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Pharmaceuticals Effects in the Environment


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DOI: 10.1016/B978-0-12-386454-3.00571-6

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From Fernndez, C., Beltrn, E.M., Tarazona, J.V., 2014. Pharmaceuticals
Effects in the Environment. In: Wexler, P. (Ed.), Encyclopedia of Toxicology, 3rd edition
vol 3. Elsevier Inc., Academic Press, pp. 844848.
ISBN: 9780123864543
Copyright 2014 Elsevier, Inc. unless otherwise stated. All rights reserved.
Academic Press

Author's personal copy


Pharmaceuticals Effects in the Environment
C Fernandez and EM Beltran, Laboratory for Ecotoxicology, Spanish National Institute for Agriculture and Food Research
and Technology, Madrid, Spain
JV Tarazona, Spanish Royal Academy of Veterinary Sciences, Spanish National Institute for Agriculture and Food Research and
Technology, Madrid, Spain
2014 Elsevier Inc. All rights reserved.

Introduction
The presence of pharmaceutically active compounds (PhACs) in
the environment can pose signicant human and wildlife health
threats. Pharmaceuticals were initially identied in the mid1970s associated with wastewater treatment plant (WWTP)
efuents in the United States. During the 1980s, there has been
only little interest in this type of contamination. It has not been
until this last decade that social concern has been aroused for
a potential risk to ecosystems.
The increased concern on the ecological effects of PhACs
was initiated largely as a result of a growing number of technical papers reporting detectable levels of pharmaceuticals in
WWTP efuents, surface waters, drinking waters, and sediments. For instance, >100 pharmaceuticals and personal care
products have been detected in efuents of WWTPs in several
countries of the European Union.
The current awareness of emergent pollutants is the result of
new advances in analytical techniques capable of revealing the
presence of these substances at very low levels. Presumably, they
have been in the environment, undetected, since their use began.
These compounds and their metabolites continuously enter
the aquatic environment largely through efuents from WWTPs
because of incomplete elimination or sporadic direct wastewater discharge. Even low concentrations of these substances
may lead to unwanted effects in aquatic systems. Although
pharmaceuticals are designed as bioactive molecules to treat
diseases, they can affect nontarget organisms, with harmful
effects reported at environmentally relevant concentrations.
Concern is such that several reviews recently published have
dealt with the exposure of humans or biota to pharmaceuticals.
The environmental concerns about these compounds are
linked to two main factors: (1) the bioactive property of
pharmaceuticals and (2) their capacity to be routinely present
in aquatic environments. This situation has resulted in their
characterization as pseudo persistent compounds.
The scientic community is in broad agreement on the
possibility that adverse effects not only for human health but
also for aquatic organisms may arise from the presence of
pharmaceuticals. Several almost negligible effects have been
shown to occur from continuous exposure during the life cycle
of aquatic vertebrates and invertebrates to subtherapeutic drug
concentrations. These effects slowly accumulate and manifest
themselves as a nal irreversible condition that is frequently
only noticed several generations later, affecting the sustainability of aquatic organism populations.

Sources of PhACs Environmental Contamination


The main pathway for environmental contamination of
medicines is via the metabolic excretion (nonmetabolized

844

parent drug, parentdrug conjugates, and bioactive metabolites) in urine and faces, although other anthropogenic mechanisms should be assumed:
a) Disposal of unused/outdated medication to sewage systems
b) Release of treated/untreated hospital wastes to domestic
sewage systems
c) Release to private septic/leach elds: treated efuent from
domestic sewage treatment plants discharged to surface
waters
d) Transfer of sewage solids (biosolids) to land as amendments/fertilizers
e) Direct release to open waters via washing, bathing, or
swimming
f) Discharge of regulated/controlled industrial manufacturing
waste streams
g) Direct release from aquaculture facilities (sh farming)

Environmental Fate
In general, a wide-dispersive environmental release should be
assumed. After human or animal treatment, most drugs are
excreted partly nonmetabolized. Some, such as X-ray contrast
media, are excreted as a parent drug. PhACs as well as disinfectants are used in medicine, which enter municipal sewage
and WWTPs.
Pharmaceuticals not readily degraded in WWTPs are being
discharged in treated efuents, resulting in the contamination
of surface waters, groundwater, and drinking water. In addition, the conjugated metabolites can be hydrolyzed, releasing
the parent drug or Phase I metabolites. When sewage sludge is
applied to agricultural elds, contamination of soil, runoff into
surface water, and drainage may occur. In addition, veterinary
drugs may enter aquatic systems via manure application to
elds and subsequent runoff. Drugs used in animal husbandry
as well as aquaculture are also discharged into the environment. Finally, PhACs reach groundwater via soil after manure
or sewage sludge application as fertilizers (see Figure 1).

