ET& C Perspectives
“Do pharmaceuticals present a risk to the environment and what needs to be done to
answer the question?”
John P Sumpter (Convener)
“Although human pharmaceuticals are currently considered as emerging contaminants,
many will have been present in the aquatic environment for decades. Two facts make the
Pharmaceuticals in the Environment (PIE) issue of concern. One is that there are a few
thousand different pharmaceuticals, and the other is that all of them are biologically active, at
east in humans. These two facts lead us, in turn, to the two key unresolved issues in the PIE
field: ‘how should we conduct a prioritisation exercise to identify those pharmaceuticals likely
to be of the greatest environmental risk?’ and ‘are typical environmental concentrations of
those pharmaceuticals anywhere close to the concentrations that produce adverse effects in
ecotoxicity tests?’ This perspective addresses those two key issues.”
Response
A Ross Brown (Industry perspective)
Pharmaceuticals are the most rigorously tested products in the world in terms of assessing
their impact on human health. Development of a new medicine can take over 10 years and
only 1 in 10,000 new chemical entities progresses from concept stage to market, passing all
required efficacy and preclinical and clinical safety tests, including those supporting the
Environmental Risk Assessment (ERA) [1]. Since 2006, approximately 200-300 new
pharmaceutical products have been tested under current regulatory ERA guidelines in the
EU [2] and none of these have been shown to present a significant risk to the environment
through routine patient use. Similarly, according to retrospective risk analyses compiled by
the Swedish Association of Pharmaceutical Industries (LIF) [3] only 2 out of 200 products are
categorized as ‘high risk’ to the environment (Figure 1), again suggesting that the risks are
low or insignificant for the vast majority of pharmaceuticals. That said, there are two
exceptions where potential and known risks to the environment have been identified. The
first is the synthetic estrogen 17-ethinylestradiol (EE2), which has been the subject of
numerous research projects, including studies on potential adverse effects on wild fish
populations [4, 5]. This has led to the inclusion of EE2 (together with 17β-estradiol (E2)) in
the EU ‘Watch List’ under the Water Framework Directive [6]. The second is the antiinflammatory drug diclofenac, which has been causally linked to the near extinction of three
species of vulture in Asia [7], due to its veterinary use in cattle and secondary poisoning of
vultures. The impact of diclofenac on populations of fish or other aquatic taxa is unknown,
but the scale of the impact on vultures has raised sufficient stakeholder concerns such that
this compound has also been placed on the EU Watch List. In addition there are also 30004000 legacy pharmaceutical products on the market which pre-date the 2006 EU ERA
guideline, and for many of these there are little or no data available to assess the risks [8].
Thus, whilst most assessed drugs are predicted to present no significant risks to the
environment, the above exceptions point towards three clear needs for better understanding
the risks of pharmaceuticals in the environment:



We need to ensure that ERA tools are fit for purpose and are able to identify any
potential risks.
We need tools and approaches to help prioritize and identify whether any of the
existing legacy products present a risk.
We need to know what further assessment and management options exist if a
potential risk is identified.
These three needs are explored in more detail in the following sections.
Ensuring ERA tools are fit for purpose: ERA generally consists of an exposure
assessment, generating the Predicted Environmental Concentration (PEC), and an effects
assessment, generating the Predicted No Effect Concentration (PNEC). Both the PEC and
PNEC are needed to characterize risk. The principal environmental exposure pathway for
pharmaceuticals is excretion from patients, collection in sewage, sewage treatment and
aqueous discharge to surface waters, since the majority of pharmaceuticals are hydrophilic
by design [9]. However there are exceptions to this rule. There are also differences in
practices and infrastructure in different countries, which may be important to the ERA. For
example, different countries have different processes and efficiencies of wastewater
treatment. Similarly, in the EU, irrigation of land using wastewater is not considered a
significant exposure pathway, but this is commonplace in drought stressed parts of the world
[10]. The need for careful evaluation of exposure pathways, including the consideration of
local climates, demographics, cultural practices, and infrastructure is exemplified by the
diclofenac/vulture story mentioned earlier.
