44630 9789241502085 Eng

User Manual: 44630

Open the PDF directly: View PDF .
Page Count: 52

PHARMACEUTICALS

IN DRINKING-WATER

PHARMACEUTICALS

IN DRINKING-WATER

PHARMACEUTICALS

IN DRINKING-WATER

WHO Library Cataloguing-in-Publication Data

Pharmaceuticals in drinking-water.

1.Water pollutants, Chemical. 2.Pharmaceutical preparations. 3.Water puriﬁcation. 4.Potable water. I.World Health Organization.

ISBN 978 92 4 150208 5 (NLM classiﬁcation: WA 30.5)

from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791

4857; e-mail: bookorders@who.int).

Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be

addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on

the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning

the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full

agreement.

The mention of speciﬁc companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the

World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of

proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However,

the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation

and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

Design by paprika-annecy.com

Printed in France

Contents

List of acronyms and abbreviations vi

Acknowledgements vii

Executive summary viii

1. Occurrence of pharmaceuticals in water 1

1.1 Advances in analytical and detection methods 3

1.2 Occurrence of pharmaceuticals in surface water 4

1.3 Occurrence of pharmaceuticals in drinking-water 6

1.4 Conclusion 6

2. Human health risk assessment for pharmaceuticals in

drinking-water 7

2.1 Introduction 8

2.2 Assessing risks associated with pharmaceuticals in drinking-water 8

2.3 Applying the MTD approach: a Drinking Water Inspectorate study 10

2.4 Applying the ADI approach 12

2.4.1 Awwa Research Foundation study 12

2.4.2 Australian Guidelines for Water Recycling 13

2.5 Conclusion 13

3. Treatment technologies for removal of pharmaceuticals

from water 15

3.1 Introduction 16

3.2 Removal of pharmaceuticals by wastewater treatment processes 16

3.3 Removal of pharmaceuticals by drinking-water treatment processes 18

3.4 Conclusion 20

4. Preventing pharmaceuticals in drinking-water 23

4.1 Improved regulations and guidance on pharmaceutical waste

management 24

4.2 Pharmaceutical take-back programmes 25

4.3 Raising consumer awareness 26

4.4 Conclusion 26

5. Conclusions, recommendations and knowledge gaps 27

5.1 Conclusions 28

5.2 Recommendations 28

5.3 Knowledge gaps and future research 29

References 30

List of acronyms and abbreviations

ADI acceptable daily intake

DWEL drinking-water equivalent level

EDC endocrine disrupting chemical

FAO Food and Agriculture Organization of the United Nations

GAC granular activated carbon

GC gas chromatography

LC liquid chromatography

LOAEL lowest-observed-adverse-effect level

LOQ limit of quantiﬁcation

MF microﬁltration

MOE margin of exposure

MS mass spectrometry

MS/MS tandem mass spectrometry

MTD minimum therapeutic dose

nd not detected

NF nanoﬁltration

NOAEL no-observed-adverse-effect level

NSAID non-steroidal anti-inﬂammatory drug

PAC powdered activated carbon

PoD point of departure

PUB Public Utilities Board (Singapore)

RO reverse osmosis

SF sand ﬁltration

TDI tolerable daily intake

UF ultraﬁltration

USA United States of America

USEPA United States Environmental Protection Agency

UV ultraviolet

WHO World Health Organization

WSH Water, Sanitation, Hygiene and Health unit (WHO)

vii

The World Health Organization (WHO) wishes to express its appreciation to all those who contributed to the preparation and development of this document

through the provision of their time, expertise and experience.

WHO thanks the United States Environmental Protection Agency (USEPA) and Public Utilities Board (PUB) Singapore for their ﬁnancial and technical support in

developing this guidance to address an emerging issue for drinking-water.

WHO acknowledges the contributions of the members of the Working Group on Pharmaceuticals in Drinking-water, who provided important technical inputs for

WHO’s consideration in the development of this document. The working group members are:

• Dr Joe Cotruvo, Independent Consultant, Joseph Cotruvo and Associates, United States of America (USA)

• Dr Mary Couper, formerly Quality Assurance and Safety: Medicines, WHO, Switzerland

• Dr David Cunliffe, Department of Health, Environmental Health Service, Australia

• Mr John Fawell, Independent Consultant, England

• Ms Michèle Giddings, Water, Air and Climate Change Bureau, Health Canada, Canada

• Dr Edward Ohanian, USEPA, USA

• Professor Choon Nam Ong, National University of Singapore, Singapore

• Dr Hans Sanderson, Danish National Environmental Research Institute, Aarhus University, Denmark

• Dr Dai Simizaki, National Institute of Public Health, Japan

• Professor Giampaolo Velo, University of Verona, Italy

Special appreciation is extended to Mr John Fawell, independent consultant, England, who provided valuable time and technical expertise in the development

of this document. Appreciation also goes to Dr Emma Goslan, Cranﬁeld University, England, who contributed technical inputs to the chapter on the efﬁcacy of

removal of pharmaceuticals during wastewater and drinking-water treatment.

The development and production of this document were coordinated and managed by staff of the Water, Sanitation, Hygiene and Health (WSH) unit of WHO,

including Mr Robert Bos (Coordinator, WSH), Mr Bruce Gordon and Mr Chee-Keong Chew (technical ofﬁcers). Ms Carolyn Vickers and Dr Angelika Tritscher,

WHO Headquarters, provided valuable inputs related to chemical risk assessments.

The professional editing services of Ms Marla Sheffer of Ottawa, Canada, and the secretarial support provided by Ms Penny Ward are also gratefully

acknowledged.

Acknowledgements

viii

Background

In the last decade, traces of pharmaceuticals, typically at levels in the nanograms

to low micrograms per litre range, have been reported in the water cycle,

including surface waters, wastewater, groundwater and, to a lesser extent,

drinking-water. Advances in analytical technology have been a key factor

driving their increased detection. Their presence in water, even at these very

low concentrations, has raised concerns among stakeholders, such as drinking-

water regulators, governments, water suppliers and the public, regarding the

potential risks to human health from exposure to traces of pharmaceuticals via

drinking-water.

Following requests from several Member States for information regarding

the potential health impacts of residual concentrations of pharmaceuticals in

drinking-water, this issue was added to the work plan of the World Health

Organization (WHO) Drinking-water Quality Committee in 2005. It was

proposed that a working group of experts be assembled to undertake a rapid

review of the state of the science of pharmaceuticals in drinking-water and

develop guidance and recommendations in a report and fact sheet.

A WHO working group that comprised experts in toxicology, water chemistry,

water quality and health, water treatment, pharmacology, and drinking-water

regulation and policy was formed in 2009. Consultations were held in 2009

and 2010 with the Drinking-water Quality Committee and additional experts

to review and summarize the available scientiﬁc knowledge and evidence.

A literature review was a key source of evidence. This examined the fate and

occurrence of pharmaceuticals in water, exposure to pharmaceuticals in drinking-

water, assessment of the human health risk associated with pharmaceuticals

in drinking-water, removal of pharmaceuticals during wastewater and drinking-

water treatment, and preventive management measures to reduce potential

exposure to pharmaceuticals in drinking-water.

This report, originally published in 2011

1, contains the key ﬁndings and

recommendations of the working group and consultations with experts in the

Drinking Water Quality Committee. It aims to provide practical guidance and

recommendations for managing the emerging concern about pharmaceuticals in

drinking-water, taking into consideration the evidence from the literature review.

1 This publication is the professionally designed version of the technical document, WHO/HSE/

WSH/11.05. This version supercedes the 2011 version.

More importantly, it emphasizes the need to prioritize this emerging issue in the

overall context of water safety management, which includes microbial and other

chemical risks that may threaten the safety of drinking-water.

Scope

This report focuses primarily on reviewing the risks to human health associated

with exposure to trace concentrations of pharmaceuticals in drinking-water. It

does not discuss the potential impacts on aquatic ecosystems or the broader

physical environment.

Occurrence of pharmaceuticals in water

Pharmaceuticals are synthetic or natural chemicals that can be found in

prescription medicines, over-the-counter therapeutic drugs and veterinary

drugs. Pharmaceuticals contain active ingredients that have been designed

to have pharmacological effects and confer signiﬁcant beneﬁts to society.

The occurrence of pharmaceuticals in the environment and the water cycle

at trace levels (in the range of nanograms to low micrograms per litre) has

been widely discussed and published in literature in the past decade. The

increase in detection is largely attributable to the advances in analytical

techniques and instrumentation. Many surveys and studies have conﬁrmed

the presence of pharmaceuticals in municipal wastewater and efﬂuents,

and these have been identiﬁed as a major source of pharmaceuticals in

drinking-water (Figure ES1).

Routine monitoring programmes to test drinking-water for pharmaceuticals

have not been implemented, as is the case for regulated chemical and

microbial parameters. Generally, data on the occurrence of pharmaceuticals

in drinking-water have resulted from ad hoc surveys or targeted research

projects and investigations. Available studies have reported that concentrations

of pharmaceuticals in surface waters, groundwater and partially treated

water are typically less than 0.1 µg/l (or 100 ng/l), and concentrations in

treated water are generally below 0.05 µg/l (or 50 ng/l).

More systematic studies will help to further our understanding of the transport,

occurrence and fate of pharmaceuticals in the environment, especially

drinking-water sources. Standardization of protocols for sampling and

analysing pharmaceuticals would help to facilitate the comparison of data.

Executive summary

Human health risk assessment for

pharmaceuticals in drinking-water

Pharmaceuticals are normally governed by stringent regulatory processes and

require rigorous preclinical and clinical studies to assess their efﬁcacy and

safety before commercialization. Therefore, pharmaceuticals are generally

better characterized than other environmental contaminants.

This report reviews human health risk assessments of pharmaceuticals in

drinking-water conducted in the United Kingdom, Australia and the United

States of America (USA). The approaches of acceptable daily intake

(ADI) or minimum therapeutic dose (MTD) were adopted as the point of

departure (PoD) in these studies to assess potential risks to human health

through exposure to pharmaceuticals in drinking-water. Margins of exposure

(MOEs) were derived by comparing measured or modelled exposure levels

in drinking-water with a reference exposure concentration, which was usually

the ADI or MTD or sometimes a drinking-water equivalent level (DWEL). A

judgement of safety could then be based on the magnitude of this MOE for

the pharmaceutical under consideration. In other words, screening values to

determine whether further action is warranted could be derived from the ADI

or the MTD, with uncertainty factors applied as appropriate.

Analysis of the results indicated that appreciable adverse health impacts

to humans are very unlikely from exposure to the trace concentrations

of pharmaceuticals that could potentially be found in drinking-water.

Figure ES1: Fate and transport of pharmaceuticals in the environment (adapted from Ternes, 1998)

Note: STP is sewage treatment plant

Human drugs

Veterinarydrugs•Feedadditives

Drinking-water

excretion

disposal

excretion

sewage

waste

(liquid) manure

STP

landﬁll site

soil

surface water groundwater

(runoff)

(digested sludge)

(leakages)

Concentrations of pharmaceuticals in drinking-water are generally more than

1000-fold below the MTD, which is the lowest clinically active dosage. The

ﬁndings from these three case-studies are in line with the evidence published

over the past decade, which suggests that appreciable risks to health arising

from exposure to trace levels of pharmaceuticals in drinking-water are

extremely unlikely.

Treatment technologies for removal of

pharmaceuticals from drinking-water

Having established that raw sewage and wastewater efﬂuents are a major

source of pharmaceuticals found in surface waters and drinking-water, it is

important to consider and characterize the efﬁciency of processes for the

removal of pharmaceuticals during wastewater and drinking-water treatment.

Most of the research has been conducted at the laboratory scale or at full

scale in developed countries, including the USA, Japan, the Republic of

Korea and countries in Europe.

Even though wastewater and drinking-water treatment processes are not

designed speciﬁcally to remove pharmaceuticals, they may do so to

varying degrees. Pharmaceuticals are not “unusual” chemicals; their removal

efﬁciencies during wastewater and drinking-water treatment are dependent

on their physical and chemical properties. In cases where regulations require

controls to mitigate risks from exposure to pesticides, treatment barriers may

already be optimized to remove pharmaceuticals.

Conventional wastewater treatment facilities generally have activated sludge

processes or other forms of biological treatment such as bioﬁltration. These

processes have demonstrated varying removal rates for pharmaceuticals,

ranging from less than 20% to greater than 90%. The efﬁciency of these

processes for the removal of pharmaceuticals varies within and between

studies and is dependent on operational conﬁguration of the wastewater

treatment facility. Factors inﬂuencing removal include sludge age, activated

sludge tank temperature and hydraulic retention time. Comparatively,

advanced wastewater treatment processes, such as reverse osmosis,

ozonation and advanced oxidation technologies, can achieve higher removal

rates for pharmaceuticals.

Studies on conventional drinking-water treatment processes have shown

that coagulation is largely ineffective in removing pharmaceuticals. Free

chlorine is able to remove up to approximately 50% of the pharmaceuticals

investigated, whereas chloramines have lower removal efﬁciency.

Compounds that showed high removal by free chlorine but low removal

by chloramines include antibiotics, such as sulfamethoxazole, trimethroprim

and erythromycin.

Advanced water treatment processes, such as ozonation, advanced

oxidation, activated carbon and membranes (e.g. nanoﬁltration, reverse

osmosis), are able to achieve higher removal rates (above 99%) for targeted

pharmaceutical compounds in various studies in the published literature.

Advanced and costly water treatment technology will not be able to

completely remove all pharmaceuticals to concentrations less than the

detection limits of the most sensitive analytical procedures at all times.

Therefore, it is imperative that the toxicological relevance of various

compounds be considered in the context of appreciable risks to human

health. An informed risk assessment is essential before scarce resources are

allocated to upgrade or invest in additional advanced treatment processes

to reduce trace concentrations of pharmaceuticals in drinking-water.

Preventing pharmaceuticals in drinking-

water

Conventional drinking-water quality monitoring that focuses on end-product

testing is resource intensive in terms of capital investment and human

resources. Coupled with an expanding list of chemical contaminants in

drinking-water and water sources that may be of insigniﬁcant health concern,

an overemphasis on end-product monitoring and the upgrading of treatment

infrastructure is not a sustainable, optimal use of limited resources.