Environmental Concentrations
Since 1976, when Garrison et al. reported the occurrence of
clobric acid, in the range 0.22 mg l1, in treated wastewater in
the United States, pharmaceuticals have been detected in many
countries around the world. In the last decade, specialized
literature has supplied a lot of data on PhAC concentration in
surface and groundwater, WWTP inuents and efuents, soils,
sediments, biosolids, biota, and so on. Environmental concentrations of pharmaceuticals have been mainly reported in WWTP
efuents and surface water. WWTP efuent concentrations range
from ng l1 to mg l1. In surface water, the level of contamination

Encyclopedia of Toxicology, Volume 3

http://dx.doi.org/10.1016/B978-0-12-386454-3.00571-6

Encyclopedia of Toxicology, Third Edition, 2014, 844848

Author's personal copy


Pharmaceuticals Effects in the Environment

PhACs for human use

Excretion
(hospital effluents)

Excretion
(WWTPs effluents)

Municipal effluents

845

PhACs for veterinary use

Disposal of
unused/outdated
medication
Domestic sewage

Excretion

Manure

Agro industrial effluents


WWTPs

Sewage
sludges

Surface water

Aquaculture

Figure 1

Landfields

Soil

Groundwater

Drinking water
Pharmaceutical
Industry

Sources, distribution, and sinks of PhACs in the environment.

is in the range of ng l1. Data have been compiled up to 2006 and


are reviewed by Fent et al., as shown in Figure 2.
After reaching WWTPs, PhACs are degradated and partitioned in efuent and sewage sludge. Mean concentration
levels of the PhACs ranged between 20 and 4000 mg kg1 dw,
15 and 1000 mg kg1 dw, 3 and 600 mg kg1 dw, and 10 and

1000 mg kg1 dw in primary, secondary, digested sludge, and


compost, respectively. The highest ecotoxicological risk, in
digested sludge and compost, was caused by the estrogenic
compound 17b-estradiol. The ecotoxicological risk signicantly decreased after the application of digested sludge or
compost to the soils.

Figure 2 PhAC concentration in treated wastewater and surface water (Fent, K., Weston, A.A., Caminada, D., 2006. Ecotoxicology of human pharmaceuticals. Aquat. Toxicol. 76, 122159.).

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846

Pharmaceuticals Effects in the Environment

A survey of 72 pharmaceuticals in US biosolids found


two (ciprooxacin, diphenhydramine) in all samples (n 84)
and eight in at least 80 of the biosolid samples analyzed.
However, 15 pharmaceuticals were not found in any sample,
and 29 were present in fewer than three samples. Maximum concentrations of tetracycline (range: 0.045.3; mean:
1.3 mg kg1 dw) and ciprooxacin (range: 0.0841.0; mean:
10.5 mg kg1 dw).