Within exposure assessment, there is also considerable scope to refine the PEC for each
environmental compartment. This is initially based on total concentrations of drug residues
in the environment, estimated from product use, and ‘worst-case’ assumptions of 100%
excretion from patients and zero removal or degradation in sewage treatment plants [2]. In
reality, actual environmental concentrations may be much lower than these predictions, but
measured data are often lacking and few studies have sought to evaluate removal
efficiencies in sewage treatment works or quantify variability [11]. Generic models capable
of linking influent and effluent concentrations in sewage treatment works and predicting or
extrapolating environmental concentrations of pharmaceuticals potentially offer powerful
tools for refining exposure assessments, providing they are appropriately calibrated with
reliable monitoring data. Such data will also support additional refinement of risk
assessments concerning metabolites or degradation products [12].
Effects assessment typically focuses on chronic developmental or reproductive endpoints in
model species representing a range of taxonomic groups, trophic levels and environments
[2]. Other more targeted endpoints reflecting the specific ‘mode of action’ (MOA) of each
pharmaceutical potentially offer increased sensitivity, provided therapeutic concentrations
and effects reliably ‘read-across’ from mammalian (human) models to wildlife or surrogate
test species [13]. Assumptions still have to be made concerning the conservation of function
of proteins targeted by drugs, along with their secondary targets and associated side-effects,
which should not be overlooked in wildlife. Nevertheless, the increasing availability of data,
including pre-clinical test data, and rapid scientific development in this area add to the future
potential of MOA/read-across based ERA of pharmaceuticals [14].
Prioritising legacy compounds: Given the number of legacy products on the market, the
fact that the ERA process is resource-intensive and requires animal testing, and since the
vast majority are likely to be of low or insignificant risk, it is clear that effective risk-based
prioritization is needed. One simple approach would be to consider usage volume alongside
therapeutic potency. An API with high potency and high total usage would obviously be a
higher priority than an API with low potency and low usage. While the sensitivities of
environmental species do not always match those of the targeted therapeutic endpoints in
humans, the minimum therapeutic doses for APIs can provide some insight into the potential
for physiological responsiveness of environmental species, at least in vertebrates. This
approach has been applied in principle to generate a shortlist of pharmaceuticals designed
to arrest cell division and growth or modulate hormonal and reproductive function, i.e., MOAs
which might relate to adverse effects in non-target organisms [15, 16]. This ‘MOA/readacross’ approach may offer further potential for prioritizing the ERA of other legacy
pharmaceuticals, however, this potential has yet to be realized. This is because very few
empirical studies have related internal doses of pharmaceuticals to specific MOA endpoints
and adverse effects measured according to traditional apical endpoints [17]. Nevertheless,
there are a number of toxicological properties in mammals (reproductive and developmental
toxicity, mutagenicity, carcinogenicity) and therapeutic targets (hormonal, anticancer, antimicrobial) that are known for pharmaceuticals and could be used to support a screening
assessment in a prioritization context.
Once a list of prioritized compounds is agreed to, a programme of testing can be initiated to
generate the data needed to conduct the ERA. The commitment to do this will require
significant resource, so it will be important that the criteria used to prioritise are agreed by all
stakeholders. To this end, the European Federation of Pharmaceutical Trade Associations
(EFPIA) and the European Commission have just launched a call for proposals under the
Innovative Medicines Initiative (IMI) to develop tools and approaches for ERA screening [18].
If successful, this programme will not only develop the tools needed but will also engage
stakeholders across industry, academia and regulators to agree how this should be done.
What to do next if a risk is identified: This is less about refining the PEC:PNEC
(discussed above under the development of fit-for-purpose tools) and more about what to do
if a refined PEC:PNEC is >1, as exemplified by EE2. In such cases there is a need to go
beyond the PEC:PNEC approach and consider ecological significance in the receiving
environment. Including EE2 on the ‘Watch List’ may result in considerably more data on
environmental concentrations but will do little to inform the risk assessment, unless the
significance or ‘consequence’ of the observed environmental concentrations can be
established.
