Environmental Technology

ISSN: 0959-3330 (Print) 1479-487X (Online) Journal homepage: http://www.tandfonline.com/loi/tent20

Human Pharmaceuticals in the Aquatic

Environment a Review

O. A. H. Jones, N. Voulvoulis & J. N. Lester

To cite this article: O. A. H. Jones, N. Voulvoulis & J. N. Lester (2001) Human Pharmaceuticals in
the Aquatic Environment a Review, Environmental Technology, 22:12, 1383-1394

To link to this article: http://dx.doi.org/10.1080/09593330.2001.11090873

Published online: 17 Feb 2015.

Submit your article to this journal

Article views: 33

View related articles

Citing articles: 63 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=tent20

Download by: [Orta Dogu Teknik Universitesi] Date: 07 March 2016, At: 05:36
 Environmental Technology. Vol. 22. pp 1383-1394
© Selper Ltd, 2001

HUMAN PHARMACEUTICALS IN THE AQUATIC

ENVIRONMENT A REVIEW

O.A.H.JONFS, N. VOULVOULISANDJ.N. LESTER•

Environmental Processes and Water Technology Group, Department of Environmental Science and Technology, Imperial
College of Science, Technology and Medicine, London, SW7 2BP, UK

(Received 1 June 2001; Accepted 2 August 2001)

ABSTRACf

There. has been increasing concern in recent years about the occurrence, fate and toxicity of pharmaceutical products in the
aquatic envrronm_ent. Many of the more commonly used drug groups (for example antibiotics) are used in quantities similar
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

to th_ose of p_e shodes and other organic micropollutants, but they are not required to undergo the same level of testing for
poss1ble environmental effects. The full extent and consequences of the presence of these compounds in the environment are
the~efore largely unknown and the issue as a whole is ill-defined. Although these compounds have been detected in a wide
vanety of envuonmental samples including sewage effluent, surface waters, groundwater and drinking water, their
concentrations generally range from the low ppt to ppb levels. It is therefore often thought to be unlikely that
pharmaceuticals will have a detrimental effect on the environment. However, the lack of validated analytical methods,
limited monitoring data and the lack of information about the fate and toxicity of these compounds and/ or their metabolites
in the aquatic environment makes accurate risk assessments very difficult.

Keywords: Pharmaceuticals, review, occurrence, fate, toxicity

INTRODUCfiON currently under investigation) have potential as endocrine

Pharmaceuticals are chemicals used for diagnosis,
treatment (cure/mitigation), alteration or prevention of
disease, health condition or structure/function of the body [1].
More than 3000 individual pharmaceutical substances are
currently licensed for use in the UK alone [2]. The EU itself
accounts for around 26% of the world pharmaceutical market
with drug spending across Europe typically accounting for
7%-15% of national health care expenditures and 0.5-1% of the
gross domestic product [3].
Regulations associated with drugs are generally
overseen by human health agencies, which usually have
limited experience in environmental issues and until recently
pharmaceuticals were not seen as potentially toxic substances.
Therefore, unlike many other anthropogenic contaminants,
they have not been subjected to detailed research regarding
their possible environmental effects.
Many individual pharmaceutical products or
metabolites have been found in the environment. Some of the
most popular groups are analgesics, antibiotics, anti
epileptics, P-blockers, P2-sypathomemetics and lipid
regulators. While concentrations are generally very low
(usually ng 1'1 to mg 1'1), many chemicals have been shown to
have effects on aquatic life at these . concentrations (e.g.
oestrogens,) (4]. In addition certain pharmaceuticals are
designed to modulate the endocrine and immune systems of
humans and as such (in contrast to many other chemicals
disrupters [2]. Drugs also tend to have particular
characteristics by design (such as being lipophilic or highly
persistent) which may lead to accumulation in the
environment [2].
Present knowledge indicates that a wide range of
pharmaceuticals, metabolites and their conjugates are
excreted into the sewerage system (5]. The processes acting on
them during wastewater treatment are not fully understood
and there are conflicting reports on how biodegradable they
are [5-7]. Pharmaceuticals are likely to be transformed-within
the treatment process depending on their physico-chemical
properties (e.g. chemical structure, aquaeous solubility,
octanol/water partition coefficient and Henry's Jaw constant)
and this will alter their behaviour with respect to partitioning
to the sludge or liquid phase. Their fate and behaviour during
wastewater ~reatment will therefore comply with the
pathways outlined by Meakins et al. [8]. Biological filters and
activated sludge are the principal types of secondary
wastewater treatment used following primary sedimentation.
Both treatments use two vessels the first, a reactor containing
large populations of micro-organisms that oxidise the
biochemical oxygen demand (BOD); the second, a tank that
serves to remove micro-organisms from the final effluent by
sedimentation. Removal pathways for organic
micropollutants during secondary biological treatment
(Figure 1) include adsorption onto the microbial floes and
removal in waste sludge, biological or chemical degradation,

1383
 volatilisation

i
unchanged, recalcitrant unchanged polar
organics organics
I
I
I
I
I
I
biotransfonnation -------,---
1
I
I
I
I
I
biodegradation
-------•
chemical degradation sedimentation of
adsorbed organics
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

adsorption

sludge treatment
and disposal

Figure 1. Removal mechanisms for organic micropollutants during secondary biological treatment. (After Meakins eta/ [8)).

transformation and volatilisation during aeration [8).
Guidelines for new pharmaceuticals have been
introduced in the USA [9). A draft on environmental risk
assessment of new pharmaceuticals is also proposed for the
EU [10). These guidelines will affect new drug compounds
and are designed to reduce the amount of drugs that
eventuaUy enter watercourses, however they do not cover the
large number of compounds already in use. Little is known
regarding occurrence and effects of most pharmaceuticals
although data do exist for groups such as endocrine
disrupters. These have been the subject of substantial research
and there Is already considerable information available [11-
21). Therefore for the purpose of this review, the term
pharmaceuticals will refer to non-hormonal drugs.
Sources of Pharmaceuticals
The sources of pharmaceuticals to the environment can
be quite varied. In the UK records of drug use are kept by the
Department of Health (for prescribed drugs,) and the
Proprietary Association of Great Britain (for over-the-counter
medicines). Both of these organisations only keep a record of
drug use in terms of number of prescription items issued [2) .
Clearly what exactly makes up a prescription item may vary
quite considerably and this type of data is therefore of little
use when trying to estimate the amount of drugs and
metabolites, which may find their way into waters in the UK.
Table 1 includes the top 10 pharmaceuticals by number of
prescription items issued in the UK in 1999. These figures give
an idea of which compounds may be found in the UK
environment most frequently but are not conclusive because
they do not take into account over-the-counter medicines or
drugs procured illegally or over the internet.
The manufacture and disposal of waste
pharmaceuticals is subject to strict control in the cases of
manufacturers, wholesalers, retailers and hospitals (10) .
Although there have been isolated cases of hospitals
disposing of unwanted drugs via the drains [22],
contamination from these sources is thought to be unlikely. In
contrast, pathways through human consumption can be more
significant. If a patient should have any medicines left over
the correct procedure (in Europe at least) is to return them to
the pharmacy, which is then responsible for disposal. In
practice the public is under no obligation to do this and such
action is dependent on whether or not clear advice is given
[23). In practice the majority of people will either flush
unused drugs down the drain or dispose of them in domestic
refuse which will ultimately enter domestic waste landfill
sites or, to a lesser degree, be incinerated.
Holm eta!. (24) described the distribution of organic