Ecotoxicological Effects
Nonsteroidal Antiinammatory Drugs (NSAIDs)
Nonsteroidal antiinammatory drugs (NSAIDs) are weak acids
that act by reversible or irreversible inhibition of one or both
isoforms of the cyclooxygenase enzymes COX-1 and COX-2,
which are involved in the synthesis of different prostaglandins
from arachidonic acid.
Diclofenac is the compound that has the highest acute
toxicity within the class of NSAIDs. For all tests performed on
this compound, the effect concentrations were <100 mg l1.
Ibuprofen also presents chronic toxicity. Female Japanese
medaka (Oryzias latipes) exposed to different concentrations of
the drug over 6 weeks, showed a sharp rise in liver weight
together with enhanced egg production, yet with a reduction in
the number of weekly spawning events.
The water ea Daphnia magna population growth rate was
signicantly reduced at concentrations ranging from 0 to
80 mg l1. Reproduction was affected at all concentrations and
completely inhibited at the highest pharmaceutical level.
Regarding aquatic photosynthetic organisms, specic effects
have been noticed. A 5-day exposure to concentrations in the
11000 mg l1 range stimulated the growth of the cyanobacterium Synechocystis sp., whereas inhibiting that of the duckweed plant Lemna minor after 7 days.
Acute toxicity tests performed on the rotifer Brachionus
calyciorus, the water ea Ceriodaphnia dubia, and the fairy
shrimp Thamnocephalus platyurus showed that naproxen had
EC50 values within the range 1100 mg l1, with photolysis
products being signicantly more toxic. Highly chronic toxic
properties were noticed with algae.
Paracetamol (or acetaminophen) is a weak inhibitor of the
cyclooxygenase enzyme, whose side effects are mainly associated with the formation of hepatotoxic metabolites, such as
N-acetyl-p-benzoquinone imine when the levels of liver glutathione are low.
Tests were carried out on algae, water eas, sh embryos,
luminescent bacteria, and ciliates. The most sensitive species
was shown to be D. magna, for which EC50 values reported
from 30 to 50 mg l1.

Blood Lipid-Lowering Agents


Statins and brates are basically the two types of antilipidemic
drugs. Both are used to decrease the concentration of cholesterol (statins and brates) and triglycerides (brates) in the
blood plasma.
Statins act by inhibiting the 3-hydroxymethylglutaryl
coenzyme A reductase, an enzyme involved in feedback control
of cholesterol synthesis. In response, the number of LDL

lipoprotein receptors at hepatocyte surfaces increases, thus


lowering the circulating LDL cholesterol.
Acute toxicity of lipid-lowering agents is not extensively
reported. Several authors found LC50 values of 1.18 and
10 mg l1 in larval and adult grass shrimp (Palaemonetes pugio),
respectively, after an exposure of 96 h to simvastatin. Simvastatin exhibited an EC50 of 22.8 mg l1 after 96 h for the marine
phytoplankton Dunaliella tertiolecta.
Atorvastatin can affect the development of the duckweed.
Lemna gibba showed an lowest observed effect concentration of
300 mg l1 for parameters such as wet mass, frond number,
chlorophyll-a, and carotenoid content for a time of exposure of
7 days.
Fibrates act by activating specic transcription factors
belonging to the nuclear hormone receptor superfamily known
as peroxisome proliferator activated receptors (PPARs) (Staels
et al., 1998). There are three types of PPARs related to different
cellular events. PPAR-a and PPAR-b play key roles in catabolism and storage of fatty acids, whereas PPAR-g plays an
important role in cellular differentiation.
According to Quinn et al. (2008), gembrozil could be
classied as toxic (EC50 110 mg l1) and bezabrate as
harmful for nontarget organisms (EC50 10100 mg l1). Toxic
properties of gembrozil were also investigated on the inhibition of the bacterium Vibrio scheri luminescence, growth
inhibition of the alga Chlorella vulgaris, and immobilization of
the D. magna. Both the bacteria and the water ea were sensitive
to gembrozil, with the latter being the most sensitive, having
an EC50 of 30 mg l1 after 72 h.

Antibiotics
The major concern is associated with the development of
resistance mechanisms by bacteria that can subsequently
compromise public health by means of treatment effectiveness.
According to Jones et al. (2002), antibiotics could be classied
as extremely toxic to microorganisms (EC50 <0.1 mg l1) and
very toxic to algae (EC50 0.11 mg l1). Chronic toxicity tests
performed on algae have shown high sensitivity to antibacterial
agents as deduced from growth inhibition measurements.
Antibiotics used in livestock production are excreted in the
urine and feces of animals and often appear in manure. They
can cause problems in terrestrial ecosystems, such as adverse
effects on nitrifying bacteria or growth inhibition of crop plants
and weeds. The presence of antibiotics in WWTP inuents may
also impair treatment processes that use bacteria and cause
toxic effects in the downstream aquatic and/or terrestrial
ecosystems at different trophic levels.
Bacterial cultures from sewage bioreactors receiving waters
from a WWTP were tested for resistance against six antibiotics,
showing that all were resistant to at least two of the antibiotics,
whereas bacteria isolated from receiving waters were only
resistant to erythromycin and ampicillin.

