Review

Carbamazepine and diclofenac: Removal in wastewater treatment

plants and occurrence in water bodies
Yongjun Zhang
*
, Sven-Uwe Geien, Carmen Gal
Department of Environmental Process Engineering, Institute of Environmental Technology, Technical University of Berlin, Strasse des 17 Juni 135, Berlin 10623, Germany
a r t i c l e i n f o
Article history:
Received 22 April 2008
Received in revised form 28 July 2008
Accepted 29 July 2008
Available online 14 September 2008
Keywords:
Micropollutant
Trace pollutant
Xenobiotic
Activated sludge
PPCP
a b s t r a c t
In the aquatic environment, pharmaceuticals have been widely found. Among them, carbamazepine and
diclofenac were detected at the highest frequency. To evaluate the worldwide environmental impacts of
both drugs, their global consumption volumes are estimated, based on the dose per capita. The metabo-
lites of these pharmaceuticals are also of environmental concerns, especially trans-10,11-dihydro-10,11-
dihydroxycarbamazepine (CBZ-diol) which probably has a similar concentration in water bodies to that
of its parent drug. The removal efciencies and mechanisms of both drugs in the wastewater treatment
plants (WWTPs) are discussed with the actual state of knowledge. The occurrences of both drugs are
examined in various water bodies including WWTP efuents, surface waters, groundwater and drinking
water. Their chemical, physical and pharmacological properties are also addressed in context, which can
largely inuence their environmental behaviors. The ecotoxicological studies of both drugs imply that
they do not easily cause acute toxic effects at their environmental concentrations. However their chronic
effects need cautious attention.
2008 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151
2. Consumption estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
4. Removal in WWTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
4.1. Removal efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
4.2. Sludge retention time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
4.3. Phototransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
5. Occurrences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
5.1. Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
5.2. Diclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
6. Ecotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
7. Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
1. Introduction
A large volume of pharmaceuticals are used for the prevention,
diagnosis and treatment of diseases in humans and animals. The
worldwide average per capita consumption of pharmaceuticals
per year is estimatedto be about 15 g andinindustrializedcountries
the value is expected to be between50 and 150 g (Alder et al., 2006).
Most pharmaceuticals are not completely degraded after applica-
tion. As a result, the pharmaceutical metabolites and some un-
changed forms of these compounds are excreted and subsequently
enter the ecosystem. In the last decade, researchers have detected
a multitude of pharmaceuticals in the aquatic environment. This
detectionhas been made feasible by the advances inanalytical tech-
nology, which makes it possible to detect contaminants at the level
of nanogram per liter (Halling-Srensen et al., 1998; Daughton and
Ternes, 1999; Heberer, 2002a; Kolpin et al., 2002).
Pharmaceutical residues are transported to water circles by dis-
tinct routes. The wastewater treatment plants (WWTPs) acts as a
gateway for human pharmaceuticals to enter water bodies while
0045-6535/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.chemosphere.2008.07.086
* Corresponding author. Tel.: +49 0 30 31425652; fax: +49 0 30 31425487.
E-mail address: yongjunzh@gmail.com (Y. Zhang).
Chemosphere 73 (2008) 11511161
Contents lists available at ScienceDirect
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j our nal homepage: www. el sevi er. com/ l ocat e/ chemospher e
most veterinary pharmaceuticals residues are discharged directly
into the ecosystem. In the rst broad investigation of drugs and
their residues in water, 80% of 32 selected drugs were detectable
in at least one sewage treatment plant efuent, and 20 different
drugs and four corresponding metabolites were detected in rivers
and streams (Ternes, 1998). On the other hand, disposal of pharma-
ceuticals may enter the environment via another pathway. Bound
and Voulvoulis (2005) carried out a survey in which they inter-
viewed the members of 400 households in the UK to investigate
the household disposal of unused and expired pharmaceuticals.
They found that about half of the respondents did not nish their
drugs and among those 63.2% discarded their unnished drugs in
household waste, 21.8% brought them back to a pharmacist, and
11.5% discarded them into the sink or toilet. In Germany, it was
estimated that amounts of up to 16000 tons of pharmaceuticals
were disposed of each year from human medical care and 60
80% of those disposed drugs were either ushed down the toilets
or disposed of with normal household waste (Scheytt et al.,
2006). Furthermore, pharmaceutical residues can be introduced
into groundwater through surface water ltration, leakage,
groundwater recharge, etc. For example, carbamazepine has been
detected in the groundwater at concentrations up to 610 ng L
1
(Drewes et al., 2002). If the pharmaceutical residues are not effec-
tively removed from the water by the drinking water treatment
facilities, the pharmaceuticals are unintentionally consumed by
humans. One such example is clobric acid, a lipid regulator
metabolite that was found in tap water in Berlin at concentrations
between 10 and 165 ng L
1
(Stan et al., 1994). Diclofenac was also
detected at less than 10 ng L
1
in a drinking water sample from a
private water tap in Berlin (Heberer, 2002b).
Carbamazepine and diclofenac were the most frequently de-
tected pharmaceutical residues in water bodies thus far. Carbam-
azepine is an antiepileptic drug used to control seizures, and
diclofenac is an important arylacetic acid non-steroidal anti-
inammatory drug (NSAID). The properties of both drugs are sum-
marized in Table 1. Carbamazepine has been proposed as an
anthropogenic marker in water bodies (Clara et al., 2004b). The
objectives of this paper are to summarize the current body of
knowledge on both drugs, including their consumption, metabo-
lism, removal in wastewater treatment plants, occurrences in all
types of water bodies, and their ecotoxicity.
2. Consumption estimation
The quantities of pharmaceuticals consumed in a region or in
the world aid in the estimating their occurrences in and their inu-
ences on the aquatic environment. Table 2 presents the annual
consumed volumes of carbamazepine and diclofenac in some re-
gions. Currently, their global consumptions cannot be found in
published literature. It is complex to collect pharmaceutical con-
sumption data since patients can obtain drugs in multiple ways.
While prescription drug data is accessible, data on the over-the-
counter is extremely difcult to collect. A given drug can be sold
under different brand names, further obscuring the data. For exam-
ple, carbamazepine has the following brands: Biston, Calepsin, Car-
batrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Tegretol,
Telesmin, Timonil, etc. Furthermore, international trading and
repackaging complicate tracking the market distributions of drugs.