As outlined in the WHO Guidelines for Drinking-water Quality, the water

safety plan approach is “the most effective means of consistently ensuring

the safety of a drinking-water supply … through the use of a comprehensive

risk assessment and risk management approach that encompasses all

steps in the water supply from catchment to consumer”. Water safety plans

highlight the importance of considering risk assessment and risk management

comprehensively from source to tap and adopting preventive measures to

address the source of risks.

Adapting the water safety plan approach to the context of pharmaceuticals

in drinking-water means that preventing pharmaceuticals from entering the

water supply cycle during their production, consumption (i.e. excretion) and

disposal is a pragmatic and effective means of risk management. Preventive

measures need to be applied as close as possible to the source of the risk

and hazard.

Inappropriate disposal practices, such as ﬂushing unwanted or excess

drugs down toilets and sinks and discarding them into household waste, are

common and may be the main contributors to pharmaceuticals in wastewater

and other environmental media, such as surface waters and landﬁll leachate.

Preventive measures, such as policies promoting or regulations governing

disposal practices at concentrated point sources (e.g. health-care and

veterinary facilities), can reduce the amount of pharmaceutical waste entering

water bodies. In addition, take-back programmes, guidance and enhanced

consumer education will support efforts for the proper disposal of medicines

and reduce the impact of pharmaceuticals entering our water sources.

Conclusions

Published literature and national studies have shown that concentrations of

pharmaceuticals in surface water and groundwater sources impacted by

wastewater discharges are typically less than 0.1 µg/l (or 100 ng/l), and

concentrations in treated drinking-water are usually well below 0.05 µg/l (or

50 ng/l). There are few comprehensive, systematic studies on the occurrence

of pharmaceuticals in drinking-water. Limited data on the occurrence of

pharmaceuticals in drinking-water are a challenge in assessing potential

human health risks from exposure to trace concentrations of pharmaceuticals

in drinking-water.

Several approaches to screen and prioritize pharmaceuticals have been

published in peer-reviewed literature. These approaches usually apply the

principles of the PoD to derive an MOE between the reported worst-case

exposure and the MTD, the ADI or sometimes the DWEL.

Targeted investigations conducted in the United Kingdom, the USA and

Australia found that pharmaceuticals are largely present in drinking-water

at concentrations several orders of magnitude (more than 1000-fold) below

the MTD and largely below the calculated ADIs and DWELs. The substantial

margins of safety for individual compounds suggest that appreciable adverse

impacts on human health are very unlikely at current levels of exposure in

drinking-water.

From a treatment perspective, pharmaceuticals are not unusual organic

chemicals, and treatment removal rates depend on the physical and

chemical properties of the compounds. Conventional treatment processes

with chlorination (free chlorine) can remove about 50% of these compounds,

whereas advanced treatment processes, such as ozonation, advanced

oxidation, activated carbon and membranes (e.g. reverse osmosis,

nanoﬁltration), can achieve higher removal rates; reverse osmosis, for

example, can remove more than 99% of large pharmaceutical molecules.

Recommendations

Trace quantities of pharmaceuticals in drinking-water are very unlikely to pose

risks to human health because of the substantial MOE or margin of safety

between the concentrations detected and the concentrations likely to evoke

a pharmacological effect.

Concerns over pharmaceuticals should not divert the attention and valuable

resources of water suppliers and regulators from the various bacterial, viral

and protozoan waterborne pathogens and other chemical priorities, such as

lead and arsenic.

The current levels of exposure to pharmaceuticals in drinking-water also

suggest that the development of formal guideline values for pharmaceuticals

in the WHO Guidelines for Drinking-water Quality is unwarranted.

Routine monitoring of pharmaceuticals in water sources and drinking-

water at the national level and the installation of specialized drinking-

water treatment infrastructure to reduce the very low concentrations of

pharmaceuticals in drinking-water are not currently deemed necessary

given the limited additional health beneﬁts. However, where speciﬁc

circumstances, such as a catchment survey, indicate a potential for elevated

concentrations of pharmaceuticals in the water cycle (surface water,

groundwater, wastewater efﬂuent and drinking-water), relevant stakeholders

could undertake targeted, well-designed and quality-controlled investigative

studies to obtain more information to assess potential health risks arising

from exposure through drinking-water. If necessary, screening values could

be developed and an assessment of the need for treatment enhancement

could also be considered within the context of other risks and priorities using

the water safety plan.

Human exposure to pharmaceuticals through drinking-water can be

reduced through a combination of preventive measures, such as take-back

programmes, regulations, public guidance and consumer education to

encourage the proper disposal of unwanted pharmaceuticals and minimize

the introduction of pharmaceuticals into the environment.

xii

Enhanced risk communication to the public and public education efforts on

water quality issues from the human health standpoint will help the public

to better understand this issue relative to other hazards, such as pathogenic

microbial risks. This means conveying the risks of exposure to very low

concentrations of pharmaceuticals in drinking-water to the public using plain

language.

Knowledge gaps and future research

Although current published risk assessments indicate that trace concentrations

of pharmaceuticals in drinking-water are very unlikely to pose risks to human

health, knowledge gaps exist in terms of assessing risks associated with long-

term exposure to low concentrations of pharmaceuticals and the combined

effects of mixtures of pharmaceuticals.

Future research in these areas may be beneﬁcial to better characterize

potential health risks from long-term, low-level exposure to pharmaceuticals,

particularly for sensitive subpopulations.

One of the key challenges in estimating exposures to pharmaceuticals

in drinking-water and assessing the potential risks to human health is the

limited occurrence data for such a diverse group of human and veterinary

pharmaceuticals. Implementing monitoring programmes is resource intensive

in terms of costs, human resources and infrastructure, and there is also a lack of

standardized sampling and analysis protocols to support monitoring studies.

Future research should focus on ﬁlling these knowledge gaps, including by

providing support to practitioners through the development of cost-effective

methods and protocols for prioritizing pharmaceuticals within the context of

an overall risk assessment for all drinking-water hazards.

Noting that pharmaceuticals in drinking-water are an emerging issue, WHO

will continue to review relevant scientiﬁc evidence and, where necessary,

update the guidance provided in this report.

1Occurrence of

pharmaceuticals in water

1. Occurrence of pharmaceuticals in water

Pharmaceuticals are synthetic or natural chemicals that can be found in

prescription medicines, over-the-counter therapeutic drugs and veterinary drugs,

and they contain active ingredients that evoke pharmacological effects and

confer signiﬁcant beneﬁts to society. The ubiquitous use of pharmaceuticals

in human and veterinary medical practices, aquaculture and agricultural

products has led to the continual release of a wide array of pharmaceutical

chemicals into our environment. As illustrated in Figure 1, pharmaceuticals

enter the environment through many routes, including human or animal excreta,

wastewater efﬂuent, treated sewage sludge, industrial waste, medical waste

from health-care and veterinary facilities, landﬁll leachate and biosolids.

Pharmaceuticals and their metabolites undergo natural attenuation by

adsorption, dilution or degradation in the environment, depending on their

hydrophobicity and biodegradability and on the temperature. Therefore,

pharmaceuticals in water sources and drinking-water are often present at

trace concentrations, as these compounds would have undergone metabolism

and removal through natural processes and, if applicable, wastewater and

drinking-water treatment processes.

Figure 1: Fate of pharmaceuticals in the environment (adapted from Ternes, 1998)

Human drugs

Veterinarydrugs•Feedadditives

Drinking-water

excretion

disposal

excretion

sewage

waste

(liquid) manure

STP

landﬁll site

soil

surface water groundwater

(runoff)

(digested sludge)

(leakages)

Note: STP is sewage treatment plant

1.1 Advances in analytical and

detection methods

The increase in reported detections of very low concentrations of

pharmaceuticals in various environmental matrices, including the water cycle

(e.g. surface water, groundwater, treated wastewater efﬂuent and drinking-

water), is mainly attributable to technological advances in the sensitivity and

accuracy of detection equipment and analytical methods. Gas chromatography

with mass spectrometry (GC-MS) or tandem mass spectrometry (GC-MS/MS)

and liquid chromatography with mass spectrometry (LC-MS) or tandem mass

spectrometry (LC-MS/MS)2 are advanced methods that are able to determine

target compounds to the nanogram per litre level and are commonly applied

for the detection of pharmaceutical compounds in water and wastewater. The

selection of methods is dependent on the physical and chemical properties of

the target compound. LC-MS/MS analysis is more suitable for measuring target

compounds that are more polar and highly soluble in water, whereas GC-MS/

MS is better for more volatile target compounds. Figure 2 provides examples

of pharmaceuticals in water and wastewater that can be detected using these

advanced analytical methods (Fatta et al., 2007).

Whereas improved detection and analytical capabilities will allow us to

learn more about the fate and occurrence of pharmaceutical chemicals in the

environment, including the water cycle, it is important to recognize that detection

of these compounds does not directly correlate to human health risks that could

be veriﬁed by available human risk assessment methods. In addition, there is

currently no standardized practice or protocol for the sampling and analytical

determination of pharmaceuticals in water or any other environmental media

that ensures the comparability and quality of the data generated.

2 GC-MS/MS and LC-MS/MS are referred to as GC-MS2 and LC-MS2, respectively, in Figure 2.

Figure 2: An illustration of analytical methods applied to detect pharmaceuticals in

water and wastewater (adapted from Fatta et al., 2007)

GC-MS or GC-MS2

without derivatization

Aspirin

Codeine

Cyclophosphamide

Galaxolide

Pentoxyfylline

Tonalide

Triclosan

LC-MS or LC-MS2

17α-Ethinylestradiol

17β-Estradiol

Acetyl-sulfamethoxazole

Amidotrizoic acid

Aminopyrine

Amoxycillin

Anhydro-erythromycin

Atenolol

Betaxolol

Bisoprolol

Chloramphenicol

Chlortetracycline

Ciproﬂoxacin

Clarithromycin

Clenbuterol

Cloxacillin

Cyclophosphamide

Dapsone

Demethyl diazepam

Dextropropoxyphene

Dicloxacillin

Doxycycline

Estrone

Hydrochlorothiazide

Iopamidol

Lofepramine

Metronidazole

Oﬂoxacin

Enalapril

Furazolidone

Ifosfamide

Ketorolac

Methicillin

Nafcillin

Erythromycin

Furosemide

Iomeprol

Lincomycin

Methotrexate

Norﬂoxacin

Oleandomycin

Simvastatin

Sotalol

Omeprazole

Oxacillin

Oxytetracycline

Penicillin G

Penicillin V

Pindolol

Piroxicam

Ranitidine

Ronidazole

Spiramycin

Sulfacetamide

Sulfadiazine

Sulfadimethoxine

Sulfadimidine

Sulfaguanidine

Sulfamethazine

Sulfapyridine

Sulfasalazine

Sulfathiazine

Tamoxifen

Terbutaline

Tetracycline

Tilmicosin

Trimethoprim

Tylosin

Virginiamycin

GC-MS or GC-MS2

after derivatization

Aspirin

Etoﬁbrate

Etofyllincloﬁbrat

Flurbiprofen

Ketoprofen

Nadolol

Tolfenamic acid

Carbamazepine

Diazepam

Ibuprofen

Paracetamol

Phenazone Bezaﬁbrate

Cloﬁbrate

Diclofenac

Fenoﬁbrate

Fenoprofen

Gemﬁbrozil

Indomethacine

Iopromide

Mefenamic acid

Metoprolol

Naproxen

Propranolol

Propyphenazone

Roxithromycin

Salbutamol

Sulfamethoxazole

1.2 Occurrence of pharmaceuticals in

surface water

Scientists demonstrated the presence of pharmaceuticals in the environment

more than 30 years ago, with studies in the United States of America (USA)

in the 1970s that reported the presence of heart medications, pain relievers

and birth control medications in wastewater (Tabak & Bunch, 1970; Garrison,

Pope & Allen, 1976; Hignite & Azarnoff, 1977). The most cited reference in

the peer-reviewed literature on the occurrence of pharmaceuticals in surface

waters is the survey by the United States Geological Survey, in which more

than 50 pharmaceuticals in 139 streams across 30 states in the USA were

investigated during 1999 and 2000 (Kolpin et al., 2002).

Many peer-reviewed and published studies have shown that the primary

sources of pharmaceuticals entering surface water are from excretion and

bathing through treated or untreated municipal wastewater efﬂuent discharges

into receiving surface water bodies (Buser, Muller & Theobald, 1998; Ternes,

1998; Buser, Poiger & Muller, 1999; Daughton & Ternes, 1999; Daughton,

2001; Heberer et al., 2001; Heberer, Reddersen & Mechlinski, 2002; Kolpin

et al., 2002) and improper disposal of pharmaceutical waste and excess

medication by consumers and health-care and veterinary facilities into sewers

and drains. Table 1 illustrates several classes of pharmaceuticals found in

wastewater inﬂuent in a study conducted by the Drinking Water Inspectorate

in the United Kingdom.

A monitoring programme in the United Kingdom focused on 12 pharmaceutical

compounds or their metabolites in surface waters (Ashton, Hilton & Thomas,

2004). The results showed that a range of pharmaceuticals from different

therapeutic classes were present in both efﬂuents from sewage treatment works

and receiving waters in England. The values reported were within the same

range as those reported in continental Europe and the USA, where more

extensive monitoring has been conducted. Results in the published literature

for studies conducted in the USA and Europe also suggest that usage data

are positively associated with concentrations of pharmaceuticals measured in

efﬂuent and in surface water bodies receiving the treated efﬂuent. Tables 2

and 3 show additional illustrative examples of pharmaceuticals that have been

found in the United Kingdom and other European countries, respectively.

