Journal of Biotechnology 113 (2004) 295–304

How to avoid pharmaceuticals in the aquatic environment

Tove A. Larsen∗ , Judit Lienert, Adriano Joss, Hansruedi Siegrist
EAWAG (Swiss Federal Institute For Environmental Science And Technology), Ueberlandstrasse 133,
P.O. Box 611, CH-8600 Duebendorf, Switzerland

Received 2 September 2003; accepted 4 March 2004

Abstract

Pharmaceuticals and other micropollutants in wastewater pose a new challenge to wastewater professionals as well as to the
pharmaceutical industry. Although there is a great deal of uncertainty concerning the possible detrimental effects on the aquatic
ecosystems, the precautionary principle – or possibly new scientific evidence – may give rise to more stringent demands on
wastewater treatment in the future. In conventional wastewater treatment plants, a combination of biological treatment with
high sludge residence times and ozonation of the effluent seems to be the most promising technology. Ozonation, however, is
an energy-intensive technology. Moreover, in conventional end-of-pipe systems a large part of the pollutants will always be
lost to the environment due to leaking, primarily during rain. In the long term, source separation offers the more sustainable
solution to the entire wastewater problem, including organic micropollutants. Urine source separation is an elegant solution to the
problems of nutrients and pharmaceuticals alike and losses of untreated pollutants to the environment can be minimized. Although
few technologies for the separate treatment of urine have been developed to date, the 100–500 times higher concentrations of
micropollutants promise more efficient conditions for all removal technologies known from conventional wastewater treatment.
© 2004 Elsevier B.V. All rights reserved.

Keywords: Cleaner production; Micropollutants; Precautionary principle; Wastewater treatment; Sustainability; Urine source separation

1. Introduction and especially synthetic female steroid hormones are

The existence of micropollutants (e.g. pharmaceu-
ticals and hormonally active substances) in the aquatic
environment and their possible effects on living or-
ganisms are giving rise to growing concern (Heberer,
2002). Substances such as natural estrogenic hormones
∗ Corresponding author. Tel.: +41-1-823-50-39;
fax: +41-1-823-53-89.
E-mail address: tove.larsen@eawag.ch (T.A. Larsen).
biologically very potent compounds. They are only
partly eliminated during conventional wastewater treat-
ment and have been measured in the effluent of vari-
ous European wastewater treatment plants (Desbrow
et al., 1998; Pickering and Sumpter, 2003; Eggen
et al., 2003). For instance, 27 of 32 pharmaceutical
substances and four of five metabolites were detected
in municipal wastewater treatment plant effluents, and
in surface waters peak values of over 1 ␮g l−1 were
measured (e.g. lipid regulating agents, antiphlogistics,

0168-1656/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jbiotec.2004.03.033
296 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
beta-blockers and antiepileptic drugs; Ternes, 1998).
To date, over 80 compounds have been found in sewage
effluents, surface waters, and even in ground waters
(Heberer, 2002).
The potential impact on the environment is largely
unknown (Länge and Dietrich, 2002) and a causal re-
lationship between e.g. estrogenic compounds and ad-
verse effects on populations of water organisms has
not yet been established. However, in many rivers and
streams in Switzerland, a 50% decline in fish catch has
been observed over the last 15 years, and there is some
evidence that organic micropollutants could contribute
to this effect (Jobling et al., 1998; Routledge et al.,
1998; Burkhardt-Holm et al., 2000, 2002). Tradition-
ally, measures of action were only undertaken, once
a sound relationship between cause and effect were
established. A combination of rising ethical concern
for the environment (Harremoës, 2003) and an increas-
ing awareness of ignorance and uncertainty in science
(Kriebel et al., 2001; Harremoës, 2003; Rogers, 2003a)
slowly changes this approach. Where scientific cause-
effect relationships have not (yet) been established, but
discharge of a substance could have potentially harm-
ful effects on the environment, the precautionary prin-
ciple comes into action (Kriebel et al., 2001; deFur and
Kaszuba, 2002; Harremoës, 2003; Rogers, 2003a). In
its most extreme interpretation, where the burden of
proof has to be carried by the risk generator, the pre-
cautionary principle can be considered as a paradigm
change regarding the introduction of chemical sub-
stances to the environment.
The current concern of micropollutants in the re-
ceiving waters may also call for new approaches in
wastewater treatment. Wastewater treatment plants are
designed to deal with bulk substances that arrive regu-
larly and in large quantities (primarily organic matter
and the nutrients nitrogen and phosphorus). Pharma-
ceuticals are entirely different. They are single com-
pounds with an individual behaviour in the treatment
plant, and they represent only a minor part of the
wastewater organic load. So far, the majority of the
compounds and their metabolites cannot even be de-
tected, since the chemical analytical methods have not
yet been developed. And at least in some cases (e.g.
the antiphlogistic drug diclofenac and the antiepilep-
tic drug carbamazepine), significant removal in con-
ventional wastewater treatment plants has not yet been
demonstrated (see Heberer, 2002 for references).
Wastewater professionals are considering various
options to deal with these new substances. The tradi-
tional end-of-pipe processes can be optimized or new
treatment steps introduced. A third approach that is re-
ceiving increasing interest by wastewater professionals
is waste design and source separation (Henze, 1997;
Larsen and Gujer, 2001). The idea is to produce a waste
with an optimal composition for further treatment and
disposal (waste design), primarily based on the sepa-
ration of different household wastewaters (source sep-
aration) and when possible in close cooperation with
the producing industry (source control).