We propose a simplied estimate of the global pharmaceutical
consumption with the following assumptions: (a) pharmaceutical
Table 1
Physical, chemical and pharmacological properties of carbamazepine and diclofenac
Carbamazepine (CBZ) Diclofenac (DFC)
Pharmacology
Structure, formula, CAS No. and
molecular weight
N
O
NH
2
1
2
3
4
5
6
7
8
9
10
11
O
HO
HN
Cl
Cl
1
2
3
4 5
6
1'
2' 3'
4'
5'
6'
C
15
H
12
N
2
O C
14
H
11
C
l2
NO
2
298-46-4 15307-86-5
236.27 g mol
1
296.16 g mol
1
Usage Analgesic, antiepileptic Analgesic, anti-inammatory
Water solubility
a
17.7 mg L
1
(25 C) 23.73 mg L
1
(25 C)
LogP (octanolwater)
a
2.45
Henrys Law Constant
a
1.09 10
5
Pa m
3
mol
1
(25 C) 4.7910
7
Pa m
3
mol
1
(25 C)
pKa neutral
b
4.15
a
Elimination half-life
c
2565 h 2 h
Excretion
d
72% of oral dosage excreted in urine, 28% in faeces Biliary excretion: 65% of oral dosage excreted in urine
Metabolites in urine (%of oral dosage) CBZ, CBZ-epoxide, CBZ-diol, CBZ-acridan, 2-OH-CBZ, 3-
OH-CBZ
e
DFC, 5-OH-DFC, 4
0
-OH-DFC, 3
0
-OH-DFC, 4
0
-5-diOH-DFC, 4
0
-OH-5-Cl-
DFC, 3
0
-OH-4
0
-CH
3
O-DFC
f
Dosage
g
Maintenance usually 8001200 mg daily. 75150 mg daily
Other Information Autoinduction, i.e., long term applications increase its
metabolism
d
Dermal applications available
h
a
SRC (2006).
b
Hoover (2005).
c
Wishart et al. (2006).
d
RxList (2006).
e
Bernus et al. (1994, 1995).
f
Schneider and Degen (1981) and Sawchuk et al. (1995).
g
Sosiak and Hebben (2005).
h
Brunner et al. (2005).
1152 Y. Zhang et al. / Chemosphere 73 (2008) 11511161
consumption is not balanced between developing countries and
developed countries because of economic, medical, and culture dif-
ferences; (b) the annual dose per capita (DPC) is the same in devel-
oping countries and also same among developed countries; (c)
developing countries only consume 20% of the global pharmaceu-
ticals despite accounting for approximately 80% of the worlds pop-
ulation (Cohen et al., 2005). The DPC of a drug in a country is
calculated by dividing the annual consumption of the drug by its
population. The average DPC of a drug in the developed countries
is calculated by dividing the volumes consumed in the countries
listed in Table 2 by the sum of their populations. The global con-
sumption is estimated to be:
Average DPI of developed countries world population 0:2
0:8
The estimated global consumptions of carbamazepine and diclofe-
nac are shown in Table 2. Since the DPC of carbamazepine in the
USA is signicantly lower than that of other countries, two average
developed country DPCs are calculated: one including the USA and
the other excluding the USA. Their mean value is accepted as the -
nal DPC of developed countries and is used to the estimate. The
globally consumed volumes of carbamazepine and diclofenac are
estimated to be 1014 tons and 940 tons per year, respectively. Both
estimated values are in accordance with IMS Health data: 942 tons
of carbamazepine and 877 tons of diclofenac were sold in 2007 in
76 major countries which are believed to account for 96% of the glo-
bal pharmaceutical market.
3. Metabolism
After administration, some pharmaceuticals are not completely
metabolized. The unmetabolized parent drugs and some metabo-
lites are subsequently excreted from the body via urine and faeces.
In places with sewage systems, these pharmaceutical residues en-
ter the WWTPs via wastewater.
Carbamazepine is used for the treatment of seizure disorders, for
relief of neuralgia, and for a wide variety of mental disorders.
Approximately 72% of orally administered carbamazepine is ab-
sorbed, while 28% is unchanged and subsequently discharged
through the faeces (RxList, 2006). After it is absorbed, carbamaze-
pine is heavily metabolized by the liver: only about 1% of dosage
leaves the body in an unaltered form. The metabolites of this drug
undergo enterohepatic cycling and nally are excreted with urine.
The elimination half-life time of carbamazepine is dose-dependent,
but is usually in the range of 2565 h post-administration (Wishart
et al., 2006). Its important urine metabolites are 10,11-dihydro-
10,11-expoxycarbamazepine (CBZ-epoxide) and trans-10,11-dihy-
dro-10,11-dihydroxycarbamazepine (CBZ-diol) (Reith et al., 2000).
Importantly, the former is pharmaceutically just as active as its par-
ent drug. This and other identied metabolites are summarized in
Table 1. The mass balance of carbamazepine metabolism is shown
in Fig. 1. CBZ-diol accounts for a large part of oral dosage, about
30%, comparable to the total portion of unchanged carbamazepine
Table 2
Annual consumed volumes of carbamazepine (CBZ) and diclofenac (DFC) in some
countries and estimation of their global volumes
Regions Annual consumption,
tons
Population
10
6
DPC, mg References
CBZ DFC CBZ DFC
Australia 10 4 19 526 211 Khan and
Ongerth (2004)
Austria 6 in 1997 6 in
1997
8 750 750 Strenn et al.
(2004)
Canada 28 in 2001 31 903 n.a. Miao et al.
(2005)
Finland 4.6 in 2005 5 920 n.a. Vieno et al.
(2007)
France 40 16 59 678 271 Ferrari et al.
(2003)
Germany 87 in 1999 82 in
1999
82 1061 915 BLAC (2003)
England 40 in 2000 26 in
2000
49 816 531 Jones et al.
(2002)
USA 43 in 2000, 35
in 2003
284 151 n.a. Thacker (2005)
World 1014 940
DPC of developed
countries, incl. USA
482
DPC of developed
countries, excl. USA
852
DPC of developed
countries, adopted
667 618
DPCdose per capita; England population UK; National Statistics (2001); EU
population EUROPA (2006); other populations UN (2005).
