PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS doc

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 Organization or the
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Environmental Health Criteria 237
PRINCIPLES FOR EVALUATING
HEALTH RISKS IN CHILDREN
ASSOCIATED WITH EXPOSURE
TO CHEMICALS
First drafts prepared by Dr Germaine Buck Louis, Bethesda, USA; Dr
Terri Damstra, Research Triangle Park, USA; Dr Fernando Díaz-
Barriga, San Luis Potosi, Mexico; Dr Elaine Faustman, Washington,
USA; Dr Ulla Hass, Soborg, Denmark; Dr Robert Kavlock, Research
Triangle Park, USA; Dr Carole Kimmel, Washington, USA; Dr Gary
Kimmel, Silver Spring, USA; Dr Kannan Krishnan, Montreal, Canada;
Dr Ulrike Luderer, Irvine, USA; and Dr Linda Sheldon, Research
Triangle Park, USA
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organization
and the World Health Organization, and produced within the
framework of the Inter-Organization Programme for the Sound
Management of Chemicals.
The International Programme on Chemical Safety (IPCS), established in 1980, is a
joint venture of the United Nations Environment Programme (UNEP), the International
Labour Organization (ILO) and the World Health Organization (WHO). The overall objec-
tives of the IPCS are to establish the scientific basis for assessment of the risk to human
health and the environment from exposure to chemicals, through international peer review
processes, as a prerequisite for the promotion of chemical safety, and to provide technical
assistance in strengthening national capacities for the 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,
the United Nations Institute for Training and Research 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 coop-
eration 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
Principles for evaluating health risks in children associated with exposure to chemicals
(Environmental health criteria ; 237)
“First drafts prepared by Dr Germaine Buck Louis [et al.].”
1.Environmental health. 2.Risk assessment. 3.Child. 4.Organic chemicals - adverse effects.
5.Inorganic chemicals - adverse effects. 6.Environmental exposure. I.Louis, Germaine
Buck. II.World Health Organization. III.Inter-Organization Programme for the Sound
Management of Chemicals. IV.Series.
ISBN 92 4 157237 X (NLM classification: WA 30.5)
ISBN 978 92 4 157237 8
ISSN 0250-863X
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iii
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA ON
PRINCIPLES FOR EVALUATING HEALTH RISKS IN
CHILDREN ASSOCIATED WITH EXPOSURE TO
CHEMICALS
PREAMBLE xi
PREFACE xvii
ACRONYMS AND ABBREVIATIONS xix
1. SUMMARY, CONCLUSIONS, AND
RECOMMENDATIONS 1
1.1 Summary 1
1.2 Conclusions and recommendations 4
2. INTRODUCTION AND BACKGROUND 7
2.1 Introduction 7
2.2 Purpose and scope of document 9
2.3 Global burden of disease in children 12

2.4 Major environmental threats to children 14
2.4.1 Economic and nutritional factors 15
2.4.2 Social, cultural, demographic, and lifestyle
factors 16
2.4.3 Chemical hazards 17
2.5 Intrinsic factors 19
2.6 The significance of a developmental stage approach 20
2.7 Summary and conclusions 21
3. UNIQUE BIOLOGICAL CHARACTERISTICS OF
CHILDREN 22
3.1 General physical growth of children 22
3.1.1 Body weight and height 22
3.1.2 Organ weights/volumes 23
3.1.3 Skin 25
3.2 Anatomical and functional characteristics 25
3.3 Physiological characteristics 26
EHC 237: Principles for Evaluating Health Risks in Children
iv
3.3.1 Breathing rate 26
3.3.2 Cardiac output 26
3.3.3 Blood flow to organs 27
3.3.4 Body composition 28
3.3.5 Tissue composition 29
3.3.6 Bone growth and composition 29
3.4 Metabolic characteristics 29
3.5 Toxicokinetics 31
3.5.1 Absorption, distribution, metabolism, and
elimination 31
3.5.2 Physiological changes in mothers and their
influence on toxicokinetics 33

3.5.2.1 Pregnancy 33
3.5.2.2 Lactation and breast milk 35
3.5.3 Dose to target 36
3.6 Normal development 39
3.6.1 Basic principles of normal development 39
3.6.2 Nervous system 40
3.6.3 Reproductive system 42
3.6.4 Endocrine system 44
3.6.4.1 Hypothalamic–pituitary axis 44
3.6.4.2 Thyroid gland 46
3.6.4.3 Adrenal glands 47
3.6.4.4 Gonads 48
3.6.4.5 Somatotropin (growth hormone),
calcium homeostasis, and bone
development 48
3.6.4.6 Pancreas 48
3.6.5 Cardiovascular system 49
3.6.6 Immune system 49
3.6.7 Respiratory system 50
3.6.8 Kidney 52
3.7 Summary and conclusions 53
4. DEVELOPMENTAL STAGE–SPECIFIC
SUSCEPTIBILITIES AND OUTCOMES IN CHILDREN 55
4.1 Introduction 55
4.2 Mortality, growth restriction, and birth defects 60
4.2.1 Mortality 60
4.2.2 Growth restriction 63
4.2.3 Birth defects (structural malformations) 64
v
4.2.3.1 Etiology 66