Table 1. Excretion rates of unmetabolized active ingredients for

selected pharmaceuticals

Compound Pharmaceutical

product group

Parent

compound

excreted (%)

Reference

Amoxycillin Antibiotic 60 Bound & Voulvoulis (2005)

Atenolol Beta blocker 90 Bound & Voulvoulis (2005)

Bezaﬁbrate Lipid regulator 50 Bound & Voulvoulis (2005)

Carbamazepine Antiepileptic 3Bound & Voulvoulis (2005)

Cetirizine Antihistamine 50 Bound & Voulvoulis (2005)

Cloﬁbric acid Active metabolite 6 Alder et al. (2006)

Diclofenac Anti-inﬂammatory 15 Alder et al. (2006)

Erythromycin Antibiotic 25 Bound & Voulvoulis (2005)

Felbamate Antiepileptic 40–50 Bound & Voulvoulis (2005)

Ibuprofen Analgesic 10 Bound & Voulvoulis (2005)

Source: DWI (2007)

Table 2. Measured concentrations of selected pharmaceuticals in the aquatic environment in the United Kingdom

Compound Median (maximum) concentration (ng/l) References

Sewage treatment works efﬂuent Stream or river waters

Bleomycin 11 (19 ) nd (17) Aherne, Hardcastle & Nield (1990)

Clotrimazole 14 (27) 21 (34) Roberts & Thomas (2006)

—7 (22) Thomas & Hilton (2004)

Diclofenac 424 (2349) < LOQ (568) Ashton, Hilton & Thomas (2004)

289 (598) < LOQ Roberts & Thomas (2006)

— < LOQ (195) Thomas & Hilton (2004)

Dextropropoxyphene 195 (585) 58 (682) Ashton, Hilton & Thomas (2004)

37 (64) 12 ( 98) Roberts & Thomas (2006)

Erythromycin — < LOQ (80) Thomas & Hilton (2004)

< LOQ (1842) < LOQ (1022) Ashton, Hilton & Thomas (2004)

Fluoxetine 202 (290) 5 (70) Roberts & Thomas (2006)

7. 6 – 5 2 .9 2–43.7 Boucard & Gravell (2006)

Ibuprofen 3086 (27 256) 826 (5044) Ashton, Hilton & Thomas (2004)

2972 (4239) 297 (2370) Roberts & Thomas (2006)

—48 (930) Thomas & Hilton (2004)

Mefenamic acid 133 (14 40 ) 62 (366) Ashton, Hilton & Thomas (2004)

340 (396) < LOQ Roberts & Thomas (2006)

— < LOQ (196) Thomas & Hilton (2004)

Norﬂuoxetine 5.2–30.7 4.5–83.0 Boucard & Gravell (2006)

Paracetamol < 20 —Roberts & Thomas (2006)

—555 Bound & Voulvoulis (2006)

Propanolol 76 (284) 29 (215) Ashton, Hilton & Thomas (2004)

304 (373) 61 (107) Roberts & Thomas (2006)

— < LOQ (56) Thomas & Hilton (2004)

Sulfamethoxazole < LOQ (132) < LOQ Ashton, Hilton & Thomas (2004)

Tamoxifen < LOQ (42) < LOQ Ashton, Hilton & Thomas (2004)

Tetracycline —~1000 Watts et al. (1983)

Theophylline —~1000 Watts et al. (1983)

Trimethoprim 70 (1288 ) < LOQ (42) Ashton, Hilton & Thomas (2004)

271 (322) 9 (19) Roberts & Thomas (2006)

—7 (569) Thomas & Hilton (2004)

LOQ, limit of quantiﬁcation; nd, not detected (below the detection limit)

Source: DWI (2007)

Table 3. Concentrations of selected pharmaceuticals found in European surface waters

Compound Median (maximum) concentrations (ng/l)

Austria Finland France Germany Switzerland

Bezaﬁbrate 20 (160) 5 (25) 102 (430) 350 ( 310 0 ) —

Carbamazepine 75 (294) 70 (370) 78 (800) 2 5 (110 ) 30 –150

Diclofenac 20 (64) 15 (40 ) 18 (41) 150 (120 0 ) 20 –150

Ibuprofen nd 10 (65) 23 (120 ) 70 (530) nd (150)

Iopromide 91 ( 211 ) —7 (17) 100 (910) —

Roxithromycin nd —9 (37) < LOQ (560) —

Sulfamethoxazole

and —25 (133) 30 (480) —

LOQ, limit of quantiﬁcation; nd, not detected (below the detection limit)

a Includes the human metabolite N4-acetyl-sulfamethoxazole.

Source: Ternes et al. (2005)

1.3 Occurrence of pharmaceuticals in

drinking-water

Most countries (if any) do not have monitoring programmes to routinely test for

pharmaceuticals in drinking-water owing to practical difﬁculties, such as high costs and

lack of availability of routine analytical technologies and laboratory infrastructure to

detect a diverse range of pharmaceuticals and their metabolites. As a result, the majority

of the occurrence data for pharmaceuticals in drinking-water and surface waters come

from targeted research projects, targeted investigations and ad hoc surveys, most of

which were designed to develop, test and ﬁne-tune detection and analytical methods.

Nevertheless, they did provide an initial indication of the presence of pharmaceuticals

in the environment.

Studies in the USA have detected very low levels of pharmaceuticals in ﬁnished

drinking-water. The highest concentration reported was 40 ng/l for meprobamate

(Benotti et al., 2009). Studies have also found several pharmaceuticals in tap water at

concentrations ranging from nanograms to low micrograms per litre in several countries

in Europe, including Germany, the Netherlands and Italy (Huerta-Fontela, Galceran &

Ventura, 2011). Two separate studies in Germany (Reddersen, Heberer & Dünnbier,

2002; Zühlke et al., 2004) found phenazone and propylphenazone (an analgesic and

an antipyretic drug, respectively) in Berlin drinking-water, with the highest concentration

being 400 ng/l for phenazone. This high value was largely attributed to groundwater,

used as a drinking-water source, contaminated with sewage (Jones, Lester & Voulvoulis,

2005). In the Netherlands, traces of antibiotics, antiepileptics and beta blockers were

detected in the drinking-water supply at concentrations below 100 ng/l, with most

concentrations below 50 ng/l (Mons, Hoogenboom & Noij, 2003).

To date, between 15 and 25 pharmaceuticals have been detected in treated drinking-

water worldwide, as reported in the peer-reviewed scientiﬁc literature (Jones, Lester

& Voulvoulis, 2005; Benotti et al., 2009). More pharmaceutical compounds have

been detected in untreated water sources, such as wastewater, surface waters

and groundwaters (Focazio et al., 2008) in the water cycle, largely attributable to

pharmaceuticals of very high usage, including antihyperlipidaemic compounds and

non-steroidal anti-inﬂammatory drugs (NSAIDs).

1.4 Conclusion

The occurrence of pharmaceuticals in the environment, including the water cycle, at

concentrations ranging from nanograms to low micrograms per litre has been widely

discussed and published in the literature in the past decade (Heberer, Schmidt-Bäumler

& Stan, 1998; Zuccato et al., 2000; Heberer et al., 2001, 2004; Stackelberg et al.,

2004, 2007; Zühlke et al., 2004; Jones, Lester & Voulvoulis, 2005; Vieno, Tuhkanen

& Kronberg, 2005; Loraine & Pettigrove, 2006; Snyder et al., 2006; Vanderford &

Snyder, 2006; Loos et al., 2007; Pérez & Barceló, 2007; Togola & Budzinski, 2008;

Mompelat, Le Bot & Thomas, 2009).

The published literature and national studies have shown that concentrations of

pharmaceuticals in surface water and groundwater sources impacted by wastewater

discharges are typically less than 0.1 µg/l (or 100 ng/l), and concentrations in treated

drinking-water are usually well below 0.05 µg/l (or 50 ng/l).

There are few comprehensive, systematic monitoring studies on pharmaceuticals in

drinking-water, and limited occurrence data are a challenge in assessing potential

human health risks from exposure to trace concentrations of pharmaceuticals in drinking-

water. In addition, there is no standardized protocol for the sampling and analytical

determination of pharmaceuticals. More systematic studies, using comparable methods,

will help further research on the transport, occurrence and fate of these compounds in

various environmental media, and standardization of protocols for their sampling and

analytical determination would help to facilitate the comparison of data.

Human health risk

assessment for pharmaceuticals

in drinking-water

Human health risk

assessment for pharmaceuticals

in drinking-water

2. Human health risk assessment for pharmaceuticals

in drinking-water

2.1 Introduction

Regulatory approval processes for pharmaceuticals require thorough

assessments to demonstrate the efﬁcacy and safety of active compounds. These

assessments determine the margin of safety associated with human consumption

and take into account the risk–beneﬁt equation. Those pharmaceuticals that

are most widely used, particularly those approved for over-the-counter sales,

require the most stringent assessment and require a substantial margin of safety.

Most of the pharmaceuticals that are likely to be found in water fall into the

high usage category, because it is those substances that will be present in

the greatest quantity. The assessments for approval for particular uses cover

a series of preclinical, clinical and sometimes mechanistic studies and are

usually performed at doses close to the intended therapeutic dose. For those

substances that will be widely used, some studies are also conducted at doses

well above those anticipated. Because of these stringent regulatory approval

processes, pharmaceuticals will be better characterized and controlled than

most environmental contaminants.

Concern has been raised, however, because exposure to pharmaceuticals

through drinking-water is an unintended and involuntary exposure over

potentially long periods of time. Moreover, there are few scientiﬁc risk

assessments of exposure to low levels of pharmaceuticals, both as individual

species or as mixtures, in drinking-water.

2.2 Assessing risks associated with

pharmaceuticals in drinking-water

Chemical risk assessment methods for substances found in food and drinking-

water involve establishing an acceptable daily intake (ADI) or tolerable daily

intake (TDI) based on a variety of calculations (e.g. from extrapolations,

applications of uncertainty factors) applied to a selected point of departure

(PoD) from the toxicological and epidemiological database. A common and

widely accepted PoD is that concentration at which no adverse effects are

detected, which is the no-observed-adverse-effect level (NOAEL), or, less

optimally, the lowest concentration at which adverse effects are detected,

which is the lowest-observed-adverse-effect level (LOAEL), in combination

with an additional uncertainty factor. The PoD may also be derived through a

benchmark dose based on statistical evaluation of the dose–response curve of

the critical study (FAO/WHO, 2009).

Health risks from pharmaceuticals in water have been most frequently assessed

using the minimum therapeutic dose (MTD, the lowest concentration that evokes

a desired therapeutic effect among target populations) as the PoD (DWI, 2007;

Bull et al., 2011). This is due to practical reasons, including the lack of readily

available toxicological data in the public domain that would be necessary

to derive a NOAEL/LOAEL or benchmark dose. The MTD is usually a dose

below those concentrations where, in rare instances, unacceptable adverse

or toxic effects are observed. Therefore, the use of the MTD as a PoD for risk

assessment would often result in the development of conservative screening

values (reference concentrations used to determine whether further action is

warranted, as described below).

The application of the MTD to inform the derivation of screening values does

present certain limitations. The MTD is determined by controlled studies in

speciﬁc preselected populations, which may not be based on the sensitivities

of vulnerable subpopulations that would not normally be given the drug. In

addition, in speciﬁc cases, such as with cytotoxic cancer treatment drugs,

the MTD may be at a concentration above which toxic effects are observed.

Notwithstanding this, especially in cases where the margins of exposure

(MOEs) are substantial, use of the MTD could be considered a pragmatic and

sensible method to broadly assess and screen risks.

The main challenges in assessing risks include the limited occurrence

data available for pharmaceuticals in drinking-water, the diverse range

of pharmaceuticals in use, the wide variation in the use of individual

pharmaceuticals between countries, the limited number of data in the public

domain and technical limitations relating to assessing risks from chronic

exposure to low doses of pharmaceuticals and mixtures. Nonetheless, several

publicly available approaches (USEPA, 2008b) have been used for screening

and prioritizing pharmaceuticals for assessing the potential risks to human

health from exposure to low concentrations of pharmaceuticals in drinking-

water. These reports (DWI, 2007; USEPA, 2008b; Bull et al., 2011) have

been subject to scrutiny and peer review. These studies have used the MTD

as the PoD for the risk assessment, with subsequent application of uncertainty

factors to derive screening values and margins of safety against which to assess

the potential risk.

These screening values are values against which to judge the likelihood that a

particular substance could be of concern at the concentrations observed and so

warrant further, more detailed investigation. Screening values are also used to

identify those substances from a long list that are the most important and should

be considered more closely. As indicated above, there are two approaches

that have been used. An ADI or TDI is an amount that can be ingested daily

for an extended period, generally a lifetime, without signiﬁcant risk to health.

The large uncertainty factors frequently involved in establishing an ADI or TDI

generally serve to provide assurance that exposure exceeding the ADI or TDI

for shorter periods, or sometimes for longer periods if the exceedance is small,

is unlikely to have any deleterious effect. However, any exceedance of the

ADI or TDI needs to be evaluated on a case-by-case basis, as it is very much

dependent on the substance and its toxicological proﬁle.

ADIs are typically set by determining the dose at which no adverse effect is

observed (the NOAEL) or, less optimally, the lowest level at which an adverse

effect is observed (the LOAEL). In both cases, uncertainty factors are applied

to reﬂect uncertainties in extrapolation from experimental animals to humans,

in the likely variation within the exposed population or important gaps in the

database, to derive the ADI. These uncertainty factors are based on expert

judgement, but there is a considerable body of experience in their use. Data

from well-conducted studies, where a clear dose–response relationship has

been demonstrated, are preferred, typically using experimental animal models;

however, where suitable data on human populations are available, these

would normally be preferred. The approaches used in developing guideline

or screening values for chemicals in drinking-water are described in chapter 8

of the WHO Guidelines for Drinking-water Quality (WHO, 2011). Using

an ADI to determine a suitable level for drinking-water requires assumptions

to be made regarding body weight, as an ADI is usually presented as an

intake per kilogram of body weight. WHO uses a value of 60 kg for an adult

and assumes consumption of 2 litres of drinking-water per day. Usually for

substances for which an ADI is derived, exposure can also be from food and

air, and so a proportion of the ADI is allocated to drinking-water to allow for

exposure from other sources. In the case of pharmaceuticals, exposure from

other sources is negligible, and so the allocation can be high, even 100%.

For individuals taking the pharmaceutical for medical purposes, the additional

amount from drinking-water is so small as to make no difference.

The MTD, or the lowest clinically effective dose, is usually equivalent to the

lowest dose prescribed or recommended and takes into account the number of

doses in a day. These values are derived from an assessment of the balance

between efﬁcacy and safety. The approach used to derive a screening value for

drinking-water is to divide the MTD by a factor that would provide reasonable

assurance that effects, either pharmacological or toxic, would be extremely

unlikely. The derivation of this factor is based on expert judgement, as are the

uncertainty factors used in the derivation of the ADI. The use of the MTD as a

starting point for assessing potential risks of pharmaceuticals to human health

or for deriving guideline values has been applied by Schwab et al. (2005) in a

human health risk assessment of pharmaceuticals in surface waters in the USA

and by Versteegh, van der Aa & Dijkman (2007), Webb et al. (2003), van der

Aa et al. (2009) and Bull et al. (2011). DWI (2007) also used the MTD as the

basis for assessing the risk from pharmaceuticals in drinking-water.

