DISINFECTANTS AND DISINFECTANT BY-PRODUCTS

UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

Environmental Health Criteria 216

This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation or the World Health Organization.

First draft prepared by G. Amy, University of Colorado, Boulder,
Colorado, USA; R. Bull, Battelle Pacific Northwest Laboratory,
Richland, Washington, USA; G.F. Craun, Gunther F. Craun and
Associates, Staunton, Virginia, USA; R.A. Pegram, US Environmental
Protection Agency, Research Triangle Park, North Carolina, USA; and M.
Siddiqui, University of Colorado, Boulder, Colorado, USA

Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization
Geneva, 2000

The International Programme on Chemical Safety (IPCS),
established in 1980, is a joint venture of the United Nations
Environment Programme (UNEP), the International Labour Organisation
(ILO) and the World Health Organization (WHO). The overall objectives
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the risk to human health and the environment from exposure to
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prerequisite for the promotion of chemical safety, and to provide
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sound management of chemicals.

The Inter-Organization Programme for the Sound Management of
Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
Agriculture Organization of the United Nations, WHO, the United
Nations Industrial Development Organization and the Organisation for
Economic Co-operation and Development (Participating Organizations),
following recommendations made by the 1992 UN Conference on
Environment and Development to strengthen cooperation and increase
coordination in the field of chemical safety. The purpose of the IOMC
is to promote coordination of the policies and activities pursued by
the Participating Organizations, jointly or separately, to achieve the
sound management of chemicals in relation to human health and the
environment.

WHO Library Cataloguing-in-Publication Data

Disinfectants and disinfectant by-products.

(Environmental health criteria ; 216)

1.Disinfectants - chemistry 2.Disinfectants - toxicity
3.Drinking water 4.Risk assessment
5.Epidemiologic studies I.Series

ISBN 92 4 157216 7 (NLM Classification: QV 220)
ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DISINFECTANTS AND DISINFECTANT
BY-PRODUCTS

PREAMBLE

ACRONYMS AND ABBREVIATIONS

1. SUMMARY AND EVALUATION
1.1. Chemistry of disinfectants and disinfectant by-products
1.2. Kinetics and metabolism in laboratory animals and humans
1.2.1. Disinfectants
1.2.2. Trihalomethanes
1.2.3. Haloacetic acids
1.2.4. Haloaldehydes and haloketones
1.2.5. Haloacetonitriles
1.2.6. Halogenated hydroxyfuranone derivatives
1.2.7. Chlorite
1.2.8. Chlorate
1.2.9. Bromate
1.3. Toxicology of disinfectants and disinfectant by-products
1.3.1. Disinfectants
1.3.2. Trihalomethanes
1.3.3. Haloacetic acids
1.3.4. Haloaldehydes and haloketones
1.3.5. Haloacetonitriles
1.3.6. Halogenated hydroxyfuranone derivatives
1.3.7. Chlorite
1.3.8. Chlorate
1.3.9. Bromate
1.4. Epidemiological studies
1.4.1. Cardiovascular disease
1.4.2. Cancer
1.4.3. Adverse pregnancy outcomes
1.5. Risk characterization
1.5.1. Characterization of hazard and dose-response
1.5.1.1 Toxicological studies
1.5.1.2 Epidemiological studies
1.5.2. Characterization of exposure
1.5.2.1 Occurrence of disinfectants and disinfectant
by-products
1.5.2.2 Uncertainties of water quality data
1.5.2.3 Uncertainties of epidemiological data

2. CHEMISTRY OF DISINFECTANTS AND DISINFECTANT BY-PRODUCTS

2.1. Background
2.2. Physical and chemical properties of common disinfectants and
inorganic disinfectant by-products
2.2.1. Chlorine
2.2.2. Chlorine dioxide

2.2.3. Ozone
2.2.4. Chloramines
2.3. Analytical methods for disinfectant by-products and
disinfectants
2.3.1. Trihalomethanes, haloacetonitriles, chloral hydrate,
chloropicrin and haloacetic acids
2.3.2. Inorganic disinfectant by-products
2.3.3. Total organic carbon and UV absorbance at 254 nm
2.3.4. Chloramines
2.4. Mechanisms involved in the formation of disinfectant
by-products
2.4.1. Chlorine reactions
2.4.2. Chlorine dioxide reactions
2.4.3. Chloramine reactions
2.4.4. Ozone reactions
2.5. Formation of organohalogen disinfectant by-products
2.5.1. Chlorine organohalogen by-products
2.5.2. Chloramine organohalogen by-products
2.5.3. Chlorine dioxide organohalogen by-products
2.5.4. Ozone organohalogen by-products
2.6. Formation of inorganic disinfectant by-products
2.6.1. Chlorine inorganic by-products
2.6.2. Chloramine inorganic by-products
2.6.3. Chlorine dioxide inorganic by-products
2.6.4. Ozone inorganic by-products
2.7. Formation of non-halogenated organic disinfectant
by-products
2.7.1. Chlorine organic by-products
2.7.2. Chloramine organic by-products
2.7.3. Chlorine dioxide organic by-products
2.7.4. Ozone organic by-products
2.8. Influence of source water characteristics on the amount and
type of by-products produced
2.8.1. Effect of natural organic matter and UV absorbance
at 254 nm
2.8.2. Effect of pH
2.8.3. Effect of bromide
2.8.4. Effect of reaction rates
2.8.5. Effect of temperature
2.8.6. Effect of alkalinity
2.9. Influence of water treatment variables on the amount and
type of by-products produced
2.9.1. Effect of ammonia
2.9.2. Effect of disinfectant dose
2.9.3. Effect of advanced oxidation processes
2.9.4. Effect of chemical coagulation
2.9.5. Effect of pre-ozonation
2.9.6. Effect of biofiltration
2.10. Comparative assessment of disinfectants
2.11. Alternative strategies for disinfectant by-product control
2.11.1. Source control
2.11.2. Organohalogen by-products

2.11.3. Inorganic by-products
2.11.4. Organic by-products
2.12. Models for predicting disinfectant by-product formation
2.12.1. Factors affecting disinfectant by-product formation
and variables of interest in disinfectant by-product
modelling
2.12.2. Empirical models for disinfectant by-product
formation
2.12.3. Models for predicting disinfectant by-product
precursor removal
2.13. Summary

3. TOXICOLOGY OF DISINFECTANTS

3.1. Chlorine and hypochlorite
3.1.1. General toxicological properties and information on
dose-response in animals
3.1.2. Reproductive and developmental toxicity
3.1.3. Toxicity in humans
3.1.4. Carcinogenicity and mutagenicity
3.1.5. Comparative pharmacokinetics and metabolism
3.1.6. Mode of action
3.2. Chloramine
3.2.1. General toxicological properties and information on
dose-response in animals
3.2.2. Reproductive and developmental toxicity
3.2.3. Toxicity in humans
3.2.4. Carcinogenicity and mutagenicity
3.2.5. Comparative pharmacokinetics and metabolism
3.3. Chlorine dioxide
3.3.1. General toxicological properties and information on
dose-response in animals
3.3.2. Reproductive and developmental toxicity
3.3.3. Toxicity in humans
3.3.4. Carcinogenicity and mutagenicity
3.3.5. Comparative pharmacokinetics and metabolism

4. TOXICOLOGY OF DISINFECTANT BY-PRODUCTS

4.1. Trihalomethanes
4.1.1. Chloroform
4.1.1.1 General toxicological properties and
information on dose-response in animals
4.1.1.2 Toxicity in humans
4.1.1.3 Carcinogenicity and mutagenicity
4.1.1.4 Comparative pharmacokinetics and metabolism
4.1.1.5 Mode of action
4.1.2. Bromodichloromethane
4.1.2.1 General toxicological properties and
information on dose-response in animals
4.1.2.2 Reproductive and developmental toxicity
4.1.2.3 Neurotoxicity
4.1.2.4 Toxicity in humans

4.1.2.5 Carcinogenicity and mutagenicity
4.1.2.6 Comparative phamacokinetics and metabolism
4.1.2.7 Mode of action
4.1.3. Dibromochloromethane
4.1.3.1 General toxicological properties and
information on dose-response in animals
4.1.3.2 Reproductive and developmental toxicity
4.1.3.3 Neurotoxicity
4.1.3.4 Toxicity in humans
4.1.3.5 Carcinogenicity and mutagenicity
4.1.3.6 Comparative pharmacokinetics and metabolism
4.1.3.7 Mode of action
4.1.4. Bromoform
4.1.4.1 General toxicological properties and
information on dose-response in animals
4.1.4.2 Reproductive and developmental toxicity
4.1.4.3 Neurotoxicity
4.1.4.4 Toxicity in humans
4.1.4.5 Carcinogenicity and mutagenicity
4.1.4.6 Comparative pharmacokinetics and metabolism
4.1.4.7 Mode of action
4.2. Haloacids
4.2.1. Dichloroacetic acid (dichloroacetate)
4.2.1.1 General toxicological properties and
information on dose-response in animals
4.2.1.2 Reproductive effects
4.2.1.3 Developmental effects
4.2.1.4 Neurotoxicity
4.2.1.5 Toxicity in humans
4.2.1.6 Carcinogenicity and mutagenicity
4.2.1.7 Comparative pharmacokinetics and metabolism
4.2.1.8 Mode of action
4.2.2. Trichloroacetic acid (trichloroacetate)
4.2.2.1 General toxicological properties and
information on dose-response in animals
4.2.2.2 Reproductive effects
4.2.2.3 Developmental effects
4.2.2.4 Neurotoxicity
4.2.2.5 Toxicity in humans
4.2.2.6 Carcinogenicity and mutagenicity
4.2.2.7 Comparative pharmacokinetics and metabolism
4.2.2.8 Mode of action
4.2.3. Brominated haloacetic acids
4.2.3.1 General toxicological properties and
information on dose-response in animals
4.2.3.2 Reproductive effects
4.2.3.3 Neurotoxicity
4.2.3.4 Toxicity in humans
4.2.3.5 Carcinogenicity and mutagenicity
4.2.3.6 Comparative pharmacokinetics and metabolism
4.2.3.7 Mode of action
4.2.4. Higher molecular weight halogenated acids

