pharmaceuticals in the environment · ence of pharmaceuticals in the environment is a widely...

EG35CH03-Kummerer ARI 13 September 2010 20:37

Pharmaceuticals inthe EnvironmentKlaus KummererDepartment of Environmental Health Sciences, University Medical Center Freiburg, 79106Freiburg, Germany; email: [email protected]

Annu. Rev. Environ. Resour. 2010. 35:57–75

First published online as a Review in Advance onAugust 18, 2010

The Annual Review of Environment and Resourcesis online at environ.annualreviews.org

This article’s doi:10.1146/annurev-environ-052809-161223

Copyright c© 2010 by Annual Reviews.All rights reserved

1543-5938/10/1121-0057$20.00

Key Words

effects, fate, green pharmacy, occurrence, risk, sustainable pharmacy

Abstract

Pharmaceuticals are chemicals that are used because of their biologicalactivity. They are often excreted unchanged and can reach the environ-ment. Throughout developed countries, the pharmaceutical concen-trations in the aquatic environment are in the same range (μg L−1 andbelow); however, it is not clear whether this holds for less-developedcountries too. The health risks of active pharmaceutical ingredients(APIs) remain poorly understood. Although there are no known short-term effects on humans, long-term effects cannot be ruled out until thereis more research. The significance of metabolites and transformationproducts resulting from the parent APIs is not yet known. Awareness ofthe presence of pharmaceuticals in the environment, coupled with someevidence of effects, suggests that precautionary management action toreduce the release of pharmaceuticals to the environment should beconsidered. As for effluent treatment, no technology works well for allcompounds. Advanced effluent treatment is not sustainable because ofenergy consumption, efficiency, and efficacy. Therefore, its appropri-ateness must be assessed on a case-by-case basis. Increased handling anduse measures at the source and better biodegradable pharmaceuticalsare necessary in the long run for the new paradigm called “sustainablepharmacy.”

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Pharmaceutical: asubstance used in thetreatment of disease

Micropollutants:chemicals that arepresent in theenvironment in lowconcentrations (ngL−1 to μg L−1)

Metabolites:chemical compoundsthat result from thechange of the chemicalstructure of a parentcompound bybiochemical processesin organisms

Transformationproducts: chemicalcompounds resultingfrom the change of thechemical structure of aparent compound bychemical processes,including biochemicalprocesses

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 58ACTIVE PHARMACEUTICAL

INGREDIENTS: WHAT THEYARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

PARENT COMPOUNDS,METABOLITES, ANDTRANSFORMATIONPRODUCTS. . . . . . . . . . . . . . . . . . . . . . 60

SOURCES FOR ACTIVEPHARMACEUTICALINGREDIENTS IN THEENVIRONMENT . . . . . . . . . . . . . . . . 61

OCCURRENCE AND FATE INTHE ENVIRONMENT . . . . . . . . . . 62

EFFECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 63HAZARDS AND RISKS. . . . . . . . . . . . . . 65RISK MANAGEMENT . . . . . . . . . . . . . . 66GREEN AND SUSTAINABLE

PHARMACY. . . . . . . . . . . . . . . . . . . . . . 67

INTRODUCTION

The history of pharmaceutical sciences is an im-pressive success story. The products of phar-maceutical industries are present everywherein everyday life. Pharmaceuticals are chemicalsthat are used because of their more or less spe-cific biological activity. They help to pursuethe modern way of living, and they contributeto our health and high standard of living. Fora long time, the production of chemicals andpharmaceuticals as well as their usage and ap-plication caused heavy pollution of the environ-ment and serious health effects. During the sec-ond half of the twentieth century, tremendousprogress was made to prevent the pollution ofthe environment and to reduce the impact ofsuch pollution on health. Now proper, effec-tive treatment and prevention of emissions intothe air, water, and soil are in place in developedcountries and are making their way worldwide.In the 1990s, it was found that the amount ofwaste generated was 50–100 kg for the synthesisof 1 kg of an active pharmaceutical compound(1). This insight triggered activities within the

pharmaceutical industries to reduce waste gen-eration by various measures, such as using dif-ferent and more appropriate (i.e., “greener”)solvents and developing new synthesis routesto avoid intensive waste.

However, since the end of the past cen-tury, it has been learned that the products ofthe pharmaceutical industries themselves, i.e.,the medicinal drugs, are presenting a new typeof environmental pollution and possible healthrisks for the consumer. It is expected that theconsumption of pharmaceuticals will increasein the future because of higher standards of liv-ing and because more people are living longerand using more drugs as they age. Because ofthe ever increasing sensitivity of analytical in-struments, pharmaceuticals have been found(as have other micropollutants, such as disin-fectants, pesticides, flame retardants, de-icingfluids, and others) present in the environmentin low concentrations (ng L−1 to μg L−1) (2–4). These molecules often end up in the envi-ronment not because of improper use but be-cause of proper use. Although some may worryabout overuse, when pharmaceuticals are notcompletely used they are sometimes discardedvia the toilet, the drain, or into waste, whichare not proper disposal procedures. The pres-ence of pharmaceuticals in the environment is awidely accepted fact. The relative rates of pro-duction, release, and use of pharmaceuticals inthe next 10 to 50 years from now is not easyto predict, but pharmaceutical loading into theenvironment is expected to increase for severalreasons. First, as the number of older peopleincreases, extensive use of drugs (e.g., several atthe same time) will increase. In addition, withan increase in living standards and with an in-crease the affordability of drugs, their usagewill increase throughout the world, especiallyin rapidly growing economies. These changeshave to be taken into account in the context ofrisk assessments of pharmaceuticals in the envi-ronment. The assumption that the productionand use of pharmaceuticals may stay approxi-mately constant is definitely wrong.

