PHARMACEUTICAL
Risk assessment of
pharmaceuticals in the
environment
T
he medicines that we take have gone through at least 10 years
of testing so that their safety for humans can be guaranteed.
However, we are not the only ones that may be exposed to
these drugs. Human drugs may also affect animals, plants and
bacteria as they can enter the environment via human excreta
or by disposal of expired medicines via the sewer. This was recognised by
the European Union and from December 2006, not only the efficacy of
pharmaceuticals and their side effects need to be evaluated, but also the
environmental impact of the active ingredients. In the present article, an
outline of the step-wise approach of the EU-EMEA guideline is given.
Background
In the last 15 to 20 years there have been several reports of pharmaceuticals
in the environment: human and veterinary drugs were detected in river
water and even in drinking water [1, 2]. Although reported levels are very
low, effects were observed, with a noteworthy example being hormone
disruption in fish due to the presence of estrogens in the environment. Drug
substances may reach the environment via use or disposal. Patients will usually
excrete a drug or its metabolites, which will then pass to a sewage treatment
plant. There, it may be (partially) degraded, it may adsorb to the sludge or it
may remain in the effluent. After processing in the sewage treatment plant,
the sludge is usually incinerated, but it may also be spread on the land, and
then leach into the soil and eventually into the groundwater. In the case
of disposal, depending on the route (drain, household or industrial waste),
pharmaceuticals may enter the groundwater and surface water via a sewage
treatment plant or by leaching from a landfill site.
Although pharmaceuticals and their metabolites in excreta will be
diluted before entering the sewage treatment plant, and even though
leaching from a landfill site may be limited, it should be kept in mind that
drugs usually are relatively stable – after all, they were developed to remain
intact in the human body, at least for a certain period. And then, as they were
developed with the objective to cause a physiological effect in humans,
other organisms may be sensitive to the mode of action as well.
In 1990, the European Medicines Agency started a discussion on the
assessment of the risk of pharmaceuticals for the environment, resulting in
a final guideline that was issued in June 2006 and has come into operation
in December 2006 [3, 4]. The new legislation applies to all new marketing
authorisations with the exclusion of vitamins, electrolytes, amino acids,
peptides, carbohydrates and lipids; also vaccines and herbal medicinal
products are exempted. The pharmaceutical industry anticipated the
finalisation of the guideline and several companies have already started
environmental and ecotoxicity studies with their active ingredients.
 WORLD PHARMA NETWORK
The EMEA guideline
The EMEA Guideline on the Environmental Risk Assessment of Medicinal
Products for Human Use has a step-wise structure, which is depicted in
Figure 1. Below, the separate steps are discussed.
Phase I: Predicted Environmental Concentration
and bioaccumulation potential
The EMEA guideline focuses on the route of excretion by patients and
does not consider disposal of (expired) drugs or manufacturer’s waste.
The first step is the estimation of the exposure by calculation of a
Predicted Environmental Concentration (PEC), based on the maximum
daily dose and the market penetration (details in Box 1). Whenever the
PEC exceeds the action limit of 0.01 μg/L, further testing is required. This
limit is easily reached: for any active ingredient with a daily dose of 2mg
per day or more the action limit is exceeded.
In addition to the estimated concentration in the environment, the
potential of the substance to accumulate in the environment should be
PEC surface water = (dose a.i. x F / (Wp x dilution)
PEC = Predicted Environmental Concentration (mg/L)
Dose a.i. = the maximum recommended dose (mg/person/day)
F = market penetration factor, standard 0.01
Wp = amount of waste water per person per day, standard
Dilution = dilution factor, standard 10
Box 1 Calculation of the Predicted EnviroNmental Concentration
(PEC)
evaluated. If the substance is lipophilic (octanol:water partition coefficient
= log Kow >4.5), this is an indication that the substance may accumulate
in the fat tissue of fish and it will have to be tested for persistence,
bioaccumulation potential and toxicity (PBT). PBT testing is described
in a separate guidance document that is also used for the evaluation of
industrial chemicals and pesticides [5].