4.3. Haloaldehydes and haloketones
4.3.1. Chloral hydrate (trichloroacetaldehyde, chloral)
4.3.1.1 General toxicological properties and
information on dose-response in animals
4.3.1.2 Toxicity in humans
4.3.1.3 Carcinogenicity and mutagenicity
4.3.1.4 Comparative metabolism and pharmacokinetics
4.3.1.5 Mode of action
4.3.2. Halogenated aldehydes and ketones other than chloral
hydrate
4.3.2.1 General toxicological properties and
information on dose-response in animals
4.3.2.2 Toxicity in humans
4.3.2.3 Carcinogenicity and mutagenicity
4.3.2.4 Comparative pharmacokinetics and metabolism
4.3.2.5 Mode of action
4.4. Haloacetonitriles
4.4.1. General toxicological properties and information on
dose-response in animals and humans
4.4.2. Reproductive and developmental toxicity
4.4.3. Carcinogenicity and mutagenicity
4.4.4. Comparative pharmacokinetics and metabolism
4.4.5. Mode of action
4.5. Halogenated hydroxyfuranone derivatives
4.5.1. General toxicological properties and information on
dose-response in animals
4.5.2. Toxicity in humans
4.5.3. Carcinogenicity and mutagenicity
4.5.3.1 Studies in bacteria and mammalian cells
in vitro
4.5.3.2 Studies in experimental animals
4.5.4. Comparative pharmacokinetics and metabolism
4.6. Chlorite
4.6.1. General toxicological properties and information on
dose-response in animals
4.6.2. Reproductive and developmental toxicity
4.6.3. Toxicity in humans
4.6.4. Carcinogenicity and mutagenicity
4.6.5. Comparative pharmacokinetics and metabolism
4.6.6. Mode of action
4.7. Chlorate
4.7.1. General toxicological properties and information on
dose-response in animals
4.7.2. Reproductive and developmental toxicity
4.7.3. Toxicity in humans
4.7.4. Carcinogenicity and mutagenicity
4.7.5. Mode of action
4.8. Bromate
4.8.1. General toxicological properties and information on
dose-response in animals
4.8.2. Toxicity in humans
4.8.3. Carcinogenicity and mutagenicity
4.8.4. Comparative pharmacokinetics and metabolism
4.8.5. Mode of action
4.9. Other disinfectant by-products

5. EPIDEMIOLOGICAL STUDIES
5.1. Epidemiological study designs and causality of
epidemiological associations
5.1.1. Experimental studies
5.1.2. Observational studies
5.1.3. Random and systematic error
5.1.4. Causality of an epidemiological association
5.2. Epidemiological associations between disinfectant
use and adverse health outcomes
5.2.1. Epidemiological studies of cancer and disinfected
drinking-water
5.2.1.1 Cancer associations in ecological studies
5.2.1.2 Cancer associations in analytical studies
5.2.1.3 Meta-analysis of cancer studies
5.2.1.4 Summary of results of cancer studies
5.2.2. Epidemiological studies of cardiovascular disease and
disinfected drinking-water
5.2.2.1 Summary of results of cardiovascular studies
5.2.3. Epidemiological studies of adverse
reproductive/developmental outcomes and disinfected
drinking-water
5.2.3.1 Summary of results of
reproductive/developmental studies
5.3. Epidemiological associations between disinfectant
by-products and adverse health outcomes
5.3.1. Epidemiological studies of cancer and disinfectant
by-products
5.3.1.1 Cancer associations in ecological studies
5.3.1.2 Cancer associations in analytical studies
5.3.1.3 Summary of results of cancer studies
5.3.2. Epidemiological studies of cardiovascular disease and
disinfectant by-products
5.3.2.1 Summary of results of cardiovascular studies
5.3.3. Epidemiological studies of adverse
reproductive/developmental outcomes and disinfectant
by-products
5.3.3.1 Summary of results of
reproductive/developmental studies
5.4. Summary

6. RISK CHARACTERIZATION

6.1. Characterization of hazard and dose-response
6.1.1. Toxicological studies
6.1.1.1 Chlorine
6.1.1.2 Monochloramine
6.1.1.3 Chlorine dioxide
6.1.1.4 Trihalomethanes
6.1.1.5 Haloacetic acids
6.1.1.6 Chlorate hydrate
6.1.1.7 Haloacetonitriles
6.1.1.8 MX
6.1.1.9 Chlorite

6.1.1.10 Chlorate
6.1.1.11 Bromate
6.1.2. Epidemiological studies
6.2. Characterization of exposure
6.2.1. Occurrence of disinfectants and disinfectant
by-products
6.2.2. Uncertainties of water quality data
6.2.3. Uncertainties of epidemiological data

7. RISK CONCLUSIONS AND COMPARISONS

7.1. Epidemiological studies
7.2. Toxicological studies
7.2.1. Diversity of by-products
7.2.2. Diversity of modes of action
7.2.3. Reproductive, developmental and neurotoxic effects
7.3. Risks associated with mixtures of disinfectant by-products

8. CONCLUSIONS AND RECOMMENDATIONS

8.1. Chemistry
8.2. Toxicology
8.3. Epidemiology

9. RESEARCH NEEDS

9.1. Chemistry of disinfectants and disinfectant by-products
9.2. Toxicology
9.3. Epidemiology

PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

RESUME ET EVALUATION

RESUMEN Y EVALUACION

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Environmental Health Criteria

PREAMBLE

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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DISINFECTANTS AND
DISINFECTANT BY-PRODUCTS

Members

Dr G. Amy, Department of Civil, Environmental, and Architectural
Engineering, University of Colorado, Boulder, Colorado, USA

Mr J. Fawell, Water Research Centre, Marlow, Buckinghamshire, United
Kingdom (Co-Rapporteur)

Dr B. Havlik, Ministry of Health, National Institute of Public Health,
Prague, Czech Republic

Dr C. Nokes, Water Group, Institute of Environmental Science and
Research, Christchurch, New Zealand (Co-Rapporteur)

Dr E. Ohanian, Office of Water/Office of Science and Technology,
United States Environmental Protection Agency, Washington, DC,
USA (Chairman)

Dr E. Soderlund, Department of Environmental Medicine, National
Institute of Public Health, Torshov, Oslo

Secretariat

Dr J. Bartram, Water, Sanitation and Health Unit, Division of
Operational Support in Environment Health, World Health
Organization, Geneva, Switzerland

Dr R. Bull, Battelle Pacific Northwest Laboratory, Richland,
Washington, USA

Mr G.F. Craun, Gunther F. Craun and Associates, Staunton, Virginia,
USA

Dr H. Galal-Gorchev, Chevy Chase, Maryland, USA (Secretary)

Mr N. Nakashima, Assessment of Risk and Methodologies,
International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland

Dr R.A. Pegram, United States Environmental Protection Agency,
Research Triangle Park, North Carolina, USA

Mr S.T. Yamamura, Water, Sanitation and Health Unit, Division of
Operational Support in Environment Health, World Health
Organization, Geneva, Switzerland

Representatives/Observers

Dr N. Drouot, Dept Toxicologie Industrielle, Paris, France
(representing European Centre for Ecotoxicology and Toxicology
of Chemicals)

Mr O. Hydes, Drinking Water Inspectorate, London, United Kingdom

Dr B.B. Sandel, Olin Corporation, Norwalk, Connecticut, USA
(representing American Industrial Health Council/International
Life Sciences Institute)

IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DISINFECTANTS AND
DISINFECTANT BY-PRODUCTS

A WHO Task Group on Environmental Health Criteria for
Disinfectants and Disinfectant By-products met in Geneva from 17 to 21
August 1998. Dr Peter Toft, Associate Director, IPCS, welcomed the
participants on behalf of the three IPCS cooperating organizations
(UNEP/ILO/WHO). The Task Group reviewed and revised the draft document
and made an evaluation of risks for human health from exposure to
certain disinfectants and disinfectant by-products.

The first draft of the chemistry section was prepared by G. Amy
and M. Siddiqui, University of Colorado, Boulder, Colorado, USA; the
toxicology section was prepared by R. Bull, Battelle Pacific Northwest
Laboratory, Richland, Washington, USA, and R.A. Pegram, US
Environmental Protection Agency, Research Triangle Park, North
Carolina, USA; and the epidemiology section was prepared by G.F.
Craun, Gunther F. Craun and Associates, Staunton, Virginia, USA.

The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.

* * *

The preparation of the first draft of this Environmental Health
Criteria monograph was made possible by the financial support afforded
to IPCS by the International Life Sciences Institute.

A financial contribution from the United States Environmental
Protection Agency for the convening of the Task Group is gratefully
acknowledged.

ACRONYMS AND ABBREVIATIONS

ALAT alanine aminotransferase
AP alkaline phosphatase
ARB atypical residual bodies
ASAT aspartate aminotransferase
AWWA American Water Works Association
BAN bromoacetonitrile
BCA bromochloroacetic acid/bromochloroacetate
BCAN bromochloroacetonitrile
BDCA bromodichloroacetic acid/bromodichloroacetate
BDCM bromodichloromethane
BUN blood urea nitrogen
bw body weight
CAN chloroacetonitrile
CHO Chinese hamster ovary
CI confidence interval
CoA coenzyme A
C_max maximum concentration
CMCF 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone
2-CP 2-chloropropionate
CPN chloropropanone
CT computerized tomography
CYP cytochrome P450
DBA dibromoacetic acid/dibromoacetate
DBAC dibromoacetone
DBAN dibromoacetonitrile
DBCM dibromochloromethane
DBP disinfectant by-product
DCA dichloroacetic acid/dichloroacetate
DCAN dichloroacetonitrile
DCPN dichloropropanone
DHAN dihaloacetonitrile
DOC dissolved organic carbon
ECD electron capture detector
ECG electrocardiogram
EEG electroencephalogram
EHEN N-ethyl- N-hydroxyethylnitrosamine
EPA Environmental Protection Agency (USA)
ESR electron spin resonance
FAO Food and Agriculture Organization of the United Nations
GAC granular activated carbon
GC gas chromatography
GGT gamma-glutamyl transpeptidase
GOT glutamate-oxalate transaminase
GPT glutamate-pyruvate transaminase
GSH glutathione-SH
GST glutathione- S-transferase
HAA haloacetic acid
HAN haloacetonitrile
HDL high-density lipoprotein
HPLC high-performance liquid chromatography
hprt hypoxanthine phosphoribosyl transferase
IARC International Agency for Research on Cancer