In faeces
CBZ
1%
CBZ-epoxide
2%
CBZ-diol
30%
CBZ-acridan
4%
2-OH-CBZ
4%
3-OH-CBZ
5%
Others
26%
Faecal CBZ
28%
In urine
Carbamazepine
Faecal metabolites
35%
4'-5-diOH-DFC
10%
DFC
6%
3'-OH-DFC
2%
4'-OH-DFC
16%
Others
26%
5-OH-DFC
6%
In urine In faeces
Diclofenac
Fig. 1. Identied metabolites of carbamazepine and diclofenac and their percentages of oral dosage. Data from Bernus et al. (1994, 1995), Schneider and Degen (1981), and
Sawchuk et al. (1995).
Y. Zhang et al. / Chemosphere 73 (2008) 11511161 1153
(28% in faeces plus 1% in urine). Furthermore, CBZ-diol is also a
metabolite of oxcarbazepine which is a derivative of carbamaze-
pine, with an extra oxygen atom on the dibenzazepine ring (Thei-
sohn and Heimann, 1982). Therefore, one may expect to observe a
higher concentration of CBZ-diol in water bodies. Unfortunately,
limited studies have been conducted on those metabolites in the
aquatic environment to date. Miao and Metcalfe (2003) and Miao
et al. (2005) investigated the occurrences of carbamazepine metab-
olites in a WWTP efuent and a surface water. They observed that
the concentration of CBZ-diol was approximately three times that
of carbamazepine. Therefore, more studies should be conducted
on the environmental fate of carbamazepine metabolites.
Diclofenac is a non-steroidal anti-inammatory drug (NSAID)
used to reduce inammation and to relieve pain, working as an
analgesic in conditions such as in arthritis or acute injury. It can
also be used to reduce menstrual pain, dysmenorrhea. After oral
administration, diclofenac is eliminated in a short period (elimina-
tion half life about 2 h, Wishart et al., 2006). Approximately 65% of
the dosage is excreted through urine in which six metabolites have
been identied (Table 1). However, the actual amount of metabo-
lites in the faeces is still not clear. The mass balance of diclofenac
metabolism is shown in Fig. 1. At least two of the metabolites in
urine are discharged at higher rates than unchanged diclofenac.
However, diclofeanc is also available in other forms for dermal
applications, eye dropping and injection. In principle, those differ-
ent forms of the drug should produce same metabolites, but in dif-
ferent proportion (Mckter, 2008). Oral application is the main
form of administration and accounted for about 70% of the world-
wide diclofenac sales in 2007 (IMS Health). The dermal application
of diclofenac, which is popular in developed countries, may reduce
the bioavailability of the drug to roughly 50% by circumventing the
biotransformation in the liver: a process called the rst pass effect
or presystemic metabolism (Mckter, 2008). Therefore, the dermal
application of diclofenac could result in greater diclofenac dis-
charges into the aquatic environments (Heberer and Feldmann,
2005). Many investigations detected diclofenac in water bodies
(discussed later). Nevertheless, no studies have been conducted
on the behavior of diclofenac metabolites in water circles.
4. Removal in WWTP
Carbamazepine, diclofenac and their metabolites are ushed
with wastewater to the WWTPs through the sewage system (exl-
tration disregarded). If not effectively removed in the WWTPs,
these compounds will nd their ways into the ecosystem. In this
section, their removal efciencies and mechanisms are discussed.
Most WWTPs use activated sludge processes wherein microor-
ganisms are applied to mineralize the pollutants to water and car-
bon dioxide, or degrade them to acceptable forms. Pollutants can
also be removed fromwater by stripping into air or by sorption onto
sludge that is regularly discharged. Some substances may be subject
to phototransformation. Therefore, the removal of pharmaceutical
residues in activated sludge processes includes four mechanisms:
biotransformation, air stripping, sorption and phototransformation.
However, the project of POSEIDON found that a Henry coefcient
more than 3 10
3
() was required for the signicant stripping
in a bioreactor with ne bubble aeration (POSEIDON, 2006). Accord-
ingly, the removal of carbamazepine and diclofenac (Henry coef-
cients: 1.09 10
5
, 4.79 10
7
(), respectively) by air stripping
is limited and thus is omitted from the following discussion.
4.1. Removal efciency
Many studies were conducted to observe the behavior of phar-
maceutical residues in wastewater treatment plants. The removal
efciencies of carbamazepine and diclofenac in the conducted
studies have been summarized in Fig. 2 with distribution rates,
where removal efciency is usually dened as the concentration
differences between inuent and efuent. Those studies employed
full scale and lab scale conventional activated sludge processes
(CAS), pilot and lab scale membrane reactors (MBR) and sequenc-
ing batch reactors (SBR). Investigations found that carbamazepine
is persistent and its removal efciencies by the WWTPs are mostly
below 10% (Fig. 2). The highest removal efciency for carbamaze-
pine in a WWTP was 53%, observed by Paxus (2004). The re-
searcher assumed that the unusually high content of silicone oil
probably enhanced the removal via extraction of carbamazepine
by the silicone oil attached to the sludge. The low removal ef-
ciency of carbamazepine can be explained by its properties. First,
it is resistant to biodegradation at low concentrations. Stamatela-
tou et al. (2003) conducted a biodegradability test of carbamaze-
pine in CH
3
COONa cultured activated sludge in both sea and
fresh water. They observed no biodegradation of the carbamaze-
pine at an initial concentration of 0.5 mg L
1
in either sea or fresh
water. In the classication scheme for pharmaceutical biodegrada-
tion, the removal status of carbamazepine is classied as no re-
moval (Joss et al., 2006). Secondly, it is hardly attached onto
sludge. Its distribution coefcient between water and secondary
sludge (K
d
) is 1:2 L kg
1
SS
(Ternes et al., 2004), far from the value
500 L kg
1
SS
required for signicant sorption onto sludge. Therefore,
the bulk of carbamazepine remains associated with the aqueous
phase.
The removal efciencies of diclofenac by WWTPs vary (Fig. 2),
ranging from 0% up to 80%, but mainly in the scope of 2140%.
0.00 0.10 0.20 0.30 0.40
No removal
1-10%
11-20%
21-30%
>30%
R
e
m
o
v
a
l

r
a
t
e
_
Distribution
a: carbamazepine
0.00 0.05 0.10 0.15 0.20
No removal
1-10%
11-20%
21-30%
31-40%
41-50%
51-60%
61-70%
>70%
R
e
m
o
v
a
l

r
a
t
e
_
Distribution
b: diclofenac
Fig. 2. Removal efciency distributions of carbamazepine and diclofenac in
WWTPs. Data from Ternes (1998), Stumpf et al. (1999), Heberer et al. (2002), Lee
et al. (2003), Clara et al. (2004a), Paxus (2004), Strenn et al. (2004), Joss et al.