A key requirement in chemical and pharmaceutical ERA is to extrapolate from individual
organism to ‘population-level’ effects, for example, using population modelling, since the
protection of wildlife populations is the widely stated minimum protection goal in
environmental legislation [19]. This is rarely done in ERAs across all chemical sectors,
although suitable tools are becoming increasingly available [20]. Extrapolating risks based
on laboratory tests to field populations could also benefit from a ‘cumulative’ risk assessment
approach, in which the exposure and effects of pharmaceuticals and other components of
environmental mixtures are considered. To some extent these cumulative effects can be
accounted for in population models. However, the inherent variation of the environment and
the complexity of sewage effluents containing pharmaceuticals make defining a ‘typical’
environmental chemical mixture virtually impossible in prospective ERA. Instead, effort
could focus on the retrospective assessment of ‘hotspots’ using sensitive biomonitoring and
chemical monitoring tools and improving wastewater treatment in those areas where
ecological health is potentially degraded. This may ultimately be the most pragmatic and
economically attractive approach for society and deliver the greatest ecological benefits,
without necessarily having to relate adverse effects in the environment to any one specific
cause, let alone one specific chemical.
In summary, the current weight of evidence suggests that the risks to the environment are
low or insignificant for the vast majority of pharmaceuticals. Where potential risks have been
identified, several tools exist to help refine the ERA, particularly with respect to the exposure
assessment, and there are several possibilities for the development of screening tools to
help prioritise testing of legacy products. Ultimately, the role of ERA is to maximize the
chances of identifying a risk to the environment before any harm occurs and, in this respect,
further research is needed to understand how we can better utilize the wealth of clinical and
pre-clinical data which are uniquely available for pharmaceuticals compared to any other
class of chemical. If, after undertaking laboratory studies, a potential risk is not excluded,
further risk refinement may lead to population-level risk assessment or monitoring in the
receiving environment. In this context, pharmaceuticals are no different to any other
chemical entering the environment and accepted, validated tools are needed to assess risk
at the population-level and provide reliable indicators of ecological health.
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Collapse of a fish population after exposure to a synthetic estrogen. Proceedings of the
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substances in the field of water policy. COM(2011) 876 Final, 2011/0429 (COD), 31.1.2012.
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Ahmed S, Chaudhry MJ, Arshad M, Mahmood S, Ali A, Khan AA. 2004. Diclofenac residues
as the cause of vulture population decline in Pakistan. Nature 427:630-633.
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Hallstrom L, Karlsson MV, Larsson DG, Lazorchak JM, Mastrocco F, McLaughlin A,
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Sibley PK, Straub JO, Szabo ND, Topp E, Tetreault GR, Trudeau VL, Van Der Kraak G.
2012. Pharmaceuticals and personal care products in the environment: what are the big
questions? Environmental Health Perspectives 120:1221-1229.
[9] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001.
Experimental and
computational approaches to estimate solubility and permeability in drug discovery and
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Potential chemical and microbiological risks on human health from urban wastewater reuse
in agriculture. Case study of wastewater effluents in Spain. J. Environmental Science &
Health, Part B, 45:300-309.
[11] Gardner M, Jones, V, Comber S, Scrimshaw M, Coello-Garcia T, Cartmell E, Lester J,
Ellor B. 2013. Performance of UK wastewater treatment works with respect to trace
contaminants. Science of the Total Environment 456-457:359-369.
[12] Holm G, Snape JR, Murray-Smith R, Talbot J, Taylor D, Sörme P. 2013. Implementing
ecopharmacovigilance in practice: challenges and potential opportunities. Drug Safety
36:533-546.
[13] Huggett DB, Cook JC, Ericson JF, Williams RF. 2003. A theoretical model for utilizing
mammalian pharmacology and safety data to prioritize potential impacts of human
pharmaceuticals to fish. Human & Ecological Risk Assessment 9:1789-1799.
[14] Winter MJ, Owen SF, Murray-Smith R, Panter GH, Hetheridge MJ, Kinter LB. 2010.
Using data from drug discovery and development to aid the aquatic environmental risk
assessment of human pharmaceuticals: concepts, considerations and challenges.
Integrated Environmental Assessment & Management 6:38-51.
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the fish plasma model for comparative hazard identification for pharmaceuticals in the
environment by extrapolation from human therapeutic data. Regulatory Toxicology &
Pharmacology 61:261-75.
[16] Roos V, Gunnarsson L, Fick J, Larsson DG, Rudén C. 2012.
Prioritising
pharmaceuticals for environmental risk assessment: Towards adequate and feasible first-tier
selection. Science of the Total Environment 421-422:102-110.