For some substances, such as those that are known to affect the
reproduction of vertebrate or lower animals at levels below 0.01 μg/L,
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Phase I
Log Kow >4.5
Determine log Kow
Calculate PEC
PEC <0.01 pg/L
+ no effects expected
at <0.01 pg/L
Phase I
or effects expected
at <0.01 pg/L
Phase II, Tier A
Adsorption-Desorption (e.g.OECD 106)
Biodegradation (OECD 301)
Water-sediment study (OECD 308)
AIgal growth inhibition test (OECD 201)
Daphnia reproduction test (OECD 211)
Fish Early Life Stage test (OECD 210)
Activated sludge Respiration Inhibition test (OECD 209)
fIGURE 1 THE STEP-WISE STRUCTURE OF THE EMEA GUIDELINE ON THE ENVIRONMENTAL RISK ASSESSMENT OF MEDICINAL PRODUCTS FOR HUMAN USE
the action limit is not applicable. They proceed to Phase II testing even
when the PEC is below the action limit and the specific mode of action
needs to be considered in the risk assessment.
Phase II, Tier A: Base set of tests
If the PEC exceeds 0.01 μg/L, an initial prediction of the risk needs to
be made by executing a primary set of aquatic toxicity and fate tests.
These tests were originally designed for the registration of pesticides,
biocides and industrial chemicals, and guidelines are already available.
The fate of the pharmaceuticals in sewage treatment plants is assessed
by biodegradation and adsorption studies and by a test in which the
dissipation of the substance from natural water and sediment is assessed.
The impact on aquatic organisms needs to be determined by a number
of aquatic toxicity tests with algae, daphnids and fish, including an early
life stage toxicity test with fish.
Phase II, Tier B: Further evaluation of the risk
Based on the results of the Tier A testing, the PEC is compared with
the Predicted No Effect Concentrations (PNEC) that were determined
in the toxicity tests. If comparison indicates that there is a risk for the
environment, further evaluation of the fate and effects of the substance
is necessary. From the study with natural water and sediment it will be
determined whether the pharmaceutical migrates from the water to the
sediment. If so, a toxicity test with sediment organisms such as mosquitoes
July 2007 
PHARMACEUTICAL
PBT testing
No further testing necessary
Risk no
yes
Phase II, Tier B
Studies depending on
results of Tier A
has to be added to the dossier to show whether the development of the
larvae is affected by the drug.
If based on the adsorption study the substance is expected to adsorb
strongly to the sludge in a sewage treatment plant, this means that it will be
removed from the effluent. In that case, or when the substance is shown
to be readily biodegradable, the predicted environmental concentration
can be refined based on this information. Further, the sludge of a sewage
treatment plant to which a pharmaceutical has adsorbed may either be
incinerated, or it may be used as fertiliser on the land. In the latter case,
the substance also reaches the soil. Therefore, Tier B testing can also
consist of terrestrial compartment testing, such as transformation in soil,
a plant growth test or an earthworm toxicity test.
If the PEC of a pharmaceutical exceeds the trigger value for testing,
and especially when Tier A results necessitate Tier B testing, sufficient
information becomes available to evaluate the impact of the compound
on the environment. If it is potentially harmful, precautionary measures
may consist of an indication of this risk on the packaging and labelling
indicating how the product should be used, stored and disposed of.
Registration of a product will not be refused based on the environmental
risk only.
Measures to limit environmental risk
The authorities require that the risks are thoroughly evaluated, but in
the end human health prevails over environmental safety and therefore
registration will not be refused. Appropriate labelling of the medicine
WORLD PHARMA NETWORK 
PHARMACEUTICAL
is the only measure that can be taken in case there is an indication of
potential harm. These actions will only partially reduce the exposure of the
environment to the drug: entrance of the drug into the environment via
human excreta, which is the basis for PEC calculation and risk estimation,
will remain unaltered. However, one can imagine that in the future the
outcome of the risk assessment may have more consequences. Easily
biodegradable medicines may be preferred over those that are persistent
and potentially harmful to the environment. This may be the consumer’s
choice, or the authorities may impose stimulating or discouraging
measures.