IC ion chromatography
i.p. intraperitoneal
IPCS International Programme on Chemical Safety
JECFA Joint FAO/WHO Expert Committee on Food Additives
LD₅₀ median lethal dose
LDH lactate dehydrogenase
LDL low-density lipoprotein
LOAEL lowest-observed-adverse-effect level
MA 3,4-(dichloro)-5-hydroxy-2(5H)-furanone
MBA monobromoacetic acid/monobromoacetate
MCA monochloroacetic acid/monochloroacetate
MNU methylnitrosourea
MOR mortality odds ratio
MRI magnetic resonance imaging
MTBE methyl tert-butyl ether
MX 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone
NADP nicotinamide adenine dinucleotide phosphate
NOAEL no-observed-adverse-effect level
NOEL no-observed-effect level
NOM natural organic matter
NTP National Toxicology Program (USA)
8-OH-dG 8-hydroxy-2-deoxyguanosine
OR odds ratio
PAS periodic acid/Schiff's reagent
PBPK physiologically based pharmacokinetic model
PFBHA O-(2,3,4,5,6-pentafluorobenzyl)-hydroxylamine
p K_a log acid dissociation constant
PPAR peroxisome proliferator activated receptor
PPRE peroxisome proliferator responsive element
RR relative risk
SCE sister chromatid exchange
SD standard deviation
SDH sorbitol dehydrogenase
SE standard error
SGOT serum glutamate-oxaloacetate transaminase
SGPT serum glutamate-pyruvate transaminase
SMR standardized mortality ratio
SSB single strand breaks
TBA tribromoacetic acid/tribromoacetate
TBARS thiobarbituric acid reactive substances
TCA trichloroacetic acid/trichloroacetate
TCAN trichloroacetonitrile
TCPN trichloropropanone
TDI tolerable daily intake
TGF transforming growth factor
THM trihalomethane
TOC total organic carbon
TOX total organic halogen
TPA 12- O-tetradecanoylphorbol-13-acetate
UDS unscheduled DNA synthesis
UV ultraviolet
UVA₂₅₄ UV absorbance at 254 nm
V_max maximum rate of metabolism
WHO World Health Organization

1. SUMMARY AND EVALUATION

Chlorine (Cl₂) has been widely used throughout the world as a
chemical disinfectant, serving as the principal barrier to microbial
contaminants in drinking-water. The noteworthy biocidal attributes of
chlorine have been somewhat offset by the formation of disinfectant
by-products (DBPs) of public health concern during the chlorination
process. As a consequence, alternative chemical disinfectants, such as
ozone (O₃), chlorine dioxide (ClO₂) and chloramines (NH₂Cl,
monochloramine), are increasingly being used; however, each has been
shown to form its own set of DBPs. Although the microbiological
quality of drinking-water cannot be compromised, there is a need to
better understand the chemistry, toxicology and epidemiology of
chemical disinfectants and their associated DBPs in order to develop a
better understanding of the health risks (microbial and chemical)
associated with drinking-water and to seek a balance between microbial
and chemical risks. It is possible to decrease the chemical risk due
to DBPs without compromising microbiological quality.

1.1 Chemistry of disinfectants and disinfectant by-products

The most widely used chemical disinfectants are chlorine, ozone,
chlorine dioxide and chloramine. The physical and chemical properties
of disinfectants and DBPs can affect their behaviour in
drinking-water, as well as their toxicology and epidemiology. The
chemical disinfectants discussed here are all water-soluble oxidants,
which are produced either on-site (e.g., ozone) or off-site (e.g.,
chlorine). They are administered as a gas (e.g., ozone) or liquid
(e.g., hypochlorite) at typical doses of several milligrams per litre,
either alone or in combination. The DBPs discussed here are measurable
by gas or liquid chromatography and can be classified as organic or
inorganic, halogenated (chlorinated or brominated) or non-halogenated,
and volatile or non-volatile. Upon their formation, DBPs can be stable
or unstable (e.g., decomposition by hydrolysis).

DBPs are formed upon the reaction of chemical disinfectants with
DBP precursors. Natural organic matter (NOM), commonly measured by
total organic carbon (TOC), serves as the organic precursor, whereas
bromide ion (Br^-) serves as the inorganic precursor. DBP formation is
influenced by water quality (e.g., TOC, bromide, pH, temperature,
ammonia, carbonate alkalinity) and treatment conditions (e.g.,
disinfectant dose, contact time, removal of NOM before the point of
disinfectant application, prior addition of disinfectant).

Chlorine in the form of hypochlorous acid/hypochlorite ion
(HOCl/OCl^-) reacts with bromide ion, oxidizing it to hypobromous
acid/hypobromite ion (HOBr/OBr^-). Hypochlorous acid (a more powerful
oxidant) and hypobromous acid (a more effective halogenating agent)
react collectively with NOM to form chlorine DBPs, including
trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles
(HANs), haloketones, chloral hydrate and chloropicrin. The dominance
of chlorine DBP groups generally decreases in the order of THMs, HAAs
and HANs. The relative amounts of TOC, bromide and chlorine will
affect the species distribution of THMs (four species: chloroform,

bromoform, bromodichloromethane [BDCM] and dibromochloromethane
[DBCM]), HAAs (up to nine chlorinated/brominated species) and HANs
(several chlorinated/brominated species). Generally, chlorinated THM,
HAA and HAN species dominate over brominated species, although the
opposite may be true in high-bromide waters. Although many specific
chlorine DBPs have been identified, a significant percentage of the
total organic halogens still remain unaccounted for. Another reaction
that occurs with chlorine is the formation of chlorate (ClO₃^-) in
concentrated hypochlorite solutions.

Ozone can directly or indirectly react with bromide to form
brominated ozone DBPs, including bromate ion (BrO₃^-). In the
presence of NOM, non-halogenated organic DBPs, such as aldehydes,
ketoacids and carboxylic acids, are formed during ozonation, with
aldehydes (e.g., formaldehyde) being dominant. If both NOM and bromide
are present, ozonation forms hypobromous acid, which, in turn, leads
to the formation of brominated organohalogen compounds (e.g.,
bromoform).

The major chlorine dioxide DBPs include chlorite (ClO₂^-) and
chlorate ions, with no direct formation of organohalogen DBPs. Unlike
the other disinfectants, the major chlorine dioxide DBPs are derived
from decomposition of the disinfectant as opposed to reaction with
precursors.

Use of chloramine as a secondary disinfectant generally leads to
the formation of cyanogen chloride (CNCl), a nitrogenous compound, and
significantly reduced levels of chlorine DBPs. A related issue is the
presence of nitrite (NO₂^-) in chloraminated distribution systems.

From the present knowledge of occurrence and health effects, the
DBPs of most interest are THMs, HAAs, bromate and chlorite.

The predominant chlorine DBP group has been shown to be THMs,
with chloroform and BDCM as the first and second most dominant THM
species. HAAs are the second predominant group, with dichloroacetic
acid (DCA) and trichloroacetic acid (TCA) being the first and second
most dominant species.

Conversion of bromide to bromate upon ozonation is affected by
NOM, pH and temperature, among other factors. Levels may range from
below detection (2 µg/litre) to several tens of micrograms per litre.
Chlorite levels are generally very predictable, ranging from about 50%
to 70% of the chlorine dioxide dose administered.

DBPs occur in complex mixtures that are a function of the
chemical disinfectant used, water quality conditions and treatment
conditions; other factors include the combination/sequential use of
multiple disinfectants/oxidants. Moreover, the composition of these
mixtures may change seasonally. Clearly, potential chemically related
health effects will be a function of exposure to DBP mixtures.

Other than chlorine DBPs (in particular THMs), there are very few
data on the occurrence of DBPs in finished water and distribution
systems. Based on laboratory databases, empirical models have been
developed to predict concentrations of THMs (total THMs and THM
species), HAAs (total HAAs and HAA species) and bromate. These models
can be used in performance assessment to predict the impact of
treatment changes and in exposure assessment to simulate missing or
past data (e.g., to predict concentrations of HAAs from THM data).

DBPs can be controlled through DBP precursor control and removal
or modified disinfection practice. Coagulation, granular activated
carbon, membrane filtration and ozone biofiltration can remove NOM.
Other than through the use of membranes, there is little opportunity
to effectively remove bromide. Source water protection and control
represent non-treatment alternatives to precursor control. Removal of
DBPs after formation is not viable for organic DBPs, whereas bromate
and chlorite can be removed by activated carbon or reducing agents. It
is expected that the optimized use of combinations of disinfectants,
functioning as primary and secondary disinfectants, can further
control DBPs. There is a trend towards combination/sequential use of
disinfectants; ozone is used exclusively as a primary disinfectant,
chloramines exclusively as a secondary disinfectant, and both chlorine
and chlorine dioxide in either role.

1.2 Kinetics and metabolism in laboratory animals and humans

1.2.1 Disinfectants

Residual disinfectants are reactive chemicals that will react
with organic compounds found in saliva and stomach content, resulting
in the formation of by-products. There are significant differences in
the pharmacokinetics of ³⁶Cl depending on whether it is obtained from
chlorine, chloramine or chlorine dioxide.

1.2.2 Trihalomethanes

The THMs are absorbed, metabolized and eliminated rapidly by
mammals after oral or inhalation exposure. Following absorption, the
highest tissue concentrations are attained in the fat, liver and
kidneys. Half-lives generally range from 0.5 to 3 h, and the primary
route of elimination is via metabolism to carbon dioxide. Metabolic
activation to reactive intermediates is required for THM toxicity, and
the three brominated species are all metabolized more rapidly and to a
greater extent than chloroform. The predominant route of metabolism
for all the THMs is oxidation via cytochrome P450 (CYP) 2E1, leading
to the formation of dihalocarbonyls (i.e., phosgene and brominated
congeners), which can be hydrolysed to carbon dioxide or bind to
tissue macromolecules. Secondary metabolic pathways are reductive
dehalogenation via CYP2B1/2/2E1 (leading to free radical generation)
and glutathione (GSH) conjugation via glutathione- S-transferase
(GST) T1-1, which generates mutagenic intermediates. The brominated
THMs are much more likely than chloroform to proceed through the
secondary pathways, and GST-mediated conjugation of chloroform to GSH
can occur only at extremely high chloroform concentrations or doses.