If the pharmaceuticals, their metabolites,and transformation products are not eliminated

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during sewage treatment or sorbed in soil, theymay enter the aquatic environment and even-tually enter drinking water supplies (Figure 1,see color insert). Pharmaceutical residues fromhuman use have been a topic for several yearsnow. Because of their biological activity, there isconcern about their presence in the aquatic en-vironment and drinking water: Are there nega-tive effects caused by these compounds on hu-mans and/or environmental organisms? In thebeginning, research was focused on the analysisand presence of these micropollutants. Later,research into the fate and (eco)toxic effects cameinto the foreground. Now, risk assessment andrisk management issues are gaining momen-tum. Although the presence of pharmaceuti-cals in the environment is still a young topic, avast amount of literature has already been pub-lished. In this article, a very brief overview of thepresent knowledge is given, and some impor-tant issues are addressed. For more detailed dataand findings, the reader is advised to consult thenumerous books and more specialized reviewsthat have that have already been published (e.g.,References 2 and 5–12).

ACTIVE PHARMACEUTICALINGREDIENTS: WHAT THEY ARE

Normally, a pharmaceutical, such as a pillor a liquid, consists of one or several activepharmaceutical ingredients (APIs), excipients,and additives, as well as inorganic salts orother organic chemicals, such as sugars,scents, pigments, and dyes. They are often ofminor importance for the environment. Somemedicines, however, may contain endocrine-disrupting chemical excipients and additives.Unfortunately, knowledge of the significanceof excipients and additives is only availableif they are chemicals that are also used forother purposes. The focus here and in ongoingresearch is on the APIs. From a chemical pointof view, APIs cover a wide range of so-calledsmall molecules (with molecular weightsthat typically range from 200 to 500 Da)with different physicochemical and biologicalproperties. Even small changes in the chemical

API: activepharmaceuticalingredient

structure of an API may have a significant im-pact on its environmental fate (13). Therefore,sometimes separate assessments are necessaryfor each type of API, even with respect todifferent environmental conditions such aspH.

Some medicines contain biopharmaceuticalmolecules, which are medical drugs producedusing biotechnology techniques other than di-rect extraction from a native (i.e., nonengi-neered) biological source. Examples are pro-teins (including antibodies), nucleic acids, andrecombinant human insulin. Their environ-mental relevance is not yet clear, and they arenot yet in focus of environmental research andrisk management. Findings show that some aremetabolized in the human body and/or arebiodegradable in sewage treatment (14). Struc-turally related compounds, such as plasmids,have been found in the environment. Further-more, it is known that the protein structuresof prions are very stable in sewage treatment1

(15). Prions are eliminated from the water bysorption onto sewage sludge, followed by en-tering sludge treatment and disposal processes.To date, knowledge about the significance ofbiopharmaceuticals in the environment is by fartoo little for any conclusions.

Because biopharmaceuticals are often ap-plied in connection with the classical smallmolecules, such as antineoplastic compounds,they do not solve the problem. Other groupsof compounds that are of interest and thatare used in medical environments are usedin diagnostic applications, such as X-raycontrast media or contrast media appliedin magnetic resonance imaging (MRI), anddisinfectants.

1Prions are infectious agents composed only of protein.They cause a number of diseases in a variety of animals andCreutzfeldt-Jakob disease (CJD) in humans. Prions are be-lieved to infect and propagate by refolding abnormally into astructure that is able to convert normal molecules of the pro-tein into an abnormally structured form. This altered struc-ture renders them quite resistant to denaturation by chemi-cal treatments and physical agents (proteases, heat, radiation,and formalin), making disposal and containment of these par-ticles difficult.

www.annualreviews.org • Pharmaceuticals in the Environment 59

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STP: sewagetreatment plant

Photolysis:transformation ordegradation of achemical by light

PARENT COMPOUNDS,METABOLITES, ANDTRANSFORMATION PRODUCTSPharmaceuticals can be classified according totheir biological activity and purpose (e.g., an-tibiotics are used topically to treat bacterialinfections, analgesics are used to lessen pain,and antineoplastics are used in anticancer ther-apy). Classification according to chemical struc-ture is used mainly for the APIs within sub-groups of medicines, e.g., within the group, orsubgroups, of antibiotics, such as β-lactams,cephalosporins, penicillins, and quinolones.Other classifications refer to the mode of ac-tion (MOA), e.g., antimetabolites or alkylatingagents within the group of cytotoxics and/orantineoplastics. In case of MOA classification,chemical structures of molecules within thesame group can be very different and result invarying environmental fates. As for their bio-logical activity, in general, all compounds are ofinterest. Because some of them are active in verylow concentrations, they are of special interestdespite their lower usage. These are endocrine-active pharmaceuticals, i.e., hormones such asethinylestradiol, the main API of birth controlpills (16–18). Other drugs of high importanceare those used in anticancer treatment (19–21)because some of them can cause cancer them-selves. Antibiotics are of special interest becauseof the possible promotion of resistance.

Many pharmaceuticals undergo a structuralchange in the bodies of humans and ani-mals (Figure 2) before excretion, resulting inmetabolites. This change is only rarely com-plete, i.e., normally a certain share of the parentcompound (the API) is excreted together withthe metabolites. Some antibiotics, for example,are metabolized up to 95%, whereas others only5%. A study of API amounts used and excre-tion rates indicated that 75% of the antibioticsused in Germany are excreted unchanged, i.e.,as still active APIs (22). Furthermore, metabo-lites, such as glucoronides and others, can be setfree again by bacterial activity in sewage treat-ment plants (STPs) and the environment.

After their excretion and introduction intothe environment, both parent compounds andmetabolites can undergo structural changes bya variety of biotic and abiotic processes. Phar-maceuticals can be incompletely transformedby organisms, such as bacteria and fungi in theenvironment (23–25), as well as by light andother abiotic chemical processes (see below).Structural transformations may also be a re-sult of technological processes, such as effluenttreatment by oxidation, hydrolysis, and pho-tolysis (26–30; P. Gupta & K. Kummerer, un-published results). The resulting molecules arecalled transformation products (Figure 3) (31).Such structural changes result in new chemicalentities with new properties.