1384
 Table 1. Top 10 UK pharmaceuticals in 1999 by number of prescription items issued.
Compound name BNF chapter
Salbutamol Respiratory
Aspirin Cardiovascular
Amoxyxillin Infections
Paracetamol CNS
Atenolol Cardiovascular
Co-proxamol CNS
Bendrofluazide Cardiovascular
Beclomethasone dipropionate Respiratory
Co-Codamol CNS
Thyroxine sodium Endocrine
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
compounds originating from pharmaceutical industry waste,
down the hydrological gradient of a landfill site (with no
leachate collection system) in Denmark. During the period
1962-1975, the landfill was used to dispose of approximately
85,000 tonnes of pharmaceutical production waste as well
as domestic refuse. Several pharmaceutical compounds
were identified in groundwater near the site including 2-
methyl-2-n-propyl-1,3-propanediol, 5,5-diallybarbituric acid,
propylphenazone and six sulphonamide derivatives. The
former was found to be present at concentrations of up to
18,000 11g 1·• at the sampling points closest to the landfill and
in one sample levels of sulfanilic acid and propylphenazone
were also greater than 1000 11g 1'1, In addition, the analgesics
ibuprofen, aminopyrine and phenazone have all been found
in concentrations up to 60 g 1' 1 in leachates from municipal
landfills in Sweden and Croatia with no record of incorrect
disposal (25).
Once administered some pharmaceuticals are degraded
in the body and may even become inactive but many others,
particularly those excreted renally or not absorbed fully from
the gut, can leave the body in their active forms [26]. Present
knowledge indicates that as a result, a wide range of
pharmaceuticals, metabolites and their conjugates are
excreted into the sewerage system. These compounds are
likely to be transformed during wastewater treatment [27) and
such transformations wiD alter their behaviour with respect to
partitioning to the sludge or liquid phase and hence their
ultimate fate. Much of the data available relates to parent
drugs rather than metabolites [27-28). This suggests that
biodegradability of pharmaceutical compounds within a
sewage treatment plant (STP) can vary in degree depending
on the type of treatment and operational factors.
Henschel et al. investigated the biodegradability of
paracetamol and methotrexate and the two drug metabolites,
salicylic acid and clofibric acid [29]. Their results were in
agreement with other studies and showed that salicylic acid
and, to a lesser extent, paracetamol, were biodegradable
whereas clofibric acid and methotrexate were not. Other
drugs, which have been investigated for their
1385
Number of prescription items (millions)
16.7
13.9
13.6
10.4
10
9.6
9.6
8.4
8.2
8.2
biodegradability, include ifosfamide and cyclophosphamide
[25, 30). Both of these compounds exhibited poor
biodegradability in the closed bottle test, and the Zahn-
Wellens/EMPA test for inherent biodegradability as well as
in a laboratory scale activated sludge plant.
Other studies on biodegradability by Richardson and
Bowron found that aspirin was readily biodegradable, as
(again) was paracetamol, after a period of acclimation [22]. In
contrast, several compounds belonging to various groups of
pharmaceuticals were identified a s being "non-
biodegradable". No other details, such as percentage removal,
were reported. Recent studies on pharmaceutical residues in
Germany have demonstrated that elimination of medium
polar pharmaceuticals in municipal sewage plants (STPs) is
often incomplete, ranging between 60 and 90% (27]. These
pharmaceuticals, (together with more polar compounds) are
directly discharged to surface waters. Pharmaceuticals
removed from wastewater by adsorption to sludge, may enter
the aquatic environment, via ground waters, sludge to land
application or land-filling but again there is a paucity of data
on this subject. Although several studies from the beginning
of the eighties suggest the presence of some pharmaceuticals
in the aquatic environment in England at concentrations of
approximately 1 11g 1'1 little data exists for many (though not
all) European countries [22]. In general the fate of compounds
within a STP may follow one of three routes. Relatively
simple molecules (such as aspirin) may often be degraded by
micro-organisms [31). However should the microflora of the
STP be unable to break down the drugs then (depending on
its binding characteristics) all or part of the substance may be
retained in the sludge. Should the drugs or metabolites be
persistent and non-binding to solids then they will not be
degraded in the works or retained in sludge and may
therefore reach the aquatic environment.
Richardson and Bowron, Ternes and Stumpf et a/. have
all conducted surveys into the fate of pharmaceuticals in STPs
concluding that at least some drugs were unlikely to be
degraded and hence likely to enter the aquatic environment
(22, 27, 28]. However, none of these studies systematically
 analysed for degradation products. Nevertheless a variety of
pharmaceuticals have been detected in sewage effluent with
levels ranging from below detection limits up to the low Jlg 1·1
range.
Garrison eta/. conducted the first study to detect drugs
in sewage effluent [32]. Clofibric acid was measured at
concentrations of up to 2 J.lg 1"1 in raw and treated wastewater
in Kansas City, USA. Hignite and Azarnoff verified those
results and measured up to 10 Jlg 1·1 of clofibric acid and 95.62
J.lg 1"1 of salicylic acid in the sewage etfluent at the same STP
[33]. However several authors have noted that the latter result
is rather high compared to more recent data [2].
Hirsch et al. analysed sewage effluents for 18 antibiotics
[34]. Of these only five were detected frequently. These
included dehydrated erythromycin, roxithromycin,
clarithromycin, sulfamethoxazole and trimethoprim. The
highest concentrations were for the metabolites of
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
erythromycin, for which a maximum value of 6 jJgs 1·' was
found . Only 5 sewage effluents were analysed for
tetracyclines and penicillins and none exhibited any
detectable amount, however this was not completely
unexpected because, due to the chemically unstable (i-lactam
ring, penicillins are readily susceptible to hydrolysis and are
therefore easily degraded [35, 36, 37].
Stumpf eta/. reported on the occurrence and behaviour
of 1 drugs and two metabolites from several different classes
of pharmaceuticals at a Brazilian STP [28]. Concentrations in
the raw sewage were between 0.3 and 1.2 J.lg 1·1 depending on
the drug and activated sludge treatment was found to be
more efficient at removing pharmaceutical residues than a
biological filter. Removal rates for activated sludge treatment
ranged from 34% for clofibric acid to 83% for indomethacine.
Only clofibric acid, fenofibric acid and gemfibrozll exhibited
less than SO% removal by this method of treatment. In
contrast removal rates by biological filters were generally less
than 30% except for indomethacine (71%) and ketoprofen
(48%). The lowest removal rates determined for fenofibric acid
(6%), diclofenac (9%) and clofibric acid and naproxen (both
15%). The authors were uncertain whether the removal of
drug compounds was a result of adsorption or degradation
however, due to the high polarities of the drugs under
investigation, adsorption to sludge was expected to be low. In
a similar study, Ternes analysed a variety of pharmaceuticals
in sewage Influent and final effluents at German STPs [27].
The elimination rates ranged from 7% (carbamazepine) to
greater than 99% (salicylic acid). Fenofibrate, paracetamol and
several metabolites of aspirin, were not detected in the
effluent, although 54 }lg 1"1 of salicylic acid was seen in the
influent. In general more than 60% of the drug residues
detected in the influent were removed. However, the average
removal rates were lower for carbamazeplne, clofibric acid,
phenazone and dimethylphenazone. Ternes et al. investigated
the occurrence of 32 pharmaceuticals (Including analgesics,
lipid regulators, psychiatric drugs, P-blockers, P2-
sympathomimetics as well as five drug metabolites) in
German sewage effluents [38). For most compounnds,
1386
concentrations in the effluent were less than 1 jJg 1·'. However,
in the case of aspirin, bezafibrate, carbamazepine, clofibric
acid, diclofenac, fenofibric acid, fenoprofen, gemfibrozil,
ibuprofen and metoprolol, concentrations of several Jlg 1·1
were detected .
Wastewater from hospitals may contain more drugs
and higher concentrations of individual compounds than
household or industrial effluent and the drugs present may be
more toxic or of higher biological activity. Most hospital
drains connect directly to the main sewers [39) although
certain waste may be disposed of separately either by a STP
on site or by special waste contractors. A number of
pharmaceuticals have been detected in hospital effluents at
the low Jlg 1·' level. Aherne eta/. detected methotrexate in an
effluent sample taken from a large oncology clinic at a
concentration of approximately 1 Jlg 1·1 [40]. Sieger-Hartmann
eta/. detected cyclophosphamide in hospital effluent at a level
of 0.146 jJg J·' and, more recently, at 0.019-4.5 J.lg 1"1 [25, 41].
Ifosfamide, has been detected at levels of 0.024 Jlg 1·' (41] and
less than 0.006 to 1.914 J.lg 1·' (median 0.109 J.lg 1"1) in hospital
effluent [30]. Hartmann et a/. detected 3-87 11 g 1·1 of
ciprofloxacin in the wastewater from a university hospital
[42]. Richardson and Bowron detected methaqualone in
sewage originating from a hospital again at approximately
111 g 1· 1 [22). Steger-Hartmann et a/. reported finding
cyclophosphamide in both the influent and effluent of a STP,
receiving wastewater from six hospitals [25]. Influent levels
ranged from below the detection limit (less than 6 ng J·') to up
to 143 ng 1·1, while treated sewage effluent levels ranged from
less than 6 to 17 ng 1· 1 • However, the authors did indicate a
high degree of analytical uncertainty with these data,
particularly the influent samples, considering the data too
unreliable to calculate a balance for cyclophosphamide. Table
2 includes the maximum concentrations of different
pharmaceuticals groups that have been detected in sewage
effluent. Concentrations for some of the more popular classes
such as antibiotics and analgesics are quite high, however
evidently some degradation and/ or dilution takes place in the
Table 2. Human pharmaceutical groups detected in sewage
effluent.
Group Maximum concentration Reference
detected (ng 1" 1)
Analgesics 6000 (Paracetamol) (27)
Antibiotics 6000 (Erythromycin-H20) [34)
Anti-inflammatories 1000 (lndomethacine) [28]
Anti-neoplastics 2900 (Ifosfamide) (27)
Anti-epileptics 6300 (Carbamazepine) (27)
Lipid regulators 4600 (Bezafibrate) (27]
!!-blockers 2200 (Metaprolol) (27)
~ sypathomemetics 180 (Cienbuterol) [27]
Psychiatric drugs 40 (Diazepam) (27)
 environment as concentrations in surface water are generally
lower (Table 3).
No data relating to the pharmaceutical concentration of
sewage sludge appears to exist in the literature. In a previous
review, Rodgers concluded that there was very little evidence
to suggest that pharmaceutical res idues were likely to be
present at significant levels in sewage sludge [46]. However,
given recent advances in analytical methodology it may no
longer be the case that these compounds cannot be detected
(43, 44, 45].
There have been occasional studies of pharmaceutical
compounds in water treatment works (WfWs). Sacher et a/.
studied the behaviour of four pharmaceutica ls known to
frequently occur in German waters (diclofenac,
carbamazepine, bezafibrate and clofibric acid) and made a
detailed study of their behaviour during different drinking
water treatment unit processes [36]. All four compounds were
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
Occurrence of Pharmaceutical Products in the Environment
Pharmaceuticals have been detected in a wide variety
of samples including, surface water, groundwater and
drinking water, at levels which are generally less than 1 j.!g 1·•.
Much of the monitoring data is from Germany (where
research has been particularly active in recent years), and to a
lesser extent Denmark and the USA. One of the most common
compounds analysed is clofibric acid, which has been found
at various locations, at concentrations of up to 220 j.!g 1"1• This
would seem to indicate widespread contamination rather
than a local phenomenon [2, 47, 48].
Aherne et al. assessed the levels of the anti cancer drug
bleomycin in sewage effluent, river and potable water
samples using a radioimmunoassay [43]. Concentrations were
between 11 and 19 ng 1"1 in the effluent but only 5 to 17 ng 1·•
in the river and potable water samples. However anti-cancer