1.2.3 Haloacetic acids

The kinetics and metabolism of the dihaloacetic and trihaloacetic
acids differ significantly. To the extent they are metabolized, the
principal reactions of the trihaloacetic acids occur in the microsomal
fraction, whereas more than 90% of the dihaloacetic acid metabolism,
principally by glutathione transferases, is observed in the cytosol.
TCA has a biological half-life in humans of 50 h. The half-lives of
the other trihaloacetic acids decrease significantly with bromine
substitution, and measurable amounts of the dihaloacetic acids can be
detected as products with brominated trihaloacetic acids. The
half-lives of the dihaloacetic acids are very short at low doses but
can be drastically increased as dose rates are increased.

1.2.4 Haloaldehydes and haloketones

Limited kinetic data are available for chloral hydrate. The two
major metabolites of chloral hydrate are trichloroethanol and TCA.
Trichloroethanol undergoes rapid glucuronidation, enterohepatic
circulation, hydrolysis and oxidation to TCA. Dechlorination of
trichloroethanol or chloral hydrate would lead to the formation of
DCA. DCA may then be further transformed to monochloroacetate (MCA),
glyoxalate, glycolate and oxalate, probably through a reactive
intermediate. No information was found on the other haloaldehydes and
haloketones.

1.2.5 Haloacetonitriles

The metabolism and kinetics of HANs have not been studied.
Qualitative data indicate that the products of metabolism include
cyanide, formaldehyde, formyl cyanide and formyl halides.

1.2.6 Halogenated hydroxyfuranone derivatives

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is the
member of the hydroxyfuranone class that has been most extensively
studied. From animal studies, it appears that the ¹⁴C label of MX is
rapidly absorbed from the gastrointestinal tract and reaches systemic
circulation. MX itself has not been measured in blood. The MX label is
largely excreted in urine and faeces, urine being the major route of
excretion. Very little of the initial radiolabel is retained in the
body after 5 days.

1.2.7 Chlorite

The ³⁶Cl from chlorite is rapidly absorbed. Less than half the
dose is found in the urine as chloride, and a small proportion as
chlorite. A significant proportion probably enters the chloride pool
of the body, but a lack of analytical methods to characterize chlorite
in biological samples means that no detailed information is available.

1.2.8 Chlorate

Chlorate behaves similarly to chlorite. The same analytical
constraints apply.

1.2.9 Bromate

Bromate is rapidly absorbed and excreted, primarily in urine, as
bromide. Bromate is detected in urine at doses of 5 mg/kg of body
weight and above. Bromate concentrations in urine peak at about 1 h,
and bromate is not detectable in plasma after 2 h.

1.3 Toxicology of disinfectants and disinfectant by-products

1.3.1 Disinfectants

Chlorine gas, chloramine and chlorine dioxide are strong
respiratory irritants. Sodium hypochlorite (NaOCl) is also used as
bleach and is frequently involved in human poisoning. These exposures,
however, are not relevant to exposures in drinking-water. There have
been relatively few evaluations of the toxic effects of these
disinfectants in drinking-water in experimental animals or humans.
Evidence from these animal and human studies suggests that chlorine,
hypochlorite solutions, chloramine and chlorine dioxide themselves
probably do not contribute to the development of cancer or any toxic
effects. Attention has focused on the wide variety of by-products that
result from reactions of chlorine and other disinfectants with NOM,
which is found in virtually all water sources.

1.3.2 Trihalomethanes

THMs induce cytotoxicity in the liver and kidneys of rodents
exposed to doses of about 0.5 mmol/kg of body weight. The vehicle of
administration significantly affects the toxicity of the THMs. The
THMs have little reproductive and developmental toxicity, but BDCM has
been shown to reduce sperm motility in rats consuming 39 mg/kg of body
weight per day in drinking-water. Like chloroform, BDCM, when
administered in corn oil, induces cancer in the liver and kidneys
after lifetime exposures to high doses. Unlike chloroform and DBCM,
BDCM and bromoform induce tumours of the large intestine in rats
exposed by corn oil gavage. BDCM induces tumours at all three target
sites and at lower doses than the other THMs. Since the publication of
the 1994 WHO Environmental Health Criteria monograph on chloroform,
additional studies have added to the weight of evidence indicating
that chloroform is not a direct DNA-reactive mutagenic carcinogen. In
contrast, the brominated THMs appear to be weak mutagens, probably as
a result of GSH conjugation.

1.3.3 Haloacetic acids

The HAAs have diverse toxicological effects in laboratory
animals. Those HAAs of most concern have carcinogenic, reproductive
and developmental effects. Neurotoxic effects are significant at the
high doses of DCA that are used therapeutically. Carcinogenic effects

appear to be limited to the liver and to high doses. The bulk of the
evidence indicates that the tumorigenic effects of DCA and TCA depend
on modifying processes of cell division and cell death rather than
their very weak mutagenic activities. Oxidative stress is also a
feature of the toxicity of the brominated analogues within this class.
Both DCA and TCA cause cardiac malformations in rats at high doses.

1.3.4 Haloaldehydes and haloketones

Chloral hydrate induces hepatic necrosis in rats at doses equal
to or greater than 120 mg/kg of body weight per day. Its depressant
effect on the central nervous system in humans is probably related to
its metabolite trichloroethanol. Limited toxicity data are available
for the other halogenated aldehydes and ketones. Chloroacetaldehyde
exposure causes haematological effects in rats. Exposure of mice to
1,1-dichloropropanone (1,1-DCPN), but not 1,3-dichloropropanone
(1,3-DCPN), results in liver toxicity.

Chloral hydrate was negative in most but not all bacterial tests
for point mutations and in in vivo studies on chromosomal damage.
However, it has been shown that chloral hydrate may induce structural
chromosomal aberrations in vitro and in vivo. Chloral hydrate has
been reported to cause hepatic tumours in mice. It is not clear if it
is the parent compound or its metabolites that are involved in the
carcinogenic effect. The two chloral hydrate metabolites, TCA and DCA,
have induced hepatic tumours in mice.

Some halogenated aldehydes and ketones are potent inducers of
mutations in bacteria. Clastogenic effects have been reported for
chlorinated propanones. Liver tumours were noted in a lifetime
drinking-water study with chloroacetaldehyde. Other halogenated
aldehydes, e.g., 2-chloropropenal, have been identified as tumour
initiators in the skin of mice. The haloketones have not been tested
for carcinogenicity in drinking-water. However, 1,3-DCPN acted as a
tumour initiator in a skin carcinogenicity study in mice.

1.3.5 Haloacetonitriles

Testing of these compounds for toxicological effects has been
limited to date. Some of the groups are mutagenic, but these effects
do not relate well to the activity of the chemicals as tumour
initiators in the skin. There are only very limited studies on the
carcinogenicity of this class of substances. Early indications of
developmental toxicity of members of this class appear to be largely
attributable to the vehicle used in treatment.

1.3.6 Halogenated hydroxyfuranone derivatives

Based on experimental studies, the critical effects of MX appear
to be its mutagenicity and carcinogenicity. Several in vitro studies
have revealed that MX is mutagenic in bacterial and mammalian test
systems. MX caused chromosomal aberrations and induced DNA damage in
isolated liver and testicular cells and sister chromatid exchanges in
peripheral lymphocytes from rats exposed in vivo. An overall

evaluation of the mutagenicity data shows that MX is mutagenic
in vitro and in vivo. A carcinogenicity study in rats showed
increased tumour frequencies in several organs.

1.3.7 Chlorite

The toxic action of chlorite is primarily in the form of
oxidative damage to red blood cells at doses as low as 10 mg/kg of
body weight. There are indications of mild neurobehavioural effects in
rat pups at 5.6 mg/kg of body weight per day. There are conflicting
data on the genotoxicity of chlorite. Chlorite does not increase
tumours in laboratory animals in chronic exposure studies.

1.3.8 Chlorate

The toxicity of chlorate is similar to that of chlorite, but
chlorate is less effective at inducing oxidative damage. It does not
appear to be teratogenic or genotoxic in vivo. There are no data
from long-term carcinogenicity studies.

1.3.9 Bromate

Bromate causes renal tubular damage in rats at high doses. It
induces tumours of the kidney, peritoneum and thyroid in rats at doses
of 6 mg/kg of body weight and above in chronic studies. Hamsters are
less sensitive, and mice are considerably less sensitive. Bromate is
also genotoxic in vivo in rats at high doses. Carcinogenicity
appears to be secondary to oxidative stress in the cell.

1.4 Epidemiological studies

1.4.1 Cardiovascular disease

Epidemiological studies have not identified an increased risk of
cardiovascular disease associated with chlorinated or chloraminated
drinking-water. Studies of other disinfectants have not been
conducted.

1.4.2 Cancer

The epidemiological evidence is insufficient to support a causal
relationship between bladder cancer and long-term exposure to
chlorinated drinking-water, THMs, chloroform or other THM species. The
epidemiological evidence is inconclusive and equivocal for an
association between colon cancer and long-term exposure to chlorinated
drinking-water, THMs, chloroform or other THM species. The information
is insufficient to allow an evaluation of the observed risks for
rectal cancer and risks for other cancers observed in single
analytical studies.

Various types of epidemiological studies have attempted to assess
the cancer risks that may be associated with exposure to chlorinated
drinking-water. Chloraminated drinking-water was considered in two
studies. Several studies have attempted to estimate exposures to total

THMs or chloroform and the other THM species, but the studies did not
consider exposures to other DBPs or other water contaminants, which
may differ for surface water and groundwater sources. One study
considered the mutagenicity of drinking-water as measured by the
Salmonella typhimurium assay. Assessments of possible cancer risks
that may be associated with drinking-water disinfected with ozone or
chlorine dioxide have not been performed.

Ecological and death certificate-based case-control studies have
provided hypotheses for further evaluation by analytical studies that
consider an individual's exposure to drinking-water and possible
confounding factors.

Analytical studies have reported weak to moderate increased
relative risks of bladder, colon, rectal, pancreatic, breast, brain or
lung cancer associated with long-term exposure to chlorinated
drinking-water. Single studies reported associations for pancreatic,
breast or brain cancer; however, the evaluation of a possible causal
relationship for epidemiological associations requires evidence from
more than a single study. In one study, a small increased relative
risk of lung cancer was associated with the use of surface water
sources, but the magnitude of risk was too small to rule out residual
confounding.

A case-control study reported a moderately large association
between rectal cancer and long-term exposure to chlorinated
drinking-water or cumulative THM exposure, but cohort studies have
found either no increased risk or a risk too weak to rule out residual
confounding.