Phase I reaction Phase II reaction

Functionalization (oxidation, reduction,

hydrolysis)

Conjugation(sulfation, glucuronidation)

Xenobiotic/ parent compound

Metabolite I Metabolite II

Figure 2Metabolites formed in the body of humans and animals. Structural change by microorganisms (in the gut, insewage treatment plants, in the environment) may result in different compounds. Reproduced withpermission from Reference 7.

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Water and wastewater

treatment

Sewage

Water

Soil

Manure

(air quality)

HumansHuman

metabolism(liver, mucosa)

Microbialmetabolism

(skin, gut)

Biologicaltransformation

(organisms)

Technical transformation(ozonolysis, photolysis, chlorination)

Nonbiologicaltransformation

(light, oxidation,hydrolysis)

Metabolites

Transformationproducts

Nonbiological metabolism (hydrolysis in the stomach)

Active pharmaceutical

(parent compound)

Figure 3Metabolites and transformation products. Reproduced with permission from Reference 7.

SOURCES FOR ACTIVEPHARMACEUTICALINGREDIENTS IN THEENVIRONMENT

The APIs used in medicine, as well as the excip-ients and additives, may enter the environmentby different routes via several different non-point sources, such as manufacturing plants,effluents of STPs, household waste, and land-fill effluent. Pharmaceuticals applied in veteri-nary medicine, as growth promoters and forother purposes, are excreted by the animals(Figure 4) and reach soil. If they are notbound to soil constituents, they may reachgroundwater. In the case of heavy rain events,some may also be transported to surface wa-ter from runoff. Usually, it is assumed thatemissions from pharmaceutical manufacturingand production are low in Europe and NorthAmerica. However, it has been found only re-cently that pharmaceutical manufacturing faci-lities can be a significant source of pharmaceu-ticals to the environment in the U.S. (http://toxics.usgs.gov/highlights/PMFs.html). InNorway, the input from a local manufacturerwas much higher for a certain antibiotic thanthe ones originating from hospitals and thegeneral public (32). Other recent investigations

discovered that in Asian countries concentra-tions up to several mg L−1 of API can be foundin effluents of manufacturing plants (33–35).These results demonstrate the need for moredata. To my knowledge, data are not availableon emissions during transport and storage.

Sediment

Drug production

Medical use

Official sales Unofficial transfers ?

Veterinary use Growthpromoter Other use

Urine Waste

Landfill

Seawater

Surface water

Potable water

STP

Alimentary cycle

Groundwater

ManureFeces

Soil

Figure 4Pathways of input and distribution of pharmaceuticals in the environment.STP, sewage treatment plant. Reproduced with permission from Reference 7.


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As expected, pharmaceuticals are present inhospital wastewater (6, 36–41). Concentrationsof pharmaceuticals in hospital wastewater arehigher than in municipal sewage. However, thetotal load is much lower than that related to mu-nicipal wastewater because of the much lowershare of usage of pharmaceuticals in hospitalscompared to the general public effluent in de-veloped countries (32, 41). Hospital wastewateris greatly diluted by municipal wastewater, i.e.,by a factor >100 (42). In other words, hospitalsare a source of minor importance, so separatetreatment of this waste may be questionable,but reduction of APIs in hospital effluent, e.g.,by proper use, is still an option (see below).

In accordance with EU legislation, discard-ing unused drugs via household waste has beenpermitted since 1994. If the trash is incinerated,this is probably the most effective and environ-mentally sound way to handle the problem. Ifthe waste is landfilled, the APIs will show upafter some years in the effluent of the landfill(43–46). If there is no collection of the efflu-ent, this may be a source for contamination ofsurface water or groundwater.

It has been found that people get rid of left-over and outdated pills and liquid pharmaceu-ticals by pouring them into the toilet (47–51;see also http://www.start-project.de). Thesefindings suggest that there is a role for patienteducation about proper disposal of unused andexpired medications in all countries. In somecountries, take-back systems are in place (52,53). Ruhoy & Daughton (51) estimate that or-phaned medications from the deceased popu-lation alone account for as many as 19.7 tonsof APIs disposed into U.S. sewage systemsannually.

Getting people to stop flushing away theirunwanted medication is one easy way to cutdown on pharmaceutical pollution. Accordingto the guidelines of the U.S. Office of NationalDrug Control Policy (ONDCP), unused, un-needed, or expired prescription drugs shouldbe removed from their original containers andthrown in the trash. To prevent accidental poi-sonings or potential drug abuse, ONDCP rec-ommends mixing the medicines with an un-

desirable substance, such as coffee grounds orkitty litter. The mix should be placed intoimpermeable, nondescript containers, such asempty cans or sealable plastic bags, before beingtossed in the trash. However, the U.S. Food andDrug Administration recommends that certaincontrolled substances, such as the painkillersOxyContin R© and Percocet R©, are best disposedof down the drain. To ensure that drugs are dis-posed of in the most environmentally friendlymanner, individual communities are develop-ing pharmaceutical take-back programs thatcollect unwanted medications and then incin-erate them.