The screening values developed are then used as reference points against which

the results of monitoring can be judged. In some cases, because monitoring

data are so limited, modelling has been used to develop worst-case estimates

of potential exposure through water. The screening values are then used as the

criteria to support decision-making when a chemical is detected in source water

or drinking-water. If the concentration of a particular pharmaceutical exceeds

the screening value, then further evaluations of the toxicity and occurrence of

the pharmaceutical compound might be warranted. On the other hand, if the

concentration is below the screening value, this strongly suggests that adverse

health impacts should not be expected.

2.3 Applying the MTD approach: a

Drinking Water Inspectorate study3

The Drinking Water Inspectorate for England and Wales commissioned a

comprehensive desk-based review of current knowledge on and estimation of

potential levels of 396 pharmaceuticals and 11 illegal drugs in drinking-water

in the United Kingdom based on speciﬁc demographic and usage data on

active pharmaceutical ingredients and using modelled concentrations based

on actual catchments. The DWI (2007) approach was to determine an MOE

for each pharmaceutical by comparing the MTD with the theoretical maximum

intake from drinking-water.

The modelled concentrations from drinking-water intake were based on two

methods: 1) a deterministic method that resulted in estimates of worst-case

concentrations in drinking-water and 2) a probabilistic method that resulted in

more realistic estimates of the concentrations in drinking-water. Pharmaceuticals

considered were ﬁrst evaluated using the deterministic method; for those

24 compounds that had the lowest MOEs, further evaluation was done using

the probabilistic method.

The health end-point used in this review was the MTD. Owing to insufﬁcient

data, an MTD value of 10 mg per day was used for topically applied

pharmaceuticals and a conservative MTD value of 1 mg per day was used for

pharmaceuticals for which there were no data, including illegal drugs. For the

DWI (2007) evaluation, an uncertainty factor of 1000 was applied for all the

compounds as a precautionary value to extrapolate below the level at which

effects might be seen. The resultant screening values were used for determining

the priority substances for further examination by probabilistic modelling. This

additional uncertainty factor, which is widely accepted as a precautionary step

by the medical profession, also provides an additional reassurance with regard

to exposure of infants and young children.

The MOE for each of the targeted pharmaceuticals was derived by comparing

the maximum estimated concentrations in drinking-water with the MTD. The

results allow an assessment of the signiﬁcance of individual pharmaceuticals

through drinking-water exposure.

3 This section is based on DWI (2007).

From the worst-case deterministic modelling, only 10 substances showed an

MOE less than 1000, of which 4 were illegal drugs, with highly precautionary

values for the lowest active dose. In only one case was the exposure ratio less

than 100, and this was a unique case, as a combined total for all NSAIDs

was used, but compared against the lowest individual MTD for any of the

NSAIDs in the group. The results therefore suggested that even in this worst-

case situation, there is no signiﬁcant health risk from intake of pharmaceuticals

via drinking-water.

When probabilistic modelling was used to obtain a more realistic estimate

of concentrations in drinking-water, the estimated concentrations of all but

one substance were signiﬁcantly lower. The MOEs for all substances were

signiﬁcantly greater than 1000, and only tetrahydrocannabinol and oseltamivir

carboxylate had an MOE less than 1000 (Table 4).

The DWI (2007) study led to the conclusion that a majority of the

pharmaceuticals had MOEs greater than 1000, suggesting a substantial

margin of safety against potential adverse health impacts from exposure to

trace concentrations of pharmaceuticals in drinking-water.

Table 4. Probabilistic modelling data for the top 24 drugs from worst-case deterministic modelling

Drug name Mean PECdw (µg/l) MTD (mg) MOE Comments

Total NSAIDs 2.74 7. 5 2 737 Combination of 19 anti-inﬂammatory drugs

Cannabis (tetrahydrocannabinol) 1.377 1726 Illegal drug

Oseltamivir carboxylate (Tamiﬂu active metabolite) 107 52 486 Used under pandemic conditions

LSD 0.097 110 309 Illegal drug

Cocaine (methylbenzoylecgonine) 0.029 134 483 Illegal drug

Aminophylline 0.15 16 667 Smooth muscle relaxant

Beclometasone 0.005 0.05 10 000 Anti-asthmatic

Zidovudine 0.057 0.5 8 772 Antiviral

Ecstasy 0.487 12 053 Illegal drug

Acamprosate 0.435 12 299 Alcoholism treatment

Total statins 1.27 53 937 Cholesterol reduction

Nitroglycerine 0.035 4 0.15 4 234 Vasodilator

Heroin (diamorphine) 0.004 49 1222 717 Illegal drug

Simvastatin 1.18 54 227 Cholesterol reduction

Codeine 0.015 7 20 1 277 139 Narcotic analgesic

Ramipril 0.153 1.25 8 177 Diuretic

Lisinopril 0.396 2.5 6 316 Angiotensin converting enzyme inhibitor

Methadone 0.082 2 112 173 Opioid agonist

Furosemide 1.74 20 11 5 0 7 Diuretic

Amphetamine 0.017 4 157 405 Illegal drug

Norethisterone 0.023 6 0.35 14 824 Progesterone derivative

Doxazosin 0.0 06 81 1146 843 Alpha blocker

Bendroﬂumethiazide 0.275 2.5 9 094 Diuretic

Cyclosporin 0.000 8 22 500 000 Immunosuppression

LSD, lysergic acid diethylamide; PECdw, predicted concentration in drinking-water

Source: DWI (2007)

2.4 Applying the ADI approach

2.4.1 Awwa Research Foundation study4

The Awwa Research Foundation commissioned a study to provide critical

information regarding the occurrence of and risk assessment for pharmaceuticals

and potential endocrine disrupting chemicals (EDCs) in drinking-water. The

study examined 62 chemicals, including 20 pharmaceuticals and active

metabolites, 26 potential EDCs, 5 steroid hormones and 11 phytoestrogens

(natural estrogens from plants). The health value applied in this study was the

ADI, and a conservative approach was taken in the process of developing the

ADI values, as illustrated in Table 5.

In this study, the ADIs were converted to drinking-water equivalent levels

(DWELs) in micrograms per litre (or parts per billion) based on assumptions of

a 70 kg body weight in adults and consumption of 2 litres per day.

Even with the use of advanced and highly sensitive analytical procedures (with

reporting limits in the nanograms per litre or parts per trillion range), none of the

pharmaceuticals tested in this study were detected in ﬁnished drinking-water

above the calculated health risk thresholds. Adopting a conservative worst-

case scenario approach, the maximum detected concentrations in ﬁnished and

piped drinking-water were used to calculate DWELs for each of the target

pharmaceuticals. It was found that none of the pharmaceuticals detected in

drinking-water exceeded their corresponding ADI.

The minimum margin of safety or MOE for each compound tested was

calculated by dividing the DWEL by the maximum detected water concentration.

According to United States Environmental Protection Agency (USEPA) policy,

compounds with MOEs greater than 100 would generally indicate a low level

of concern. Table 6 contains the calculated MOEs for some of the compounds

that were detected in drinking-water; these were orders of magnitude above

100, suggesting a low level of concern.

4 This section is based on Snyder et al. (2008).

Table 5. Principles for deriving ADIs for compounds considered

in this study

Category of analytes Derivation of ADIs

Compounds that are not

carcinogenic

Dividing the highest dose at

which an effect was not observed

(NOAEL) or the lowest dose at

which an effect was observed

(LOAEL) in animal or human toxicity

studies by uncertainty factors

to account for extrapolation to

potentially sensitive populations

Compounds with positive evidence

of carcinogenicity in high-dose

animal studies and data on tumour

incidence per dose level

A linear extrapolation model was

used to predict the tumorigenic

response at low dose level

Carcinogenic compounds with

reported evidence in animal studies,

but no available tumour incidence

data

A safe dose corresponding to a

cancer risk of one in a million was

estimated

Table 6. MOEs calculated for compounds considered in the Awwa

Research Foundation study

Compound MOE

Atenolol 2 700

Diazepam 110 000

Fluoxetine 41 000

Meprobamate 6 000

Norﬂuoxetine 44 000

Sulfamethoxazole 6 000 000

Triclosan 2 200 000

2.4.2 Australian Guidelines for Water

Recycling5

The Australian Guidelines for Water Recycling were developed to serve as an

authoritative reference for using recycled wastewater to augment drinking-water

supplies. These guidelines were established to protect against microbial and

chemical risks, including pharmaceuticals. The pharmaceuticals considered

were categorized into two groups: those used solely for humans and those

used for agricultural and veterinary purposes.

For veterinary pharmaceuticals, the health end-point is determined based

on ADIs established for pharmaceuticals used for agricultural and veterinary

purposes by organizations such as the Joint FAO/WHO Expert Committee

on Food Additives, the Australian Therapeutic Goods Administration and the

European Medicines Agency.

For human pharmaceuticals, the health end-point was a surrogate ADI, which

was derived by dividing the lowest daily therapeutic dose by safety factors

ranging from 1000 to 10 000. The use of the lowest daily therapeutic dose as

a starting point for deriving guideline values or assessing risk has been adopted

by others (Webb et al., 2003; Schwab et al., 2005; DWI, 2007; Versteegh,

van der Aa & Dijkman, 2007; Bull et al., 2011). With respect to pharmaceutical

metabolites in source waters, it was considered that the activity of metabolites

is generally lower than that of the parent compound, and application of safety

factors in the range of 1000–10 000 should provide a safety buffer that is

sufﬁciently conservative.

For most pharmaceuticals, a safety factor of 1000 was applied to the lowest

daily therapeutic dose; it consists of a 10-fold factor for sensitive humans,

a 10-fold factor for infants and children and a 10-fold factor for the lowest

therapeutic dose not being a no-effect level. In addition, a factor of 10 was

added for cytotoxic drugs as a result of the higher toxicity associated with

these compounds and for hormonally active steroids, which are active at very

low concentrations and for which there is a high public perception of adverse

effects.

In applying the guidelines, the calculated guideline values for the

pharmaceuticals were compared with the highest concentrations measured in

secondary treated efﬂuent to derive the MOEs. Most of the calculated MOEs

are more than 1000; given that this does not take into account reductions

achieved by treatment processes, it is unlikely that pharmaceutical chemicals

will be present at levels approaching the recommended guideline values or

cause any adverse impacts on human health.

5 This section is based on NRMMC, EPHC & NHMRC (2008).

2.5 Conclusion

Risk assessments from the United Kingdom, the USA and Australia have applied

the ADI or the MTD approaches, in conjunction with uncertainty factors, to

derive screening values for pharmaceuticals in drinking-water. Analysis of the

results indicated that adverse human health impacts are very unlikely from

exposure to the trace concentrations of pharmaceuticals that could potentially

be found in treated drinking-water. Available data have shown that for

those substances that have been detected, the concentrations are more than

1000-fold less than the MTD, which is the lowest clinically active dosage.

These ﬁndings are in line with other studies over the past decade that also

supported the conclusion that discernible risks to health arising from trace levels

of pharmaceuticals in drinking-water are extremely unlikely (e.g. Christensen,

1998; Schulman et al., 2002; Webb et al., 2003; Jones, Lester & Voulvoulis,

2005; Bercu et al., 2008; Snyder, 2010).

Given the low likelihood of human health risk, it is not considered necessary

to implement routine monitoring programmes that are resource intensive and

detract from other drinking-water concerns that are more important and more

acute, particularly the threat of waterborne pathogens. However, where speciﬁc

circumstances indicate a potential for elevated concentrations, screening values

and targeted investigative monitoring could be considered.

Future research could consider investigating the robustness and feasibility

of adapting the concept of the threshold of toxicological concern, which

is currently more widely used for food additives and contaminants, as an

alternative screening-level risk assessment, rather than developing values

for each substance individually (Kroes et al., 2004). Research could also

look into improvement to risk assessment methodology to address concerns

related to pharmaceutical mixtures and the effects of chronic, low-level

exposure to pharmaceutical, including exposure of sensitive subpopulations,

such as pregnant women and patients with particular diseases and medical

treatments (Rowney, Johnson & Williams, 2009). The WHO Framework for Risk

Assessment of Combined Exposure to Multiple Chemicals (Meek et al., 2011)

could be utilized to further consider the issue of mixtures.

3Treatment technologies for

removal of pharmaceuticals

from water

3. Treatment technologies for removal of

pharmaceuticals from water

3.1 Introduction

Many studies have reported the presence of pharmaceuticals in efﬂuents

from wastewater treatment facilities (Ternes, 1998; Andreozzi et al., 2003;

Miao et al., 2004; Paxéus, 2004; Castiglioni et al., 2006; Vieno, Tuhkanen

& Kronberg, 2007) and identiﬁed these efﬂuents as the main conveyors of

pharmaceuticals and their metabolites into receiving water sources, such as

rivers, lakes, reservoirs and groundwater aquifers, that are used for drinking-

water supply (Heberer, 2002; Ternes & Joss, 2006; Xu et al., 2007; Zhang,

Geissen & Gal, 2008; Huerta-Fontela, Galceran & Ventura, 2011).

The presence of trace concentrations of pharmaceuticals in the water cycle,

typically in the nanogram to low microgram per litre range, has raised questions

concerning the efﬁcacy of drinking-water and wastewater treatment processes

in removing pharmaceuticals. The majority of research studies on treatment

efﬁcacy have been conducted in Europe and the USA, with some studies

conducted in developed countries in Asia (Lee et al., 2008; Simazaki et al.,

2008; Van De Steene, Stove & Lambert, 2010; Huerta-Fontela, Galceran

& Ventura, 2011). In addition, there are more studies that focus on removal

efﬁcacies at laboratory scale or by single treatment processes rather than at

full scale, especially for drinking-water treatment processes.

This chapter provides an overview of the removal of pharmaceuticals by

conventional and advanced wastewater and drinking-water treatment

processes based on the published literature.