In addition to imposing this legislation on industry, other preventive
actions to reduce the risk of pharmaceuticals in the environment can be
thought of. Purification of waste water in sewage treatment plants could
be intensified. However, this would imply a significant increase of the
expenses on waste water treatment. More effectively, specific attention
could be given to specific sources of pharmaceuticals in the waste
water, such as hospitals and homes for the elderly. Not only will total
drug concentrations be relatively high in their waste water, in hospitals
also toxic or very persistent substances are taken and excreted, such as
cytostatics and X-ray contrast reagents. Separate collection of waste water
from hospitals and homes for the elderly, or temporary urine collection
from patients at home, would allow more intensive treatment of a small
amount of “high risk” waste.
Environmental risk assessment outside the EU
There is not only concern in Europe about pharmaceutical active
ingredients in the environment: also the US and Canada have legislation
on this subject and in Japan a guideline will be issued in 2008 [6, 7]. In
Canada, a selection of existing pharmaceuticals also needs to be tested
for their environmental risk, while in Europe and the US only new actives
and substances for which there is an increase in the environmental
exposure need to be evaluated. Each country also has its own action limit
and its own approach with regard to which tests should be performed
first. For example, the US trigger value for testing is 1 μg/L, whereas
in Europe it is 0.01 μg/L. And while the European authorities ask for a
“worst-case” calculation followed by a base set of tests, the US approach
starts off with a microbial inhibition test and determination of depletion
mechanisms such as photolysis or metabolism. Depending on the results
and the expected environmental concentration, this leads to only one
acute toxicity test or several chronic studies, or to the conclusion that no
further tests are required. In the future, at least partial harmonisation of
the various regulations may be desirable.
For veterinary medicines the guidelines already underwent a
harmonisation process, and this may be taken as a model for harmonisation
of guidelines for human medicines.
Conclusion
With the adoption of a European guideline for the environmental risk
assessment of human medicines, the environment is shown as a potential
“victim” of our use of pharmaceuticals. Even though the intervention
by the authorities remains restricted, the new regulations will lead to
a better understanding of the risk and they will enhance awareness of
manufacturers and users of the impact of drugs on the environment.
Improper use and disposal of human medicine use will be reduced. The
step-wise approach of the guideline provides the industry with clear
guidance on whether and which tests need to be performed. However,
 WORLD PHARMA NETWORK
comparison with other countries’ regulations shows that more than one
approach can be chosen.
References:
[1] Richardson M.L. and Bowron J.M. (1985). The fate of pharmaceuticals in the
aquatic environment. Journal of Pharmacy and Pharmacology (37): 1-12.
[2] Halling-Sørensen B., Nors Nielsen S., Lanzky P.F., Ingerslev F., Holten Lützhoft
H.C. and Jørgensen (1998). Occurrence, fate and effects of pharmaceutical
substances in the environment – A review. Chemosphere 36 (2): 257-393.
[3] Guideline on the environmental risk assessment of medicinal products for
human use (European Medicines Agency, June 1, 2006) www.emea.eu.int
[4] Directive 2001/83/EC of the European Parliament and of the council of 6
November 2001 on the community code relating to medicinal products for
human used, as amended (Article 8(3)).
[5] European Chemicals Bureau (2003) Technical Guidance Document in support
of Commission Directive 93/67/EEC on Risk Assessment for new notified
substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for
existing substance and Directive 98/8/EC of the European Parliament and of
the Council concerning the placing of biocidal products on the market.
[6] Environmental Assessment of Human Drug and Biologics Applications
(July 1998) www.fda.gov./cder/guidance/1730fnl.pdf
[7] www.healthcanada.gc.ca/eii; www.hc-sc.gc.ca/ewhsemt/
contaminants/person/eval/index e.html
Contact:
Erik Hamminga
Sales & Marketing Manager Pharmaceuticals
E-mail: erik.hamminga@notox.nl
Biography
BRIGITTE VAN NOORLOOS
Brigitte van Noorloos graduated with an
MSc in Chemistry from the University of
Nijmegen, The Netherlands. Since 2000
she has supervised environmental fate
and metabolism studies at NOTOX in ‘s-
Hertogenbosch, The Netherlands. Initially
the work mainly concerned agrochemicals
and industrial chemicals, but now also
pharmaceuticals have become a major area
of environmental testing. Brigitte was also
involved in dossier preparation of high production volume chemicals
and the risk evaluation of agrochemicals for the Dutch Board for the
Authorisation of Pesticides (CTB).
July 2007