reported to be readily biodegraded using slow sand filtration.
In contrast, flocculation by Iron (III) chloride was an
ineffective treatment. Ozoneation removed carbamazepine
and diclofenac but only eliminated bezafibrate and clofibric
acid, to a limited degree. Granular activated carbon (GAC)
was effective for the removal of carbamazepine, diclofenac,
and bezafibrate, however its elimination of clofibric acid was
depend ent on both the quality of the water and the
processing-time. Zwiener and Frimmel investigated the
degradability of clofibric acid, diclofe nac and ibuprofen
during oxidative water treatment in wrws [37]. Laboratory
scale experiments were carried out using ozone and
ozone/hydrogen peroxide combinations. When just ozone
was used only diclofenac was degraded, (by approximately
97%). However, the combined application of ozone and
hydrogen peroxide improved the degradation efficiency of all
the compounds investigated. Degradation was more than 90%
at a concentration of 3.7 mg 1·• ozone and 1.8 mg 1·• hydrogen
peroxide and over 98% at a concentration of 5 mg t·• ozone
and 1.8 mg 1·• hydrogen peroxide.
drugs are often limited to areas with hospitals treating cancer
patients while other more commonly used dru gs may be
more ubiquitously distributed . For example Buser et a/.
identified clofibric acid in the ng 1·• range in several Swiss
lakes [6] . Buser et a/. also studied the occurrence and fate of
diclofenac, again in Swiss lakes [49] . The concentrations
ranged from less than 1 up to 12 ng t· 1 with higher
concentrations of 5-370 ng 1'1 observed in the river Aabach
and its tributaries. However the drug was not found in the
sediments of the lakes studied. Concentrations in the inflow
of one lake were found to be much higher than those of the
outflow. This loss was suggested to be the result of
photodegradation. A similar study by Buser et a/. found
ibuprofen to be present in STP influent at concentrations of up
to 3mg 1' 1 with a high enantiomeric excess of th e
pharmacologically active 'S' enantiomer [1]. The principal
human metabolites of ibuprofen (hydroxy-ibuprofen
and carboxy-ibuprofen) were also observed in the influent
at even higher concentrations. However in contrast to other