3.2 Removal of pharmaceuticals by

wastewater treatment processes

Conventional wastewater treatment facilities typically have biological

degradation using the activated sludge process, whereas advanced facilities

have tertiary treatment processes, such as reverse osmosis, ozonation and

advanced oxidation technologies. Pharmaceuticals are a diverse group of

chemicals, with varying physical and chemical properties (Jelic et al., 2011).

Treatment efﬁcacy depends on these physical and chemical characteristics

(e.g. hydrophobicity), their reactivity towards different treatment processes

and process control, such as solids retention time, temperature and hydraulic

retention time. For example, the majority of pharmaceuticals are relatively

hydrophobic and therefore less effectively removed by sorption to sludge

(Vieno, Tuhkanen & Kronberg, 2007). Treatment removal efﬁciency could

therefore vary signiﬁcantly between different treatment facilities or at different

time periods within the same treatment facility (Vieno, Tuhkanen & Kronberg,

2007).

Table 7 collates the results of several studies to illustrate the removal rates that

can be expected by different wastewater treatment processes. These are based

on observations of treatment processes ranging from single unit processes to

full-scale wastewater treatment facilities found in the various studies.

Table 7 demonstrates that conventional wastewater treatment facilities with

activated sludge processes can achieve higher removal efﬁciency than

simple biological ﬁlters. Removal rates for pharmaceuticals can vary and

could sometimes be limited (Kasprzyk-Hordern, Dinsdale & Guwy, 2009),

depending on such factors as sludge age (DWI, 2007), activated sludge tank

temperature and hydraulic retention time (Wick et al., 2009; Gabet-Giraud et

al., 2010).

Advanced wastewater treatment processes, such as ozonation, membrane

treatment and advanced oxidation, can generally achieve higher removal rates

(up to 100%) for pharmaceuticals compared with conventional processes.

For example, another bench-scale study showed that advanced oxidation

processes can achieve up to 100% removal for diclofenac (Klavarioti,

Mantzavinos & Kassinos, 2009).

Prediction of removal rates for wastewater treatment processes is possible

for pharmaceuticals with very similar chemical structures. However, practical

difﬁculties do exist in predicting removal rates between different wastewater

treatment facilities, as highly variable removal rates are obtained for beta

blockers, depending on the wastewater treatment facility under consideration.

For example, the beta blockers betaxolol, bisprolol, carazolol and metprolol

are signiﬁcantly removed by activated sludge processes, with reported removal

rates varying from 65% to about 90% (Ternes, 1998; Gabet-Giraud et al.,

2010), whereas low removal rates of less than 20% and approximately 32%

are reported for soltalol and propranolol, respectively, in other studies (Bendz

et al., 2005; Gabet-Giraud et al., 2010).

Table 7. Conventional and advanced wastewater treatment processes and their expected range of removal efﬁciency for pharmaceuticals

Treatment process Removal range (%) Water source Areas studied Reference

> Conventional wastewater treatment processes

Activated sludge 11– 9 9 Raw sewage Australia Watkinson, Murby & Costanzo (2007)

7–100 Primary settled sewage Europe, Japan DWI (2007)

< 20–80 Primary settled sewage France Gabet-Giraud et al. (2010)

−193–86

aPrimary settled sewage Europe Vieno, Tuhkanen & Kronberg (2007)

8–98 Not speciﬁed Brazil, Europe, Japan Ziylan & Ince (2011)

Biological ﬁltration 6–71 Primary settled sewage Europe DWI (2007)

Primary settling 3–45 Not speciﬁed Brazil, Europe, Japan Ziylan & Ince (2011)

Coagulation, ﬁltration and settling 5–36 Not speciﬁed

Sand ﬁltration 0–99 Activated sludge efﬂuent

> Advanced wastewater treatment processes

Ozonation 1–99 Activated sludge efﬂuent Brazil, Europe, Japan Ziylan & Ince (2011)

86–100 Secondary efﬂuent France Gabet-Giraud et al. (2010)

Ozonation/ultrasound and sonocatalysis 23–45 Not speciﬁed Europe, India, Japan,

Turkey, USA

Ziylan & Ince (2011)

Ozonation and catalytic ozonation > 9–100

UV irradiation 29 Not speciﬁed Brazil, Europe, Japan Ziylan & Ince (2011)

Photolysis (UV/hydrogen peroxide) 52–100 Not speciﬁed Europe, India, Japan,

Turkey, USA

Ziylan & Ince (2011)

Dark and light Fenton 80 –100

UV/TiO2> 95

Biomembrane 23–99 Treated efﬂuent Brazil, Europe, Japan Ziylan & Ince (2011)

Microﬁltration and reverse osmosis 91–100 Secondary treated

efﬂuent

Australia Watkinson, Murby & Costanzo (2007)

Reverse osmosis 62–97 Secondary treated

efﬂuent

France Gabet-Giraud et al. (2010)

Ultrasound 24–100 Not speciﬁed Europe, India, Japan,

Turkey, USA

Ziylan & Ince (2011)

UV, ultraviolet

a The removal of some pharmaceuticals appears to be negative. This has been attributed to the way in which removal is calculated, without hydraulic retention time being considered. This

means that the efﬂuent sample does not directly correspond to the inﬂuent sample. In the case of carbamazepine, the increase observed was consistent, and the most probable cause was

reported to be conversion of carbamazepine glucuronides and other conjugated metabolites to the parent compound by enzymatic processes in the treatment plant (Ternes et al., 1999; Vieno,

Tuhkanen & Kronberg, 2007).

3.3 Removal of pharmaceuticals by

drinking-water treatment processes

Treated efﬂuents from wastewater treatment facilities that have an impact on

receiving water bodies constitute the main source of pharmaceuticals in surface

waters, which could be used for drinking-water supply (Rahman, Yanful &

Jasim, 2009). Other possible pathways of pharmaceuticals to drinking-water

sources include leaching of pharmaceuticals to groundwater (Gomes & Lester,

2003) from sources such as leaking sewage systems and pipes.

None of the wide range of drinking-water treatment processes available have

been designed speciﬁcally to remove pharmaceuticals that may be present

in source waters. Nonetheless, removal of pharmaceuticals during drinking-

water treatment is largely dependent on their physical and chemical properties,

and treatment processes can therefore achieve some level of removal. For

example, biodegradation on slow sand ﬁlters and/or sorption to particles

removed by coagulation may help reduce the levels of some pharmaceuticals

present in drinking-water sources; granular activated carbon (GAC) and

powdered activated carbon (PAC) are increasingly adopted in drinking-

water treatment to remove pesticides and improve taste and odour, and these

processes may remove some pharmaceuticals by sorption (or biodegradation

on GAC). Groundwater sources that are used for drinking-water typically have

low particulate matter and organic matter content. Therefore, drinking-water

treatment is mostly single-stage disinfection, without multiple treatment barriers.

Table 8 summarizes the ﬁndings in various published studies on the removal

efﬁciencies of conventional and advanced water treatment processes for

pharmaceuticals in drinking-water. The majority of these studies focused

on bench-scale removal by spiking water samples with target compounds,

subjecting these samples to treatment and measuring the resulting

concentrations. However, some full-scale studies at drinking-water treatment

facilities have been carried out.

Bench-scale studies using both alum and ferric chloride as coagulants

for natural water or pure water samples spiked with pharmaceutical target

compounds showed that coagulation (with or without chemical softening) is

largely ineffective in removing pharmaceutical target compounds (Westerhoff

et al., 2005; Yoon et al., 2006; Snyder et al., 2007). An Awwa Research

Foundation project also concluded that coagulation was largely ineffective for

pharmaceutical removal in bench-scale, pilot-scale and full-scale investigations

(Khiari, 2007).

Chlorination and ozonation can achieve higher removal rates, with efﬁcacy

a function of chemical structure and treatment conditions, such as pH and

oxidant dose (Zwiener & Frimmel, 2000; Adams et al., 2002; Huber et al.,

2003, 2005; Snyder et al., 2003; Ternes et al., 2003; Pinkston & Sedlak,

2004; Kim et al., 2007). In some studies, free chlorine was found to oxidize

approximately half of the pharmaceuticals investigated, but chloramine was

comparatively less efﬁcient. Antibiotics such as sulfamethoxazole, trimethroprim

and erythromycin are among the compounds that showed high removal by

free chlorine (Khiari, 2007). Advanced oxidation processes using ozone with

hydrogen peroxide greatly improve oxidation and are frequently applied in

wastewater recycling processes for indirect potable reuse to convert recalcitrant

organic chemicals.

PAC and GAC can achieve high removal of pharmaceutical target compounds,

especially hydrophobic compounds. Removal efﬁcacy is a function of contact

time, organic loading, chemical structure, solubility and carbon type (Ternes

et al., 2002; Yoon et al., 2003; Snyder et al., 2006). Iopromide, ibuprofen,

meprobamate, sulfamethoxazole and diclofenac were some of the compounds

found to be most resistant to activated carbon removal (Khiari, 2007).

Membrane treatment is highly effective in removing chemicals from water, and

removal efﬁcacy is a function of physical and chemical properties, such as

molecular weight, hydrophobicity, polarity, chemical nature and pore size of

the membranes. Some studies (Yoon et al., 2006; Khiari, 2007) suggested

that nanoﬁltration (NF) can achieve better removal rates for most target

compounds than ultraﬁltration (UF)/microﬁltration (MF) membranes as a result

of both hydrophobic adsorption and size exclusion. Higher molecular weight

substances would be removed by size exclusion, especially by NF membranes.

Reverse osmosis (RO) was highly effective, despite trace quantities of some

target compounds breaching RO membranes. However, a double-pass RO

system was reported to remove all target compounds to below detection limits

(Khiari, 2007).

Ultraviolet (UV) irradiation at typical disinfection dosages was ineffective

for removing most target compounds, even though it can achieve more

than 50% removal of sulfamethoxazole (antibiotic), triclosan (antimicrobial)

and diclofenac (NSAID). However, a combination of higher-dose UV

(400 mJ/cm2 and higher) with hydrogen peroxide (3 mg/l and above)

removed most target compounds (Rosenfeldt & Linden, 2004; Khiari, 2007).

Table 8. Drinking-water treatment processes and their expected range of removal of pharmaceuticals

Treatment process Removal range (%) Scale Country studied (no.

of compounds) Reference

RO > 99 Pilot Germany (6) Heberer, Reddersen & Mechlinski (2002)

RO1 70 – 91 Bench Japan (6) Kimura et al. (2004)

RO2 10–85 Bench

UV/H2O23 – > 95 Bench USA (2) Rosenfeldt & Linden (2004)

Coag 24–72 Bench USA (49) Westerhoff et al. (2005)

PAC (20 mg/l) > 80 Bench

PAC (1 mg/l) 40 –75 Bench

CI225–75 Bench

O35–95 Bench

O333–100 Bench Germany (9) McDowell et al. (2005)

ClO20–100 Bench G e r m a n y (11) Huber et al. (2005)

NF1 > 98 Bench Australia (3) Nghiem, Schäfer & Elimelech (2005)

NF2 > 80 Bench

UF < 30 Bench USA (27) Yoon et al. (2006)

NF 30–90 Bench

Coag < 5–30 Bench Finland (5) Vieno, Tuhkanen & Kronberg (2006)

Cl220 –100 Bench Japan (9) Simazaki et al. (2008)

PAC > 98 Bench

Coag < 15 Bench

Constructed wetlands 28–60 Pilot Singapore (4) Zhang et al. (2011)

Aeration/SF 25 – > 95 Full Germany (5) Reddersen, Heberer & Dünnbier (2002)

O3/Coag/Sed/Cl2100 Full USA (2) Boyd et al. (2003)

PAC/Coag/Sed 0Full USA (1)

Cl2100 Full USA (1)

Coag 0Full Republic of Korea (6) Kim et al. (2007)

UF 0Full

GAC 100 Full

Treatment process Removal range (%) Scale Country studied (no.

of compounds) Reference

NF 30 – > 90 Full Sp ain (12) Radjenović et al. (2008)

RO 45 – > 90 Full

Disinfection 2–97 Full France (7)aANSES (2011)

Physical and chemical 31– 94 Full

O3 + AC 47–97 Full

Membranes 6–68 Full

Pre-Cl20 – > 99 Full Spain (35) Huerta-Fontela, Galceran & Ventura (2011)

Coag/Floc/SF < 30–100 Full

O35 – > 99 Full

GAC 55 – > 75 Full

Cl214–100 Full

AC, activated carbon; Cl2, chlorine; ClO2, chlorine dioxide; Coag, coagulation; Floc, ﬂocculation; GAC, granular activated carbon; H2O2, hydrogen peroxide; NF, nanoﬁltration; O3,

ozonation; PAC, powdered activated carbon; RO, reverse osmosis; Sed, sedimentation; SF, sand ﬁltration; UF, ultraﬁltration; UV, ultraviolet

a Note that this was a national study incorporating 78 instances of pharmaceutical removal.

Conclusion

This chapter has provided an overview of the removal of pharmaceuticals

by conventional and advanced wastewater and drinking-water treatment

processes based on the published literature.

Conventional wastewater treatment typically consists of activated sludge

processes. Biological treatment, such as activated sludge and bioﬁltration,

has demonstrated signiﬁcant removal rates for pharmaceuticals that are

biodegradable or readily bind to particles (Ternes et al., 1999; Joss et al.,

2005; Kim et al., 2007). However, removal rates for pharmaceuticals can

vary within and between studies (Kasprzyk-Hordern, Dinsdale & Guwy, 2009;

Wick et al., 2009), depending on such factors as sludge age (DWI, 2007),

activated sludge tank temperature and hydraulic retention time. For example,

diclofenac removal in the activated sludge process ranges from 21% to 50%,

but this can be optimized by operating the process at a sludge age of eight

days or more (Ziylan & Ince, 2011).

Advanced wastewater treatment processes that comprise membranes,

advanced oxidation technologies, etc. have shown higher removal efﬁciencies

for pharmaceuticals (e.g. advanced oxidation processes can achieve up to

100% removal for diclofenac) (Klavarioti, Mantzavinos & Kassinos, 2009).

However, conventional treatment is generally sufﬁcient to meet regulatory

requirements, and capital-intensive advanced treatment processes are not

commonly adopted for wastewater treatment (Spellman, 2010).