With the rise of initiatives such as “Responsible
Care”, “Green Chemistry” or “Cleaner Production”
the pharmaceutical industry itself is giving increasing
attention to environmental and sustainability issues
(Brandt, 2002). Source control and optimization of
the production process have been successfully applied
by industry (e.g. Kahn et al., 2001; Overcash, 2002).
However, to achieve the goal of a “minimal waste
society”, ongoing technological innovation to generate
extremely low levels of waste as well as low toxicity
and persistence of wastes is needed (Norberg-Bohm,
1999). Including not only waste at the production site
but also the waste products occurring after the pharma-
ceuticals have passed through the human metabolism
into this process is an additional challenge that calls
for cooperation between industry and wastewater
professionals. In this paper, we discuss the different
technical possibilities for dealing with this waste and
the possible motivation of the pharmaceutical industry
to cooperate with wastewater professionals on this task.
2. Technical possibilities of removing
pharmaceuticals from wastewater
Basically, four different approaches for removal of
micropollutants from wastewater are distinguished: op-
timizing existing treatment technology, upgrading ex-
isting treatment plants with new end-of-pipe technol-
ogy, source separation methods, and source control
measures. Improving wastewater treatment plants and
applying source control measures are the traditional
weapons to improve the quality of wastewater emis-
sions to receiving waters. Source separation is a re-
cent approach, which receives increasing acceptance in
the wastewater treatment community (see e.g. Henze,
1997; Larsen and Gujer, 2001).
 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
Fig. 1. Biological degradation resp. transformation of a micropollutant depends on the aerobic solids retention time, SRT (Siegrist et al., 2003).
2.1. Elimination processes in wastewater
treatment plants
In a typical European wastewater treatment plant,
biological degradation is the only real elimination pro-
cess of micropollutants. Where sewage sludge is incin-
erated, however, sorption will also contribute to elim-
ination. In special cases, physical processes produce a
concentrated solution of micropollutants that can also
be incinerated. Photochemical processes, which can
contribute to the elimination of micropollutants in the
aquatic ecosystems (Jürgens et al., 2002), only play a
minor role in wastewater treatment plants. Chemical
oxidation in the effluent is a new treatment technology,
still mainly in the experimental phase. Sorption is an
important process for the final distribution of micropol-
lutants, but actual elimination depends on the fate of the
treatment sludge. Stripping shifts the micropollutants
from the aquatic environment to the atmosphere.
2.1.1. Biological degradation or transformation in
wastewater treatment plants
In wastewater treatment plants, organic micropol-
lutants occur in concentrations of 10−5 to 10−9 g l−1
(Golet et al., 2002). Their degradation is only partial:
some compounds are not removed, some partly, and
some below the detection limit (Golet et al., 2002). Pa-
rameters influencing the degradation efficiency are not
yet fully understood; in the focus of current research
are sludge age (solids retention time, Fig. 1), sub-
strate availability (substrate inhibition), redox condi-
tions (aerobic, anoxic or anaerobic), sorption (as com-
petitive reaction), and reactor configuration (number of
cascaded compartments, biofilm growth surface, sand
filtration).
297
Due to the extremely small concentrations of or-
ganic micropollutants in wastewater, the mechanisms
of biological transformation and degradation are not
fully understood. In the case of NTA (a synthetic metal-
chelating agent), Egli (2001) showed that enzyme in-
duction depended on concentration and the availability
of a primary substrate.
2.1.2. Chemical oxidation in wastewater
treatment plants
A new end-of-pipe technology discussed in con-
nection with the problem of organic micropollutants
is the ozonation of wastewater effluents. Ternes et al.
(2003) showed that ozone doses of 10 and 15 mg l−1
were capable of reducing the concentrations of all tar-
get pharmaceuticals (five antibiotics, five betablockers,
four antiphlogistics, two lipid regulator metabolites,
and the antiepileptic carbamazepine), of the natural es-
trogen estrone, and of two polycyclic musk fragrances
below the detection limit in the effluent of a biologi-
cal wastewater treatment plant. However, information
on transformation products is still lacking and iodi-
nated X-ray contrast media were detected in apprecia-
ble concentrations. These results were supported also
by kinetic experiments (Huber et al., 2002).
Ozonation of wastewater effluent is not expen-
sive, but rather energy intensive. With approximately
0.1 kWh m−3 , ozonation would cause a 40–50% in-
crease in the energy demand of a normal treatment
plant.
2.1.3. Sorption in wastewater treatment plants
Sorption of organic micropollutants to the sludge in
treatment plants (Fig. 2) depends on two main mech-
anisms: absorption and adsorption. Absorption is the
298 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
Fig. 2. Absorption and adsorption of micropollutants to particulate
matter. As observed for norfloxacin (Golet et al., 2002).
hydrophobic interactions of the aliphatic and aromatic
groups of a compound with the lipophilic cell mem-
brane of the microorganisms and with the lipid frac-
tion of the sludge. Adsorption is the electrostatic inter-
actions of positively charged groups of the chemicals
with the negatively charged surfaces of the biomass
(Schwarzenbach et al., 2003, p. 275ff). With the con-
centrations of micropollutants encountered in waste-
water, an approximate linear correlation between par-
ticulate and solute concentration of a given compound
can be assumed:
Xi = Kd,i · Xss · Si (1)
Xi is the particulate concentration of the micropollutant
i; Xss the sludge concentration; Si the soluble concentra-
tion of the micropollutant i; Kd,i the sorption constant.