Table3. Human pharmaceutical groups detected in surface water.

Group Maximum concentration Reference

detected (ng 1'1)

Analgesics 530 (Ibuprofen) [27]

Antibiotics 1700 (Erythromycin-H20) [34]
Anti-inflammatories 340 (Dimethylaminophenazone) [27]
Anti-neoplastics 17 (Bleomycin) [43]
Anti-epileptics 1100 (Carbamazepine) (27]
Lipid regulators 3100 (Bezafibrate) [27]
jl-blockers 2900 (Bisoprolol) [27]
l!rsypathomemetics 61 (Fenoterol) [27]

1387
 pharmaceutical compounds these were then efficiently
degraded by greater than 95% during wastewater treatment
and this was also confirmed in laboratory experiments. In
rivers and lakes ibuprofen was detected at concentrations of
up to 8 !Jg 1· 1 generally with some excess of the 'S' enantiomer,
but the metabolites were not detected.
Heberer eta/. screened 30 surface water samples from
the Berlin area and found drug residues at concentrations of
up to 1 !Jg I·' [50). The pharmaceuticals most frequently
detected were clofibric acid, diclofenac, ibuprofen, and
propylphenazone. Clofibric acid and diclofenac were often
detected at levels above 100 ng 1'1 whereas the levels were
generally lower for ibuprofen and propylphenazone. Stumpf
et a/. studied 18 Brazilian surface waters and found that
clofibric acid, diclofenac and naproxen were often detected
[28). Maximum concentrations often exceeded 100 ng J·' and in
the case of fenofibric acid, ibuprofen, ketoprofen, diclofenac,
bezafibrate and naproxen were up to 500 ng 1"1• In a similar
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
study Ternes eta/. screened German surface waters. Twenty
. different drugs and three metabolites were found with
maximum concentrations of up to 3.11!g I·' [38).
Studies conducted in the UK in the 1980s detected only
a few human pharmaceuticals in surface water at
concentrations up to approximately 1 l!g 1· 1• For example,
Watts et a/. identified erythromycin, tetracycline and
theophylline at approximately 11Jg 1·1 (51) and Fielding et al.
qualitatively identified clofibric acid (52).
Large uncertainties exist with regard to the presence of
polar organic pollutants in marine systems (53). Weigel et at.
found ng 1·1 concentrations of caffeine, carbamazepine and
propylphenazone in samples from the German Bight in the
North Sea [54). Stumpf et at. detected clofibric acid, didofenac
and naproxen at concentrations of up to 100 ng 1·• in
Guanabara Bay, Brazil (28). While Buser et a/. detected
clofibric add in the central region of the North Sea at levels of
1-2 ng 1"1 and 7.8 ng t 1 at a North Sea sampling station in the
plume of the River Elbe [6). Table 3 shows the concentrations
of different drug groups that have been found in surface
waters. There is a large cross section of compounds and it is
unknown how they might interact within the aquatic
environment and what effects they might have on aquatic life,
however a particular concern is the possibility_of increasing
antibiotic resistance in bacterial populations.
Table4. Human pharmaceutical groups detected in groundwater.
Group Maximum concentration
detected (ng 1"1)
Analgesics 1465 (Propylphenazone)
Antibiotics 470 (Sulfamethoxazole)
Anti-epileptics Positive identification (Phensuximide)
Lipid regulators 45 (Fenofibrate)
1388
There are several reports of pharmaceuticals occurring
in groundwater (32, 34, 55) . The most significant
contamination is usually associated with landfills, but it could
also occur via groundwater recharge from tertiary treated
sewage and pollution of groundwater due to incorrect
disposal of wastes by hospitals and pharmaceutical
companies has also been reported (22). Eckel et al. analysed
samples taken from a groundwater well in Florida in 1984 and
found several compounds including meprobamate,
pentobarbital, and phensuximide (56). The source was
thought to be a landfill 300m away that had received waste
from a naval hospital in 1968/69. In 1991, the well was re-
analysed, and phenobarbital and four sulphonamide drugs
were found. In all cases however, the identification was only
qualitative. Heberer et al. analysed 17 water samples from
groundwater wells in the catchment of a water treatment
works in Germany and found that clofibric acid, phenazone
and propylphenazone were all detected at levels above 1 !Jg J·'
[47). In contrast, Hirsch eta/. looking at antibiotics in German
groundwaters found that in nearly all cases the levels were
below 20-50 ng 1·• (the limit of detection) [34). Contamination
of groundwater is of concern because it is often used for
public water supply and the half-lives of nearly all chemicals
can be much longer in this environment since microbial
activity is lower. In Table 4 the maximum concentrations of
different pharmaceuticals groups that have been detected in
groundwater are presented. The number of therapeutic
classes is lower than for other aquatic compartments
indicating the possibility that some compounds are filtered or
degraded before they can reach aquifers. Nevertheless the fact
that drugs have been found in this medium indicates that
some compounds at least may be quite persistent in the
environment.
There are currently no regulatory requirements for
monitoring pharmaceuticals in drinking water. Although
human pharmaceuticals have occasionally been detected at
concentrations generally less than 10 !Jg 1·• water companies
do not routinely test for these compounds because the
amounts present are thought to be trivial compared to those
of more well-known pollutants such as pesticides [57).
Clofibric acid has been qualitatively detected in samples from
UK water treatment works [52). In addition Heberer and Stan
quantified a maximum concentration of up to and including
Reference
[50)
[34)
[57)
[50)
 170ng t·' of clofibric acid in samples collected from one of
fourteen waterworks in Germany [55]. Values were below 75
ng J·' for samples taken from the remaining thirteen works,
with two samples below the level of detection of 1 ng t·'. Table
5 shows the concentrations of different groups of
pharmaceutical compounds that have been detected in
drinking water. The concentrations and range of compound
groups are lower than those found in sewage effluent and
surface waters. Some drugs are evidently not totally degraded
by water treatment but thert! is only a small possibility they
could have an affect on humans [57, 58].
Fate of Pharmaceuticals
After ingestion, pharmaceuticals are generally well
absorbed by organisms and will then undergo complete or
extensive phase I and phase II metabolism [27]. Phase I
reactions usually consist of oxidation, reduction or hydrolysis
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
whereas Phase II involves conjugation. These processes yield
polar metabolites, which normally exhibit insignificant
pharmacological activity excreted in the urine. However in
some cases there is also excretion of 50-80% of the parent
compound [34] and there is always the possibility that
bacterial action could result in the reformation of an active
compound from its conjugate. Nonetheless, it is important to
emphasise that significant, pharmacological activity in human
excreta is the exception rather than the rule [34).
Once in the environment, pharmaceuticals may be acted
on by a number of processes. Hydrolysis and photolysis
(chemical transformation), and biodegradation and
mineralisation (biotransformation) being the most common
mechanisms of degradation and depletion of drug residues
[27]. These processes coupled with dilution with surface water
are the main methods of drug residue reduction in the
environment and this can lead to potentially low risk
exposure assessments for many drugs. However research into
the fate of human drugs in the environment is still in its
preliminary phase, and further information is required before
any firm conclusions can be made [28]. As more evidence is
amassed, regulatory agencies are increasingly taking the view
that it would be beneficial to take a precautionary approach
and to try and regulate and reduce the pathways by which
Table 5. Human pharmaceutical groups detected in drinking
water.
Group Maximum concentration Reference
detected (ng 1'1)
Analgesics 6 (Diclofenac) [28)
Anti-neoplastic& 13 (Bleomycin) [43]
Lipid regulators 27 (Bezafibrate) [28)
Psychiatric drugs 10 (Diazapam) [59)
1389
pharmaceutical products enter the environment, without
waiting for the science to catch up.
Toxicity of Pharmaceuticals
Although the effects of this type of pollution on aquatic
life are not know they have the potential to be particularly
troublesome [59]. Levels are generally low (usually below 1
Jlg 1"1) making acute toxic effects unlikely however because of
their continual input there is the possibility of chronic effects
that may not become apparent for many years.
Estimating the likely toxicity of pharmaceuticals in the
environment requires knowledge of their availability to the