Sex Hormones
Sex hormones are extremely active biological compounds
producing intense therapeutic effects even at very low doses. They
can exist as either natural or synthetic substances, mimicking
the effects of endogenous estrogens as endocrine-disrupting

Encyclopedia of Toxicology, Third Edition, 2014, 844848

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Pharmaceuticals Effects in the Environment

compounds (EDCs) through binding to specic receptors


common to nontarget organisms (invertebrates, sh, reptiles,
birds, and mammals).
In sh, estrogens are involved in several physiological
functions, including (1) vitellogenin synthesis, (2) vitelline
envelope (eggshell) protein production, (3) gonadal differentiation, (4) development of secondary sexual characteristics,
(5) gonadotropin secretion, (6) synthesis of estrogen receptors,
(7) pheromonal communication, (8) bone formation, and (9)
calcium homeostasis. The enhanced production of the vitellogenin found in the blood of male and juvenile sh provides
a useful biomarker of aquatic contamination by compounds
with estrogenic activity.
Ethinylestradiol (EE2) is a synthetic estrogen found in oral
contraceptive pills with marked estrogenic effects in sh. The
life cycle exposure of fathead minnows to EE2 concentrations
<1 ng l1 gave an increased female population and for EE2
concentrations >3.5 ng l1, sh became completely feminized.
Similar ndings for zebrash males were registered.
Amphibians and reptiles exposed to environmental estrogens showed sex reversal as well as signicant changes in
secondary sex characteristics.

Antiepileptics
These drugs act in the central nervous system (CNS) by
reducing the overall neuronal activity. This is achieved either by
blocking voltage-dependent sodium channels (carbamazepine) or enhancement of the inhibitory effects of the g-aminobutyric acid (GABA) neurotransmitter (benzodiazepines).
Diazepam and carbamazepine are considered potentially
harmful to aquatic organisms because most of the acute toxicity
data are <100 mg l1. Carbamazepine is lethal to zebrash at
43 mg l1 and sublethal changes occurred in Daphnia sp. at
92 mg l1.
It is important to know that carbamazepine can absorb to
sediments, in this way threatening aquatic organisms that feed
on organic matter.

b-Blockers
b-blockers act by competitive inhibition of b-adrenergic
receptors, a class of receptors critical for normal functioning in
the sympathetic branch of the vertebrate autonomic nervous
system. Within the most commonly used b-blockers propranolol is a nonspecic antagonist, blocking both b1 and b2
receptors, whereas metoprolol and atenolol present b1 receptor
specicity.
Fish possess b receptors in the heart, liver, and reproductive
system; therefore, prolonged exposure to these drugs may cause
negative effects.
The acute toxicity of propranolol was assessed on the
invertebrates Hyalella azteca, D. magna, and C. dubia, obtaining
LC50 values of 29.8, 1.6, and 0.8 mg l1, respectively, after a 48h exposure. Acute exposure to nadolol did not affect the
survival of the invertebrates. Regarding metoprolol, D. magna
and C. dubia exhibited LC50 values of 63.9 and 8.8 mg l1,
respectively.
Several authors have described signicant reduction in heart
rate, fecundity, and biomass of D. magna, with LOEC values of

847

55, 110, and 440 mg l1, respectively, after chronic exposure to


propranolol (9 days), whereas chronic exposure to metoprolol
showed higher values. Chronic toxicity tests performed in algae
also evidenced their sensitivity to b-blockers, with no observed
effect concentration values <1 mg l1.