[17] Rand-Weaver M, Margiotta-Casaluci L, Patel A, Panter GH, Owen SF, Sumpter JP.
2013. The read-across hypothesis and environmental risk assessment of pharmaceuticals.
Environmental Science & Technology 47:11384-11395.
[18] European Commission, European Federation of Pharmaceutical Industry Associations
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Innovative Medicines Initiative (IMI). Directory of ongoing projects URL:
http://www.imi.europa.eu/, accessed April 2014
[19] Forbes VE, Calow P, Grimm V, Hayashi T, Jager T, Palmqvist A, Pastorok R, Salvito D,
Sibly R, Spromberg J, Stark J, Stillman RA. 2010. Integrating population modeling into
ecological risk assessment. Integrated Environmental Assessment & Management 6:191193.
[20] European Commission 2012b. Addressing the new challenges for risk assessment:
Discussion paper approved for public consultation in view of receiving feedback from
stakeholders for its further development. Scientific Committee on Emerging and Newly
Identified Health Risks (SCENIHR), Scientific Committee on Consumer Safety (SCCS),
Scientific Committee on Health and Environmental Risks (SCHER). ISBN 978-92-79-XX.
% of pharmaceuticals per risk class
Figure 1:
100
90
80
70
60
50
40
30
20
10
0
amoxycillin
acetlysalicylic acid
allopurinol
mycophenolate
permethrin
propranolol
raloxifene
sertraline
Insignificant
Low
Moderate
High
Risk class
Environmental risk prioritization for pharmaceuticals (Fass.se database)
enthinylestradiol
estradiol
Response
Gerd Maack (governmental perspective)
The answer to the question: “Do human pharmaceuticals present a risk to the environment”
is gaining knowledge and closing data gaps.
In Germany alone there are about 1,200 human pharmaceutical substances on the market
(IMS MIDAS®, 2013), which are likely to occur at physiologically relevant concentrations in
the environment. The majority of them lack a proper Environmental Risk Assessment (ERA).
This is especially true for those substances that received European Medicines Agency
(EMA) marketing authorization before 2006, i.e., before ERA became obligatory in Europe
[1]. Even for well known substances such as ibuprofen, diclofenac and carbamazepine there
are insufficient data available for a complete ERA, thus, not fulfilling the legal requirements
according to the EMA guideline.
It is necessary to develop a concept, which allows a proper judgment of the environmental
impact of these substances, individually and in mixtures with other substances, including
pesticides, biocides, and industrial chemicals. So far, this concept is far away from being
available. Such a concept needs to include all available information, in-vitro, in-silico, and
also the translation of existing non-clinical toxicological data. The fundamental requirements
from this knowledge base are:



knowledge regarding the translation of in-vitro data into quantitative population
information,
knowledge regarding the calibration of models for a more accurate read-across and
knowledge of how the effects data and also the “no-effects” data from toxicological
studies can be used for an ERA.
However, up to now, this knowledge is not available. Not even for the best understood
pathway, estrogen receptor activation. A search in literature databanks with the search terms
“*estradiol” and “fish reproduction” reveals more than 8,000 publications (ScienceDirect,
June 2014). However, not even for this pathway is a quantitative risk assessment is
possible. Molecular and biochemical endpoints usually do not provide sufficient information
for a quantitative risk assessment for any one chemical. Even the extensive knowledge of
how a potent estrogen receptor (ER) agonist such as 17-α ethynylestradiol (EE2) behaves,
informs only how one would approach the evaluation of other potential estrogenic
compounds in a focused, cost-effective manner [2].
An ERA for a human pharmaceutical needs to be conducted prior to the market application,
but at an advanced stage of development of a new substance, meaning that quite a lot of
therapeutic information is already available. Unfortunately, this information from the preclinical studies is often not usable and not transferrable to an ERA. This is mainly because
toxicological studies need to answer different questions and also the protection goal is
different. For environmental studies, the protection goal is the population compared to the
individual in pre-clinical toxicological studies. This makes the translation of information
difficult in the first instance. It is often not possible to extrapolate the assessed endpoints of
toxicological studies to population effects. Table 1 compares the different endpoints and
differences in designs in toxicological and ecotoxicological studies. The same applies to the
“read-across” process: Although many drug targets and enzyme molecular structures are
conserved in human (mammals) and in vertebrates e.g. fish and even in invertebrates [3],
the mechanism of action in wildlife for most pharmaceuticals is not yet completely
understood [4].