cell [35]. However as most pharmaceuticals were designed to
affect mammalian physiology it is not known what effects
they could have on organisms such as aquatic insects. A major
stumbling block to this type of research is that
pharmaceuticals were generally never designed to have any
intended effects on wildlife. Therefore knowledge as to what
types of effects to look for is limited and although
pharmaceutical chemicals receive considerable
pharmacological and clinical testing, information on their
environmental toxicity is generally insufficient. This situation
is not helped by current regulatory guidance, which only
requires pharmaceuticals to undergo standard acute toxicity
tests (this is often only required for algae, Daphnia and fish)
unless there is good reason to believe the compound may
bioaccumulate [2]. Indeed, this aspect has been highlighted by
a number of researchers who have considered that when
assessing the environmental risks of pharmaceuticals chronic
effect testing should be used because conventional acute
toxicity tests may be inappropriate [60].
Hospital wastewater is often assumed to be the most
toxic to aquatic life and there are indeed several studies in
which genotoxic activity of hospital wastewater has been
confirmed. Gartiser et a/. demonstrated the genotoxicity of
some hospital effluents with the chromosome aberration test
(hamster cell line V79) [61]. However, the authors could not
attribute the observed genotoxic effects to a specific substance
or group of substances. Guiliani et al. found that out of over
BOO hospital effluent samples from a large cancer hospital13%
were genotoxic in the umuC assay [62]. Genotoxic samples
were detected throughout a 24-hour period with the morning
hours showing the highest activity. Of the toxic wastewater
samples 96% showed genotoxic potential without detectable
cytotoxic effects. The authors considered that anti-neoplastic
agents were the possible causative agents however they
concluded that there was no obvious pollution hazard
attributable to the waste because no genotoxic activity was
detected in the influx of the STP receiving the wastewater of
the hospital.
Some workers have tried to identify the causal agents of
genotoxicity activity in hospital wastewater. Steger-Hartmann
et al. investigated the effects of cyclophosphamide in the
umuC assay [25]. No genotoxic effects were found at
concentrations of up to 1 g J·1• This was in agreement with the
 SOS chromotest in which Hellmer and Bolcsfoldi did not
detect a genotoxic effect of cyclophosphamide at
concentrations of up to 4.6g 1' 1 [63). Hartmann et al. found
evidence to suggest that one single class of antibiotic drug, the
fluoroquinolone antibiotics (e.g. ciprofloxacin) were
responsible for the genotoxic activity for a specific hospital
under investigation [42]. However Aherne et al. concluded
that the risk from ingesting drugs through drinking water was
minimal due to the extremely low levels involved [43).
X-ray contrast media, which biodegrade very slowly
and may contribute to the adsorbable organic halogen (AOX)
load, were investigated by Steger-Hartmann et al. who studied
the widely used compound iopromide [64). The authors
calculated the predicted environmental concentration (PEC) in
surface water, to be 2 pg 1·1• This was then compared with the
predicted no-effect concentration as derived from a range of
ecotoxicity tests. In short-term toxicity tests with bacteria
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016
(Vibrio fisheri, Pseudomonas putida), algae (Scenedesmus
subspicatus), crustaceans (Daphnia magna), and fish (Dania rerio,
Leuciscus idus) no toxic effects were detected at the highest
tested concentration of 10 g 1· 1• 1n a chronic toxicity test with
D. magna no effect was observed at the highest tested
concentration of 1 g 1'1• Using an assessment factor of 100, the
ratio between the predicted environmental concentration
(PEC) and the predicted no-effect concentration (PNEC) was
calculated to be less than 0.0002. The authors concluded that
this low value indicates that no environmental risk must be
expected as a result of the release of iopromide into the
aquatic environment.
There has been concern that antibiotics found in SfP
effluent may cause increased resistance amongst natural
bacterial populations [60). Many antibiotic-resistant isolates of
micro-organisms can be found in the environment and
although the subject remains controversial the significant
increase in the number of bacterial strains resistant to multiple
antibiotics has often been attributed to the irrational use of
antibiotics and the increase in discharges to wastewater [65).
The three well-established mechanisms of gene transfer, (i.e.
conjugation, transduction and transformation) are all believed
to occur in the aquatic environment [65). As a result, streams
and rivers could provide a source and a reservoir of resistant
genes as well as a medium for their spread and studies of
antibiotic-resistant organisms in water and wastewater show
a significant occurrence of resistant strains [65]. Apart from
this, some non-target organisms (such as cyanobacteria) may
be adversely affected by antibiotics, which could have an
indirect effect on the aquatic food chain.
Some authol'll have claimed that antibiotics in hospital
wastewater may be sufficient to induce resistance but this is
not a widely supported view [2]. Grabow et at. studied
coliforms resistant to ampicillin, chloramphenicol,
streptomycin, kanamycin and tetracycline. Their findings
suggest that conventional sewage treatment has a limited
effect on the incidence of drug resistance in bacteria [66). Bell
obtained similar results in bacteria isolated from domestic
sewage before and after treatment in an aerobic lagoon in
1390
Canada [67).
DISCUSSION
Drugs in the environment are an e merging
environmental issue. Although some environmental
contamination may come from landfill leachate or incorrect
disposal of waste drugs, these are likely to be relatively small
sources of environmental contamination. Most human
pharmaceuticals are released by excretion from the patient or,
to a lesser extent, in aqueous waste produced by
manufacturing. Sewage treatment plants may therefore be
reasonably expected to be the main point of collection and
subsequent release into the environment. However,
conventional sewage treatment facilities were never designed
to deal with pharmaceutical compounds and due to their
highly variable physical and chemical properties, the
efficiencies by which they are removed vary substantially. It is
also not known if sewage treatment facilities could be cost-
effectively modified to reduce pharmaceutical emissions.
A wide range of pharmaceuticals from many
therapeutic classes has been detected throughout the aquatic
environment in both marine and freshwater systems [27,55),
the levels to date being at least one (often several) order(s) of
magnitude below the standard doses applied in human (or
veterinary) medicine. Nevertheless, while the individual
concentrations of pharmaceuticals in natural waters might be
low, the combined concentrations from the variety and
numbers of substances in active use could prove significant
with regard to effects on aquatic life. This would be especially
true when multiple pharmaceuticals share the same mode of
action raising the possibility of synergistic effects.
Figure 2 shows the possible pathways by which
pharmaceuticals could enter the environment. It can be seen
that these are many and varied and hence controlling this
problem may prove to be quite difficult. While reasonably
detailed information is available for some pathways
(indicated by a heavily weighted line) information in other
areas is lacking (indicated by a lightly weighted, dashed line).
Data regarding the toxicity of pharmaceutical compounds are
quite rare and the data that do exist mostly refers to acute
toxic effects. However due to the low levels of these
compounds in the environment chronic effects are more likely
to occur and more research is needed in this area before the
full extent of this problem will be known.
In the future, analytical techniques are likely to become
more sensitive and detection limits lower. Hence
pharmaceutical products may be found in an even greater
variety of samples in the future. If pharmaceuticals
eventually do prove to be an environmental concern, then
prevention is preferable to remediation (proactive vs. reactive
approaches). Since the use of pharmaceuticals cannot be
restricted, other methods will need to be found to control
and/or reduce their input to the aquatic environment. The
potentially large social and economic impacts of regulating
drugs mean the need for reviewing these products is all the
 r·-·-· -·-·-·-·-
Application of Pharmaceuticals (by doctors, j Manufacture & !
pharmacies, over the counter medication etc.) i Transport____ J!