Antidepressants
Serotonin is an important neurotransmitter in hormonal and
neuronal mechanisms participating in different regulatory and
endocrine functions. Altered levels may cause changes in
appetite, the immune system, reproduction, and other behavioral functions. It is also important to lower vertebrates and
invertebrates, although associated with different physiological
mechanisms from those observed for mammals. In therapeutics, the selective serotonin reuptake inhibitors (SSRIs) uoxetine, uvoxamine, paroxetine, and sertraline are the most
widely used synthetic antidepressants.
Fluoxetine is apparently the most acute toxic human pharmaceutical reported so far, with acute toxicity ranging from an
EC50 (48 h, alga) value of 0.024 mg l1 to LC50 (48 h) value of
2 mg l1. Fluoxetine seems to affect phytoplankton more
strongly than other aquatic organisms.
Fluoxetine, uvoxamine, paroxetine, citalopram, and sertraline showed negative effects on C. dubia reproduction by
reducing the number of neonates or brood per female after 78
days of exposure. For the most active compound, sertraline, the
LOEC was 45 mg l1 and the NOEC was 9 mg l1.

Mixture Effects
Pharmaceuticals do not occur alone in the environment, but as
a mixture of different active substances, their metabolites, and
transformation products. Ecotoxicological data show that
mixtures might have different effects than single compounds,
but in general knowledge about the toxicity of the mixture of
active substances is still sparse. The simultaneous presence of
several pharmaceuticals in the environment might result in
a greater toxicity to nontarget organisms than that predicted for
individual active substances. An approximation to assess the
combined risk of PhACs detected along a basin, based on an
additive model that calculates the maximum risk index (RI) for
each sampling date and sampling site can be performed as
follows:
#
"
23 

X
Tox j; k OMECj; k i  0:1
Max RIj; k
i1

where i selected PhAC, j sampling site, k sampling date,


Toxj,k acute toxicity for a PhAC, and MEC measured environmental concentrations.
The gure obtained with this approach represents the
maximum value that a single PhAC or a combination of PhACs
should have for indicating that the measured concentrations do
not exceed the acceptable level of long-term risk.
The acute/chronic toxicity ratio for a variety of organisms
and chemicals was typically on the order of about 10, but much
higher values are expected for pharmaceuticals. Thus, the Max
RI represents an indicator of potential environmental risk: the
lower the value, the higher the potential risk.

Encyclopedia of Toxicology, Third Edition, 2014, 844848

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848

Pharmaceuticals Effects in the Environment

Comparison of Environmental Concentrations and


Ecotoxicological Effect Concentrations
The potential risk of a substance to the environment is often
characterized by comparing the predicted environmental
concentration (PEC) with the predicted no effect concentration
(PNEC). Because of the lack of experimental ecotoxicity data
(particularly chronic) estimation of PNEC, and therefore
hazard and risk assessment, is difcult or even impossible to
perform.
Differences between LOEC and NOEC with maximum
concentrations found in WWTP efuent are about one or two
orders of magnitude. However, some compounds such as
diclofenac, propranolol, or uoxetine have LOEC values close
to WWTP efuent concentration, showing that the safety
margin is very small.
In any case, more experimental data on chronic toxicity and
on the potential bioaccumulation is needed to assess the real
environmental risk. Pharmaceuticals are biologically active
substances, either with biocidal or physiological activity.
Consequently, large inter-endpoint and interspecies sensitivities should be expected. The use of standard approaches, for
example, standardized toxicity test with xed endpoints and
species should be considered carefully. The relevance of the
species and endpoints should be considered on a case-by-case
on the basis of the pharmacokinetics and pharmacodynamics
of the specic chemical and drug family.

See also: Toxic and Nontoxic: Conrming Critical


Terminology Concepts and Context for Clear Communication;
Cumulative (Combined Exposures) Risk Assessment;
Ecotoxicology; Aquatic Ecotoxicology; Ecotoxicology, Aquatic
Invertebrates; Environmental Exposure Assessment;
Environmental Fate and Behavior; Environmental Risk
Assessment, Aquatic; Environmental Risk Assessment,
Terrestrial; Pollution, Soil; Pollution, Water; Terrestrial
Microcosms and Multispecies Soil Systems; The European
Medicines Agency (EMA); Toxicity Testing, Aquatic.

Further Reading
Cunningham, V.L., Buzby, M., Huthcinson, T., Mastrocco, F., Parke, N., Roden, N.,
2006. Effects of human pharmaceuticals on aquatic life: next steps. Environ. Sci.
Technol. 40, 34563462.