For most pharmaceuticals, insufficient laboratory studies and/or environmental monitoring
data are available to answer the question as to whether environmental concentrations of
pharmaceuticals are anywhere close to those that produce adverse effects in ecotoxicity
tests. However, for a few pharmaceutical substances the answer is “Yes”. An assessment
according to the EMA guideline identifies a potential environmental risk for the environment
for some hormones, some neurological drugs, and some cytostatics. Furthermore, as global
consumption of pharmaceuticals rises, an inevitable consequence is an increased level of
contamination of surface and ground waters with these biologically active drugs, and thus in
turn a greater potential for adverse effects in aquatic wildlife [5].
How can we prioritize and identify pharmaceuticals of the greatest environmental risk?
This ranking of pharmaceutical active substances has to include effect and exposure. It is
necessary to assess the potential effect concentrations but also the amount of a specific
substance actually entering the environment. Giving two extreme examples: (i) ibuprofen,
with a steadily increasing consumption in Germany of now nearly 1,000,000 kg/year and (ii)
EE2, where the consumption is slowly but continuously reducing to 47 kg/ year in 2012 (IMS
MIDAS®, 2013). The effect concentrations of ibuprofen for the aquatic compartment are in
the µg/L range e.g. [6], whereas the highly specific receptor-mediated effects of EE2 are in
the low ng/L range or even less [7, 8]. Beside this, fate and degradation also have to be
accounted for. EE2 is relatively stable and therefore found in surface waters in the range of
the effect concentration. On the other hand ibuprofen is easy degradable under aerobic
conditions, but due to the high consumption rate, it can be found in surface waters in the
range of the effect concentrations as well [9]. In addition, metabolites and transformation
products should not be ignored, as for several products, such as carbamazepine, different
environmentally relevant transformation products exist.
To assess an environmental concentration of a specific substance normally the Predicted
Environmental Concentration (PEC) of an individual product will be estimated. This results in
short-comings in both directions. It either overestimates the environmental concentration, as
potential degradation is not included, but it also underestimates the environmental impact as
the PEC is calculated for individual products only, neglecting the fact that nearly all active
ingredients are used by more than one pharmaceutical product. This is especially true for the
high consumption products like the above mentioned ibuprofen, diclofenac and
carbamazepine. Therefore, for highly consumed products, Measured Environmental
Concentrations (MEC) would be the alternative; however, these are lacking for most
pharmaceuticals. Although several monitoring programmes measure selected
pharmaceuticals on local, national and international levels, a general co-ordination is lacking.
As a consequence, there is basically not a single pharmaceutical measured all over Europe.
The European Community recognised this and is now considering, for the first time, three
pharmaceuticals, diclofenac, 17-α ethynylestradiol and 17-β estradiol (E2) as candidates for
future control via environmental quality standards (EQS). Johnson et al. [10] estimated the
concentration of these three substances in European rivers by using a geographic based
water model and found that the concentration of EE2 would exceed the EQS standard in
12 % of the European rivers, whereas the concentration of E2 and diclofenac would exceed
it in 1% and 2% of the rivers, respectively.
After identifying the priority substances for testing, the next step has to be: Testing to a level
and quality acceptable for an ERA. For substances receiving marketing authorisation before
2006, UBA has recommended for several years a monographic system, where the results of
environmental relevant data are made publically available in a substance-specific
monograph. In this way the industry, both research based and generic companies, can share
the financial burden. In very rare cases companies have already formed a consortium to gain
the data for a shared ERA. This testing can be done, even without waiting for “the final”
prioritisation list. There are several substances and transformation products, other than
diclofenac, ibuprofen, and carbamazepine, that rank highly in prioritization schemes. [11].
For these compounds, testing should be started immediately, as the environmental
relevance of these substances is more than obvious.
In conclusion, the marketing authorisation of human pharmaceuticals alone, especially for
substances authorized before 2006, is not sufficient to evaluate the long term potential risk
for the environment. The basis for ERA is reliable data; therefore additional post marketing,
environmental monitoring is a suitable option for gaining these data.