Excretion Disposal

Excretion
Excretion Waste
I X.·._=:.:-:_::-:.:::.,:;---;:=__).__...,
r" • -

: Leakage---, !_~.:_~_:.~~?~ .1· Excretion

Digested
------+I
....__..,.._ __, ---"sludge Soil
----~
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

~-~-~~--~R~~-o~-· -,.----*~~·----~
.___.,....------~ __Gr_o_un~d_w_a_te_r
_ ___.
.-' ~#

Drinking
...... water
Sediment

,-----~·- ·-
·-. ·- ..............
r---=~----·-
. Effects on ! I· Effects on I.
aquatic I j human health !
lL--·-·-·-·-·_.i
organisms .
1--·-·-·-·-·...:
Figure 2.Possible pathways of human pharmaceuticals in the environment.
(Key to figure,.----- strong evidence, ---------- medium evidence, -·-·-·-·- unknown/weak evidence).

more important. Before any changes in policy are considered
it is recommended that environmental monitoring for the
more commonly used pharmaceuticals or groups of
pharmaceuticals should be undertaken as a priority and
detailed toxicity testing utilising a wide variety of test
organisms and compounds should be performed in light of
observed concentrations.
CONCLUSIONS
The data presented here confirm that pharmaceutical
compounds can be present in a wide variety of aqueous
environmental samples at concentrations to rival those of
some pesticides. The use and release of antibiotics and
natural/synthetic steroids to the environment have generated
most controversy to date, but a plethora of other drugs have
yet to be examined. Pharmaceuticals as a group, have widely
varying physical and chemical properties and some at least
are highly mobile and persistent in the aquatic environment
and continuous input may impart a persistent quality to those
compounds that otherwise possess no inherent environmental
stability. Despite this, the full extent, magnitude, and
ramifications .of the presence of drugs in the aquatic
environment are largely unknown and more research is
required before a clear picture emerges of the true nature and
extent of the problem. It would therefore be u.nwise to
conclude that these compounds are not causing a significant
environmental effect until there is conclusive scientific
evidence to the contrary. The focus for the future should
therefore be on proper and sufficient science for establishing
occurrence, exposure, susceptibility and effects, so that sound
decisions can be made regarding human and ecological
health.