(2005), Lindqvist et al. (2005), Miao et al. (2005), Quintana et al. (2005), Surez et al.
(2005), Castiglioni et al. (2006), Lishman et al. (2006), Benotti and Brownawell
(2007), Kim et al. (2007), Kimura et al. (2007), Santos et al. (2007), and Vieno et al.
(2007).
1154 Y. Zhang et al. / Chemosphere 73 (2008) 11511161
The sorption behavior of diclofenac onto sludge is similar to that of
carbamazepine. Its watersludge distribution coefcient is
16 L kg
1
SS
(Ternes et al., 2004). Although larger than that of carbam-
azepine, the coefcient is still too low for signicant attachment
onto the sludge. Diclofenac and carbamazepine were classied in
the same biodegradability group of below 0:1 L kg
1
SS
d
1
when con-
sidering a rst order degradation constant (k
biol
) in WWTPs (Joss
et al., 2006). Quintana et al. (2005) investigated the biodegradation
of diclofenac by activated sludge. They found no transformation of
diclofenac over 28 days, neither when diclofenac was the sole
source of carbon (20 mg L
1
), nor when it was dispersed in milk
powder (2 mg L
1
per 50 mg L
1
). The poor biodegradation of dic-
lofenac was conrmed recently by Kimura et al. (2007) in batch
elimination experiments using sludge from WWTPs and MBR,
respectively.
It is interesting that the removal efciency of diclofenac could
be up to 80% while that of carbamazepine was mostly below
10%. One possible explanation for this difference might be that car-
bamazepine is extraordinarily persistent to biodegradation at low
concentrations while biodegradation of diclofenac may be possible
under some conditions. Zwiener and Frimmel (2003) conducted a
short-term biodegradation test on diclofenac. In a pilot sewage
treatment plant, with an initial concentration of 10 lg L
1
, diclofe-
nac was not degraded (9699% of its initial concentration) after
55 h treatment. Similar results were obtained in an oxic biolm
reactor after 48 h treatment; however, diclofenac was better de-
graded in an anoxic biolmreactor (6266% of its initial concentra-
tion). Therefore, the anoxicoxic ratios may inuence the removal
of diclofenac, which could partly explain the wide variety of its re-
moval efciencies. Another inuencing factor may be the acidic
conditions. Urase and Kikuta (2005) conducted a series of bench-
scale experiments to evaluate the sorption and degradation of sev-
eral pharmaceuticals in activated sludge processes, including car-
bamazepine and diclofenac. They found that an acidic operational
condition (pH 4.4) was preferable for the removal of the acidic
pharmaceutical substances, such as diclofenac and clobric acid,
by increasing the watersludge partition coefcients, whereas car-
bamazepine appeared to be more hardly degraded at acid condi-
tions. Furthermore, phototransformation contributes differently
to the removal of carbamazepine and diclofenac as discussed later.
An interesting phenomenon is the increased efuent concentra-
tions of carbamazepine (Clara et al., 2004b; Joss et al., 2005; Vieno
et al., 2007) and diclofenac (Lishman et al., 2006). One explanation
is the daily concentration uctuations during the sampling period
(Clara et al., 2004b), which could be avoided by long term observa-
tion. The other explanation for the increased concentrations is the
cleavage of glucuronide conjugates of those pharmaceuticals by
enzymatic processes in the treatment plant (Ternes, 1998; Vieno
et al., 2007). In the biological treatment processes, this cleavage
makes it complex to evaluate the biodegradation of those residues
since it is difcult to distinguish the bio-reduction from the cleav-
age increase.
4.2. Sludge retention time
In activated sludge processes, it is the microorganism that min-
eralizes or transforms pollutants. Only organisms that are able to
reproduce themselves during the designed sludge retention time
(SRT) can be detained and enriched in the system (Kreuzinger
et al., 2004; Clara et al., 2005a). Therefore, high SRTs allow for
the enrichment of slowly growing bacteria and, consequently, the
establishment of a more diverse biocoenosis with broader physio-
logical capabilities, as compared to WWTPs that are operated at
low SRTs.
The removal efciencies of carbamazepine and diclofenac in
WWTPs running at various SRTs can be found in literature. Fig. 3
shows the removal efciencies plotted against SRT. In the whole
range of SRT plotted, the removal efciency of carbamazepine is
no more than 30%. In most cases, it is below 10%, and is clearly
independent of the SRT. The removal efciencies of diclofenac are
signicantly scattered with the increasing of SRT, showing no cor-
relation between them. Clara et al. (2004a) studied a full scale
WWTP at SRTs up to 275 days and found no removal of carbamaz-
epine and approximately 60% removal of diclofenac. An SRT more
than 500 days also resulted in no removal of carbamazepine and
did not improve the removal of diclofenac (Clara et al., 2005a).
Additional studies proved that the removal efciencies of both
drugs are independent of the SRT. Kreuzinger et al. (2004) evalu-
ated the inuence of SRT on the removal of several drugs including
carbamazepine and diclofenac and found no clear effects of SRT (up
to 300 days) on the removal of both drugs. Lishman et al. (2006)
studied the removal behaviors of diclofenac in several WWTPs
and observed that diclofenac removal was not SRT dependent with
SRTs ranging from 3 days to over 30 days.
In the above studies, removal efciencies at different SRTs were
obtained from many WWTPs where the wastewater composition
and other operational parameters could inuence the removal ef-
ciencies. Strenn et al. (2004) studied the removal of both drugs in a
lab scale sequencing batch reactor (SBR) with synthetic wastewa-
ter. They evaluated the removal at SRTs from one day to 30 days
and did not nd an improvement in removal efciencies of car-
bamazepine or diclofenac by increasing SRTs. Joss et al. (2005)
studied the removal of carbamazepine and diclofenac in a pilot
membrane bioreactor (MBR) with SRTs of 16 days to 75 days. Bio-
degradation of both drugs was independent of SRTs and sorption
onto sludge did not increase either.