OCCURRENCE AND FATE INTHE ENVIRONMENT

Meanwhile, there is evidence of the occurrenceof some 160 different APIs in the aquatic envi-ronment. APIs have been found in the effluentfrom medical care units, landfills, municipalsewage, and STPs, and also in surface water,seawater, groundwater, and drinking water(2, 5–8, 54). Seasonal variations have beenstudied in sewage and reclaimed waste as wellas in finished water (the resulting water aftertechnical treatment) (55, 56). They are alsodetected in the Arctic environment (57). Theconcentrations of pharmaceuticals in surfacewater and effluent from STPs have been shownto be in the ng L−1 to μg L−1 range. Onlyrecently, has the presence of psychoactive andillicit drugs (such as amphetamine, cocaine andits metabolite benzoylecgonine, morphine,6-acetylmorphine, 11-nor-9-carboxy-�-9-tetrahydrocannabinol, methadone and itsmain metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, and amphetamines)been detected in surface water and wastewater(58–61). Despite the fact that knowledge aboutpharmaceuticals in sewage sludge and biosolidsis necessary for the proper understanding oftheir fates and for risk assessment, only littleinformation is available (62).

Not much is known about the occurrence,fate, and activity of metabolites. Importantquestions to be addressed are whether the

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glucoronides, methylates, glycinates, acety-lates, and sulfates are still active and whetherthey can be cleaved back by bacteria duringsewage treatment and in the environment. Thiswould result in the active compound being setfree again. Other types of metabolites are alsoexcreted and can be detected in wastewater (63).Their effects on environmental organisms maybe lower than that of their parent compounds.However, in the case of prodrugs, the situa-tion is probably different, as it may be for themetabolites of several other pharmaceuticals ashas been shown for norfluoxetin (64).

The predominant fate processes for theremoval of pharmaceuticals in and fromthe different environmental compartmentsare sorption (of importance, for example,for tetracyclines and quinolones) (65) and(bio)degradation. Photodegradation and hy-drolysis can also be significant in surface waterand technical treatment processes. Sorptionmay have an impact on the spread (particle-bound transport) and (bio)availability ofpharmaceuticals in the environment. Bindingto particles or the formation of complexes maycause a loss in detectability as well as a loss inactivity. Sorbing APIs may diffuse into biofilmspresent in sewage pipes, sludge flocks, orstones in rivers and lakes. Colloids seem to bean important sink for pharmaceuticals: Resultsreported by Maskaoui & Zhou (66) provideevidence that sorption to colloids providesan important sink for the pharmaceuticals inthe aquatic environment. Such strong phar-maceutical/colloid interactions may provide along-term storage of pharmaceuticals, hence,increasing their persistence while reducingtheir bioavailability in the environment. Ingeneral, sorption may result in a biased riskestimate as concentration in such “reservoirs”may be much higher than when they are freein water. As aquatic colloids are abundant,ubiquitous, and highly powerful sorbents, animpact on bioavailability and bioaccumulationof pharmaceuticals is expected (66). The effectsand behavior of antibiotics in such biosolidswith high bacterial density and special condi-tions have not yet been investigated, so little

Elimination: theremoval of a chemicalcompound from acertain environmentalcompartment byphysical (e.g.,sorption) or(bio)chemicalprocesses, such as(bio)degradation

is known about these issues. Even much less isknown about the conjugates, other metabolites,and transformation products in this respect.

Bacteria and fungi are the two groups of or-ganisms that are best able to degrade organiccompounds. Fungi are particularly important insoils, but they do not usually play an importantrole in the aquatic environment. Therefore, inSTPs and in surface-, ground- and seawater,bacteria are assumed to be responsible for mostbiodegradation processes. The rate and degreeof biodegradation of APIs in sewage treatmentand the aquatic environment depend on thetype and number of microorganisms presentand the API itself. The presence of pharmaceu-ticals in the aquatic environment demonstratesat least incomplete degradation and eliminationin sewage treatment and also that removal pro-cesses in the aquatic environment are slow.

Often, it is assumed that metabolism andtransformation of APIs, e.g., by advanced ef-fluent treatment, results in decreased toxicity.In some cases, however, metabolism leadsto more active compounds (e.g., in the caseof prodrugs). The same has been found forphototransformation and other oxidizing pro-cesses. However, often only one end point wasmonitored with one specific test. Mutagenicand other toxic properties have been foundfor the reaction products of photolysis and(photo)oxidation processes (28, 30, 67–73;P. Gupta, R. Gmiski, T. Haddas, N. Mathurc,V. Mersch-Sundermann, K. Kummerer,unpublished).

EFFECTS

The risks posed to humans from pharmaceu-ticals in the environment seem to concernenvironmental hygiene rather than toxicologyand pharmacology (74). However, there aresome exceptions: Endocrine-active compoundsand hormones may interfere with sexualdevelopment in humans, as they are highlyactive compounds that interact with hormonesystems (75–78). In addtion, some anticancerdrugs may cause cancer themselves—even atvery low doses—one of the threats of modern


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chemotherapy, and antibiotics may contributeto the selection of bacteria that are resistantagainst antibiotics (79). Little knowledge ofthese issues is available.

The maximum possible intake with contam-inated water within a life span (2 liters drinkingwater per day over 70 years) is far below thedosages used in general therapy. However, thisstatement relies on some assumptions: (a) thatthe effects and side effects during therapeuticuse (short-term, high dosage) are the same inquality and quantity as during a lifelong inges-tion (long-term ingestion, low dosage); (b) thatthe effects are the same for fetuses, babies, chil-dren, healthy adults, and elderly people; (c) andthat the risk imposed by a single compound iscomparable to the one imposed by a mixture.How to extrapolate data from high-dose short-term ingestion during therapy to a low-doselong-term ingestion, i.e., medication receivedvia drinking water, is still an unresolved issue intoxicology and in ecotoxicology. Elderly peo-ple, little children, and pregnant women maybe at risk (21, 80); however, they are often notspecifically addressed in risk assessments.