With mainly hydrophobic interactions, the sorp-
tion constant Kd,i (1 gss −1 ) can be estimated from the
octanol–water partition coefficient Kow (or even better
from the partitioning coefficient to particulate organic
matter Koc ), whereas by electrostatic interactions, Kd,i
is found empirically.
Since sorption only involves a phase shift of the pol-
lutants and no degradation or even transformation, the
fate of the sewage sludge is central to the environmental
evaluation of this process. In Switzerland, the spreading
of sewage sludge on agricultural land is banned with
immediate effect for market gardens and forage crops,
and from 2006 on for other crops (Seyman, 2003). In-
cineration of sludge is to become standard practice.
The main reason for the ban was the application of the
precautionary principle, as consequence of increasing
doubts about food safety, mad cow disease, accumula-
tion of heavy metals in the soil, and potentially danger-
ous effects of micropollutants (Seyman, 2003). In most
other countries, a significant part of the sewage sludge
is still disposed of on agricultural land, a far cheaper
solution with the additional advantage of being able to
recycle phosphorus from human waste.
2.1.4. Stripping in wastewater treatment plants
Stripping takes place in the aerobic part of a waste-
water treatment plant due to the intensive aeration of
the mixed liquor. Stripping depends on the aeration
intensity and the Henry coefficient of a given com-
pound. Stripping removes about 90% of perchlorethy-
lene (H = 0.77), but only 5% of the musk compound
tonalide (H ≈ 0.005). Since the majority of pharmaceu-
ticals have a molecular mass above 250 g mol−1 and
are hydrophobic with a Henry coefficient below 0.005
(Schwarzenbach et al., 2003, Appendix C), stripping is
not of much practical concern.
2.1.5. Physical removal processes in wastewater
treatment plants
In membrane bioreactors (MBR), the secondary
clarifier (characteristic for conventional activated
sludge wastewater treatment) is substituted by mem-
branes. Since the micro- and ultrafiltration membranes
used for this purpose have a pore size between 100 and
1000 times bigger than the physical size of compounds
qualifying as micropollutants (molecular weight be-
tween 100 and 1000 g mol−1 ), no direct physical re-
tention of the compounds by membrane bioreactors
can be expected, if not in connection to the previously
discussed sorption or biological degradation. One im-
portant feature of MBR is that the solids retention time
can be increased significantly above the levels that can
be obtained with secondary clarifiers. Its impact on the
degradation of micropollutant is currently being stud-
ied. Generally MBR do have a rather high energy de-
mand (1 kWh m−3 ) and high costs: membrane biore-
actors are economically competitive where sensitive
surface water require advanced treatment or where the
space availability is very limited (Walther, 2001).
The removal of organic micropollutants in the ef-
fluent from wastewater treatment plants by nanofiltra-
tion, reverse osmosis or activated carbon are mainly
discussed in view of reuse of wastewater (Schafer et al.,
2003; Wintgens et al., 2002), because of the high en-
ergy (ca. 1 kWh m−3 only for this membrane filtration
 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
step) and material demand of these technologies (Côté
et al., 1997; Nghiem et al., 2002; Wintgens et al., 2002).
Hartig et al. (2001) suggest a combination of ultrafil-
tration to remove the bulk organic matter, followed by
treatment with activated carbon.
2.2. The source separation approach
Traditionally, there have been two ways of reducing
impact from anthropogenic substances in the aquatic
ecosystems: removal of the substance in wastewater
treatment plants or giving up (voluntarily or follow-
ing a ban) production of the substance. Industry, how-
ever, invented a third approach: more intelligent pro-
duction processes to reduce the emission of pollutants.
In the last 15–20 years there was a dramatic increase
in pollution prevention programmes within advanced
industrialized countries, which is often referred to as a
paradigm shift (Overcash, 2002). Recently, these ideas
have been taken up for pollutants from households as
well. The reason for this was not the occurrence of
micropollutants, but the wish to find more sustainable
solutions to the complex task of protecting the environ-
ment from the hazards of water-borne pollution (see
Henze, 1997; Larsen and Gujer, 1997). Synergies be-
tween this general wish and the wish to tackle more effi-
ciently the problem of organic micropollutants rapidly
became obvious (Larsen et al., 2001). Here, we will
shortly review the discussion of waste design in gen-
eral and the issue of urine separation in particular, the
latter being of special interest for the question of phar-
maceuticals in wastewater.
2.2.1. Waste design
Henze (1997) introduced the notion of waste design,
defined as measures taken in households (and indus-
try) with the goal of producing a waste with an optimal
composition for further treatment and disposal. Flexi-
bility and adaptability are important aspects of this ap-
proach. Possible actions in households would be stor-
age (e.g. of urine, Larsen and Gujer, 1996), source sepa-
ration of mixed toilet wastewater followed by anaerobic
treatment (Otterpohl, 2002), or integration of treatment
technology in different wastewater producing devices
like the washing machine (Larsen and Gujer, 2001). In
the case of pharmaceuticals, a pre-treatment of highly
contaminated wastewater from hospitals (Giger et al.,
2003) would be an obvious example of waste design.
