer-Vintr, I., 2002. Prevalencia del
consumo de medicamentos en la poblacin adulta de Catalua. Gaceta Sanitaria
16, 121130.
Spanish Society of Cardiology, 2009. Sociedad Espaola de Cardiologa Available
from: <http://secardiologia.es> (accessed February 2010).
Stumpf, M., Ternes, T.A., Wilken, R.D., Rodrigues, S.V., Baumann, W., 1999. Polar
drug residues in sewage and natural waters in the state of Rio de Janeiro, Brazil.
Sci. Total Environ. 225, 135141.
Ternes, T., 1998. Occurrence of drugs in German sewage treatment plants and
rivers. Water Res. 32, 32453260.
Ternes, T., 2001. Analytical methods for the determination of pharmaceuticals in
aqueous environmental samples. Trac Trends Anal. Chem. 20, 419434.
Togola, A., Budzinski, H., 2008. Multi-residue analysis of pharmaceutical
compounds in aqueous samples. J. Chromatogr. A 1177, 150158.
Vanderford, B.J., Pearson, R.A., Rexing, D.J., Snyder, S.A., 2003. Analysis of endocrine
disruptors, pharmaceuticals, and personal care products in water using liquid
chromatography/tandem mass spectrometry. Anal. Chem. 75, 62656274.
Vieno, N.M., Harkki, H., Tuhkanen, T., Kronberg, L., 2007. Occurrence of
pharmaceuticals in river water and their elimination in a pilot-scale drinking
water treatment plant. Environ. Sci. Technol. 41, 50775084.
World Health Organization, 2002. World Health Report. Geneva, 5758 pp.
Yoon, Y., Ryu, J., Oh, J., Choi, B.G., Snyder, S.A., 2010. Occurrence of endocrine
disrupting compounds, pharmaceuticals, and personal care products in the Han
River (Seoul, South Korea). Sci. Total Environ. 408, 636643.
Zhang, Y., Geissen, S.U., Gal, C., 2008. Carbamazepine and diclofenac: removal in
wastewater treatment plants and occurrence in water bodies. Chemosphere 73,
11511161.
Zuccato, E., Calamari, D., Natangelo, M., Fanelli, R., 2000. Presence of therapeutic
drugs in the environment. Lancet 355, 17891790.
Zuccato, E., Castiglioni, S., Fanelli, R., Reitano, G., Bagnati, R., Chiabrando, C., Pomati,
F., Rossetti, C., Calamari, D., 2006. Pharmaceuticals in the environment in Italy:
causes, occurrence, effects and control. Environ. Sci. Pollut. Res. Int. 13, 1521.