Information about the effects of the activesubstances on organisms in the aquatic and ter-restrial environments is increasing but still toolittle (81). Effects on fish, daphnia, algae, andbacteria have been demonstrated using low con-centrations in long-term tests (82, 83). For di-clofenac, the effective concentration for chronicfish toxicity was in the range of wastewaterconcentrations (see References 84–87), whereasthose of propranolol and fluoxetine for zoo-plankton and benthic organisms were near themaximally measured STP effluent concentra-tions (81). In surface water, concentrations arelower and so are the environmental risks. How-ever, targeted ecotoxicological studies are al-most entirely lacking, and such investigationsare needed to focus on subtle environmen-tal effects (81). Chronic effects often do nothave clearly visible results. Instead, they maycause subtle changes within longer time spans.Therefore, such effects are often overlooked,and a direct cause-and-effect relationship can-not be established on an ecosystem level.

All risk assessments are based on single com-pounds (74), but it has been found that mix-tures might exhibit effects that differ from sin-gle compounds (16, 88–90). In addition, it hasbeen shown that a standardized test may un-derestimate the effects (91). It has also beenfound that detrimental effects may happen bythe transfer of compounds within the food web.For example, diclofenac has undeniably had ex-tremely negative impacts on vulture popula-tions in Southeast Asia, and possibly elsewhere.This nonsteroidal anti-inflammatory drug isused in veterinary practice to treat sick live-stock in Asia. Dead livestock are consumed byold world vultures, which ingest the diclofenacremaining in the carcass. Unfortunately, vul-tures are exquisitely sensitive to this drug, anda dose of only 1 mg causes acute kidney fail-ure and death within a few days (92). Between2000 and 2003, high annual adult and subadultmortality (5–86%) of the oriental white-backedvulture occurred, and resulting population de-clines (34–95%) were associated with renal fail-ure and visceral gout. Diclofenac residues andrenal disease were reproduced experimentallyin oriental white-backed vultures by direct oralexposure and through feeding vultures the re-mains of diclofenac-treated livestock (92). Ev-idence from studies of one of these speciesstrongly implicates mortality caused by inges-tion of residues of the veterinary nonsteroidalanti-inflammatory drug diclofenac. Other find-ings also show that veterinary use of diclofenacis likely to have been the major cause of therapid vulture population declines across thesubcontinent (93, 94). This one pharmaceuticalhas caused the deaths of tens of millions of vul-tures in Asia and left three species on the brinkof extinction (populations of all species have de-clined by over 99% in the past decade). Onlyrecently it was found that the nonsteroidal anti-inflammatory drug ketoprofen has the sameeffects on these animals. New world vulturessuch as the condor are seemingly not affectedby diclofenac. Old world vultures do not reactto other structurally related nonsteroidal anti-inflammatory drugs. Therefore, this ecologi-cal catastrophe would probably not have been

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anticipated by testing. As we will never be ableto test all drugs against all organisms because wedo not have the knowledge, the time, and themoney, other surprises cannot be ruled out inthe future. This example demonstrates clearlythe need to reduce the input and presence ofdrugs into the environment.

A subtle example of indirect effects of antibi-otics was reported by Hahn & Schulz (95). Re-sults of food selection experiments with Gam-marus pulex demonstrated clear preferences forleaves conditioned in the absence versus thoseconditioned in the presence of two antibiotics,oxytetracycline and sulfadiazine.

Antibiotics are one of the most importantgroups of APIs used in medicine, and they arenow present in the aquatic environment (9,79). The unwanted effects of microbial growthhave long been controlled through the use ofantimicrobials such as antibiotics. In general,the emergence of resistance to antimicrobialsis a highly complex process, which is not yetfully understood with respect to the significanceof the interaction of bacterial populations andantibiotics, even in a medicinal environment.Bacteria resistant to antibiotics have been foundin the aquatic environment (79, 96–99). Is theinput of antibiotics into the environment an im-portant factor for the emergence of resistantbacteria in the environment or is the trans-fer of resistance from already resistant bacte-ria following improper use of antibiotics muchmore important than the input of the antibioticcompounds themselves? The links between thepresence of antimicrobials and the favoring ofresistant bacteria as well as the transfer of resis-tance at concentrations as low as those found forantimicrobials in the environment have not yetbeen established. Knowledge of subinhibitoryconcentrations of antimicrobials and their ef-fects on environmental bacteria is scarce andcontradictory, especially with respect to resis-tance (for details, see Reference 79). In anycase, prudent use of antibiotics is crucial for theavoidance of resistance.

Despite the presence of a large numberof different human pharmaceuticals in theenvironment, there are very few documented

EE2: 17-α-ethinylestradiol

examples whereby a pharmaceutical hasbeen conclusively shown to adversely affectan ecosystem. By the 1990s, sex steroidsand, in particular, estrogens, such as 17-α-ethinylestradiol (EE2), were identified in theaquatic environment. They are likely to affectreproduction of fish. EE2 is used exclusivelyin the contraceptive pill. It is widespread inthe aquatic environment, albeit at sub-ng L−1

concentrations in most rivers (75). However,fish are so sensitive to this drug that very low ngL−1 concentrations in their water can changethe female-to-male sex ratio in favor of the fe-males because of a lack of sexual differentiationoccurring in males (76) and lead to populationcrashes (77). Fortunately, real-world con-centrations of EE2 are lower than those thatdramatically affect fish, although the margin ofsafety is not particularly large (75, 78).

One of these examples of medicinal drugson fauna, that of EE2, could, and probablyshould, have been foreseen (18), whereas theother (diclofenac causing the death of old worldvultures) came as a complete surprise.

HAZARDS AND RISKS

The current state of knowledge on possiblehazards for the fauna and flora by the occur-rence of pharmaceuticals in water is stronglylimited. The examples of EE2 and diclofenac,however, as well as the issue of antibiotic re-sistance demonstrate our current lack of abilityto predict the environmental consequences ofwidespread contamination of the environmentby a plethora of human pharmaceuticals. Fur-thermore, the examples of EE2 and diclofenacdemonstrate that, although concentrations ofpharmaceuticals will, in nearly all locations, bevery low, such low concentrations can still, incertain circumstances, exert adverse effects onwildlife. The key uncertainties are in identify-ing which pharmaceuticals are of concern andwhich species are particularly sensitive.