Gerd Maack
Department of Pharmaceuticals
Federal Environment Agency (UBA)
Dessau, Germany
References
[1] EMA. 2006. Guideline on the environmental risk assessment of medicinal products for
huma use. (Doc Ref EMEA/CHMP/SWP/4447/00 corr 1*).
[2] Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR,
Nichols JW, Russom CL, Schmieder PK, Serrrano JA, Tietge JE, Villeneuve DL. 2010.
Adverse outcome pathways: a conceptual framework to support ecotoxicology research and
risk assessment. Environmental Toxicology & Chemistry 29:730-741
[3] Gunnarsson L, Jauhiainen A, Kristiansson E, Nerman O, Larsson DG. 2008. Evolutionary
conservation of human drug targets in organisms used for environmental risk assessments.
Environmental Science & Technology 42:5807-5813.
[4] Rand-Weaver M, Margiotta-Casaluci L, Patel A, Panter GH, Owen SF, Sumpter JP. 2013.
The read-across hypothesis and environmental risk assessment of pharmaceuticals.
Environmental Science & Technology 47:11384-11395.
[5] Corcoran J, Winter MJ, Tyler CR. 2010. Pharmaceuticals in the aquatic environment: a
critical review of the evidence for health effects in fish. Critical Reviews in Toxicology
40:287-304.
[6] Flippin JL, Huggett D, Foran CM. 2007. Changes in the timing of reproduction following
chronic exposure to ibuprofen in Japanese medaka, Oryzias latipes. Aquatic Toxicology
81:73-78.
[7] Parrott JL, Blunt BR. 2005. Life-cycle exposure of fathead minnows (Pimephales
promelas) to an ethinylestradiol concentration below 1 ng/L reduces egg fertilization success
and demasculinizes males. Environmental Toxicology 20:131-141.
[8] Zha J, Sun L, Zhou Y, Spear PA, Ma M, Wang Z. 2008. Assessment of 17αethinylestradiol effects and underlying mechanisms in a continuous, multigeneration
exposure of the Chinese rare minnow (Gobiocypris rarus). Toxicology and Applied
Pharmacology 226:298-308.
[9] Ternes TA. 1998. Occurrence of drugs in German sewage treatment plants and rivers.
Water Research 32:3245-3260.
[10] Johnson AC, Dumont E, Williams RJ, Oldenkamp R, Cisowska I, Sumpter JP. 2013. Do
concentrations of ethinylestradiol, estradiol, and diclofenac in european rivers exceed
proposed eu environmental quality standards? Environmental Science & Technology
47:12297-12304.
[11] Miao X-S, Metcalfe CD. 2003. Determination of carbamazepine and Its metabolites in
aqueous samples using liquid chromatography−electrospray tandem mass spectrometry.
Analytical Chemistry 75:3731-3738.
Table 1: Comparison of study designs and endpoints in toxicology and ecotoxicology
Toxicology
Ecotoxicology
Protection goal: the individual
(humans)
Protection goal: the population
(the death of a certain amount of
individuals in a specific population is
acceptable)
Testing on individuals
(mouse, rat, guinea pig, rabbit, mini-pig,
monkey)
Study design is flexible:
 in vitro and in vivo exposure varies
(substance-specific effects)
Testing on small groups / populations
(microoragnisms, algae, daphnids,
fish, sediment organisms, plants)
Study design is fixed:
 standard battery is used
(tiered approach)
Duration of the study depends on:
 concentration
 formulation
 indication/administration
Duration of the studies fixed
Study types:
 general toxicity,
 genotoxicity,
 carcinogenicity,
 reproduction toxicity,
 mutagenicity,
 local tolerance,
 antigenicity,
 CNS safety,
 pulmonary function,
 cardiovascular safety,
 juvenile animal,
 abuse potential,
 phototoxicity nephrotoxicity
 Hershberger assay
Study types:
 activated sludge: respiration,
 algae: growth inhibition,
 daphnia: reproduction,
 fish: early-life stage, full lifecycle,
 sediment organisms:
development,
 plants: growth inhibition
Endpoints:
 body weight,
 mortality,
 behaviour,
 pathology-histology (organic weights,
macro- and microscopic change in
several tissues)
Endpoints:
 mortality,
 growth, development
 reproduction (fish: pathologyhistopathology and behaviour
possible)