Decreased bladder cancer risk was associated with increased
duration of exposure to chloraminated drinking-water, but there is no
biological basis for assuming a protective effect of chloraminated
water.

Although several studies found increased risks of bladder cancer
associated with long-term exposure to chlorinated drinking-water and
cumulative exposure to THMs, inconsistent results were reported among
the studies for bladder cancer risks between smokers and non-smokers
and between men and women. Estimated exposure to THMs was considered
in three of these studies. In one study, no association was found
between estimated cumulative exposure to THMs. In another study, a
moderately strong increased relative risk was associated with
increased cumulative exposure to THMs in men but not in women. The
third study reported a weak increased relative risk associated with an
estimated cumulative exposure of 1957-6425 µg of THMs per litre-year;
weak to moderate associations were also reported for exposure to THM
concentrations greater than 24, greater than 49 and greater than 74
µg/litre. No increased relative risk of bladder cancer was associated
with exposure to chlorinated municipal surface water supplies,
chloroform or other THM species in a cohort of women, but the
follow-up period of 8 years was very short, resulting in few cases for
study.

Because inadequate attention has been paid to assessing exposure
to water contaminants in epidemiological studies, it is not possible
to properly evaluate the increased relative risks that were reported.
Specific risks may be due to other DBPs, mixtures of by-products or
other water contaminants, or they may be due to other factors for
which chlorinated drinking-water or THMs may serve as a surrogate.

1.4.3 Adverse pregnancy outcomes

Studies have considered exposures to chlorinated drinking-water,
THMs or THM species and various adverse outcomes of pregnancy. A
scientific panel recently convened by the US Environmental Protection
Agency reviewed the epidemiological studies and concluded that the
results of currently published studies do not provide convincing
evidence that chlorinated water or THMs cause adverse pregnancy
outcomes.

Results of early studies are difficult to interpret because of
methodological limitations or suspected bias.

A recently completed but not yet published case-control study has
reported moderate increased relative risks for neural tube defects in
children whose mothers' residence in early pregnancy was in an area
where THM levels were greater than 40 µg/litre. Replication of the
results in another area is required before this association can be
properly evaluated. A previously conducted study in the same
geographic area reported a similar association, but the study suffered
from methodological limitations.

A recently reported cohort study found an increased risk of early
miscarriage associated with heavy consumption of water (five or more
glasses of cold tapwater per day) containing high levels (>75
µg/litre) of THMs. When specific THMs were considered, only heavy
consumption of water containing BDCM (>18 µg/litre) was associated
with a risk of miscarriage. As this is the first study to suggest an
adverse reproductive effect associated with a brominated by-product, a
scientific panel recommended that another study be conducted in a
different geographic area to attempt to replicate these results and
that additional efforts be made to evaluate exposures of the cohort to
other water contaminants.

1.5 Risk characterization

It should be noted that the use of chemical disinfectants in
water treatment usually results in the formation of chemical
by-products, some of which are potentially hazardous. However, the
risks to health from these by-products at the levels at which they
occur in drinking-water are extremely small in comparison with the
risks associated with inadequate disinfection. Thus, it is important
that disinfection not be compromised in attempting to control such
by-products.

1.5.1 Characterization of hazard and dose-response

1.5.1.1 Toxicological studies

1) Chlorine

A WHO Working Group for the 1993 Guidelines for drinking-water
quality considered chlorine. This Working Group determined a
tolerable daily intake (TDI) of 150 µg/kg of body weight for free
chlorine based on a no-observed-adverse-effect level (NOAEL) of
approximately 15 mg/kg of body weight per day in 2-year studies in
rats and mice and incorporating an uncertainty factor of 100 (10 each
for intra- and interspecies variation). There are no new data that
indicate that this TDI should be changed.

2) Monochloramine

A WHO Working Group for the 1993 Guidelines for drinking-water
quality considered monochloramine. This Working Group determined a
TDI of 94 µg/kg of body weight based on a NOAEL of approximately 9.4
mg/kg of body weight per day, the highest dose tested, in a 2-year
bioassay in rats and incorporating an uncertainty factor of 100 (10
each for intra- and interspecies variation). There are no new data
that indicate that this TDI should be changed.

3) Chlorine dioxide

The chemistry of chlorine dioxide in drinking-water is complex,
but the major breakdown product is chlorite. In establishing a
specific TDI for chlorine dioxide, data on both chlorine dioxide and
chlorite can be considered, given the rapid hydrolysis to chlorite.
Therefore, an oral TDI for chlorine dioxide is 30 µg/kg of body
weight, based on the NOAEL of 2.9 mg/kg of body weight per day for
neurodevelopmental effects of chlorite in rats.

4) Trihalomethanes

Cancer following chronic exposure is the primary hazard of
concern for this class of DBPs. Because of the weight of evidence
indicating that chloroform can induce cancer in animals only after
chronic exposure to cytotoxic doses, it is clear that exposures to low
concentrations of chloroform in drinking-water do not pose
carcinogenic risks. The NOAEL for cytolethality and regenerative
hyperplasia in mice was 10 mg/kg of body weight per day after
administration of chloroform in corn oil for 3 weeks. Based on the
mode of action evidence for chloroform carcinogenicity, a TDI of 10
µg/kg of body weight was derived using the NOAEL for cytotoxicity in
mice and applying an uncertainty factor of 1000 (10 each for inter-
and intraspecies variation and 10 for the short duration of the
study). This approach is supported by a number of additional studies.
This TDI is similar to the TDI derived in the 1998 WHO Guidelines
for drinking-water quality, which was based on a 1979 study in which
dogs were exposed for 7.5 years.

Among the brominated THMs, BDCM is of particular interest because
it produces tumours in rats and mice and at several sites (liver,
kidneys, large intestine) after corn oil gavage. The induction of
colon tumours in rats by BDCM (and by bromoform) is also interesting
because of the epidemiological associations with colo-rectal cancer.
BDCM and the other brominated THMs are also weak mutagens. It is
generally assumed that mutagenic carcinogens will produce linear
dose-response relationships at low doses, as mutagenesis is generally
considered to be an irreversible and cumulative effect.

In a 2-year bioassay, BDCM given by corn oil gavage induced
tumours (in conjunction with cytotoxicity and increased proliferation)
in the kidneys of mice and rats at doses of 50 and 100 mg/kg of body
weight per day, respectively. The tumours in the large intestine of
the rat occurred after exposure to both 50 and 100 mg/kg of body
weight per day. Using the incidence of kidney tumours in male mice
from this study, quantitative risk estimates have been calculated,
yielding a slope factor of 4.8 × 10^-3 [mg/kg of body weight per
day]^-1 and a calculated dose of 2.1 µg/kg of body weight per day for
a risk level of 10^-5. A slope factor of 4.2 × 10^-3 [mg/kg of body
weight per day]^-1 (2.4 µg/kg of body weight per day for a 10^-5 risk)
was derived based on the incidence of large intestine carcinomas in
the male rat. The International Agency for Research on Cancer (IARC)
has classified BDCM in Group 2B (possibly carcinogenic to humans).

DBCM and bromoform were studied in long-term bioassays. In a
2-year corn oil gavage study, DBCM induced hepatic tumours in female
mice, but not in rats, at a dose of 100 mg/kg of body weight per day.
In previous evaluations, it had been suggested that the corn oil
vehicle may play a role in the induction of tumours in female mice. A
small increase in tumours of the large intestine in rats was observed
in the bromoform study at a dose of 200 mg/kg of body weight per day.
The slope factors based on these tumours are 6.5 × 10^-3 [mg/kg of
body weight per day]^-1 for DBCM, or 1.5 µg/kg of body weight per day
for a 10^-5 risk, and 1.3 × 10^-3 [mg/kg of body weight per day]^-1 or
7.7 µg/kg of body weight per day for a 10^-5 risk for bromoform.

These two brominated THMs are weakly mutagenic in a number of
assays, and they were by far the most mutagenic DBPs of the class in
the GST-mediated assay system. Because they are the most lipophilic
THMs, additional concerns about whether corn oil may have affected
their bioavailability in the long-term studies should be considered. A
NOAEL for DBCM of 30 mg/kg of body weight per day has been established
based on the absence of histopathological effects in the liver of rats
after 13 weeks of exposure by corn oil gavage. IARC has classified
DBCM in Group 3 (not classifiable as to its carcinogenicity to
humans). A TDI for DBCM of 30 µg/kg of body weight was derived based
on the NOAEL for liver toxicity of 30 mg/kg of body weight per day and
an uncertainty factor of 1000 (10 each for inter- and intraspecies
variation and 10 for the short duration of the study and possible
carcinogenicity).

Similarly, a NOAEL for bromoform of 25 mg/kg of body weight per
day can be derived on the basis of the absence of liver lesions in
rats after 13 weeks of dosing by corn oil gavage. A TDI for bromoform
of 25 µg/kg of body weight was derived based on this NOAEL for liver
toxicity and an uncertainty factor of 1000 (10 each for inter- and
intraspecies variation and 10 for the short duration of the study and
possible carcinogenicity). IARC has classified bromoform in Group 3
(not classifiable as to its carcinogenicity to humans).

5) Haloacetic acids

The induction of mutations by DCA is very improbable at the low
doses that would be encountered in chlorinated drinking-water. The
available data indicate that DCA differentially affects the
replication rates of normal hepatocytes and hepatocytes that have been
initiated. The dose-response relationships are complex, with DCA
initially stimulating division of normal hepatocytes. However, at the
lower chronic doses used in animal studies (but still very high
relative to those that would be derived from drinking-water), the
replication rate of normal hepatocytes is eventually sharply
inhibited. This indicates that normal hepatocytes eventually
down-regulate those pathways that are sensitive to stimulation by DCA.
However, the effects in altered cells, particularly those that express
high amounts of a protein that is immunoreactive to a c-Jun antibody,
do not seem to be able to down-regulate this response. Thus, the rates
of replication in the pre-neoplastic lesions with this phenotype are
very high at the doses that cause DCA tumours to develop with a very
low latency. Preliminary data would suggest that this continued
alteration in cell birth and death rates is also necessary for the
tumours to progress to malignancy. This interpretation is supported by
studies that employ initiation/promotion designs as well.

On the basis of the above considerations, it is suggested that
the currently available cancer risk estimates for DCA be modified by
incorporation of newly developing information on its comparative
metabolism and modes of action to formulate a biologically based
dose-response model. These data are not available at this time, but
they should become available within the next 2-3 years.