Comprehensive ecotoxicological studies areonly available for a few substances. The rea-son is not only the huge amount of sub-stances, but also the fact that meaningful


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results can only be derived form long-termstudies. The identification of chronic effects,however, comes along with increased tempo-ral and financial costs. Most of the APIs studiedso far exhibit acute toxicity for aquatic organ-isms only at concentrations well above currentmeasurements in surface water.

Data allowing for a sound risk assessmentfor metabolites and transformation productsare missing more or less completely. Further-more, up to now, risk assessments have beenundertaken for single substances only and notfor mixtures. Some of the APIs have carcino-genic, mutagenic, or reproductive toxic effects,so they are called CMR compounds. It is un-clear how such compounds should be handledwithin the risk assessment process (100). A sub-group of this particular group of compoundsis the pharmaceuticals used for anticancertreatment. Information on the fate and effectsin the environment and the significance forhumans is scarce. For cyclophosphamide andifosfamide, for example, risk assessments areavailable. With the use of different databasesand different approaches, the results vary.Some state no risk, whereas others present dataand include additional information that resultin findings that “risk cannot be ruled out”(21). In addition to toxicity, the property ofpersistence is of particular importance for theassessment of the environmental significanceof substances. Persistent organic pollutantsincrease the potential for long-term, variedeffects, and longer exposures may result in mul-tiple contaminations of the ecosystem. Suchproblems cannot be determined in advancewith the presently available test systems (101).

RISK MANAGEMENT

Combinations of management strategies willlikely be most effective in mitigating therisks presented by pharmaceuticals, such aspharmaceutical-return programs, consultingstakeholders, advanced effluent treatment, andincentives for the development of “green”pharmaceuticals (102). All of them are neededfor an effective reduction of the input of phar-

maceuticals (and other chemicals) into the en-vironment. The one strategy that has beenmost extensively discussed within recent yearsis advanced effluent treatment. As for the thirdstrategy, environmental protection has to in-clude the shareholders, stakeholders, and peo-ple using the compounds, i.e., patients, doctors,nurses, and pharmacists when seeking workablesolutions. The fourth strategy is emerging fromthe field of green chemistry. In terms of sustain-ability, it seems to be the most promising onein the long run.

The advanced treatment of effluents hasbeen investigated using (photochemical) oxida-tion processes (e.g., 68, 96, 103), filtration (104,105), application of powdered charcoal (106,107), and constructed wetlands (108). Reviewson the advantages and disadvantages of the dif-ferent technologies are available (12, 109–111).It has been found that each type of advancedeffluent treatment has its specific limitationsand, in general, some severe drawbacks (110–112). For example, mutagenic and toxic proper-ties have been found for the reaction productsof (photo)oxidation processes (28, 30, 67, 68,70, 71). Therefore, advanced effluent treatmentshould not be considered as a general solutionto the problem. Instead, it should be consid-ered only as part of the solution on a case-by-case basis. Hospital contributions to the totalload of pharmaceuticals in municipal wastewa-ter is for most compounds below 10% and usu-ally even below 3% (22, 32, 41, 105, 113–115).Therefore, it is questionable whether separatetreatment of hospital effluent is an economicallyvalid environmental goal.

A major unknown with respect to drugs aspollutants is what fractions of drug residuesoccurring in the ambient environment re-sult from discarded leftover drugs (47, 51).Therefore, proper instructions to doctors,pharmacists, and patients can contribute to thereduction of the input of APIs into the aquaticenvironment (116). Initial results show thatthis approach could help to reduce the inputof pharmaceuticals with unwanted environ-mental properties (A. Wennmalm, personalcommunication). Data are needed on the types,

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quantities, and frequencies with which drugsaccumulate in households, hospitals, facilitiesfor elderly people, and rehabilitation hospitals(51). In a mid- to long-term perspective, pre-scription, therapy, and consultation practicesof physicians and pharmacists as well as thepatients’ use and disposal patterns of pharma-ceuticals should be changed toward a higherenvironmental sensibility. The relationshipbetween physicians and patients plays a key rolewithin this strategy: Knowledge concerning theenvironmental relevance and problems of phar-maceuticals increases the awareness of physi-cians during their consultations with patients.To facilitate the integration of the problemsinto physicians’ everyday practice, the envi-ronmental effects of medicinal drugs should beincluded in the medical education and advancedtraining by instructors of health education andhealth policy. Sources of health funds can fosterthe demand for better ecological alternatives bychanging the funding of, or reimbursement for,pharmaceuticals and therapies. This increaseddemand can support the pharmaceuticalindustry in supplying a sustainable productrange (e.g., varieties of packaging sizes andpotencies).

If an internal commission of a hospital pro-vides a list of recommended pharmaceuticalsthat is the basis for hospital purchasing activ-ities, the variety of products is reduced, result-ing in savings. Limiting the drug storage spacein wards reduces the share of outdated medica-ments and thereby the environmental burden.The internal system should allow the wards togive back not yet outdated, broken, and not yetused packages to the pharmacy. The pharmacistcan handle these remainders properly. A physi-cian familiar with infectious diseases should bepresent to provide advice on the proper use ofantibiotics. Proper hygiene, which is not toomuch and not too little, at the right place andthe right time can also reduce infections and theneed for pharmaceuticals and disinfectants.