1391
 REFERENCES

1. Buser H .R., Poiger T. and Muller M.D. Occurrence and environmental behavior of the chiral Pharmaceutical Drug
Ibuprofen in surface waters and wastewater. Environ. Sci. Techno/., 33, 2529-2535, (1999).
2. Ayscough N.J., Fawell J., Franklin G. and Young W. Review of Human Pharmaceuticals in the Environment. R&D Technical
Report No. P390. Environment Agency, Bristol,UK, 106pp (2000).
3. European Commission. Pollutants in Urban Wastewater and Sewage Sludge. Office for Official Publications of the European
Community, ~uxembourg City, Luxembourg, 232pp, (2001)
4. Larsson D.G.J., Asolfsson-Erici M., Parkkonen J., Petterson M., Berg A.H., Olsson P.E. and Fortin L. Ethinyloestradiol- an
undesired fish contraceptive? Aquatic Toxicol., 45,91-97, (1999) .
5. Ternes T. Pharmaceuticals and metabolites as contaminants of the aquatic environment: An overview. Abst. Papers Am.
Chern. Soc., 219, 301-309, (2000).
6. Buser H., Muller M.D. and Theobald N. Occurrence of the pharmaceutical drug clofibric acid and the herbicide mecoprop
in various Swiss lakes and in the North Sea. Environ. Sci. Techno/., 32, 188-189, (1998).
7. Daughton C.G. Pharmaceuticals in the environment: Overarching issues and concerns. Abst. Papers Am. Chern. Soc., 219, 317-
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

318, (2000).
8. Meakins N.C., Bubb J.M. and Lester J.N. The fate and behaviour of organic micropollutants during wastewater treatment
processes: a review./nt. J. Environ. Pollut., 4, 27-58, (1994).
9. FDA Centre for Drug Evaluation and Research (CDER). Guidance for industry for the submission of an environmental
assessment in human drug applications and supplements. Food and Drug Administration, Rockville, USA, 39pp. (1995).
10. EU. Assessment of potential risks to the environment posed by medicinal products for human use, excluding products
containing live genetically modified organisms. EU ad hoc working party, ID/5504/94 Draft 4, (1994)
11. Akingbemi B.T. and Hardy M.P. Oestrogenic and antiandrogenic chemicals in the environment: effects on male
reproductive health. Ann. Med., 33,391-403, (2001)
12. Schmitt E., Dekant W. and Stopper H. Assaying the estrogenicity of phytoestrogens in cells of different estrogen sensitive
tissues. Toxicol. In Vitro, 15, 433-439, (2001)
13. Foster W.G. Endocrine disruption and human reproductive effects: An overview. Water Qual. Res. f. Can.,36, 253, (2001)
14. Asano T., Yoon B.O. and Hara M. Concentration and removal of endocrine disruptors through a hydrophobic polymeric
membrane by pervaporation. Abst. Papers Am. Chern. Soc., 222, 176-ENVR Part 1, (2000).
15. Yoon B.O., Asano T. and Hara M. Removal of endocrine disruptors by sorption method using PDMS membranes. Abst.
Papers Am. Chern. Soc., 222: 178-ENVR Part 1, (2001).
16. Aloisi A.M., Seta D.O. and Ceccarelli I. Bisphenol-A differently affects estrogen receptors-alpha in estrous-cycling and
lactating female rats. Neurosci. Lett. 310, 49-52, (2001).
17. Iguchi T., Watanabe H. and I<atsu Y. Developmental effects of estrogenic agents on mice, fish, and frogs: A mini-review.
Horm. Behav., 40, 248-251, (2001).
18. Lai K.M., Scrimshaw M.D. and Lester J.N. The effects of natural and synthetic steroid Estrogens in relation to their
environmental occurrence. Crit. Rev. Toxicol. (in press) (2002).
19. Lai K.M., Johnson K.L., Scrimshaw M.D. and Lester J.N. Binding of waterborne steroid Estrogens to solid phases in river
and estuarine systems. Environ. Sci. Techno/., 34, 3890-3894, (2000).
20. Garcia-Reyero N., Grau E., Castillo M., De Aida M . J. L., Barcelo D. and Pina B. Monitoring of endocrine disruptors in
surface waters by the yeast recombinant assay. Environ. Toxicol. Chern., 20,1152, (2001).
21. LangeR., Hutchinson T.H., Croudace C.P. and Siegmund F. Effects of the synthetic estrogen 17 alpha-ethinylestradiol on
the life-cycle of the fathead minnow (Pimephales promelas). Environ. Toxicol. Chern.,20, 1216-1227, ( 2001).
22. Richardson M.L. and Bowron J.M. The fate of pharmaceutical chemicals in the environment. f. Pharm. Pharmacal., 37, 1-12,
(1985).
23. Daughton C.G. and Ternes T.A. Pharmaceuticals and personal care products in the environment: Agents of subtle change?
Environ. Health Perspec., 107,907-938, (1999),
24. Holm J.V., Riigge, K., Bjerg P.L. and Christensen T.H. Occurrence and distribution of pharmaceutical organic compounds in
the groundwater downgtadient of a landfill (Grinstead, Denmark). Environ. Sci. Techno/.,29, 1415-1420, (1995).
25. Steger-Hartmann T., Kiimmerer K. and Hartman A. Biological degradation of cyclophosphamide and its occurrence in
sewage water. Ecotoxicol. Environ. Safety, 36, 174-179, (1997).
26. Ares M.E. The affect of antibiotics on freshwater bacterial communities. Ph.D. Dissertation, Imperial College, London,
United Kingdom, 234pp (1999).
27. Ternes T. Occurrence of drugs in German sewage treatment plants and rivers. Water Res., 32, 3245-3260, (1998).

1392
 28.Stumpf M., Ternes T.A., Wilken R.D., Rodrigues S.V. and Baumann, W. Polar drug residues in sewage and natural waters
in the state of Rio de Janeiro, Brazil. Sci. Total Environ., 225, 135-141, (1999).
29. Henschel K.P., Wenzel A., Diedrich M. and Fliedner, A. Environmental hazard assessment of pharmaceuticals. Reg~ll .
Toxicol. Pharmacal., 25,220-225 (1997).
30. Kiimmerer L., Sterger-Hartmann T. and Meyer M. Biodegradability of the anti-tumour agent ifosfamide and its occurrence
in hospital effluents and communal sewage. Water Res., 31, 2705-2710, (1997).
31. Raloff J. Drugged Waters: does it matter that pharmaceuticals are turning up in our water supply? Sci. News, 153, 187-189,
(1998)
32. Garrison A.W., Pope J.D. and Allen F.R. In: Identification and Analysis of Organic Pollutants in Water. Ann Arbor Science
Publishers, MI, USA, pp.-517-566, (1976).
33. Hignite C. and Azarnoff D.L. Drugs and drug metabolites as environmental contaminants: chlorophenoxyisobutyrate and
salicylic acid in sewage water effluent. Life Sci., 20, 337-341, (1977).
34. Hirsch R., Ternes T., Haberer K. and Kratz K.L. Occurrence of antibiotics in the aquatic environment. Sci. Total Environ., 225,
109-118, (1999).
35. Stryer, L. Biochemistry, 4th edition. W.H. Freeman and Company, New York, USA, (1996).
36. Sacher F., Haist-Gulde B., Brauch H .] ., Zullei-Seibert N., Preuss G., Meisenheimer M., Welsch H. and Ternes T.A. Behavior
of selected pharmaceuticals during drinking-water treatment. Abst. Papers Am. Chern. Soc., 219, 45-ENVR, Part 1, (2000).
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