The effects of DCA appear to be closely associated with doses
that induce hepatomegaly and glycogen accumulation in mice. The
lowest-observed-adverse-effect level (LOAEL) for these effects in
an 8-week study in mice was 0.5 g/litre, corresponding to
approximately 100 mg/kg of body weight per day, and the NOAEL was
0.2 g/litre, or approximately 40 mg/kg of body weight per day. A TDI
of 40 µg/kg of body weight has been calculated by applying an
uncertainty factor of 1000 to this NOAEL (10 each for inter- and
intraspecies variation and 10 for the short duration of the study and
possible carcinogenicity). IARC has classified DCA in Group 3 (not
classifiable as to its carcinogenicity to humans).

TCA is one of the weakest activators of the peroxisome
proliferator activated receptor (PPAR) known. It appears to be only
marginally active as a peroxisome proliferator, even in rats.

Furthermore, treatment of rats with high levels of TCA in
drinking-water does not induce liver tumours. These data strongly
suggest that TCA presents little carcinogenic hazard to humans at the
low concentrations found in drinking-water.

From a broader toxicological perspective, the developmental
effects of TCA are the end-point of concern. Animals appear to
tolerate concentrations of TCA in drinking-water of 0.5 g/litre
(approximately 50 mg/kg of body weight per day) with little or no
signs of adverse effect. At 2 g/litre, the only sign of adverse effect
appears to be hepatomegaly. Hepatomegaly is not observed in mice at
doses of 0.35 g of TCA per litre in drinking-water, estimated to be
equivalent to 40 mg/kg of body weight per day.

In another study, soft tissue anomalies were observed at
approximately 3 times the control rate at the lowest dose
administered, 330 mg/kg of body weight per day. At this dose, the
anomalies were mild and would clearly be in the range where
hepatomegaly (and carcinogenic effects) would occur. Considering the
fact that the PPAR interacts with cell signalling mechanisms that can
affect normal developmental processes, a common mechanism underlying
hepatomegaly and the carcinogenic effects and developmental effects of
this compound should be considered.

The TDI for TCA is based on a NOAEL estimated to be 40 mg/kg of
body weight per day for hepatic toxicity in a long-term study in mice.
Application of an uncertainty factor of 1000 (10 each for inter- and
intraspecies variation and 10 for possible carcinogenicity) to the
estimated NOAEL gives a TDI of 40 µg/kg of body weight. IARC has
classified TCA in Group 3 (not classifiable as to its carcinogenicity
to humans).

Data on the carcinogenicity of brominated acetic acids are too
preliminary to be useful in risk characterization. Data available in
abstract form suggest, however, that the doses required to induce
hepatocarcinogenic responses in mice are not dissimilar to those of
the chlorinated acetic acids. In addition to the mechanisms involved
in the induction of cancer by DCA and TCA, it is possible that
increased oxidative stress secondary to their metabolism might
contribute to their effects.

There are a significant number of data on the effects of
dibromoacetic acid (DBA) on male reproduction. No effects were
observed in rats at doses of 2 mg/kg of body weight per day for
79 days, whereas an increased retention of step 19 spermatids was
observed at 10 mg/kg of body weight per day. Higher doses led to
progressively more severe effects, including marked atrophy of the
seminiferous tubules with 250 mg/kg of body weight per day, which was
not reversed 6 months after treatment was suspended. A TDI of 20 µg/kg
of body weight was determined by allocating an uncertainty factor of
100 (10 each for inter- and intraspecies variation) to the NOAEL of
2 mg/kg of body weight per day.

6) Chloral hydrate

Chloral hydrate at 1 g/litre of drinking-water (166 mg/kg of body
weight per day) induced liver tumours in mice exposed for 104 weeks.
Lower doses have not been evaluated. Chloral hydrate has been shown to
induce chromosomal anomalies in several in vitro tests but has been
largely negative when evaluated in vivo. It is probable that the
liver tumours induced by chloral hydrate involve its metabolism to TCA
and/or DCA. As discussed above, these compounds are considered to act
as tumour promoters. IARC has classified chloral hydrate in Group 3
(not classifiable as to its carcinogenicity to humans).

Chloral hydrate administered to rats for 90 days in
drinking-water induced hepatocellular necrosis at concentrations of
1200 mg/litre and above, with no effect being observed at 600 mg/litre
(approximately 60 mg/kg of body weight per day). Hepatomegaly was
observed in mice at doses of 144 mg/kg of body weight per day
administered by gavage for 14 days. No effect was observed at 14.4
mg/kg of body weight per day in the 14-day study, but mild
hepatomegaly was observed when chloral hydrate was administered in
drinking-water at 70 mg/litre (16 mg/kg of body weight per day) in a
90-day follow-up study. The application of an uncertainty factor of
1000 (10 each for inter- and intraspecies variation and 10 for the use
of a LOAEL instead of a NOAEL) to this value gives a TDI of 16 µg/kg
of body weight.

7) Haloacetonitriles

Without appropriate human data or an animal study that involves a
substantial portion of an experimental animal's lifetime, there is no
generally accepted basis for estimating carcinogenic risk from the
HANs.

Data developed in subchronic studies provide some indication of
NOAELs for the general toxicity of dichloroacetonitrile (DCAN) and
dibromoacetonitrile (DBAN). NOAELs of 8 and 23 mg/kg of body weight
per day were identified in 90-day studies in rats for DCAN and DBAN,
respectively, based on decreased body weights at the next higher doses
of 33 and 45 mg/kg of body weight per day, respectively.

A WHO Working Group for the 1993 Guidelines for drinking-water
quality considered DCAN and DBAN. This Working Group determined a
TDI of 15 µg/kg of body weight for DCAN based on a NOAEL of 15 mg/kg
of body weight per day in a reproductive toxicity study in rats and
incorporating an uncertainty factor of 1000 (10 each for intra- and
interspecies variation and 10 for the severity of effects).
Reproductive and developmental effects were observed with DBAN only at
doses that exceeded those established for general toxicity (about 45
mg/kg of body weight per day). A TDI of 23 µg/kg of body weight was
calculated for DBAN based on the NOAEL of 23 mg/kg of body weight per
day in the 90-day study in rats and incorporating an uncertainty
factor of 1000 (10 each for intra- and interspecies variation and 10
for the short duration of the study). There are no new data indicating
that these TDIs should be changed.

LOAELs for trichloroacetonitrile (TCAN) of 7.5 mg/kg of body
weight per day for embryotoxicity and 15 mg/kg of body weight per day
for developmental effects were identified. However, later studies
suggest that these responses were dependent upon the vehicle used. No
TDI can be established for TCAN.

There are no data useful for risk characterization purposes for
other members of the HANs.

8) MX

The mutagen MX has recently been studied in a long-term study in
rats in which some carcinogenic responses were observed. These data
indicate that MX induces thyroid and bile duct tumours. An increased
incidence of thyroid tumours was seen at the lowest dose of MX
administered (0.4 mg/kg of body weight per day). The induction of
thyroid tumours with high-dose chemicals has long been associated with
halogenated compounds. The induction of thyroid follicular tumours
could involve modifications in thyroid function or a mutagenic mode of
action. A dose-related increase in the incidence of cholangiomas and
cholangiocarcinomas was also observed, beginning at the low dose in
female rats, with a more modest response in male rats. The increase in
cholangiomas and cholangiocarcinomas in female rats was utilized to
derive a slope factor for cancer. The 95% upper confidence limit for a
10^-5 lifetime risk based on the linearized multistage model was
calculated to be 0.06 µg/kg of body weight per day.

9) Chlorite

The primary and most consistent finding arising from exposure to
chlorite is oxidative stress resulting in changes in the red blood
cells. This end-point is seen in laboratory animals and, by analogy
with chlorate, in humans exposed to high doses in poisoning incidents.
There are sufficient data available with which to estimate a TDI for
humans exposed to chlorite, including chronic toxicity studies and a
two-generation reproductive toxicity study. Studies in human
volunteers for up to 12 weeks did not identify any effect on blood
parameters at the highest dose tested, 36 µg/kg of body weight per
day. Because these studies do not identify an effect level, they are
not informative for establishing a margin of safety.

In a two-generation study in rats, a NOAEL of 2.9 mg/kg of body
weight per day was identified based on lower auditory startle
amplitude, decreased absolute brain weight in the F₁ and F₂
generations, and altered liver weights in two generations. Application
of an uncertainty factor of 100 (10 each for inter- and intraspecies
variation) to this NOAEL gives a TDI of 30 µg/kg of body weight. This
TDI is supported by the human volunteer studies.

10) Chlorate

Like chlorite, the primary concern with chlorate is oxidative
damage to red blood cells. Also like chlorite, 0.036 mg of chlorate
per kg of body weight per day for 12 weeks did not result in any

adverse effect in human volunteers. Although the database for chlorate
is less extensive than that for chlorite, a recent well conducted
90-day study in rats identified a NOAEL of 30 mg/kg of body weight per
day based on thyroid gland colloid depletion at the next higher dose
of 100 mg/kg of body weight per day. A TDI is not derived because a
long-term study is in progress, which should provide more information
on chronic exposure to chlorate.

11) Bromate

Bromate is an active oxidant in biological systems and has been
shown to cause an increase in renal tumours, peritoneal mesotheliomas
and thyroid follicular cell tumours in rats and, to a lesser extent,
hamsters, and only a small increase in kidney tumours in mice. The
lowest dose at which an increased incidence of renal tumours was
observed in rats was 6 mg/kg of body weight per day.

Bromate has also been shown to give positive results for
chromosomal aberrations in mammalian cells in vitro and in vivo
but not in bacterial assays for point mutation. An increasing body of
evidence, supported by the genotoxicity data, suggests that bromate
acts by generating oxygen radicals in the cell.

In the 1993 WHO Guidelines for drinking-water quality, the
linearized multistage model was applied to the incidence of renal
tumours in a 2-year carcinogenicity study in rats, although it was
noted that if the mechanism of tumour induction is oxidative damage in
the kidney, application of the low-dose cancer model may not be
appropriate. The calculated upper 95% confidence interval for a 10^-5
risk was 0.1 µg/kg of body weight per day.

The no-effect level for the formation of renal cell tumours in
rats is 1.3 mg/kg of body weight per day. If this is used as a point
of departure from linearity and if an uncertainty factor of 1000 (10
each for inter- and intraspecies variation and 10 for possible
carcinogenicity) is applied, a TDI of 1 µg/kg of body weight can be
calculated. This compares with the value of 0.1 µg/kg of body weight
per day associated with an excess lifetime cancer risk of 10^-5.