Although high SRTs were obtained in MBR, micro- and ultra-l-
tration membranes did not promote any additional detention of
both drugs. The removal efciencies in MBR were comparable to
conventional activated sludge processes operating at the same
sludge age (Clara et al., 2005b).
4.3. Phototransformation
WWTPs are usually operated in an open environment, which
exposes wastewater to direct sunlight. Although the turbidity of
wastewater blocks some sunlight, water in the top layer and water
in secondary clariers is exposed to sunlight irradiation, especially
in summer. Therefore, some contaminants may be affected by
phototransformation.
Phototransformation has been identied as the main elimina-
tion process of diclofenac in a lake (Greifensee) (Buser et al.,
1998; Poiger et al., 2001; Tixier et al., 2003). Buser et al. (1998) esti-
mated that more than 90% of the diclofenac entering the lake was
0
10
20
30
40
50
60
70
80
0 10 20 30 40 50 60 70 80 90 100 110
SRT,day
R
e
m
o
v
a
l

r
a
t
e
,

%
Carbamazepine
Diclofenac
Fig. 3. Removal efciencies of carbamazepine and diclofenac in WWTPs at different
SRTs. Data from Clara et al. (2004a), Strenn et al. (2004), Joss et al. (2005), Quintana
et al. (2005), Surez et al. (2005), and Vieno et al. (2007).
Y. Zhang et al. / Chemosphere 73 (2008) 11511161 1155
eliminated most likely by photolytic degradation. In that study,
incubation of lake water that was fortied with diclofenac at
100 ng L
1
showed no degradation in the dark, suggesting minimal
chemical and biological degradation; however, rapid photodegra-
dation was observed when the fortied water was exposed to sun-
light. The half-life of diclofenac exposed to sunlight was less than
1 h. The initial photoproduct was 8-chlorocarbazole-1-acetic acid
which photodegraded even faster than the parent compound (Poi-
ger et al., 2001). The presence of isopropyl alcohol, a radical quench-
er, led to more rapid phototransformation of diclofenac in puried
water, de-ionized water and Mississippi River water (Packer et al.,
2003). Other studies (Andreozzi et al., 2003; Prez-Estrada et al.,
2005) also conrmed the direct photolysis of diclofenac in the
aquatic environment.
Carbamazepine can be photolysed under sunlight irradiation
but only at relatively low rate. Andreozzi et al. (2002) studied
the phototransformation of carbamazepine in double-distilled
water and calculated its half-life to be 121.6 h, which is much low-
er than that of diclofenac shown above. In a study of Andreozzi
et al. (2003), the half-life of carbamazepine was approximately
100 days in double distilled water; however, under the same con-
ditions sulphamethoxazole, diclofenac, ooxacin and propranolol
underwent fast degradation with half-lives of 2.4, 5.0, 10.6 and
16.8 days, respectively. Thus, the phototransformation of carbam-
azepine in WWTPs is negligible.
However, attentions should be put upon the presence of photo-
sensitizers andinner lters inwastewater. For example, humic acids
were found to act as inner lters for carbamazepine and diclofenac,
decreasing their phototransformation, but as photosensitizers for
sulphamethoxazole, clobric acid, oaxocin and propranolol,
improving their phototransformation (Andreozzi et al., 2003). Fur-
thermore, attentions ought to be paid to the byproducts of photo-
sensitive compounds. It has been reported that diclofenac can form
a product, chlorocarbazole 2a, which causes cell lysis with a mark-
edly higher efciency than the parent drug (Encinas et al., 1998).
5. Occurrences
Due to their wide use, pharmaceuticals are expected to be pres-
ent in WWTPs where sewage systems are established. However,
some of drugs are not effectively removed by the WWTPs and sub-
sequently nd their way to water bodies. Carbamazepine and dic-
lofenac, as discussed above, are examples of drugs that are poorly
removed by WWTPs. They have been detected in WWTP efuents,
surface waters, groundwater and occasionally in drinking water,
withcascading concentrations due to dilutionand some elimination
processes like soil retention and phototransformation. They have
been detected in Europe, America and Asia. The average detected
values in WWTP efuents and in surface waters in some countries
have been summarized in Fig. 4. All concentration data was col-
lected from available publications. The majority of surface water
data in the gure is fromrivers with a fewfromlakes and estuaries;
however, the occurrence of both drugs in groundwater and drinking
water is inadequate in the literature and is therefore not presented
in this gure. The concentrations of carbamazepine and diclofenac
are signicantly different among countries as shown in Fig. 4. One
explanation for this difference is the diverse consumption rates of
both pharmaceuticals in those countries. Another explanation is
that the higher concentrations insome countries might not be found
yet due to the insufcient investigations conducted so far.
5.1. Carbamazepine
WWTP efuents are important gateways where carbamazepine
can enter the water cycle. In a survey conducted by Ternes (1998),
carbamazepine was detected in all 30 WWTP efuents with a 90-
percentile of 3700 ng L
1
and in 24 of 26 samples from 20 rivers
with a 90-percentile of 820 ng L
1
. The maximum concentration
of carbamazepine in WWTP efuents was 6300 ng L
1
, which
was also the maximum detected concentration of all 32 drugs in
the survey. Carbamazepine has been found in WWTP efuents
around the world: Europe, the USA, Canada, Japan, and South Korea
(Fig. 4). This list is expected to grow in the future. Carbamazepine
concentrations in WWTP efuents are usually around hundreds of
nanograms per liter, but can sometimes occur in micrograms per
liter, with values varying from one country to another.
Hospital wastewater is another contributor to pharmaceutical
residues in the sewage efuent due to the high consumption den-
sity of some drugs in the hospital. Heberer and Feldmann (2005)
investigated a municipal WWTP that treats both household sewage
(96000 inhabitants) and ve hospital efuents (2339 beds to-
gether) and found that 26% and 17% of the total carbamazepine
and diclofenac, respectively, in the WWTP was from the hospitals.