299
2.2.2. Urine source separation
Source separation of urine is one of the main
research topics related to waste design. Since anthro-
pogenic organic chemicals are in general metabolized
to a polar water-soluble form to allow excretion by
the kidney (Sheldon et al., 1986), this technology is
of special interest for the question of pharmaceuticals
in wastewater. Different varieties of urine-separation
toilets exist (see http://www.novaquatis.eawag.ch) and
a number of larger European wastewater authorities
run pilot projects to test the technology, especially the
functionality of the urine-separating toilets (Johansson,
2001; Bastian et al., 2002; Kühni et al., 2002; Peter-
Fröhlich et al., 2003). Major reasons for introducing
urine source separation are the possibility of better
water pollution control with respect to nutrients and
micropollutants and the possibility of closing the
nutrient cycles. Although urine constitutes less than
1% of the wastewater volume, it contains most of the
nutrients ending up in wastewater and many micropol-
lutants from the human metabolism (pharmaceuticals,
hormones). Besides the therapeutic application, waste
disposal of unused pharmaceuticals via the toilet in
private households presumably also contributes to the
contamination of wastewater with micropollutants,
but this seems to be of minor importance (Heberer,
2002). In most cases, efficient urine source separation
would render nutrient removal at treatment plants
obsolete; to obtain more stringent threshold values
for phosphorus, merely a small technical effort would
be necessary (Larsen and Gujer, 1996). Additional
to water pollution control, urine source separation
offers an elegant solution to nutrient recycling, a
sustainability issue especially for phosphorus (Driver
et al., 1999; Lienert et al., 2003; Maurer et al., 2003).
Perhaps the most important aspect of urine separation
is the possibility of flexible adaptation of the present
wastewater system without losing capital bound in
existing infrastructure (sewers and treatment plants).
Larsen and Gujer (1996) suggested transition scenarios
with storage of urine in households and subsequent
release when nitrogen is required at the treatment plant
(a typical example of waste design). Furthermore,
storage capacity could be chosen such that urine in
combined sewer overflow (CSO, release of untreated
wastewater to receiving waters during rain) could be
avoided. In a typical Swiss wastewater treatment plant,
Rauch et al. (2003) showed that with a very moderate
300 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
storage capacity (10 l per toilet), which could possibly
be integrated into the toilet itself, and a simple control
strategy, a 30% increase of nitrification capacity and
a 50% reduction of urine in CSOs can be achieved.
For the question of pharmaceuticals in wastewater,
the transition scenarios are primarily of interest due to
the possibility of reducing the amount of urine in CSOs.
Further reaching scenarios with separate treatment of
urine promise better chances of removing pharmaceu-
ticals and their metabolites quantitatively at an accept-
able price. The perhaps most important advantage of
tackling the problem of pharmaceuticals as close to the
‘source’ as possible, is the inherent problem of leaking
of pollutants from the wastewater system. Due to loss
of wastewater from leaky pipes, households not con-
nected to the sewer system, failures of the treatment
plants and CSOs, it is hardly possible to obtain more
than 80% treatment efficiency from prevailing waste-
water systems (Larsen and Gujer, 2001).
2.3. Removal mechanisms in source separated
urine
Research on removal mechanisms in source sep-
arated urine considerably lags behind research in
conventional wastewater treatment plants. The most
prominent reasons for this are the pioneering charac-
ter of the projects and the requirement for building up
experimental routines for dealing with urine. The fol-
lowing comparison with removal possibilities in con-
ventional wastewater treatment plants is therefore to a
large part based on theoretical considerations and pre-
liminary experience with different treatment technolo-
gies.
2.3.1. Biological degradation or transformation in
source separated urine
Urine is a concentrated mixture containing a num-
ber of water-soluble waste products from the human
metabolism. Due to rapid hydrolysis of urea once urine
has left the urinary tract, the concentration of ammo-
nia/ammonium and pH rise rapidly in source separated
urine. Research on biological treatment of urine has
mainly concentrated on partial nitrification, either to
stabilize urine for further treatment (decreasing the pH
below 7 and thereby preventing stripping of ammonia)
or as a first step in nitrogen removal by autotrophic
denitrification (Udert et al., 2003). From this experi-
mental work it is known that about 85% of the organic
fraction in urine is biologically degradable (Udert,
2002).
Specific results on biological degradation of micro-
pollutants in source separated urine are still too
scarce to be conclusive. First results indicate that
the half-life of natural estrogens in a biological
reactor treating urine is less than 15 min (Maurer,
personal communication). Compared to wastewater
treatment plants, we would expect a higher degree of
transformation/degradation of pharmaceuticals due to
substantially higher concentrations (100–500 times
larger than in wastewater) and the possibility of obtain-
ing a substantially higher solids retention time at very
low costs (because of the small organic loading from
urine). Substrate inhibition, which may possibly occur
in wastewater treatment plants due to peak organic
loadings, can be avoided more easily in urine-treating
systems, but this will demand some storage capacity.
2.3.2. Chemical oxidation in source-separated
urine (ozonation)
The efficiency of the ozonation process is expected
to depend mainly on the concentration ratio between
the target compound and the soluble background or-
ganic carbon (von Gunten et al., 2003). Since biolog-
ically treated urine contains about 10 times less solu-
ble organic matter per person than the effluent from a
typical wastewater treatment plant, we would expect
ozonation in biologically treated urine to be substan-
tially more energy-efficient. However, this still has to
be proven experimentally.
2.3.3. Sorption in source separated urine
To our knowledge, no experience with sorption
of micropollutants to organic or inorganic material
in urine has been published, although there is some
experience with sorption of nutrients to different
inorganic materials (Lind et al., 2000). In biological
systems, the most important aspect of sorption is the
fate of the sludge produced in the process. Due to
the very low organic load of urine (only 5% of the
wastewater organic load, Larsen and Gujer, 1996) and
the possibilities of obtaining very large solids retention
times, sludge production in biological systems treating
urine is extremely small. Accordingly, incineration
will be the logical route for this sludge, hereby elim-
inating any possible problem with micropollutants in
 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
agriculture. If for some reason phosphorus precipitates
are mixed with the sludge, a technology for recovery
of this valuable element must be developed. The
sorption process will be influenced by various factors,
including the concentration of micropollutants and the
amount of sludge (Eq. (1)).