At present, there are insufficient data to permit a decision on
whether bromate-induced tumours are a result of cytotoxicity and
reparative hyperplasia or a genotoxic effect.

IARC has assigned potassium bromate to Group 2B (possibly
carcinogenic to humans).

1.5.1.2 Epidemiological studies

Epidemiological studies must be carefully evaluated to ensure
that observed associations are not due to bias and that the design is
appropriate for an assessment of a possible causal relationship.
Causality can be evaluated when there is sufficient evidence from
several well designed and well conducted studies in different
geographic areas. Supporting toxicological and pharmacological data

are also important. It is especially difficult to interpret
epidemiological data from ecological studies of disinfected
drinking-water, and these results are used primarily to help develop
hypotheses for further study.

Results of analytical epidemiological studies are insufficient to
support a causal relationship for any of the observed associations. It
is especially difficult to interpret the results of currently
published analytical studies because of incomplete information about
exposures to specific water contaminants that might confound or modify
the risk. Because inadequate attention has been paid to assessing
exposures to water contaminants in epidemiological studies, it is not
possible to properly evaluate the increased relative risks that were
reported. Risks may be due to other water contaminants or to other
factors for which chlorinated drinking-water or THMs may serve as a
surrogate.

1.5.2 Characterization of exposure

1.5.2.1 Occurrence of disinfectants and disinfectant by-products

Disinfectant doses of several milligrams per litre are typically
employed, corresponding to doses necessary to inactivate
microorganisms (primary disinfection) or doses necessary to maintain a
residual in the distribution system (secondary disinfection).

A necessary ingredient for an exposure assessment is DBP
occurrence data. Unfortunately, there are few published international
studies that go beyond case-study or regional data.

Occurrence data suggest, on average, exposure to about 35-50 µg
of total THMs per litre in chlorinated drinking-water, with chloroform
and BDCM being the first and second most dominant species. Exposure to
total HAAs can be approximated by a total HAA concentration (sum of
five species) corresponding to about one-half of the total THM
concentration (although this ratio can vary significantly); DCA and
TCA are the first and second most dominant species. In waters with a
high bromide to TOC ratio or a high bromide to chlorine ratio, greater
formation of brominated THMs and HAAs can be expected. When a
hypochlorite solution (versus chlorine gas) is used, chlorate may also
occur during chlorination.

DBP exposure in chloraminated water is a function of the mode of
chloramination, with the sequence of chlorine followed by ammonia
leading to the formation of (lower levels of) chlorine DBPs (i.e.,
THMs and HAAs) during the free-chlorine period; however, the
suppression of chloroform and TCA formation is not paralleled by a
proportional reduction in DCA formation.

All factors being equal, bromide concentration and ozone dose are
the best predictors of bromate formation during ozonation, with about
a 50% conversion of bromide to bromate. A study of different European
water utilities showed bromate levels in water leaving operating water

treatment plants ranging from less than the detection limit (2
µg/litre) up to 16 µg/L. The brominated organic DBPs formed upon
ozonation generally occur at low levels. The formation of chlorite can
be estimated by a simple percentage (50-70%) of the applied chlorine
dioxide dose.

1.5.2.2 Uncertainties of water quality data

A toxicological study attempts to extrapolate a laboratory
(controlled) animal response to a potential human response; one
possible outcome is the estimation of cancer risk factors. An
epidemiological study attempts to link human health effects (e.g.,
cancer) to a causative agent or agents (e.g., a DBP) and requires an
exposure assessment.

The chemical risks associated with disinfected drinking-water are
potentially based on several routes of exposure: (i) ingestion of DBPs
in drinking-water; (ii) ingestion of chemical disinfectants in
drinking-water and the concomitant formation of DBPs in the stomach;
and (iii) inhalation of volatile DBPs during showering. Although the
in vivo formation of DBPs and the inhalation of volatile DBPs may be
of potential health concern, the following discussion is based on the
premise that the ingestion of DBPs present in drinking-water is the
most significant route of exposure.

Human exposure is a function of both DBP concentration and
exposure time. More specifically, human health effects are a function
of exposure to complex mixtures of DBPs (e.g., THMs versus HAAs,
chlorinated versus brominated species) that can change
seasonally/temporally (e.g., as a function of temperature, nature and
concentration of NOM) and spatially (i.e., throughout a distribution
system). Each individual chemical disinfectant can form a mixture of
DBPs; combinations of chemical disinfectants can form even more
complex mixtures. Upon their formation, most DBPs are stable, but some
may undergo transformation by, for example, hydrolysis. In the absence
of DBP data, surrogates such as chlorine dose (or chlorine demand),
TOC (or ultraviolet absorbance at 254 nm [UVA₂₅₄]) or bromide can be
used to indirectly estimate exposure. While TOC serves as a good
surrogate for organic DBP precursors, UVA₂₅₄provides additional
insight into NOM characteristics, which can vary geographically. Two
key water quality variables, pH and bromide, have been identified as
significantly affecting the type and concentrations of DBPs that are
produced.

An exposure assessment should first attempt to define the
individual types of DBPs and resultant mixtures likely to form, as
well as their time-dependent concentrations, as affected by their
stability and transport through a distribution system. For
epidemiological studies, some historical databases exist for
disinfectant (e.g., chlorine) doses, possibly DBP precursor (e.g.,
TOC) concentrations and possibly total THM (and, in some cases, THM
species) concentrations. In contrast to THMs, which have been
monitored over longer time frames because of regulatory scrutiny,
monitoring data for HAAs (and HAA species), bromate and chlorite are

much more recent and hence sparse. However, DBP models can be used to
simulate missing or past data. Another important consideration is
documentation of past changes in water treatment practice.

1.5.2.3 Uncertainties of epidemiological data

Even in well designed and well conducted analytical studies,
relatively poor exposure assessments were conducted. In most studies,
duration of exposure to disinfected drinking-water and the water
source were considered. These exposures were estimated from
residential histories and water utility or government records. In only
a few studies was an attempt made to estimate a study participant's
water consumption and exposure to either total THMs or individual
species of THMs. In only one study was an attempt made to estimate
exposures to other DBPs. In evaluating some potential risks, i.e.,
adverse outcomes of pregnancy, that may be associated with relatively
short term exposures to volatile by-products, it may be important to
consider the inhalation as well as the ingestion route of exposure
from drinking-water. In some studies, an effort was made to estimate
both by-product levels in drinking-water for etiologically relevant
time periods and cumulative exposures. Appropriate models and
sensitivity analysis such as Monte Carlo simulation can be used to
help estimate these exposures for relevant periods.

A major uncertainty surrounds the interpretation of the observed
associations, as exposures to a relatively few water contaminants have
been considered. With the current data, it is difficult to evaluate
how unmeasured DBPs or other water contaminants may have affected the
observed relative risk estimates.

More studies have considered bladder cancer than any other
cancer. The authors of the most recently reported results for bladder
cancer risks caution against a simple interpretation of the observed
associations. The epidemiological evidence for an increased relative
risk of bladder cancer is not consistent -- different risks are
reported for smokers and non-smokers, for men and women, and for high
and low water consumption. Risks may differ among various geographic
areas because the DBP mix may be different or because other water
contaminants are also present. More comprehensive water quality data
must be collected or simulated to improve exposure assessments for
epidemiological studies.

2. CHEMISTRY OF DISINFECTANTS AND DISINFECTANT BY-PRODUCTS

2.1 Background

The use of chlorine (Cl₂) as a water disinfectant has come under
scrutiny because of its potential to react with natural organic matter
(NOM) and form chlorinated disinfectant by-products (DBPs). Within
this context, NOM serves as the organic DBP precursor, whereas bromide
ion (Br^-) serves as the inorganic precursor. Treatment strategies
generally available to water systems exceeding drinking-water
standards include removing DBP precursors and using alternative
disinfectants for primary and/or secondary (distribution system)
disinfection. Alternative disinfectant options that show promise are
chloramines (NH₂Cl, monochloramine), chlorine dioxide (ClO₂) and
ozone (O₃). While ozone can serve as a primary disinfectant only and
chloramines as a secondary disinfectant only, both chlorine and
chlorine dioxide can serve as either primary or secondary
disinfectants.

Chloramine presents the significant advantage of virtually
eliminating the formation of chlorination by-products and, unlike
chlorine, does not react with phenols to create taste- and
odour-causing compounds. However, the required contact time for
inactivation of viruses and Giardia cysts is rarely obtainable by
chloramine post-disinfection at existing water treatment facilities
(monochloramine is significantly less biocidal than free chlorine).
More recently, the presence of nitrifying bacteria and nitrite
(NO₂^-) and nitrate (NO₃^-) production in chloraminated distribution
systems as well as the formation of organic chloramines have raised
concern.

The use of chlorine dioxide, like chloramine, can reduce the
formation of chlorinated by-products during primary disinfection.
However, production of chlorine dioxide, its decomposition and
reaction with NOM lead to the formation of by-products such as
chlorite (ClO₂^-), a compound that is of health concern.

If used as a primary disinfectant followed by a chloramine
residual in the distribution system, ozone can eliminate the need for
contact between DBP precursors and chlorine. Ozone is known to react
both with NOM to produce organic DBPs such as aldehydes and increase
levels of assimilable organic carbon and with bromide ion to form
bromate.

A thorough understanding of the mechanisms of DBP formation
allows microbial inactivation goals and DBP control goals to be
successfully balanced. This chapter examines a range of issues
affecting DBP formation and control to provide guidance to utilities
considering the use of various disinfecting chemicals to achieve
microbial inactivation with DBP control.

2.2 Physical and chemical properties of common disinfectants and
inorganic disinfectant by-products

The important physical and chemical properties of commonly used
disinfectants and inorganic DBPs are summarized in Table 1.

2.2.1 Chlorine

Chlorine, a gas under normal pressure and temperature, can be
compressed to a liquid and stored in cylindrical containers. Because
chlorine gas is poisonous, it is dissolved in water under vacuum, and
this concentrated solution is applied to the water being treated. For
small plants, cylinders of about 70 kg are used; for medium to large
plants, tonne containers are common; and for very large plants,
chlorine is delivered by railway tank cars or road (truck) tankers.
Chlorine is also available in granular or powdered form as calcium
hypochlorite (Ca(OCl)₂) or in liquid form as sodium hypochlorite
(NaOCl; bleach).