With respect to conventional drinking-water treatment, bench-scale studies

showed that coagulation (with or without chemical softening) is largely

ineffective in removing pharmaceuticals (Westerhoff et al., 2005; Yoon et al.,

2006; Snyder et al., 2007). Free chlorine was found to oxidize approximately

half of the pharmaceuticals investigated, and chloramine was less efﬁcient.

Antibiotics such as sulfamethoxazole, trimethroprim and erythromycin are

among the compounds that showed high removal by free chlorine (Khiari,

2007).

Table 8. (continued)

Advanced water treatment processes such as ozonation, advanced oxidation,

activated carbon and membrane processes (nanoﬁltration, reverse osmosis)

were demonstrated to achieve higher removal rates (above 99%) for targeted

pharmaceutical compounds in various published literature studies. However,

advanced oxidation processes can lead to incomplete degradation products,

such as metabolites, and future research could consider the value and feasibility

of studying the formation and impact of these metabolites (Celiz, Tso & Aga,

2009).

For drinking-water sources that are contaminated with pesticides, advanced

treatment may already be in place to meet regulations. In such cases, removal

of pharmaceuticals during treatment may already be optimized.

Most importantly, it is prudent to note that advanced and costly water

treatment technology will not be able to completely remove all micropollutants

to concentrations below the detection limits of the most sensitive analytical

procedures at all times. Therefore, it is imperative to consider the toxicological

relevance of various compounds in the context of appreciable risks to human

health. Increased or rapidly changing exposure arising from speciﬁc local

circumstances (e.g. a signiﬁcant increase in the concentration of pharmaceuticals

in surface waters impacted by wastewater discharge) should be investigated.

An informed risk assessment considering the above principles is essential

before allocating scarce resources to upgrade or invest in additional advanced

treatment processes to reduce trace concentrations of pharmaceuticals in

drinking-water.

In view of the substantial margin of safety for consumption of very low

concentrations of pharmaceuticals in drinking-water (Chapter 2 in this report),

concerns over pharmaceuticals should not divert the attention and resources of

water suppliers and regulators from other chemical and pathogenic microbial

priorities. For example, although the government in Australia has issued

proposed guideline values for 84 pharmaceuticals for water reuse schemes,

microbial pathogens remain their overriding priority in water reuse (NRMMC,

EPHC & NHMRC, 2008).

Preventing pharmaceuticals

in drinking-water

4. Preventing pharmaceuticals in drinking-water

Conventional drinking-water quality monitoring that places emphasis

on end-product testing is very resource intensive in terms of capital

investment and human resources. With an expanding list of chemical

contaminants detected in drinking-water and water sources that may

be of insigniﬁcant health concern, an overemphasis on end-product

monitoring and the upgrading of treatment infrastructure is clearly not

sustainable or an optimal use of limited resources.

Chapter 4 in the fourth edition of the WHO Guidelines for Drinking-

water Quality states that the water safety plan is “the most effective

means of consistently ensuring the safety of a drinking-water

supply… through the use of a comprehensive risk assessment and

risk management approach that encompasses all steps in the water

supply from catchment to consumer” (WHO, 2011). The key principles

of water safety plans underline the importance of looking at risk

assessment and risk management across the entire water cycle starting

at source. Adapting this full life cycle approach to pharmaceuticals in

drinking-water means that preventing pharmaceuticals from entering

the environment during their production, consumption and disposal is a

pragmatic and effective means of risk management.

Inappropriate disposal practices, such as ﬂushing unwanted or excess

drugs down toilets and sinks and discarding them in household waste,

are common and often a signiﬁcant contributor of pharmaceuticals

present in wastewater and other environmental media (e.g. surface

waters and landﬁll leachate). A survey from Germany’s Management

Strategies for Pharmaceutical Residues in Drinking Water research

programme showed that consumers discarded 23% of liquid

pharmaceuticals prescribed and 7% of tablets. While some went into

household trash, the equivalent amount of pharmaceuticals that was

ﬂushed away is approximately 364 tons every year (Lubick, 2010).

Another survey of households in the United Kingdom in 2003 found that

63% of unwanted pharmaceuticals were discarded in household waste

and 11.5% were ﬂushed down sinks or toilets (Bound & Voulvoulis,

2005). Similarly, proper and well-managed disposal practices at

concentrated point sources such as health-care and veterinary facilities

will help mitigate the entry of pharmaceuticals into our environment.

Currently, tighter rules and regulations apply to controlled substances

and cytotoxic drugs than for other pharmaceuticals. Despite this,

disposal to sewers is not precluded (USEPA, 2008a). Disposal of non-

controlled substances tends to be more variable and is often developed

on a local, jurisdictional or regional basis. A scan of the current

literature, which is not exhaustive, revealed a few broadly categorized

preventive measures in Australia, Canada, the USA and European

countries that could potentially reduce the entry of pharmaceuticals into

our environment. These measures are described below.

4.1 Improved regulations and

guidance on pharmaceutical waste

management

All health-care facilities should have policies and procedures in place

for the correct management of pharmaceutical waste. In Australia,

the Environmental Protection Authority and the National Health and

Medical Research Council had guidelines on the management of

waste generated in health-care facilities. The National Health and

Medical Research Council stated that, where possible, pharmaceutical

waste should be incinerated and should not be sent to landﬁlls or

discharged to sewers (NHMRC, 1999). Licensed waste disposal

companies collected all clinical and pharmaceutical waste for disposal

in authorized waste disposal facilities.

In the USA, frequently used pharmaceuticals, such as epinephrine,

warfarin and selected chemotherapeutic agents, are regulated as

hazardous waste under the Resource Conservation and Recovery

Act. Failure to comply with the regulations under this Act through

improper management and disposal of waste can potentially constitute

serious violations and incur heavy penalties. To guide stakeholders on

acceptable disposal practices, the USEPA supported the development of

Managing Pharmaceutical Waste: A 10-Step Blueprint for Health Care

Facilities in the United States, which recommends a stepwise approach

to help health-care facilities develop and implement a comprehensive

pharmaceutical hazardous waste management programme. This

blueprint adopts the best practices in waste minimization to meet

regulatory compliance for pharmaceutical waste disposal and

safeguard human health and the environment in a cost-effective manner

(Pines & Smith, 2006).

To this end, the USEPA (2010b) has also drafted a guidance document,

Best Management Practices for Unused Pharmaceuticals at Health Care

Facilities, to advise health-care and veterinary facilities on reducing

pharmaceutical waste, on pharmaceutical waste management and

on application of disposal regulations. The aim is to help reduce the

amount of pharmaceuticals that are discharged to water bodies.

4.2 Pharmaceutical take-back

programmes

To augment regulations, take-back programmes have been established

by government and private organizations in several countries to reduce

the amount of drugs entering our environment (Daughton, 2003,

2004; Glassmeyer et al., 2009; Teleosis Institute, 2009). A survey of

households in the United Kingdom in 2003 showed that 22% of excess

pharmaceuticals were returned to pharmacists; although take-back

programmes were effective, further improvement is needed (Bound &

Voulvoulis, 2005).

These programmes can be of different scales, ranging from small one-day

collection events to regular and systematic regional collection, ongoing

return of unused and excess medicines to participating pharmacies and

mail-back programmes where excess medicines are returned in prepaid

packs to government-supervised mailboxes (SCBWMI, 2005). Several

household hazardous waste collection programmes have also added

pharmaceuticals to the list over the years (Glassmeyer et al., 2009).

In Australia, the Commonwealth Department of Health & Ageing

Services provided funds to establish a system for the collection and

disposal of unwanted medicines, known as the Return Unwanted

Medicines (RUM) Project. Estimates from RUM showed that in 2010–

2011, more than 34 tonnes of unwanted medicines on average were

collected monthly by community pharmacies across Australia and

subsequently incinerated according to guidelines (RUM, 2011).

In the USA, many scheduled pharmaceutical collection events facilitate

prudent disposal of unwanted medications at the regional level, such

as the successful “Great Lakes Earth Day Challenge”, which collected

4.5 million pills for safe disposal. The USEPA has also awarded grants

to support take-back of non-controlled, unused medicines at pharmacies

and mail-back of unused medicines with appropriate involvement of

law enforcement (USEPA, 2010a). Other mechanisms to reduce the

entry of pharmaceuticals into the environment include establishing

best management practices for handling solid wastes and minimizing

discharge from landﬁlls.

Canada has formal stewardship programmes for household

pharmaceutical waste at the provincial level or in cities that provide

convenient options for consumers to return pharmaceuticals to community

pharmacies for safe disposal.

Europe has widespread standardized take-back programmes. In the

2010 report Pharmaceuticals in the Environment: Results of an EEA

Workshop, the European Environment Agency (EEA, 2010) stated that

most countries in Europe collect unused drugs separately from household

waste, usually at pharmacies (a handful also have separate collection

sites alongside pharmacies). The national systems are operated and

funded by the pharmaceuticals industry, retail pharmacies or the

public sector. The operation of the take-back programmes may be the

responsibility of the retail pharmacies or of public or private waste

contractors (Teleosis Institute, 2009).

4.3 Raising consumer awareness

Consumers are accustomed to disposing of unwanted and expired

medicines through household waste and sewers. Such improper

disposal practices release pharmaceuticals into our environment,

wastewater and water sources. There is therefore a need to raise

public awareness and encourage consumers to adopt proper disposal

practices for unwanted pharmaceuticals. In Australia, the RUM Project

focuses on raising consumer awareness to inform consumers of the

appropriate option for drug disposal (RUM, 2010). In addition to

regulations under New York’s Drug Management and Disposal Act, the

New York State Department of Environmental Conservation publishes

posters for all pharmacies and retail stores that sell drugs to advise

consumers on the proper storage and disposal of unwanted medication

(DEC, 2010). Consumers can then serve as environmental stewards to

reduce water pollution.

4.4 Conclusion

Appropriate regulations governing disposal practices at point sources of

hazards, widespread take-back programmes, guidance and enhanced

consumer education will support efforts for the proper disposal of

unwanted and excess medicines and reduce the environmental impact

of pharmaceuticals entering our environment, including water sources.

As most pharmaceuticals enter the water cycle through wastewater

discharges or from poorly controlled manufacturing or production

facilities that are primarily associated with generic medicines, the

discharge of untreated or poorly treated wastewater to water bodies

used as drinking-water sources should be strongly discouraged.

5Conclusions,

recommendations

and knowledge gaps

5. Conclusions, recommendations and knowledge gaps

Pharmaceuticals are synthetic or natural chemicals that can be found in

prescription medicines, over-the-counter therapeutic drugs and veterinary drugs.

They contain active ingredients that are designed to achieve pharmacological

effects and confer signiﬁcant beneﬁts to society. Pharmaceuticals are primarily

introduced into the environment via human excretion, sewage efﬂuent, improper

drug disposal, agricultural runoff, and livestock and veterinary waste. The

ubiquitous use of pharmaceuticals in various settings has resulted in a continuous

discharge of pharmaceuticals and metabolites into the environment, leading to

their “pseudo-persistence” in the environment. Signiﬁcant advancements in the

sensitivity of detection and analytical technologies and methods have made it

possible to detect very low concentrations of pharmaceuticals in the range of

nanograms to low micrograms per litre in the water cycle. As pharmaceuticals

contain active ingredients that are designed to achieve speciﬁc pharmacological

effects based on their biological reactivity and biochemical properties, their

presence at trace concentrations in the water cycle has generated concerns

among various stakeholders, including governments, regulators and the public,

over potential risks to human health through very low level exposure via

drinking-water.

5.1 Conclusions

Targeted investigative studies conducted in the United Kingdom, the USA and

Australia have shown that concentrations of pharmaceuticals in surface water

and groundwater sources impacted by wastewater discharges are typically

less than 0.1 µg/l (or 100 ng/l). Detection in treated drinking-water is rare;

if pharmaceuticals are present, their concentrations are usually well below

0.05 µg/l (or 50 ng/l). There are, however, very few systematic monitoring

programmes or comprehensive, systematic studies on the occurrence of

pharmaceuticals in drinking-water, and limited occurrence data present one

of the key challenges in assessing the potential risks associated with trace

concentrations of pharmaceuticals in drinking-water.

Nonetheless, several approaches to screen and prioritize pharmaceuticals have

been published in the peer-reviewed literature. MTDs, ADIs and sometimes the

DWELs have been used as reference values by which to derive a margin of

safety between these and the reported or predicted worst-case exposure in

drinking-water.

Targeted investigations conducted in the above-mentioned countries found

that traces of pharmaceuticals in drinking-water are largely present at several

orders of magnitude (more than 1000-fold) below the lowest therapeutic dose

and largely below the calculated ADIs. The substantial margins of safety for

individual compounds suggest that appreciable adverse impacts on human

health are very unlikely at current levels of exposure in drinking-water.

From a treatment perspective, pharmaceuticals are not unusual organic

chemicals, and treatment removal rates are reasonably predictable based

upon the physical and chemical properties of the compounds. Conventional

treatment processes with coagulation, ﬁltration and chlorination can remove

about 50% of these compounds, whereas advanced treatment, such as

ozonation, advanced oxidation, activated carbon and membrane processes

(e.g. reverse osmosis, nanoﬁltration), can achieve higher removal rates; reverse

osmosis, for example, can remove more than 99% of large pharmaceutical

molecules.

5.2 Recommendations

The substantial margin of safety for consumption of very low concentrations of

pharmaceuticals in drinking-water suggests that appreciable adverse impacts on

human health are very unlikely. As such, concerns over pharmaceuticals should

not divert attention and valuable resources of water suppliers and regulators

from other priorities, such as pathogenic microbial water quality issues. The

low risk to human health from current levels of exposure in drinking-water

suggests that development of formal guideline values for pharmaceuticals in the

WHO Guidelines for Drinking-water Quality and the installation of specialized

treatment processes to reduce trace concentrations of pharmaceuticals are not

warranted.

Routine monitoring programmes for pharmaceuticals in water sources and

drinking-water and additional or specialized drinking-water treatment to reduce

very low concentrations of pharmaceuticals in drinking-water are not deemed

necessary due to the limited public health beneﬁts. However, where local

circumstances, such as a catchment survey, indicate a potential for elevated

levels of pharmaceuticals in the water cycle (surface water, groundwater,

wastewater efﬂuent and drinking-water), relevant stakeholders could undertake

targeted, well-designed and quality-controlled investigative studies to obtain

more information with which to assess the potential health risks arising from

exposure through drinking-water. If necessary, screening values could be

developed based on the MTD or the ADI approaches, and an assessment

of the need for treatment enhancement could also be considered within the

context of other risks and priorities using water safety plans.