Considering all of other pharmaceuticals largely used in hospitals,
treating hospital wastewaters separately from household efuents
could prevent pharmaceutical residues entering the aquatic envi-
ronment to some extent. By treating the hospital wastewater sep-
arately, the possible recovery efciencies of X-ray contrast media,
antibiotics and cytostatics in Germany could be 35%, 50% and
30%, respectively (Fitzke et al., 2003). It is also technologically
advantageous to treat hospital efuents separately due to the rel-
atively high concentrations. For example, cytostatics and disinfec-
tants in hospital wastewaters were much higher than those in
municipal wastewaters (550 lg L
1
vs a few ng L
1
and 6 mg L
1
vs 0.050.1 mg L
1
, respectively) (Kmmerer, 2001). To treat hos-
pital wastewater, MBR has been proven effective for the removal
of conventional parameters (Wen et al., 2004; Pauwels et al.,
2006). A promising process to further remove pharmaceuticals is
a combination of MBR with other advanced treatment technologies
which are effective to remove pharmaceuticals, like ozonation (Hu-
ber et al., 2005) and activated carbon (Westerhoff et al., 2005). A
project is ongoing to evaluate the impact of pharmaceuticals in
the hospital wastewater and to test the combination of MBR and
ozonation (Moser, 2007). However, separate treatment of hospital
wastewater cannot signicantly reduce the input of pharmaceuti-
cals into the environment in general. In places with a high hospital
density or without complete sewage system it is an option to be
evaluated.
In surface waters, carbamazepine concentrations are relatively
low and also diverse in different countries (Fig. 4b). The highest de-
tected concentration of carbamazepine in surface water was found
in Berlin (1075 ng L
1
) (Heberer et al., 2002). It was also detected
in sea water, although at a very low concentration (2 ng L
1
) (Wei-
gel et al., 2001). Research conducted by the US Geological Survey
(USGS) found an average carbamazepine concentration of
60 ng L
1
in water and 41.6 ng mg
1
in the sediment of 44 rivers
across the US (Thacker, 2005). Other US studies have detected car-
bamazepine in surface waters: 9 ng L
1
in Huron River (Skadsen
et al., 2004), 0.30.8 ng L
1
in Detroit River (Hua et al., 2006),
and about 535 ng L
1
in Jamaica Bay, New York (Benotti and
Brownawell, 2007). Tixier et al. (2003) investigated the presence
of carbamazepin in Lake Greifensee, Switzerland, which has a
mean water residence time of 408 days. The inuents consisted
of three WWTP efuents and two rivers receiving the discharge
of four other WWTPs. Those inuents brought 29.2 g of carbamaz-
epine and 18.9 g of diclofenac daily into the lake which totally con-
tained 1 kg diclofenac and 7 kg carbamazepine. The half-lives of
carbamazepine and diclofenac in the epilimnion were 63 days
and 8 days, respectively. These half-lives include ushing as a re-
moval process which is a main route responsible for the removal
of carbamazepine. The shorter half-life of diclofenac is mainly
1156 Y. Zhang et al. / Chemosphere 73 (2008) 11511161
due to the phototransformation process which, however, is not as
effective in the hypolimnion. Lfer et al. (2005) also found that
carbamazepine was highly recalcitrant to elimination in a water/
sediment system at laboratory scale. The time required for a 50%
reduction (DT50) of its initial concentrations (100 lg L
1
) was
328 days, as calculated by rst-order elimination kinetics. It is also
worth mentioning that in this study, CBZ-diol remained nearly sta-
ble at a level of 35% of the initial concentration (100 lg L
1
) after
the rst month until the end of the experiment, although its
DT50 value was low (8 days). The authors did not observe miner-
alization of these substances.
Carbamazepine is probably able to pass through an unsaturated
underground zone and reach an aquifer. Clara et al. (2004b) found
that carbamazepine was not subjected to any degradation or
adsorption during its underground/groundwater passage. Recently,
Scheytt et al. (2006) conducted laboratory sand column transport
experiments to study the transport behavior of carbamazepine,
diclofenac, ibuprofen, and propyphenazone under unsaturated
conditions. The test water was comprised of articial sewage efu-
ent to simulate the inltration of reused wastewater. These column
experiments revealed that carbamazepine was not eliminated from
the wastewater. In contrast, in a saturated column experiment, car-
bamazepine showed a signicant retardation factor (R
f
) of 2.8
(Mersmann et al., 2002). Moreover, the organic content of a partic-
ular soil may largely inuence the sorption of carbamazepine. In a
study by Stamatelatou et al. (2003), carbamazepine attachment
was greater in soil with over 10% organic content than in soil with
12% organic content.
Groundwater samples containing carbamazepine have also
been found. Heberer et al. (2001) detected carbamazepine at
20 ng L
1
in an abandoned drinking water well located 100 maway
from a lake where carbamazepine was measured at 135 ng L
1
.
Rabiet et al. (2006) investigated seven drinking water wells in a
watershed in the Mediterranean region. Carbamazepine was de-
tected in two wells at concentrations of 43.2 and 13.9 ng L
1
. The
chance of presence in groundwater would be increased in regions
where WWTP efuents are employed for groundwater recharging.
Drewes et al. (2002) investigated two groundwater recharging
0
500
1000
1500
2000
2500
3000
3500
A
u
s
t
r
i
a
D
a
n
m
a
r
k
F
i
n
l
a
n
d
F
r
a
n
c
e
G
e
r
m
a
n
y
G
r
e
e
c
e
I
t
a
l
y
S
p
a
i
n
S
w
e
d
e
n
S
w
i
t
z
e
r
l
a
n
d
U
K
C
a
n
a
d
a
U
S
A
B
r
a
z
i
l
J
a
p
a
n
S
o
u
t
h

K
o
r
e
a
Carbamazepine
Diclofenac
a: in WWTP effluent, ngL
-1
0
100
200
300
400
500
600
A
u
s
t
r
i
a
F
i
n
l
a
n
d
F
r
a
n
c
e
G
e
r
m
a
n
y
N
e
t
h
e
r
l
a
n
d
s
S
w
i
t
z
e
r
l
a
n
d
U
K
C
a
n
a
d
a
U
S
A
B
r
a
z
i
l
J
a
p
a
n
S
o
u
t
h

K
o
r
e
a
Carbamazepine
Diclofenac
b: in surface water, ngL
-1
Fig. 4. Average detected concentrations of carbamazepine and diclofenac in WWTP efuents (a) and surface waters (b) in some countries (error bars for standard deviation).