Chlorine is used in the form of gaseous chlorine or hypochlorite
(OCl^-). In either form, it acts as a potent oxidizing agent and often
dissipates in side reactions so rapidly that little disinfection is
accomplished until amounts in excess of the chlorine demand have been
added. As an oxidizing agent, chlorine reacts with a wide variety of
compounds, in particular those that are considered reducing agents
(hydrogen sulfide [H₂S], manganese(II), iron(II), sulfite [SO₃^2-],
Br^-, iodide [I^-], nitrite). From the point of view of DBP formation
and disinfection, these reactions may be important because they may be
fast and result in the consumption of chlorine.

Chlorine gas hydrolyses in water almost completely to form
hypochlorous acid (HOCl):

Cl₂ + H₂O -> HOCl + H⁺ + Cl^-

The hypochlorous acid dissociates into hydrogen ions (H⁺) and
hypochlorite ions in the reversible reaction:

HOCl <-> H⁺ + OCl^-

Hypochlorous acid is a weak acid with a p K_a of approximately
7.5 at 25°C. Hypochlorous acid, the prime disinfecting agent, is
therefore dominant at a pH below 7.5 and is a more effective
disinfectant than hypochlorite ion, which dominates above pH 7.5.

The rates of the decomposition reactions of chlorine increase as
the solution becomes more alkaline, and these reactions can
theoretically produce chlorite and chlorate (ClO₃^-); they occur
during the electrolysis of chloride (Cl^-) solutions when the anodic
and cathodic compartments are not separated, in which case the
chlorine formed at the anode can react with the alkali formed at the
cathode. On the other hand, hypochlorous acid/hypochlorite (or
hypobromous acid/hypobromite, HOBr/OBr^-) can be formed by the action
of chlorine (or bromine) in neutral or alkaline solutions. The

Table 1. Physical and chemical properties of commonly used disinfectants and inorganic disinfectant by-products

Chemical^a E^o (V)^b Oxidation number lamba_max (nm)^c e (mol^-1 litre^-1 cm^-1)^d p epsilon^{o e} pK_a ^f
of Cl or Br

HOCl/Cl^- +1.49 +1 254 60 +25.2 7.5
292 (OCl^-) 419
ClO₂/ClO₂^- +0.95 +4 359 1250 +16.1 -
NH₂Cl - +1 245 416 - -
O₃/O₂ +2.07 - 254 3200 +35.0
HOBr/Br^- +1.33 +1 330 50 +22.5 8.7
ClO₂^-/Cl^- +0.76 +3 262 - +12.8 1.96
ClO₃^-/Cl^- +0.62 +5 360 - +10.5 1.45
BrO₃^-/Br^- +0.61 +5 195 - 0.72

^a Half-cell reactants/products.
^b E^o = standard electrode potential (redox potential) in water at 25 °C. The oxidation-reduction state of an aqueous
environment at equilibrium can be stated in terms of its redox potential. In the chemistry literature, this is generally
expressed in volts, E, or as the negative logarithm of the electron activity, p epsilon. When p epsilon is large, the
electron activity is low and the system tends to be an oxidizing one: i.e., half-reactions tend to be driven to the left.
When p epsilon is small, the system is reducing, and reactions tend to be driven to the right.
^c lambda_max = maximum absorbance wavelength of that particular solution in nm.
^d e = molar absorptivity (molar extinction coefficient), in mol^-1 litre^-1 cm^-1. This can be used for quantitative
determination of the various species of chemicals and is the only direct physical measurement. There is often some
background absorbance that may interfere with the measurement in natural waters that should be considered.
^e p epsilon^o = - log {e^-} where {e^-} = electron activity.
^f pK_a = negative logarithm of the acid ionization constant (e.g., at pH 7.5, the molar concentration of HOCl is same as that
of OCl^-). As this parameter is dependent upon temperature, the values listed were determined at 25 °C.

decomposition of hypohalites (XO^-) is favoured in alkaline solutions
(2XO^- -> X^- + XO₂^-) and is such that there is no longer any
domain of thermodynamic stability for the hypohalite ions. These
oxyhalites are further converted to stable oxyhalates as follows:

XO^- + XO₂^- -> X^- + XO₃^-

Another reaction that occurs in waters containing bromide ion and
hypochlorite is the production of hypobromous acid:

HOCl + Br^- -> HOBr + Cl^-

This reaction is irreversible, and the product hypobromous acid is a
better halogenating agent than hypochlorous acid and interferes with
common analytical procedures for free chlorine. The presence of
bromide in hypochlorite solutions can ultimately lead to the formation
of bromate (BrO₃^-).

Hypobromous acid is a weak acid (p K_a = 8.7); like
hypochlorite, hypobromite is metastable. In alkaline solution, it
decomposes to give bromate and bromide:

3OBr^- -> BrO₃^- + 2Br^-

Bromic acid (HBrO₃) is a strong acid (p K_a = 0.7). Bromic acid
and bromate can be obtained by the electrolytic oxidation of bromide
solutions or bromine water using chlorine. Bromic acid and bromate are
powerful oxidizing agents, but the speed of their oxidation reactions
is generally slow (Mel et al., 1953).

2.2.2 Chlorine dioxide

Chlorine dioxide is one of the few compounds that exists almost
entirely as monomeric free radicals. Concentrated chlorine dioxide
vapour is potentially explosive, and attempts to compress and store
this gas, either alone or in combination with other gases, have been
commercially unsuccessful. Because of this, chlorine dioxide, like
ozone, must be manufactured at the point of use. Chlorine dioxide in
water does not hydrolyse to any appreciable extent. Neutral or acidic
dilute aqueous solutions are quite stable if kept cool, well sealed
and protected from sunlight.

Chlorine dioxide represents an oxidation state (+4) intermediate
between those of chlorite (+3) and chlorate (+5). No acid or ion of
the same degree of oxidation is known. Chlorine dioxide is a powerful
oxidizing agent that can decompose to chlorite; in the absence of
oxidizable substances and in the presence of alkali, it dissolves in
water, decomposing with the slow formation of chlorite and chlorate:

2ClO₂ + H₂O -> ClO₂^- + ClO₃^- + 2H⁺

Chlorine dioxide has an absorption spectrum with a maximum at 359
nm, with a molar absorptivity of 1250 mol^-1 litre^-1 cm^-1. This
extinction coefficient is independent of temperature, pH, chloride and

ionic strength. Chlorine dioxide is readily soluble in water, forming
a greenish-yellow solution. It can be involved in a variety of redox
reactions, such as oxidation of iodide ion, sulfide ion, iron(II) and
manganese(II). When chlorine dioxide reacts with aqueous contaminants,
it is usually reduced to chlorite ion. The corresponding electron
transfer reactions are comparable to those occurring when singlet
oxygen acts as an oxidant (Tratnyek & Hoigne, 1994).

Bromide (in the absence of sunlight) is not oxidized by chlorine
dioxide. Therefore, water treatment with chlorine dioxide will not
transform bromide ion into hypobromite and will not give rise to the
formation of bromoform (CHBr₃) or bromate. This is an important
difference between the use of chlorine dioxide as an oxidant and the
use of chlorine or ozone as an oxidant.

2.2.3 Ozone

Ozone is a strong oxidizing agent ( E^o = 2.07 V). Oxidation
reactions initiated by ozone in water are generally rather complex; in
water, only part of the ozone reacts directly with dissolved solutes.
Another part may decompose before reaction. Such decomposition is
catalysed by hydroxide ions (OH^-) and other solutes. Highly reactive
secondary oxidants, such as hydroxyl radicals (OH.), are thereby
formed. These radicals and their reaction products can additionally
accelerate the decomposition of ozone. Consequently, radical-type
chain reactions may occur, which consume ozone concurrently with the
direct reaction of ozone with dissolved organic material.

Many oxidative applications of ozone have been developed,
including disinfection, control of algae, removal of tastes and
odours, removal of colour, removal of iron and manganese,
microflocculation, removal of turbidity by oxidative flocculation,
removal of organics by oxidation of phenols, detergents and some
pesticides, partial oxidation of dissolved organics and control of
halogenated organic compounds. For disinfection and for oxidation of
many organic and inorganic contaminants in drinking-water, the
kinetics of ozone reactions are favourable; on the other hand, for
many difficult-to-oxidize organic compounds, such as chloroform
(CHCl₃), the kinetics of ozone oxidation are very slow (Hoigne et
al., 1985).

2.2.4 Chloramines

Monochloramine has much higher CT values¹ than free chlorine
and is therefore a poor primary disinfectant. Additionally, it is a
poor oxidant and is not effective for taste and odour control or for
oxidation of iron and manganese. However, because of its persistence,

¹ The CT value is the product of the disinfectant concentration C
in mg/litre and the contact time T in minutes required to inactivate
a specified percentage (e.g., 99%) of microorganisms.

it is an attractive secondary disinfectant for the maintenance of a
stable distribution system residual. The use of disinfectants such as
ozone or chlorine dioxide combined with chloramines as a secondary
disinfectant appears to be attractive for minimizing DBP formation
(Singer, 1994b).

Monochloramine is the only useful ammonia-chloramine
disinfectant. Dichloramine (NHCl₂) and nitrogen trichloride (NCl₃)
are too unstable to be useful and highly malodorous. Conditions
practically employed for chloramination are designed to produce only
monochloramine.

2.3 Analytical methods for disinfectant by-products and disinfectants

Analytical methods for various DBPs and their detection limits
are summarized in Table 2. Methods for disinfectants are summarized in
APHA (1995).

2.3.1 Trihalomethanes, haloacetonitriles, chloral hydrate,
chloropicrin and haloacetic acids

Gas chromatographic (GC) techniques are generally employed
for organic DBPs. Detection and quantification of haloacetonitriles
(HANs) and chloral hydrate in chlorinated natural waters are
complicated by (i) hydrolysis of dihaloacetonitriles and chloral
hydrate to dihaloacetic acids and chloroform, respectively; (ii)
degradation of HANs by dechlorinating agents such as sodium sulfite
and sodium thiosulfate; (iii) low purge efficiency for the HANs and
chloral hydrate in the purge-and-trap technique; and (iv) low
extraction efficiency for chloral hydrate with pentane in the
liquid-liquid extraction normally used. Although chloral hydrate is
not efficiently extracted