Fent, K., Weston, A.A., Caminada, D., 2006. Ecotoxicology of human pharmaceuticals.
Aquat. Toxicol. 76, 122159.
Fernndez, C., Alonso, C., Babn, M.M., Pro, J., Carbonell, G., Tarazona, J.V., 2004.
Ecotoxicological assessment of Doxycycline in aged pig manure using multispecies
soil systems (MS,3). Sci. Total Environ. 323, 6369.
Fernndez, C., Gnzalez-Doncel, M., Pro, J., Carbonel, G., Tarazona, J.V., 2010.
Occurrence of pharmaceutically active compounds in surface waters of the
Henares-Jarama-Tajo river system (Madrid, Spain) and a potential risk characterization. Sci. Total Environ. 408, 543551.
Halling-Sorensen, B., Nors, S., Nielsen, P.F., Lanzky, F., Ingerslev, H.C., Holten, H.C.,
Jorgensen, S.E., 1998. Occurrence, fate and effects of pharmaceutical substances
in the environment a review. Chemosphere 36, 357393.
Jones, O.A.H., Voulvoulis, N., Lester, J.N., 2002. Aquatic environmental assessment of the top 25 English prescription pharmaceuticals. Water Res. 36,
50135022.
Kmmerer, Klauss (Ed.), 2004. Pharmaceuticals in the Environment: Sources, Fate,
Effects and Risks. Springer-Verlag, Berlin, Heiddelberg, New York. ISBN 3-54021342-2.
Quinn, B., Gagne, F., Blaise, C., 2008. An investigation into the acute and chronic
toxicity of eleven pharmaceuticals (and their solvents) found in wastewater efuent
on the cnidarian, Hydra attenuata. Sci. Total Environ. 389, 306314.
Santos, L., Araujo, A.N., Fachini, A., Pena, A., Delerue-Matos, C.,
Montenegro, M.C.B.S.M., 2010. Ecotoxicological aspects related to the presence
of pharmaceuticals in the aquatic environment. J. Hazard. Mat. 175, 4595.
Staels, B., Dallongeville, J., Auwerx, J., Schoonjans, K., Leitersdorf, E., Fruchart, J.-C.,
1998. Mechanism of action of brates on lipid and lipoprotein metabolism.
Circulation 98, 20882093.
Tarazona, J.V., Buzby, M.E., Hartmann, A., Housenger, J.E., Olejniczak, K., Sager, N.,
Servos, M.R., Tolson, N.D., 2005. Scientic basis for aquatic environmental impact
assessment of human pharmaceuticals, pp. 269302. In: Williams, R. (Ed.),
Science for Assessing the Impacts of Human Pharmaceuticals on Aquatic
Ecosystems. SETAC Press, Pensacola, FL, 368 pp.
US EPA, 2009. Targeted National Sewage Sludge Survey Statistical Analysis Report.
EPA-822-R-08-018. United States Environmental Protection Agency Ofce of
Water, Washington, DC.
Williams, R.T. (Ed.), 2005. Human Pharmaceuticals: Assessing the Impacts on Aquatic
Ecosystems. SETAC Press, Pensacola, FL. ISBN 1-880611-82-1.
Zuccato, E., Castiglioni, S., Fanelli, R., Reitano, G., Bagnati, R., Chiabrando, C.,
Pomati, F., Rossetti, C., Clamari, D., 2006. Pharmaceuticals in the environment in
Italy: causes, occurrence, effects and control. Environ. Sci. Pollut. Res. Int. 13 (1),
1521.

Relevant Websites
Pharmaceuticals and Personal Care Products as Pollutants (PPCPs). US Environmental
Protection Agency. www.epa.gov/ppcp/
Cemagref, 2007. Environmental database for pharmaceuticals: http://pharmaecobase.
lyon.cemagref.fr/.
GHS, 2007. Globally Harmonized System for the classication and labelling of
chemicals: http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html.
NOAA, 2006. United States National Oceanic and Atmospheric Administration (NOAA),
Pharmaceuticals in the environment: http://www.chbr.noaa.gov/peiar/.
Roche, 2007. Pharmaceuticals sustainability database: http://www.roche.com/home/
sustainability/

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