At this time, improvement of synthesis isvery prominent in drug design, whereas theenvironmental properties of the molecules aresomewhat underestimated. According to the

Benign by design:the targeted design ofa chemical withoptimized propertiesfor its application andfast and fullmineralization after itreaches theenvironment

principles of green chemistry, the functionalityof a chemical should not only include theproperties of a chemical necessary for itsapplication, but also easy and fast degradabilityafter its use. Taking into account the full lifecycle of pharmaceuticals leads to a differentunderstanding of the functionality necessaryfor a pharmaceutical (112). It means that easydegradability after use or application is takeninto account even before a pharmaceutical’ssynthesis (“benign by design”). Such an ap-proach is not completely new. For example, itis quite common during the development ofpharmaceuticals with respect to unwanted sideeffects. This can also result in economic advan-tages in the long run (102, 112). Researchersand drug companies should apply these prin-ciples and the knowledge of green chemistryto pharmaceuticals. The contributions ofdifferent stakeholders to the managementand mitigation of pharmaceuticals in theenvironment are summarized in Table 1.

GREEN AND SUSTAINABLEPHARMACY

Green pharmacy includes the design ofpharmaceutical products and processes thateliminate or reduce significantly the use andgeneration of hazardous substances and theprevention and/or reduction of environmentalsafety and health impacts at the source (117).“Green” focuses on the pharmaceutical itself,including only the environmental aspects.These are important points. There are ad-ditional considerations. For example, a newpharmaceutical can be green in terms ofthe quality and quantity of waste generatedduring its synthesis, and renewable feedstockmight have been used, but the pharmaceuticalmay accumulate in the environment afterexcretion and create environmental or healthproblems. If reproduction of the renewablefeedstock needs much water and fertilizer, is incompetition with food production, or dependson an endangered species, it may not be calledsustainable. The same holds if the compound it-self is green or even sustainable, but the material


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Table 1 Opportunities to reduce the input of pharmaceuticals into the environmenta

Stakeholders Possible measures and activitiesb

Science andhumanities

Move on to green and sustainable pharmacy, establish together with the pharmaceutical companies andregulators criteria for the quality of data necessary for risk assessment and risk management, introduce findingsinto teaching, begin research into benign compounds and green and sustainable pharmacy, develop models andprocesses for proper information and involvement of stakeholders

Pharmaceuticalcompanies

Publish data relevant for environmental assessment; publish analytical methods and results; offer suitable packagesizes; integrate environmental aspects in the development of new APIs and new therapies; follow green andsustainable pharmacy practices; offer fewer over-the-counter products; establish take-back systems where notalready in place; offer proper information to doctors, pharmacists, and the general public; develop a newunderstanding of and promote shareholder value; and adopt corporate sustainability responsibility

Wholesalers Deliver not only pharmaceuticals but also proper information to usersPatients Improve compliance, take APIs only if necessary and only after prescription by a physician, do not put outdated

medicaments down the drain, return drugs to the pharmacy if a take-back system is established or put into thehousehold waste if appropriate (check with local authorities and pharmacies), do not use lifestyle drugs,investigate alternative treatments such as acupuncture for pain treatment

Pharmacists Inform patients and doctors, participate in take-back systems if appropriate (check with local authorities)Hospitals Integrate the delivering pharmacy/wholesaler into the handling of outdated medicaments, inform doctors and

patients, establish proper procurement, apply the Swedish classification system of pharmaceuticals(http://www.fass.se)

Physicians Prescribe medication according to environmental criteria if alternatives are available, apply the Swedishclassification system of pharmaceuticals (http://www.fass.se), provide proper disposal information to patients

Health insurancecompanies

Maintain appropriate medical standards for pharmaceuticals; inform doctors, pharmacists, and patients of theproper ways to use and dispose of drugs; apply the Swedish classification system of pharmaceuticals(http://www.fass.se); and create incentives for companies to dedicate themselves to sustainable pharmacy

Wastewaterhandling andtreatment

Repair broken sewers and piping, reduce total water flow treated by separate piping of wastewater and rain waterand thereby increase the concentration of APIs, apply affordable technologies, develop less water- andenergy-demanding treatment systems and technologies, establish appropriateness of advanced treatment on acase-by-case basis

Drinking watertreatment

Extend monitoring, use advanced treatment if necessary, inform the general public about the issue ofpharmaceuticals in the environment

Banks Include sustainability in the rating of pharmaceutical companiesAuthorities/governmentagencies

Initiate communication between all stakeholders; develop limits and/or thresholds for APIs in differentenvironmental areas and in drinking water; include APIs in environmental legislation; establish a morerestrictive connection between environmental properties and the authorization of human pharmaceuticals;improve legislation for the management of outdated medicaments; establish incentives for the development ofgreener drugs, e.g., prolonged patent lifetime and funds for research; establish a country-adapted classificationsystem for pharmaceuticals as is already in place in Sweden

aSource: Reference 7.bAPI, active pharmaceutical ingredient.

flows connected to its production, distribution,and usage are very large (in terms of quantityand/or in terms of quality) or depend onnonrenewable resources. Another point is thatgreener products or chemicals may become lessgreen or even problematic if they are producedand applied in high volumes. For example, if agreen packaging material contains an antimi-

crobial to preserve its content, such as foodfrom spoilage, this antimicrobial can contributeto resistance by being transferred to the foodor by being set free into the environment whenthe packaging is discarded. Thus, a packagingmay be green but not sustainable. A sustainableview is much broader (118). It would also askwhat the origin of the food is (local, regional, or

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distant source) and how long we want—versuswe need—to store it. Educating people on howto handle and store food properly would be amuch more sustainable approach to reduce foodspoilage rather than increasing the risk of an-tibiotic resistance via antibiotic packaging.

These examples demonstrate the need tokeep the full life cycle in focus (Figure 5). Thisalso includes other aspects, such as corporatesocial responsibility and ethical questions. Forexample, one may argue that we cannot affordsustainable pharmaceuticals because this wouldresult in fewer active compounds reaching themarket. Or is every pharmaceutical sustainablesince it offers some benefit? However, a dif-ferent viewpoint is to consider how many peo-ple do not have access to suitable medication atall (119), e.g., for financial reasons. Or why arethere symptoms for which no new pharmaceuti-cals are available? What are the costs comparedto the benefits? What are undesirable side ef-fects?