Data from: Austria (POSEIDON, 2006), Denmark (Paxus, 2004), Finland (POSEIDON, 2006; Vieno et al., 2007), France (Paxus, 2004; Vieno et al., 2005; POSEIDON, 2006;
Rabiet et al., 2006), Germany (Ternes, 1998; Heberer et al., 2001; Heberer, 2002b; Deng et al., 2003; Weigel et al., 2004; POSEIDON, 2006; Osenbrck et al., 2007), Greece
(Koutsouba et al., 2003; Paxus, 2004), Italy (Paxus, 2004; Castiglioni et al., 2006), Netherlands (van Stee et al., 2002), Spain (Santos et al., 2007), Sweden (Paxus, 2004),
Switzerland (Soulet et al., 2002; Tixier et al., 2003; POSEIDON, 2006), UK (Ashton et al., 2004; Thomas and Hilton, 2004), Canada (Lee et al., 2003; Miao and Metcalfe, 2003;
Sosiak and Hebben, 2005; Lishman et al., 2006), USA (Drewes et al., 2002; Skadsen et al., 2004; Thacker, 2005; Hua et al., 2006; Benotti and Brownawell, 2007; Palmer et al.,
2008; Spongberg and Witter, 2008), Brazil (Stumpf et al., 1999), Japan (Nakada et al., 2006; Kimura et al., 2007; Nakada et al., 2007), South Korea (Kim et al., 2007).
Y. Zhang et al. / Chemosphere 73 (2008) 11511161 1157
sites using WWTP efuents. At one site, the concentrations of car-
bamazepine in the WWTP efuent and in the monitoring well were
155 ng L
1
and 90 ng L
1
, respectively. A signicant removal of car-
bamazepine during the groundwater recharge was not obvious
though the sampled groundwater represented travel times of more
than six years in the subsurface. Recently, Osenbrck et al. (2007)
investigated the sources and transport processes of micropollu-
tants including carbamazepine in the groundwater underlying
the city of Halle (Saale), Germany, using isotopic and chemical
tracers. They found that the presence of carbamazepine in ground-
water (max. 83 ng L
1
) was mainly due to river water inltration.
Their study also indicated that carbamazepine concentrations tend
to decrease with increasing distance from the river.
5.2. Diclofenac
In a survey by Ternes (1998), diclofenac was detected in all 49
WWTP efuents with a 90-percentile of 1600 ng L
1
in all 43 sam-
ples from 22 rivers with a 90-percentile of 800 ng L
1
. Paxus
(2004) detected diclofenac in all ten sampled WWTP efuents in
the ve EU countries he sampled. The concentrations of diclofenac
ranged from 140 ng L
1
to 1480 ng L
1
, with a median value of
290 ng L
1
. The input of diclofenac through tributaries down-
stream of the WWTPs around Lake Greifensee in Switzerland was
estimated to be in the range of 1029 g d
1
(Buser et al., 1998). It
was also detected in a stream (24.5 ng L
1
) in Ohio, USA.
Diclofenac has been found in estuaries as well. Thomas and Hil-
ton (2004) investigated ve estuaries in the UK and detected dic-
lofenac at a maximum concentration of 195 ng L
1
(Mersey
estuary) and a median concentration of less than 8 ng L
1
. In the
estuary of the river Elbe at the North Sea, it was detected at a con-
centration of 6.2 ng L
1
(Weigel et al., 2002). No data have been re-
ported on its presence in the marine environment. The maximum
concentration of diclofenac in surface waters is reported as
1030 ng L
1
, detected in Berlin by Heberer et al. (2002).
Diclofenac showed high retardation factors in the column
experiments (R
f
= 2.0 in Scheytt et al., 2004, and R
f
= 2.6 in Mers-
mann et al., 2002), which indicated that it has its low mobility in
the groundwater. The column experiments of Scheytt et al.
(2006) found a 35% removal of diclofenac. Its low mobility may
prevent it from having a large presence in groundwater to some
extent. Although diclofenac was still detected in the groundwater
in some cases, its concentrations were generally lower than those
of carbamazepine. It was found in six of seven drinking water wells
in the Hrault watershed in the Mediterranean region at concen-
trations around 2 ng L
1
(Rabiet et al., 2006). The maximum con-
centration in groundwater was found to be 380 ng L
1
in the
catchment area of a drinking water plant in Berlin (Heberer
et al., 1998). It has only been detected in drinking water in a sam-
ple taken from a private drinking water tap in Berlin at a concen-
tration of less than 10 ng L
1
(Heberer, 2002b).
6. Ecotoxicology
Carbamazepine and diclofenac are widely present in water
bodies. Therefore, it is necessary to evaluate their impact on the
ecosystems where they are present. Many studies have assessed
their ecotoxicology (Table 3). Ferrari et al. (2003) studied the toxic
effects of carbamazepine and diclofenac on bacteria, algae, micro-
crustaceans, and sh. They observed that both substances had a
relatively limited acute ecotoxicity on the tested organisms. In
the worst cases of acute toxicity tests, concentrations that cause
50% of effect (EC
50
) were 13800 lg L
1
for carbamazepine on
D.magna over 48 h and 11454 lg L
1
for diclofenac on the Micro-
tox

system over 30 min. However, chronic tests displayed higher

toxicity than acute tests. In the chronic toxicity tests, the worst
cases of no observed effect concentrations (NOEC) were 25 lg L
1
for carbamazepine and 246 lg L
1
for diclofenac on B. calyciorus
over 48 h. In contrast, Andreozzi et al. (2002) found no toxicity of
carbamazepine on algae Ankistrodesmus braunii and also found that
the concentration of carbamazepine progressively decreased in the
culture of the algae. After 60 days, over 50% of the substance had
disappeared from the medium. Furthermore, no signicant
amounts of carbamazepine could be detected in A. braunii cells
during the course of the experiment. The authors assumed that
carbamazepine was taken up by algal cells and entered into bio-
chemical processes.
Regarding the predicted no-effect concentrations (PNEC), car-
bamazepine appeared to be the more hazardous compound (Table
3). At the worst cases, its PNEC was found at 0.42 lg L
1
. Compar-
ing this value with the detected concentrations in Fig. 4, it can be
seen that carbamazepine has the potential to cause ecological ef-
fects. Jos et al. (2003) found that carbamazepine was not expected
to produce acute toxic effects on the aquatic biota (EC
50
4.5
383.5 mg L
1
) and they proposed that chronic effects and synergis-
tic effects with other chemicals could not be excluded but did not
provide additional evidences to support this assertion. According
to the results of their research and the present European legislation
on the classication and labeling of chemicals (92/32/EEC), they
classied carbamazepine as R52/53 Harmful to aquatic organisms
and may cause long term adverse effects in the aquatic environ-
ment. Later, Cleuvers (2004) demonstrated the synergistic toxicity
of diclofenac, ibuprofen, naproxen, and acetylsalicylic acid. The
mixture toxicity of those substances at the EC
50
and EC
80
doses
was as high as or even higher than that predicted by concentration
addition.