2.3.4. Stripping in source separated urine
As for sorption, no results of stripping of micropol-
lutants from urine have been reported in the literature.
Under identical aeration conditions, however, stripping
would be increased in comparison to wastewater treat-
ment plants due to the high concentrations of micro-
pollutants. As in the case of sorption, we expect that
possible detrimental effects of stripping can be pre-
vented more easily in small biological urine-treating
reactors than in large wastewater treatment plants (e.g.
treatment of the exhaust air).
2.3.5. Physical processes in source separated
urine
In conventional wastewater treatment plants, mem-
brane processes are extremely energy-intensive due to
the large amount of water to be treated. For the removal
of micropollutants from urine, first promising results
have been obtained with nanofiltration. The energy de-
mand of reverse osmosis of wastewater effluent and the
energy demand of nanofiltration of source separated
urine is in the same order of size (1 kWh m−3 for re-
verse osmosis of wastewater effluent; 0.5–5 kWh m−3
for nanofiltration of urine, depending on the conditions,
Pronk, personal communication). With the very small
production rate of urine (less than 1% of the wastewa-
ter production rate), the energy demand for this latter
process is considerably smaller. The rapid progress in
membrane technology in other areas (Matsuura, 2001)
is very promising for the development of suitable mem-
brane technology for urine treatment.
3. Role of the industry
It is clearly in the interest of the involved industry to
support the efforts of wastewater professionals to solve
the problems of organic micropollutants in wastewater.
There is a long tradition for such cooperation; a good
example is the increased biodegradability of washing-
powders and even pharmaceutical products. However,
301
recognizing that there might still be a problem of mi-
cropollutants in domestic wastewater may call for a
more conceptual discussion.
The chemical industry – including the pharmaceu-
tical industry – is becoming increasingly aware of en-
vironmental problems and many companies have suc-
ceeded in strongly improving their ecological perfor-
mance during production processes (see e.g. Kahn
et al., 2001; Overcash, 2002). Reasons can be ethical
ones, legislative restrictions or socio-economic pres-
sure, i.e. because “Green Technology” products sell
better. Also environmental catastrophes such as Bhopal
(1984) or the pollution of the Rhine after the fire in a
storehouse of Sandoz in 1996 lead to a re-orientation
in the environmental policy of the chemical industry
(see Brandt, 2002 for references). One major initiative
was launched by the chemical industry itself: the “Re-
sponsible Care Initiative”. It was initiated in Canada
in 1984 and adapted to European conditions by the
European Chemical Industry Council, CEFIC a few
years later (Brandt, 2002). Its goal is to contribute to an
ecologically, economically and societal sustainable fu-
ture by implementing individual programs in chemical
companies. Other programs have been launched by na-
tional and international organizations (“Green Chem-
istry” by US Environmental Protection Agency (EPA),
1991; “Eco-Efficiency” by World Business Council for
Sustainable Development (WBCSD), 1992; “Cleaner
Production” by UNEP, 1998).
All these initiatives strongly focus on the optimiza-
tion of the production process within an industry and
of waste disposal connected to the production of phar-
maceuticals. Until lately, ecological considerations and
“waste disposal” of pharmaceuticals once they had left
the industry was hardly an issue; one major reason
presumably being that human health will always rank
higher than ecological safety. Hence, pharmaceuticals
are designed to have the desired effect within the hu-
man body, without too much consideration for effect
on ecosystems after having passed through the human
metabolism. However, in Sweden, an environmental
classification system for pharmaceuticals has recently
been developed in cooperation with industry. This la-
belling would allow physicians and patients to choose
the pharmaceutical with the least negative impacts on
the environment (Wennmalm, 2003). The European
Commission’s present policy for regulating chemicals
in the EU does include risk assessment targeted at the
302 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
chemicals of greatest concern or with an indication of
unacceptable risk (Rogers, 2003b). So far data regard-
ing adverse effects of pharmaceuticals in the environ-
ment are very scarce, the methodologies have not yet
been fully established, and possible cause-effect rela-
tionships were not made, so that at the moment phar-
maceuticals will be subject to closer scrutiny only as
an exception.
3.1. The precautionary principle
There are indications that the approach towards
pharmaceuticals in the environment may change in the
future, primarily due to the implementation of the pre-
cautionary principle. The precautionary principle is ar-
ticulated in different international treaties such as the
Rio Declaration and became part of the European law
in 1992—it is directly related to uncertainty due to
lack of scientific knowledge, and may be invoked to
decide on appropriate risk management actions (deFur
and Kaszuba, 2002; Harremoës, 2003; Rogers, 2003a).
Wastewater treatment was one of the first areas to expe-
rience the paradigm change caused by the precaution-
ary principle. When in the 1980s the necessity of quick
action to prevent further pollution and degradation of
the North Sea was recognized, the precautionary prin-
ciple was applied to all point source discharges, even if
there was no hard scientific evidence that specific sub-
stances were harmful to the environment (deFur and
Kaszuba, 2002).