37. Zwiener C. and Frimmel F.H. Oxidative treatment of pharmaceuticals in water. Water Res., 34, 1881-1885, (2000).
38. Ternes T., Hirsch R., Mueller J. and Haberer K. Methods for the determination of neutral drugs as well as betablockers and
~-sympathomimetics in aqueous matrices using GC/MS and LC/MS/MS. Fresenius J. Anal. Chern ., 362,329-340, (1998).
39. Kiimmerer K. Drugs in the environment: emission of drugs, diagnostic aids and disinfectants into wastewater by hospitals
in relation to other sources- a review. Chemosphere, 45,957-969, (2001).
40. Aherne G. W., English J. and Marks V. lmmunoassays in the analysis of water. Ecotoxicol. Environ. Safety, 9, 79-83, (1985).
41. Steger-Hartmann T., Kiimmerer K. and Schecker J. Trace analysis of the antineoplastics ifosfamide and cyclophosphamide
in sewage water by two step solid phase extraction and gas chromatography-mass spectrometry. J. Chromatogr. A, 726, 179-
184, (1996)
42. Hartmann A., Alder A.C, Koller T. and Widmer, R.M. Identification of fluoroquinolone antibiotics as the main source of
umuC genotoxidty in native hospital wastewater. Environ. Toxico/. Chern., 17, 377-382, (1998).
43. Aherne G.W., Hardcastle A., Nield A.H. Cytotoxic drugs and the aquatic environment- estimation of bleomycin in river
and water samples. f. Pharm. Pharmaco/., 42,741-742, (1990).
44. Aherne G.W. and Briggs R. The relevance of the presence of certain synthetic steroids in the aquatic environment. J. Phamz.
Pharmaco/., 41, 735-736, (1989).
45. Desbrow C., Routledge E.J., Brighty G.C., Sumpter J.P and Waldeck M. Identification of estrogenic chemicals in STW
effluent. 1. Chemical fractionation and in vitro biological screening. Environ. Sci. Techno/., 32, 1549-1558, (1998).
46. Rogers H.R. Sources, behaviour and fate of organic contaminants during sewage treatment and in sewage sludges. Sci. Total
Environ., 185, 3-26, (1996).
47. Heberer T., Schmidt-Baumler K. and Stan H.J. Occurrence and distribution of organic contaminants in the aquatic system in
Berlin. Part 1: Drug residues and other polar contaminants in Berlin surface and groundwater. Acta Hydrochim. Hydrobiol.,
26, 272-278 (1998).
48. Stan H.J. and Heberer T. Pharmaceuticals in the aquatic environment. Anal. Magazine. 25, M20-M23, (1997).
49. Buser H.R., Poiger T. and Muller M.D. Occurrence and fate of the pharmaceutical drug diclofenac in surface waters: Rapid
photodegradatlon in a lake. Environ. Sci. Techno/., 32, 3449-3456, (1998).
50. Heberer T., DUnnbier U., Reilich C.H. and Stan, H.J. Detection of drugs and drug metabolites in ground water samples of a
drinking water treatment plant. Fresenius Environ. Bull., 6, 438-443, (1997).
51. Watts C.D., Crathome B., Fielding M. and Stell, C.P. In: Analysis of Organic Micropollutants in Water. Reidal Publishing Co.
Derdrecht, Germany, 1983, pp120-131, (1983)
52. Fielding M., Gibson T.M., James H.A., McLoughlin K. and Steel C.P. Organic Micropollutants in Drinking Water. WRc Report
No. TR159, WRc, Medmenham, UK (1983).
53. Aherne G.W. The use and significance of immunoassays in the analysis of water. Proc. Royal Soc. Chern., 21, 177-179 (1984).
54. Weigel S., Bester K. and HOhnerfuss H.J. New method for rapid solid-phase extraction of large-volume water samples and
its application to non-target screening of North Sea water for organic contaminants by gas chromatography- mass
spectrometry. J. Chromatogr. A, 9U, 151-161, (2001).
55. Heberer T. and Stan H.J. Determination of clofibric acid and N-(phenylsulfonyl)· sarcosine in sewage, river and drinking
water. Int. J. Environ. Anal. Chern., 67,113-124, (1997).
56. Eckel W.P., Ross B. and Isensee R.K. Pentobarbital found in ground water. Goundwater, 31, 801-804, (1993).
57. Holgate G. The safe disposal of clinical waste: The legislative regime. Environ. Waste Manag., 2, 247-253.

1393
 58. Waggott A. Trace organic substances in the River Lee. In: Chemistry in Water Reuse, Cooper W.J., (ed.), Ann Arbor Science.
Ann Arbor, MI, USA. pp. 55-99
59. Christensen, F.M. Pharmaceuticals in the environment- A human risk? Regul. Toxico/. Pharm., 28,212-221, (1998).
60. Halling-Serenson B., Nors-Nielsen S., Lanzky P.F., lngerslev F., Holten-Liitzheft H.C. and Jergensen S.E. Occurrence, fate
and effects of pharmaceutical substances in the environment- A review. Chemosphere, 36,357-393, (1998).
61. Gartiser R., Brinker L., Uhl A., Willmun R., Kummerer K. and Dachner, F. Investigation of hospital effluents- the example
of the Frieburg university hospital.Industrieabwasser, 9, 1618-1624, (1994).
62. Giuliani F., Koler T., Wiirgler F.E. and Widmer, R.M. Detection of genotocic activity in native hospital waste water by the
umuC test. Mutat. Res., 368, 49-57. (1996).
63. Hellmer L. and Bolcsfoldi, G. An evaluation of the E.coli K-12 uvrB/recA DNA repair host-mediated assay. I. In vitro
sensitivity of the bacteria to 61 compounds, Mutat. Res., 272, 145-160, (1992).
64. Steger-Hartmann T., Lange R. and Schweinfurth H. Environmental risk assessment for the widely used iodinated X-ray
contrast agent iopromide (Ultravist), Ecotoxicol. Environ. Safety, 42,274-281, (1999).
65. Cooke M.D. Antibiotic resistance in colifrom and faecal coliform bacteria from natural waters and effluents. New Zealand f.
Mar. Freshwater Res., 10, 391-397, (1983).
66. Grabow W.O.K., Van Zyl M. and Prozesky O.W. Behaviour in conventional sewage purification process of coliform bacteria
with transferable or non-transferable drug resistance. Water Res., 10, 717-723, (1976)
Downloaded by [Orta Dogu Teknik Universitesi] at 05:36 07 March 2016

67. Bell, R.B. Antibiotic resistance of faecal coliforms isolated from domestic sewage before and after treatment in an aerobic
lagoon. Can. f. Microbiol., 24, 886-888, (1978).

1394