Dietrich and Prietz (1999) investigated the lethality and terato-
genicity of diclofenac on zebra sh embryos after a 96 h exposure
Table 3
Toxicity data of carbamazepine and diclofenac in the literatures
Acute toxicity
EC
50
Chronic toxicity
NOEC
PNEC References
Carbamazepine >13.8
81 mg L
1
25100 mg L
1
0.42 lg L
1
Ferrari
et al.
(2003)
110 mg L
1
6.359 lg L
1
Jones et al.
(2002)
4.5
383.5 mg L
1
Jos et al.
(2003)
75.1
502.6 mg L
1
Laville
et al.
(2004)
Diclofenac 11.5
22.7 mg L
1
110 mg L
1
116 lg L
1
Ferrari
et al.
(2003)
110 mg L
1
138.74 lg L
1
Jones et al.
(2002)
3.3
142.2 mg L
1
Laville
et al.
(2004)
90 20 lg L
1
on zebra sh
embryos.
Dietrich
and Prietz
(1999)
68 mg L
1
45 mg L
1
Cleuvers
(2004)
1 mg L
1
on
Daphnia magna
and 1 lg L
1
on
on
histopathological
lesions
Schwaiger
et al.
(2004)
EC
50
: concentrations that cause 50% of effect.
NOEC: no observed effect concentration.
PNEC: predicted no-effect concentrations.
1158 Y. Zhang et al. / Chemosphere 73 (2008) 11511161
and reported that the lethal concentration of diclofenac is
480 50 lg L
1
(LC50/96 h) and the effect concentration is
90 20 lg L
1
(EC
50
/96 h). In chronic toxicity tests of Daphnia
magna reproduction, the NOEC of diclofenac was reported to be
1 mg L
1
and the LOEC (lowest observed effect concentration) to
be 0.2 mg L
1
(Schwaiger et al., 2004). In order to evaluate suble-
thal toxic effects of diclofenac on sh, Schwaiger et al. (2004)
and Triebskorn et al. (2004) studied rainbow trout (Oncorhynchus
mykiss) exposed to diclofenac in doses ranging from 1 lg L
1
to
500 lg L
1
over a period of 28 days. Histopathological examina-
tions of exposed sh revealed alterations in the kidney and gills.
The lowest observed effect concentration (LOEC) causing renal le-
sions and alterations of the gills was found to be 5 lg L
1
(Schwai-
ger et al., 2004). Schwaiger et al. (2004) also observed the
bioaccumulation of diclofenac in sh. The highest concentrations
of diclofenac were detected in the liver, followed by the kidney
and then the gills. Its bioconcentration factors (BCF) were calcu-
lated as 122732 in the liver, 5971 in the kidney, 3763 in the
gills, and 0.369 in the muscle. Triebskorn et al. (2004) found that
the cytological alterations in liver, kidney and gills occurred even
at diclofenac concentration of 1 lg L
1
. Comparing those results
with the detected concentrations in Fig. 4, diclofenac denitely
poses a risk on the ecosystems where it is present.
Pharmaceutical residues may be transported through food
chains and severely harm other species. Studies have related the
decline of the population of vultures in the India subcontinent to
their exposure to diclofenac residues (Green et al., 2004; Oaks
et al., 2004; Shultz et al., 2004). Vultures used to be a common rap-
tor in the region; however, the raptors population has declined
signicantly since the 1990s. These studies found that diclofenac
residues in treated livestock bodies that were scavenged by the
vultures caused the renal failure and death of the vultures.
Based on knowledge obtained so far, it seems that the acute
ecotoxicity of both drugs is rather unlikely, but that the chronic ef-
fects are still not clear. Long term studies are needed for the better
characterization of chronic ecological effects. The synergistic toxic-
ity of these drugs with other compounds also needs more studies.
Furthermore, information on the ecological effects of their metab-
olites and intermediates is also needed.
7. Conclusions and outlook
The global consumed volumes of carbamazepine and diclofenac
can be estimated by the dose per capita, with differences between
developed and developing countries. According to our estimation,
1014 tons of carbamazepine and 940 tons of diclofenac are con-
sumed annually worldwide. After administration, some of these
drugs are degraded and some are excreted in unchanged forms.
Approximately 30% of an oral carbamazepine dose is excreted
unaltered in urine and in faeces together, while its urine metabo-
lite, CBZ-diol, accounts for around 30% of oral dosage and is poten-
tially present in water bodies. Some metabolites of diclofenac that
are recovered from urine represent a higher proportion of an oral
dose than unchanged diclofenac and therefore, could build up at
higher concentrations at the WWTPs as well. However, studies
on those metabolites in the environment are insufcient.
Both carbamazepine and diclofenac are ineffectively removed
by WWTPs. The removal efciency of carbamazepine is less than
10% in most cases while that of diclofenac varies from 0% to 80%,
depending on the operation conditions of WWTPs (e.g. anoxicoxic
ratios, acidic conditions and sunlight irradiation conditions).
Sludge retention time does not have a noticeable inuence on
the removal efciencies of either compound. As a result of ineffec-
tive removal, they pass through WWTPs and are widely detected in
downstream water bodies, with concentrations cascading from
WWTP efuents, to surface waters, to groundwater. According to
the measured concentrations and available ecotoxicology data,
both of them are unlikely to cause acute toxic effects, but their
chronic effects cannot be excluded. Notably, carbamazepine
showed a very low PNEC in ranges that are comparable to some
concentrations detected in the environment. More studies are
needed to observe the chronic effects of the two drugs and their
potential synergistic toxicity with other compounds. Removal
techniques need to be developed that are effective both in terms
of yield and cost.
Acknowledgements
Yongjun Zhang is supported by a scholarship from the State
of Berlin under the program of Nachwuchsfrderungsgesetz
(NaFG). We thank Dr. Harald Mckter (Walther-Straub-Institut,
Ludwig-Maximilians-Universitt Mnchen) for his generous
support. We also appreciate the anonymous reviewers whose
excellent comments signicantly improved the quality of this
manuscript.
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