The precautionary principle is open to different in-
terpretations ranging from “lack of full certainty is not
a justification for preventing an action that might be
harmful” to “take no action unless you are certain that
it will do no harm” (Rogers, 2003a). According to
Wiener and Rogers (2002) the many versions can be
divided into three categories: (1) lack of full scientific
certainty about a risk shall not justify postponing ac-
tion to prevent it, (2) uncertainty about a risk justifies
action to prevent it, and (3) the proponent of an activ-
ity posing uncertain risk bears the burden of proving
that the activity poses “no” or an “acceptable” risk be-
fore the activity can go forward. In the last case, the
proof that the risk level is acceptable has to be pro-
vided by the generator of the risk; i.e. the producer of
a pharmaceutical (reversal of the burden of proof). It is
never stated, which action should be undertaken, if any
of the versions of the precautionary principle are in-
voked (Rogers, 2003a). Currently, the European Com-
mission’s position seems to lie somewhere between
version 1 and 2 (Rogers, 2003a,b). However, it is think-
able that this could change and that a stronger policy
could be adopted, at least in special cases such as en-
docrine disruptive substances in the environment. The
European Council has for instance already stressed the
need to develop criteria for allergenic and endocrine-
disrupting substances (Rogers, 2003b).
3.2. Applying the precautionary principle to
pharmaceuticals
Even if the strongest version of the precautionary
principle were applied, i.e. the burden of proof be car-
ried by the producer of a substance, and even if it could
be shown with relative large certainty that the substance
does indeed adversely affect the environment, it may
still be difficult to prevent the substance from reach-
ing the receiving waters because a ban might not out-
weigh the societal benefits in the case of pharmaceuti-
cals. Rogers (2003a) gives three examples of difficult
decisions regarding uncertain risks as opposed to socio-
economic benefits (of the herbicide atrazine, low-dose
cadmium, and hydrogen fluoride). In our case, it is
clearly in the interest of all parties to develop a technical
solution that keeps pharmaceuticals (and other organic
micropollutants) out of the aquatic ecosystems with a
high degree of certainty. From the technical point of
view there is a choice between end-of-pipe technolo-
gies and more fundamental changes in wastewater man-
agement. End-of-pipe technologies may be developed
within a relatively short time, but they will never be
able to solve the problem entirely, and it is likely that
a large degree of uncertainty will remain (see above).
More fundamental changes based on source separation
measures will take significantly longer to implement,
but are – from the conceptual point of view – more
suitable for the complex task of dealing with micro-
pollutants.
4. Conclusion
Pharmaceutical and their metabolites are found in
the effluent of wastewater treatment plants and in the
aquatic environment. Although there is still little scien-
tific evidence as to the detrimental effects of these com-
 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
pounds on aquatic organisms, the precautionary princi-
ple may give rise to more stringent requirements in the
future. Previous experience shows that the precaution-
ary principle is well applied to wastewater treatment
technologies, and consequently technologies are un-
der development that will alleviate the situation in the
aquatic environment with respect to organic micropol-
lutants. End-of-pipe wastewater treatment concentrates
on improved biological treatment and ozonation of the
effluent. In the long term, source separation of urine
that contains many of the pharmaceuticals and their
transformation products from the human metabolism
may offer the more effective solution to the problem of
pharmaceuticals in the environment. Due to the higher
concentrations of micropollutants, biological as well as
physical processes are expected to be more efficient in
urine than in diluted wastewater. Chemical oxidation
(ozonation) may profit from the higher micropollutant
to soluble organic matter ratio in biologically treated
urine in comparison to the effluent from a conventional
wastewater treatment plant.
References
Bastian, A., Schirmer, G., Londong, J., 2002. Zukunftsfähiges Abw-
assermanagement, Workshop in der Lambertsmühle. KA Wasser-
wirtschaft Abwasser Abfall 49 (10), 1339–1342 (in German).
Brandt, Ch., 2002. Sustainable development and responsible
care—Die chemische Industrie auf dem Weg in eine grüne
Zukunft? Chemie in unserer Zeit 36 (4), 214–224 (in German).
Burkhardt-Holm, P., Wahli, T., Meier, W., 2000. Nonylphenol affects
the granulation pattern of epidermal mucous cells in rainbow
trout, Oncorhynchus mykiss. Ecotox. Environ. Safety 46, 34–40.
Burkhardt-Holm, P., Peter, A., Segner, H., 2002. Decline of fish catch
in Switzerland—project fishnet: a balance between analysis and
synthesis. Aquat. Sci. 64, 36–54 (also see www.fischnetz.ch).
Côté, P., Buisson, H., Pound, C., Arakaki, G., 1997. Immersed mem-
brane activated sludge for the reuse of municipal wastewater.
Desalination 113 (2–3), 189–196.
deFur, P.L., Kaszuba, M., 2002. Implementing the precautionary
principle. Sci. Total Environ. 288, 155–165.
Desbrow, C., Routledge, E.J., Brighty, G.C., Sumpter, J.P., Waldock,
M., 1998. Identification of estrogenic chemicals in STW efflu-
ent. 1. Chemical fractionation and in vitro biological screening.
Environ. Sci. Technol. 32 (11), 1549–1558.
Driver, J., Lijmbach, D., Steen, I., 1999. Why recover phosphorus
for recycling, and how? Environ. Technol. 20, 651–662.
Eggen, R.I.L., Bengtsson, B.-E., Bowmer, C.T., Gerritsen, A.A.M.,
Gibert, M., Hylland, K., Johnson, A.C., Leonards, P., Nakari,
T., Norrgren, L., Sumpter, J.P., Suter, M.J.-F., Svenson, A.,
Pickering, A.D., 2003. Search for the evidence of endocrine
disruption in the aquatic environment: lessons to be learned
303
from joint biological and chemical monitoring in the European
Project COMPREHEND. Pure Appl. Chem. 75 (11–12), 2445–
2450.