Reduction of human exposure to pharmaceuticals through drinking-water can

be achieved through a combination of preventive measures, such as take-

back programmes, regulations, public guidance and consumer education to

encourage the proper disposal of unwanted pharmaceuticals and minimize

the introduction of pharmaceuticals into the environment. It is also imperative

to enhance public communication and education on water quality issues from

the human health standpoint. For example, conveying to the public the potential

health risks from exposure to very low concentrations of pharmaceuticals in

drinking-water will help them to better understand this issue relative to other

hazards, such as waterborne pathogenic microorganisms. However, in the

long term, improvement of wastewater treatment to more efﬁciently remove

a range of organic substances that are seen as emerging contaminants of

concern would provide a more sustainable and comprehensive solution in

preventing their entry into the water environment.

5.3 Knowledge gaps and future

research

Although current risk assessments indicate that very low concentrations of

pharmaceuticals in drinking-water are very unlikely to pose any risks to human

health, there are knowledge gaps in terms of assessing the risks associated

with long-term, low-level exposures to pharmaceuticals and possible combined

effects of chemical mixtures, including pharmaceuticals. Future research

investigating the possible additive or synergistic effects of mixtures would be

beneﬁcial for an accurate exposure assessment to determine whether there are

any potential risks to human health, taking into account sensitive subpopulations.

One of the key challenges in estimating exposures to pharmaceuticals in

drinking-water and assessing the potential risks to human health is the limited

occurrence data for the diverse group of human and veterinary pharmaceuticals

in use today. Implementing monitoring programmes is resource intensive in

terms of costs, human resources and infrastructure, and there is also a lack of

standardized sampling and analysis protocols to support monitoring studies.

As such, future research looking into cost-effective methods to prioritize

pharmaceuticals within the context of an overall risk assessment will beneﬁt our

appreciation of low levels of pharmaceuticals in drinking-water from a human

health perspective.

References

Adams C et al. (2002).

Removal of antibiotics from surface and distilled water in conventional water

treatment processes. Journal of Environmental Engineering, 128:253–260.

Aherne GW, Hardcastle A, Nield AH (1990).

Cytotoxic drugs and the aquatic environment: estimation of bleomycin in river and

water samples. Journal of Pharmacy and Pharmacology, 42:741–742 [cited in

DWI, 2007].

Alder AC et al. (2006).

Consumption and occurrence. In: Ternes TA, Joss A, eds. Human pharmaceuticals,

hormones and fragrances: the challenge of micropollutants in urban water

management. London, IWA Publishing [cited in DWI, 2007].

Andreozzi R et al. (2003).

Ozonation and H2O2/UV treatment of cloﬁbric acid in water: a kinetic investigation.

Journal of Hazardous Materials, B103:233–246.

ANSES (2011).

Campagne nationale d’occurrence des résidus de médicaments dans les eaux

destinées à la consommation humaine. Ressources en eaux brutes et eaux traitées.

Nancy, Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement

et du travail, Laboratoire d’Hydrologie de Nancy.

Ashton D, Hilton M, Thomas KV (2004).

Investigating the environmental transport of human pharmaceuticals to streams in the

United Kingdom. Science of the Total Environment, 333:167–184 [cited in DWI,

2007].

Bendz D et al. (2005).

Occurrence and fate of pharmaceutically active compounds in the environment, a

case study: Hoje River in Sweden. Journal of Hazardous Materials, 122:195 –204.

Benotti MJ et al. (2009).

Pharmaceuticals and endocrine disrupting compounds in U.S. drinking water.

Environmental Science & Technology, 43 (3):597–603.

Bercu JP et al. (2008).

Human health risk assessment for three neuropharmaceutical compounds in surface

waters. Regulatory Toxicology and Pharmacology, 50:420–427.

Boucard T, Gravell A (2006).

Personal communication: Concentrations of ﬂuoxetine and norﬂuoxetine in UK

sewage efﬂuents and river waters. United Kingdom Environment Agency [cited in

DWI, 2007].

Bound JP, Voulvoulis N (2005).

Household disposal of pharmaceuticals as a pathway for aquatic contamination in

the United Kingdom. Environmental Health Perspectives, 113 :17 0 5 –1711.

Bound JP, Voulvoulis N (2006).

Predicted and measured concentrations for selected pharmaceuticals in UK rivers:

implications for risk assessment. Water Research, 40:2885–2892 [cited in DWI,

2007].

Boyd GR et al. (2003).

Pharmaceuticals and personal care products (PPCPs) in surface water and treated

waters of Louisiana, USA and Ontario, Canada. Science of the Total Environment,

311:13 5 –14 9.

Bull RJ et al. (2011).

Therapeutic dose as the point of departure in assessing potential health hazards

from drugs in drinking water and recycled municipal wastewater. Regulatory

Toxicology and Pharmacology, 60:1–19.

Buser HR, Muller MD, Theobald N (1998).

Occurrence of the pharmaceutical drug cloﬁbric acid and the herbicide mecoprop

in various Swiss lakes and in the North Sea. Environmental Science & Technology,

32(1):188–192.

Buser HR, Poiger T, Muller MD (1999).

Occurrence and environmental behavior of the chiral pharmaceutical drug ibuprofen

in surface waters and in wastewater. Environmental Science & Technology,

33(15):2529–2535.

Castiglioni S et al. (2006).

Removal of pharmaceuticals in sewage treatment plants in Italy. Environmental

Science & Technology, 40:357–363.

Celiz MD, Tso J, Aga DS (2009).

Pharmaceutical metabolites in the environment: analytical challenges and ecological

risks. Environmental Toxicology and Chemistry, 28(12):2473–2484.

Christensen FM (1998).

Pharmaceuticals in the environment—a human risk? Regulatory Toxicology and

Pharmacology, 28:212–221.

Daughton CG (2001).

Pharmaceuticals and personal care products in the environment: overarching issues

and overview. ACS Symposium Series, 791:2–38.

Daughton CG (2003).

Cradle-to-cradle stewardship of drugs for minimizing their environmental disposition

while promoting human health. II. Drug disposal, waste reduction and future

directions. Environmental Health Perspectives, 111: 7 75 –78 5.

Daughton CG (2004).

PPCPs in the environment: future research—beginning with the end always in mind.

In: Kümmerer K, ed. Pharmaceuticals in the environment, 2nd ed. Springer, pp.

463–495.

Daughton CG, Ternes TA (1999).

Pharmaceuticals and personal care products in the environment: agents of subtle

change? Environmental Health Perspectives, 107(Suppl. 6):907–938.

DEC (2010).

Drugs in New York’s waters: how drugs get into our waters and why DEC

is concerned. New York State Department of Environmental Conservation

(http://www.dec.ny.gov/chemical/45083.html).

DWI (2007).

Desk based review of current knowledge on pharmaceuticals in drinking water and

estimation of potential levels. Final report prepared by Watts and Crane Associates

for Drinking Water Inspectorate, Department for Environment, Food and Rural Affairs

(Defra Project Code: CSA 7184/WT02046/DWI70/2/213; http://dwi.defra.

gov.uk/research/completed-research/reports/dwi70-2-213.pdf).

EEA (2010).

Pharmaceuticals in the environment: results of an EEA workshop. Copenhagen,

European Environment Agency (EEA Technical Report No. 1; http://www.eea.europa.

eu/publications/pharmaceuticals-in-the-environment-result-of-an-eea-workshop).

FAO/WHO (2009).

Principles and methods for the risk assessment of chemicals in food. Rome, Food

and Agriculture Organization of the United Nations; Geneva, World Health

Organization (Environmental Health Criteria 240).

Fatta D et al. (2007).

Analytical methods for tracing pharmaceutical residues in water and wastewater.

Trends in Analytical Chemistry, 26 (6):515–533.

Focazio MJ et al. (2008).

A national reconnaissance for pharmaceuticals and other organic wastewater

contaminants in the United States—II) Untreated drinking water sources. Science of

the Total Environment, 402:201–216.

Gabet-Giraud V et al. (2010).

Occurrence and removal of estrogens and beta blockers by various processes in

wastewater treatment plants. Science of the Total Environment, 408:4257–4269.

Garrison AW, Pope JD, Allen FR (1976).

GC/MS analysis of organic compounds in domestic wastewaters. In: Keith LH, ed.

Identiﬁcation and analysis of organic pollutants in water. Ann Arbor, MI, Ann Arbor

Science Publishers Inc., pp. 517–556.

Glassmeyer ST et al. (2009).

Disposal practices for unwanted residential medications in the United States.

Environment International, 35:566–572.

Gomes RL, Lester JN (2003).

Endocrine disrupters in drinking water and water reuse. In: Birkett JW, Lester JN, eds.

Endocrine disrupters in wastewater and sludge treatment processes. Boca Raton, FL,

CRC Press, pp. 219–266.

Heberer T (2002).

Occurrence, fate, and removal of pharmaceutical residues in the aquatic

environment: a review of recent research data. Toxicology Letters, 131 : 5 –17.

Heberer T, Reddersen K, Mechlinski A (2002).

From municipal sewage to drinking water: fate and removal of pharmaceutical

residues in the aquatic environment in urban areas. Water Science & Technology

46:81–88.

Heberer T, Schmidt-Bäumler K, Stan HJ (1998).

Occurrence and distribution of organic contaminants in the aquatic system in

Berlin. Part II: Substituted phenols in Berlin surface water. Acta Hydrochimica et

Hydrobiologica, 26:272–278.

Heberer T et al. (2001).

Occurrence of pharmaceutical residues in sewage, river, ground, and drinking

water in Greece and Berlin (Germany). In: Daughton C, Jones-Lepp T, eds.

Pharmaceuticals and personal care products in the environment; scientiﬁc and

regulatory issues. Washington, DC, American Chemical Society.

Heberer T et al. (2004).

Field studies on the fate and transport of pharmaceutical residues in bank ﬁltration.

Ground Water Monitoring and Remediation, 2 4 : 7 0 –7 7.

Hignite C, Azarnoff DL (1977).

Drugs and drug metabolites as environmental contaminants: chlorophenoxyisobutyrate

and salicylic acid in sewage water efﬂuent. Life Sciences, 20 (2):337–341.

Huber MM et al. (2003).

Oxidation of pharmaceuticals during ozonation and advanced oxidation processes.

Environmental Science & Technology, 37:1016–1024.

Huber MM et al. (2005).

Oxidation of pharmaceuticals during water treatment with chlorine dioxide. Water

Research, 39:3607–3617.

Huerta-Fontela M, Galceran MT, Ventura F (2011).

Occurrence and removal of pharmaceuticals and hormones through drinking water

treatment. Water Research, 45:1432–1442.

Jelic A et al. (2011).

Occurrence, partition and removal of pharmaceuticals in sewage water and sludge

during wastewater treatment. Water Research, 4 5 :116 5 –1176 .

Jones OA, Lester JN, Voulvoulis N (2005).

Pharmaceuticals: a threat to drinking water? Trends in Biotechnology, 23 (4):163–

16 7.

Joss A et al. (2005).

Removal of pharmaceuticals and fragrances in biological wastewater treatment.

Water Research, 39:3139 –3152.

Kasprzyk-Hordern B, Dinsdale RM, Guwy AJ (2009).

The removal of pharmaceuticals, personal care products, endocrine disruptors and

illicit drugs during wastewater treatment and its impact on the quality of receiving

waters. Water Research, 43:363–380.

Khiari D (2007).

Endocrine disruptors, pharmaceuticals, and personal care products in drinking

water: an overview of AwwaRF research to date. Denver, CO, Awwa Research

Foundation.

Kim SD et al. (2007).

Occurrence and removal of pharmaceuticals and endocrine disruptors in South

Korean surface, drinking, and waste waters. Water Research, 41:1013–1021.

Kimura K et al. (2004).

Rejection of neutral endocrine disrupting compounds (EDCs) and pharmaceutical

active compounds (PhACs) by RO membranes. Journal of Membrane Science,

245(1–2):71–78.

Klavarioti M, Mantzavinos D, Kassinos D (2009).

Removal of residual pharmaceuticals from aqueous systems by advanced oxidation

processes. Environment International, 3 5 : 4 0 2 – 417.

Kolpin DW et al. (2002).

Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S.

streams, 1999–2000: a national reconnaissance. Environmental Science &

Technology, 36:1202–1211.

Kroes R et al. (2004).

Structure-based thresholds of toxicological concern (TTC): guidance for application

to substances present at low levels in the diet. Food and Chemical Toxicology,

42:65–83.

Lee S et al. (2008).

Efﬁcient removals of tris(2-chloroethyl) phosphate (TCEP) and perchlorate using NF

membrane ﬁltrations. Desalination, 221:234–237.

Loos R et al. (2007).

Polar herbicides, pharmaceutical products, perﬂuorooctanesulfonate (PFOS),

perﬂuorooctanoate (PFOA), and nonylphenol and its carboxylates and ethoxylates

in surface and tap waters around Lake Maggiore in Northern Italy. Analytical and

Bioanalytical Chemistry, 387:1469–1478.

Loraine GA, Pettigrove ME (2006).

Seasonal variations in concentrations of pharmaceuticals and personal care

products in drinking water and reclaimed wastewater in Southern California.

Environmental Science & Technology, 40:687–695.

Lubick N (2010).

Drugs in the environment: do pharmaceutical take-back programs make a

difference? Environmental Health Perspectives, 118 ( 5 ) : A 211– A 214 .

McDowell DC et al. (2005).

Ozonation of carbamazepine in drinking water: identiﬁcation and kinetic study of

major oxidation products. Environmental Science & Technology, 39:8014–8022.

Meek ME et al. (2011).

Risk assessment of combined exposure to multiple chemicals: a WHO/IPCS

framework. Regulatory Toxicology and Pharmacology, 60:S1–S14.

Miao X-S et al. (2004).

Occurrence of antimicrobials in the ﬁnal efﬂuent of wastewater treatment plants in

Canada. Environmental Science & Technology, 38(13):3533–3541.

Mompelat S, Le Bot B, Thomas O (2009).