In 2002, the European Parliament and theEuropean Commission agreed that within ageneration chemicals should be produced andapplied that do not have any impact on theenvironment (120). This should also hold forpharmaceuticals.

Raw materials

Manufacturing

Use

Excretion and disposal

Synthesis

Design

Distribution and storage

Treatment

Effectivity, efficacy, specifity, side effects, environment

Petrol based, renewable, GMOs, patented organisms

Energy, water, waste, solvent, exhaust, E-factor

Packaging

Energy, waste, exhaust, E-factor

Material, waste, exhaust, noise

Selling Carbon dioxide emissions, ethics

Carbon dioxide emissions, safety, stability

Energy, effectivity, efficacy, specifity, stability persistency, unwanted by-products

Effectivity, efficacy, specifity, safety, compliance, costs, availability

Package size, information, safety

Figure 5The life cycle of a pharmaceutical and some selected points that are relevant forsustainability. Reproduced with permission from Reference 118.

SUMMARY POINTS

1. Pharmaceuticals and other chemical compounds are present as mixtures in drinking waterand the environment.

2. Some pharmaceuticals are transformed to other products (i.e., metabolites and transfor-mation products).

3. Effects and risk assessments are now performed based on single compounds.

4. Knowledge of the fate, effects, and risk of pharmaceutical discharge into the environmentis not sufficient for a final risk assessment.

5. Different measures are part of risk management.

6. Benign by design is the main building block of green and sustainable pharmacy, whichis the paradigm of the future.


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FUTURE ISSUES

Directions for future research include the following:1. Reduced release of pharmaceuticals into the environment;

2. Improved knowledge of the fate, effects, and risks of pharmaceuticals into the environ-ment, including the mixtures and transformation products;

3. Distribution of proper information to patients, pharmacists, and physicians;

4. Improvement of sewage treatment;

5. Improvement in the (bio)degradability of pharmaceuticals (benign by design pharma-ceuticals);

6. Promotion of sustainable pharmacy; and

7. Introduction of sustainable pharmacy in the curricula of physicians and pharmacists.

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

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of the Council of 22 July 2002 laying down the Sixth Community Environment ActionProgramme. 10.9.2002. Off. J. Eur. Communities L242/1–15, 2002. 24. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2002:242:0001:0015:EN:PDF


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Deposition,resuspension,

and desorption

Dilution andDilution anddiffusiondiffusion

Dilution anddiffusion

Biodegradation andBiodegradation andtransformationtransformation

Biodegradation andtransformation

HydrolysisHydrolysis

PhotolysisPhotolysis

Hydrolysis

Photolysis

Municipal or industrialMunicipal or industrialsewage dischargesewage discharge

Municipal or industrialsewage discharge

VolatilizationVolatilizationto atmosphereto atmosphereVolatilization

to atmosphere

SorptionSorptiononto sedimentsonto sediments

Sorptiononto sediments

Deposition andaccumulation

Bioconcentration

Dep

osit

ion

Parti

cle transport

Parti

cle transport

Dissolved transport

Dissolved transport

Figure 1Fate of pollutants in the aquatic environment (source: U.S. Geological Survey, http://toxics.usgs.gov/regional/emc/transport_fate.html).

www.annualreviews.org • Pharmaceuticals in the Environment C-1

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EG35-FM ARI 18 September 2010 7:49

Annual Review ofEnvironmentand Resources

Volume 35, 2010 Contents

Preface � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �v

Who Should Read This Series? � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �vii

I. Earth’s Life Support Systems

Human Involvement in Food WebsDonald R. Strong and Kenneth T. Frank � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Invasive Species, Environmental Change and Management, and HealthPetr Pysek and David M. Richardson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �25

Pharmaceuticals in the EnvironmentKlaus Kummerer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �57

II. Human Use of Environment and Resources

Competing Dimensions of Energy Security: An InternationalPerspectiveBenjamin K. Sovacool and Marilyn A. Brown � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �77

Global Water Pollution and Human HealthRene P. Schwarzenbach, Thomas Egli, Thomas B. Hofstetter, Urs von Gunten,

and Bernhard Wehrli � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 109

Biological Diversity in Agriculture and Global ChangeKarl S. Zimmerer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 137

The New Geography of Contemporary Urbanization and theEnvironmentKaren C. Seto, Roberto Sanchez-Rodrıguez, and Michail Fragkias � � � � � � � � � � � � � � � � � � � � � 167

Green Consumption: Behavior and NormsKen Peattie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 195

viii

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EG35-FM ARI 18 September 2010 7:49

III. Management, Guidance, and Governance of Resources and Environment

Cities and the Governing of Climate ChangeHarriet Bulkeley � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 229

The Rescaling of Global Environmental PoliticsLiliana B. Andonova and Ronald B. Mitchell � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 255

Climate RiskNathan E. Hultman, David M. Hassenzahl, and Steve Rayner � � � � � � � � � � � � � � � � � � � � � � � � � 283

Evaluating Energy Efficiency Policies with Energy-Economy ModelsLuis Mundaca, Lena Neij, Ernst Worrell, and Michael McNeil � � � � � � � � � � � � � � � � � � � � � � � � � 305

The State of the Field of Environmental HistoryJ.R. McNeill � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 345

Indexes

Cumulative Index of Contributing Authors, Volumes 26–35 � � � � � � � � � � � � � � � � � � � � � � � � � � � 375

Cumulative Index of Chapter Titles, Volumes 26–35 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 379

Errata

An online log of corrections to Annual Review of Environment and Resources articles maybe found at http://environ.annualreviews.org

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