Egli, T., 2001. Biodegradation of metal-complexing aminopolycar-
boxylic acids. J. Biosci. Bioeng. 92 (2), 89–97.
EPA—US Environmental Protection Agency, 1991. Green Chem-
istry. http://www.epa.gov/greenchemistry. Last update: 24 June
2003, last visit to website: 31 July 2003.
Giger, W., Alder, A., Golet, E., Kohler, H., McArdell, C, Molnar,
E., Pham Thi, N., Siegrist, H., 2003. Antibiotikaspuren auf dem
Weg von Spital- und Gemeindeabwasser in die Fliessgewässer:
Umweltanalytische Untersuchungen über Einträge und Verhal-
ten. Tutzing Symposium, March 2003, D (in German).
Golet, E.M., Alder, A.C., Giger, W., 2002. Environmental expo-
sure and risk assessment of fluoroquinolone antibacterial agents
in wastewater and river water of the Glatt Valley Watershed,
Switzerland. Environ. Sci. Technol. 36 (17), 3645–3651.
Harremoës, P., 2003. Ethical aspects of scientific incertitude in en-
vironmental analysis and decision making. J. Clean. Prod. 11,
705–712.
Hartig, C., Ernst, M., Jekel, M., 2001. Membrane filtration of two
sulphonamides in tertiary effluents and subsequent adsorption on
activated carbon. Water Res. 35 (16), 3998–4003.
Heberer, T., 2002. Occurrence, fate, and removal of pharmaceutical
residues in the aquatic environment: a review of recent research
data. Toxicol. Lett. 131, 5–17.
Henze, M., 1997. Waste design for households with respect to water,
organics and nutrients. Water Sci. Technol. 35 (9), 113–120.
Huber, M., Canonica, S., Park, G., von Gunten, U., 2002. Oxidation of
pharmaceuticals during ozonation and advanced oxidation pro-
cesses. Environ. Sci. Technol. 37, 1016–1024.
Jobling, S., Nolan, M., Tyler, C.R., Brighty, G., Sumpter, J.P., 1998.
Widespread sexual disruption in wild fish. Environ. Sci. Technol.
32 (17), 2498–2506.
Johansson, M., 2001. Urine separation—closing the nutrient cycle.
Final report. Stockholm Water Company, Stockholm, S.
Jürgens, M.D., Holthaus, K.I.E., Johnson, A.C., Smith, J.J.L., Het-
heridge, M., Williams, R.J., 2002. The potential for estradiol and
ethinylestradiol degradation in English rivers. Environ. Toxicol.
Chem. 21, 480–488.
Kahn, F.I., Natrajan, B.R., Revathi, P., 2001. GreenPro: a new
methodology for cleaner and greener process design. J. Loss Pre-
vent. Proc. 14, 307–328.
Kriebel, D., Tickner, J., Epstein, P., Lemons, J., Levins, R., Loech-
ler, E.L., Quinn, M., Rudel, R., Schettler, T., Stoto, M., 2001.
The precautionary principle in environmental science. Environ.
Health Perspect. 109 (9), 871–876.
Kühni, M., Koch, G., Ott, E., 2002. Zukunftsweisende Sanitar-
und Abwassertechnik—erstes Pilotprojekt der Schweiz fur
Urinseparierung, -speicherung und -steuerung im technischen
Massstab. gwa (Gas Wasser Abwasser) 11, 827–835 (in German).
Länge, R., Dietrich, D., 2002. Environmental risk assessment of phar-
maceutical drug substances—conceptual considerations. Toxi-
col. Lett. 131, 97–104.
Larsen, T.A., Gujer, W., 1996. Separate management of anthro-
pogenic nutrient solutions (human urine). Water Sci. Technol.
34 (3–4), 87–94.
304 T.A. Larsen et al. / Journal of Biotechnology 113 (2004) 295–304
Larsen, T.A., Gujer, W., 1997. The concept of sustainable urban water
management. Water Sci. Technol. 35 (9), 3–10.
Larsen, T.A., Gujer, W., 2001. Waste design and source control lead
to flexibility in wastewater management. Water Sci. Technol. 43
(5), 309–318.
Larsen, T.A., Peters, I., Alder, A., Eggen, R., Maurer, M., Muncke,
J., 2001. Re-engineering the toilet for sustainable wastewater
management. Environ. Sci. Technol. 35, 192A–197A.
Lienert, J., Haller, M., Berner, A., Stauffacher, M., Larsen, T.A.,
2003. How farmers in Switzerland perceive fertilizers from recy-
cled anthropogenic nutrients (urine). Water Sci. Technol. 48 (1),
47–56.
Lind, B., Zsófia, B., Byden, S., 2000. Nutrient recovery from hu-
man urine by struvite crystallization with ammonia adsorption
on zeolite and wollastonite. Bioresour. Technol. 73, 169–174.
Matsuura, T., 2001. Progress in membrane science and technol-
ogy for seawater desalination—a review. Desalination 134 (1–3),
47–54.
Maurer, M., personal communication. EAWAG, P.O. 611, CH-8600
Dübendorf, Switzerland, max.maurer@eawag.ch.
Maurer, M., Schwegler, P., Larsen, T.A., 2003. Nutrients in urine:
energetical aspects of removal and recovery. Water Sci. Technol.
48 (1), 37–46.