Occurrence and fate of pharmaceutical products and by-products, from resource to

drinking water. Environment International, 35:803–814.

Mons MN, Hoogenboom AC, Noij THM (2003).

Pharmaceuticals and drinking water supply in the Netherlands. Nieuwegein, Kiwa

Water Research (Kiwa Report No. BTO 2003.040).

Nghiem LD, Schäfer AI, Elimelech M (2005).

Pharmaceutical retention mechanisms by nanoﬁltration membranes. Environmental

Science & Technology, 39 (19):7698–7705.

NHMRC (1999).

National guidelines for waste management in the health industry. Canberra,

National Health and Medical Research Council (http://www.nhmrc.gov.au/_ﬁles_

nhmrc/ﬁle/publications/synopses/withdrawn/eh11.pdf).

NRMMC, EPHC, NHMRC (2008).

Australian guidelines for water recycling: managing health and environmental risks

(PHASE 2). Augmentation of drinking water supplies. Natural Resource Management

Ministerial Council, Environment Protection and Heritage Council and National

Health and Medical Research Council (http://www.qwc.qld.gov.au/prw/pdf/

agwr-augmentation-drinking-water-supplies-08-05.pdf).

Paxéus N (2004).

Removal of selected non-steroidal anti-inﬂammatory drugs (NSAIDs), gemﬁbrozil,

carbamazepine, β-blockers, trimethoprin and triclosan in conventional wastewater

treatment plants in ﬁve EU countries and their discharge to the aquatic environment.

Water Science & Technology, 50(5):253–260.

Pérez S, Barceló D (2007).

Application of advanced MS techniques to analysis and identiﬁcation of human

and microbial metabolites of pharmaceuticals in the aquatic environment. Trends in

Analytical Chemistry, 26(6):494–514.

Pines E, Smith C (2006).

Managing pharmaceutical waste: a 10-step blueprint for health care facilities in

the United States. Hospitals for a Healthy Environment (http://www.premierinc.

com/quality-safety/tools-services/safety/topics/pharma-waste/downloads/h2e-

pharma-blueprint-04-15-06.pdf).

Pinkston KE, Sedlak DL (2004).

Transformation of aromatic ether- and amine-containing pharmaceuticals during

chlorine disinfection. Environmental Science & Technology, 38:4019–4025.

Radjenović J et al. (2008).

Rejection of pharmaceuticals in nanoﬁltration and reverse osmosis membrane

drinking water treatment. Water Research, 42(14):3601–3610.

Rahman MF, Yanful EK, Jasim SY (2009).

Occurrences of endocrine disrupting compounds and pharmaceuticals in the

aquatic environment and their removal from drinking water: challenges in the context

of the developing world. Desalination, 248:578–585.

Reddersen K, Heberer T, Dünnbier U (2002).

Identiﬁcation and signiﬁcance of phenazone drugs and their metabolites in ground-

and drinking water. Chemosphere, 49:539–544.

Roberts PH, Thomas KV (2006).

The occurrence of selected pharmaceuticals in wastewater efﬂuent and surface

waters of the lower Tyne catchment. Science of the Total Environment, 356:143–

153 [cited in DWI, 2007].

Rosenfeldt EJ, Linden KG (2004).

Degradation of endocrine disrupting chemicals bisphenol A, ethinyl estradiol and

estradiol during UV photolysis and advanced oxidation processes. Environmental

Science & Technology, 38:5476–5486.

Rowney NC, Johnson AC, Williams RJ (2009).

Cytotoxic drugs in drinking water: a prediction and risk assessment exercise for the

Thames catchment in the United Kingdom. Environmental Toxicology and Chemistry,

28(12):2733–2743.

RUM (2010).

Consumer awareness. Cheltenham, The National Return and Disposal of Unwanted

Medicine Limited, Returning Unwanted Medicine Project (http://www.returnmed.

com.au/consumer-awareness).

RUM (2011).

Collection 2010–2011. Cheltenham, The National Return and Disposal of Unwanted

Medicine Limited, Returning Unwanted Medicine Project (http://www.returnmed.

com.au/collections).

SCBWMI (2005).

Discussion paper on pharmaceutical disposal to sewer systems. White paper

prepared by the Emerging Contaminants Working Group of the Santa Clara Basin

Watershed Management Initiative (http://www.scbwmi.org/PDFs/WMI_Pharm_

White_Paper_FinalMarch05.pdf).

Schulman LJ et al. (2002).

A human health risk assessment of pharmaceuticals in the aquatic environment.

Human and Ecological Risk Assessment, 8:657–680.

Schwab RW et al. (2005).

Human pharmaceuticals in US surface waters: a human health risk assessment.

Regulatory Toxicology and Pharmacology, 42:296 –312.

Simazaki D et al. (2008).

Removal of selected pharmaceuticals by chlorination, coagulation–sedimentation

and powdered activated carbon treatment. Water Science & Technology,

58 ( 5 ) :112 9 –113 5.

Snyder SA (2010).

Occurrence of pharmaceuticals in U.S drinking water. ACS Symposium Series,

1048:69–80.

Snyder SA et al. (2003).

Pharmaceuticals, personal care products and endocrine disruptors in water:

implications for the water industry. Environmental Engineering Science, 20:449–

469.

Snyder SA et al. (2006).

Role of membranes and activated carbon in the removal of endocrine disruptors

and pharmaceuticals. Desalination, 202:156–181.

Snyder SA et al. (2007).

Removal of EDCs and pharmaceuticals in drinking water and reuse treatment

processes. Denver, CO, Awwa Research Foundation.

Snyder SA et al. (2008).

Toxicological relevance of EDCs and pharmaceuticals in drinking water. Denver,

CO, Awwa Research Foundation.

Spellman FR (2010).

Spellman’s standard handbook for wastewater operators. Volume III. Advanced

level, 2nd ed. CRC Press.

Stackelberg PE et al. (2004).

Persistence of pharmaceutical compounds and other organic wastewater

contaminants in a conventional drinking-water treatment plant. Science of the Total

Environment, 329:99–113.

Stackelberg PE et al. (2007).

Efﬁciency of conventional drinking-water-treatment processes in removal of

pharmaceuticals and other organic compounds. Science of the Total Environment,

377(2–3):255–272.

Tabak HH, Bunch RL (1970).

Steroid hormones as water pollutants. I. Metabolism of natural and synthetic

ovulation-inhibiting hormones by microorganisms of activated sludge and primary

settled sewage. Developments in Industrial Microbiology, 11:367–376.

Teleosis Institute (2009).

Medicine take back locations. Berkeley, CA, Teleosis Institute (http://www.teleosis.

org/gpp-locations.php).

Ternes T (1998).

Occurrence of drugs in German sewage treatment plants and rivers. Water

Research, 32:3245–3260.

Ternes TA, Joss A, eds (2006).

Human pharmaceuticals, hormones and fragrances: the challenge of micropollutants

in urban water management. London, IWA Publishing.

Ternes TA et al. (1999).

Behavior and occurrence of estrogens in municipal sewage treatment plants—1.

Investigations in Germany, Canada and Brazil. Science of the Total Environment,

225:81–90.

Ternes TA et al. (2002).

Removal of pharmaceuticals during drinking water treatment. Environmental Science

& Technology, 36:3855–3863.

Ternes TA et al. (2003).

Ozonation: a tool for removal of pharmaceuticals, contrast media and musk

fragrances from wastewater? Water Research, 37:1976–1982.

Ternes TA et al. (2005).

Assessment of technologies for the removal of pharmaceuticals and personal care

products in sewage and drinking water to improve the indirect potable water reuse.

POSEIDON project detailed report (EU Contract No. EVK1-CT-2000-00047).

Thomas KV, Hilton MJ (2004).

The occurrence of selected human pharmaceutical compounds in UK estuaries.

Marine Pollution Bulletin, 49:436–444 [cited in DWI, 2007].

Togola A, Budzinski H (2008).

Multi-residue analysis of pharmaceutical compounds in aqueous samples. Journal of

Chromatography A, 1177:150 –158.

USEPA (2008a).

Health services industry study: management and disposal of unused pharmaceuticals

(interim technical report). Washington, DC, United States Environmental Protection

Agency (EPA-821-R-08-013).

USEPA (2008b).

Approaches to screening for risk from pharmaceuticals in drinking-water and

prioritization for further evaluation. Washington, DC, United States Environmental

Protection Agency (Contract No. C-07-021, WA-B-02, Task 6 under the supervision

of Dr O. Conerly).

USEPA (2010a).

Report released on pharmaceutical mail-back pilot program funded by EPA: Agency

provided $150,000 grant to University of Maine’s Center on Aging to undertake

study. Washington, DC, United States Environmental Protection Agency (h t t p : //

yosemite.epa.gov/opa/admpress.nsf/d0cf6618525a9efb85257359003fb69d

/97c00306844616bb852577270052ab58!OpenDocument).

USEPA (2010b).

Guidance document: Best management practices for unused pharmaceuticals at

health care facilities. Draft. Washington, DC, United States Environmental Protection

Agency (EPA-821-R-10-006; http://water.epa.gov/scitech/wastetech/guide/upload/

unuseddraft.pdf).

van der Aa NGFM et al. (2009).

Drugs of abuse and tranquilizers in Dutch surface waters, drinking water and

wastewater. Results of screening monitoring 2009. Bilthoven, National Institute for

Public Health and the Environment (RIVM Report No. 703719064/2010).

Vanderford BJ, Snyder SA (2006).

Analysis of pharmaceuticals in water by isotope dilution liquid chromatography/

tandem mass spectrometry. Environmental Science & Technology, 40:7312–7320.

Van De Steene JC, Stove CP, Lambert WE (2010).

A ﬁeld study on 8 pharmaceuticals and 1 pesticide in Belgium: removal rates in

waste water treatment plants and occurrence in surface water. Science of the Total

Environment, 408:3448–3453.

Versteegh JFM, van der Aa NGFM, Dijkman E (2007).

Pharmaceuticals in drinking water and drinking water sources. Results of the

monitoring program 2005/2006. Bilthoven, National Institute for Public Health and

the Environment, pp. 1–53 (RIVM Report No. 703719016/2007).

Vieno NM, Tuhkanen T, Kronberg L (2005).

Seasonal variation in the occurrence of pharmaceuticals in efﬂuents from a sewage

treatment plant and in the recipient water. Environmental Science & Technology,

39:8220–8226.

Vieno N, Tuhkanen T, Kronberg L (2006).

Removal of pharmaceuticals in drinking water treatment: effect of chemical

coagulation. Environmental Technology, 27:183–192.

Vieno N, Tuhkanen T, Kronberg L (2007).

Elimination of pharmaceuticals in sewage treatment plants in Finland. Water

Research, 41:1001–1012.

Watkinson AJ, Murby EJ, Costanzo SD (2007).

Removal of antibiotics in conventional and advanced wastewater treatment:

implications for environmental discharge and wastewater recycling. Water Research,

41(18):416 4–4176.

Watts CD et al. (1983).

Identiﬁcation of non-volatile organics in water using ﬁeld desorption mass

spectrometry and high performance liquid chromatography. In: Angeletti G, Bjørseth

A, eds. Analysis of organic micropollutants in water. Dordrecht, D. Reidel Publishing

Co., pp. 120–131 [cited in DWI, 2007].

Webb S et al. (2003).

Indirect human exposure to pharmaceuticals via drinking water. Toxicology Letters,

14 2 :15 7 –16 7.

Westerhoff P et al. (2005).

Fate of endocrine disruptor, pharmaceutical, and personal care product chemicals

during simulated drinking water treatment processes. Environmental Science &

Technology, 39(17):6649–6663.

WHO (2011).

Guidelines for drinking-water quality, 4th ed. Geneva, World Health Organization.

Wick A et al. (2009).

Fate of beta blockers and psycho-active drugs in conventional wastewater treatment.

Water Research, 43(4):1060–1074.

Xu W-H et al. (2007).

Determination of selected antibiotics in the Victoria Harbour and the Pearl River,

South China using high-performance liquid chromatography–electrospray ionization

tandem mass spectrometry. Environmental Pollution, 145(3):672–679.

Yoon Y et al. (2003).

HPLC-ﬂuorescence detection and adsorption of bisphenol A, 17β-estradiol,

and 17α-ethynyl estradiol on powdered activated carbon. Water Research,

37(14):3530–3537.

Yoon Y et al. (2006).

Nanoﬁltration and ultraﬁltration of endocrine disrupting compounds, pharmaceuticals

and personal care products. Journal of Membrane Science, 270:88–100.

Zhang DQ et al. (2011).

Removal of pharmaceutical compounds in tropical constructed wetlands. Ecological

Engineering, 37(3):460–464.

Zhang YJ, Geissen SU, Gal C (2008).

Carbamazepine and diclofenac: removal in wastewater treatment plants and

occurrence in water bodies. Chemosphere, 73 ( 8 ) :1151–1161.

Ziylan A, Ince NH (2011).

The occurrence and fate of anti-inﬂammatory and analgesic pharmaceuticals

in sewage and fresh water: treatability by conventional and non-conventional

processes. Journal of Hazardous Materials, 187(1–3):24–36.

Zuccato E et al. (2000).

Presence of therapeutic drugs in the environment. Lancet, 355(9217):1789–1790.

Zühlke S et al. (2004).

Detection and identiﬁcation of phenazone-type drugs and their microbial

metabolites in ground and drinking water applying solid-phase extraction and gas

chromatography with mass spectrometric detection. Journal of Chromatography A,

1050:201–209.

Zwiener C, Frimmel FH (2000).

Oxidative treatment of pharmaceuticals in water. Water Research, 34 ( 6 ):1881–

1885.

Reports of trace concentrations of pharmaceuticals

in the water cycle have raised concerns among

various stakeholders, such as drinking-water

regulators, governments, water suppliers and the

public, over potential human health risks from

exposure to very low levels of pharmaceuticals in

drinking-water.

This technical report aims to provide practical

guidance and recommendations in managing

concerns over pharmaceuticals in drinking-water,

taking into consideration the available scientiﬁc

knowledge and evidence. It emphasizes the

importance to prioritize this emerging issue in the

overall context of water safety management, which

includes microbial and other chemical risks that may

threaten the safety of drinking-water.

ISBN 978 92 4 150208 5

44630 9789241502085 Eng

Navigation menu

Versions of this User Manual:

Views

Navigation