Nghiem, L.D., Schafer, A.I., Waite, T.D., 2002. Adsorptive interac-
tions between membranes and trace contaminants. Desalination
147 (1–3), 269–274.
Norberg-Bohm, V., 1999. Stimulating “green” technological inno-
vation: an analysis of alternative policy mechanisms. Policy Sci.
32, 13–38.
Otterpohl, R., 2002. Options for alternative types of sewerage and
treatment systems directed to improvement of the overall perfor-
mance. Water. Sci. Technol 45 (3), 149–158.
Overcash, M., 2002. The evolution of US pollution prevention,
1976–2001: a unique chemical engineering contribution to the
environment—a review. J. Chem. Technol. Biot. 77, 1197–1205.
Peter-Fröhlich, A., Kraume, I., Lesouëf, A., Oldenburg, M.,
2003. Separate discharge and treatment of urine, faeces and
greywater—pilot project. Hydroplus 135, 82–86.
Pickering, A.D., Sumpter, J.P., 2003. COMPREHENDing endocrine
disrupters in aquatic environments. Environ. Sci. Technol. 37
(17), 331A–336A.
Pronk, W., personal communication. EAWAG, P.O. 611, CH-8600
Dübendorf, Switzerland. wouter.pronk@eawag.ch.
Rauch, W., Brockmann, D., Peters, I., Larsen, T.A., Gujer, W., 2003.
Combining urine separation with waste design: an analysis using
a stochastic model for urine production. Water Res. 37, 681–689.
Rogers, M.D., 2003a. Risk analysis under uncertainty, the precau-
tionary principle, and the new EU chemicals strategy. Regul.
Toxicol. Pharm. 37, 370–381.
Rogers, M.D., 2003b. The European Commission’s White Paper
“strategy for a future chemicals policy”: a review. Risk Anal.
23 (2), 381–388.
Routledge, E.J., Sheahan, D., Desbrox, C., Brighty, G.C., Waldock,
M., Sumpter, J.P., 1998. Identification of estrogenic chemicals
in sewage treatment works effluent. 2. In vivo responses in trout
and roach. Environ. Sci. Technol. 32, 1559–1565.
Schafer, A.I., Nghiem, L.D., Waite, T.D., 2003. Removal of the nat-
ural hormone estrone from aqueous solutions using nanofiltra-
tion and reverse osmosis. Environ. Sci. Technol. 37 (1), 182–
188.
Schwarzenbach, R.P., Gschwend, P.M., Imboden, D.M., 2003. En-
vironmental Organic Chemistry, second ed. Wiley-Interscience.
ISBN 0-471-35750-2.
Seyman, I., 2003. Sewage sludge—no more land treatment in
Switzerland. Hydroplus 135, 21.
Sheldon, L., Umana, M., Bursey, J., Gutknecht, W., Handy, R., Hyld-
burg, P., Michael, L., Moseley, A., Raymer, J., Smith, D., Spara-
cino, C., Warner, M., 1986. Biological Monitoring Techniques for
Human Exposure to Industrial Chemicals. Noyes Publications,
USA.
Siegrist, H., Joss, A., Alder, A., Gobel, A., Keller, E.,
McArdell, C., Ternes, T.A., 2003. Mikroverunreinigungen—
Abwasserentsorgung vor neuen Anforderungen. EAWAG News
57, 7–10 (in German).
Ternes, T.A., 1998. Occurrence of drugs in German sewage treatment
plants and rivers. Water Res. 32 (11), 3245–3260.
Ternes, T.A., Stüber, J., Herrmann, N., McDowell, D., Ried, A.,
Kampmann, M., Teiser, B., 2003. Ozonation: a tool for removal
of pharmaceuticals, contrast media and musk fragrances from
wastewater? Water Res. 37, 1976–1982.
Udert, K.M., 2002. The fate of nitrogen and phosphorus in source-
separated urine. Dissertation ETH, No. 14847. ETH-Zürich,
CH.
Udert, K.M., Fux, C., Munster, M., Larsen, T.A., Siegrist, H., Gujer,
W., 2003. Nitrification and autotrophic denitrification of source-
separated urine. Water Sci. Technol. 48 (1), 119–130.
UNEP—United Nations Environment Programme, 1998. Interna-
tional declaration on cleaner production, http://www.uneptie.org/
pc/cp/declaration. unepie@unep.fr. Last visit to website: 31 July
2003.
von Gunten, U., Huber, M., Ternes, T.A., Ried, A., 2003.
Oxidation of pharmaceuticals during ozonation of drinking
water and wastewater (abstract), Proceedings of the IWA
Leading Edge Conference on Drinking Water and Waste-
water, 26–28 May 2003, Noordwijk/Amsterdam, NL, pp. 82–83.
Walther, H., 2001. Berücksichtigung der Membrantechnik im re-
gionalen Abwasserentsorgungskozept. Kommunale Abwasser-
behandlung 48 (8), 1092–1097 (in German).
Wennmalm, A., 2003. A proposed environmental classification sys-
tem for medicinal products. Envirpharma Conference, Lyon, F.
Wiener, J.B., Rogers, M.D., 2002. Comparing precaution in the US
and Europe. J. Risk Res. 5, 317–349.
Wintgens, T., Gallenkemper, M., Melin, T., 2002. Endocrine dis-
rupter removal from wastewater using membrane bioreactor and
nanofiltration technology. Desalination 146 (1–3), 387–391.
WBCSD—World Business Council for Sustainable Development,
1992. Eco-Efficiency. http://www.wbcsd.ch.engel@wbcsd.org.
Last visit to website: 31 July 2003.