4.2.3.2 Functional developmental toxicity 67
4.3 Specific organ systems 68
4.3.1 Nervous system 68
4.3.1.1 Periods of susceptibility and
consequences of exposures 69
4.3.1.2 Specific examples 72
4.3.2 Reproductive system 78
4.3.2.1 Periods of susceptibility 79
4.3.2.2 Consequences of exposures 80
4.3.3 Endocrine system 85
4.3.3.1 Periods of susceptibility 85
4.3.3.2 Consequences of exposures 92
4.3.4 Cardiovascular system 95
4.3.4.1 Periods of susceptibility 96
4.3.4.2 Consequences of exposures 96
4.3.5 Immune system 97
4.3.5.1 Periods of susceptibility 98
4.3.5.2 Consequences of exposures 101
4.3.6 Respiratory system 105
4.3.6.1 Periods of susceptibility 105
4.3.6.2 Consequences of exposures 106
4.3.7 Kidney 113
4.3.7.1 Periods of susceptibility 113
4.3.7.2 Consequences of exposures 114
4.4 Cancer 115
4.4.1 Childhood cancers that may have
environmental causes 116
4.4.1.1 Lymphoid tissues 116
4.4.1.2 Liver 118
4.4.1.3 Thyroid 118

4.4.1.4 Brain and nervous system 119
4.4.1.5 Other organ sites 119
4.4.2 Adult cancers related to childhood
exposures 120
4.4.2.1 Brain and nervous system 120
4.4.2.2 Thyroid 121
4.4.2.3 Female breast 122
4.4.2.4 Female reproductive tract 122
4.4.2.5 Integument 122
4.4.2.6 Other organ sites 123
Contents
EHC 237: Principles for Evaluating Health Risks in Children
vi
4.4.3 Chemical exposures of special concern 123
4.5 Summary and conclusions 126
5. EXPOSURE ASSESSMENT OF CHILDREN 129
5.1 Introduction 129
5.2 General principles of exposure assessments 129
5.3 Methods for conducting exposure assessments 133
5.3.1 Direct methods 133
5.3.2 Biomarkers of exposure 136
5.3.3 Modelling 137
5.4 Unique characteristics of children that affect
exposure 139
5.5 Exposure as it relates to children around the world 144
5.5.1 Sources/geographical location 144
5.5.2 Pathways of exposure 145
5.5.2.1 Ambient air exposure pathway 145
5.5.2.2 Indoor exposure pathways 150
5.5.2.3 Water exposure pathway 152

5.5.2.4 Soil exposure pathway 153
5.5.2.5 Food-chain exposure pathway 154
5.5.2.6 Human to human exposure
pathways 155
5.5.3 Settings/microenvironments 156
5.5.3.1 Residential 157
5.5.3.2 School 157
5.5.3.3 Child-care centres 157
5.5.3.4 Recreational 158
5.5.3.5 Special settings 159
5.5.4 Environmental equity factors (vulnerable
communities) 161
5.6 Special considerations for children’s exposure:
case-studies 162
5.6.1 Influence of activities 162
5.6.1.1 Arsenic 162
5.6.1.2 Insecticides 162
5.6.1.3 Environmental tobacco smoke
(ETS) 162
5.6.1.4 Lead 163
5.6.2 Hazardous waste sites 163
5.6.3 Aggregate exposure 164
5.6.3.1 Chlorpyrifos 164
vii
5.6.3.2 Smelter areas 165
5.6.3.3 Malarious areas 165
5.6.4 Cumulative exposure 165
5.7 Summary and conclusions 166
6. METHODOLOGIES TO ASSESS HEALTH
OUTCOMES IN CHILDREN 168

6.1 Introduction 168
6.1.1 Methodological approaches for children’s
health studies 168
6.1.1.1 Epidemiological methods 171
6.1.1.2 Comparison of study designs 171
6.1.1.3 Descriptive designs 176
6.1.1.4 Analytic designs 178
6.1.1.5 Unique methodological
considerations 180
6.1.2 Methodological approaches for animal
studies 181
6.1.2.1 Developmental stage susceptibility,
dosing periods, and assessment of
effects 184
6.1.2.2 Dosing of fetuses and pups 190
6.2 Growth and development 190
6.2.1 Human studies 190
6.2.1.1 Puberty 194
6.2.1.2 Birth defects 195
6.2.2 Animal studies 195
6.2.2.1 Body weight and postnatal growth 195
6.2.2.2 Pre-, peri-, and postnatal death 196
6.2.2.3 Physical and functional
developmental landmarks 196
6.2.2.4 Birth defects and malformations 198
6.3 Reproductive development and function 198
6.3.1 Human studies 198
6.3.2 Animal studies 202
6.3.2.1 Malformations of reproductive
organs 202

6.3.2.2 Anogenital distance 203
6.3.2.3 Nipple/areola retention 204
6.3.2.4 Sexual maturation and puberty 204
Contents
viii
6.3.2.5 Fertility 204
6.3.2.6 Histopathology of reproductive
organs 206
6.3.2.7 Sperm quality and estrous cyclicity 207
6.4 Neurological and behavioural effects 207
6.4.1 Human studies 207
6.4.2 Animal studies 208
6.4.2.1 Motor activity 208
6.4.2.2 Motor and sensory functions 209
6.4.2.3 Learning and memory 209
6.4.2.4 Evaluation of effects 210
6.5 Cancer 211
6.5.1 Human studies 211
6.5.2 Animal studies 212
6.6 Immune system effects 212
6.6.1 Human studies 212
6.6.2 Animal studies 213
6.7 Respiratory system effects 213
6.7.1 Human studies 213
6.7.2 Animal studies 213
6.8 Haematopoietic/cardiovascular, hepatic/renal,
skin/musculoskeletal, and metabolic/endocrine
system effects 214
6.8.1 Human studies 214
6.8.2 Animal studies 214

6.9 Summary and conclusions 214
7. IMPLICATIONS AND STRATEGIES FOR RISK
ASSESSMENT FOR CHILDREN 217
7.1 Introduction 217
7.2 Problem formulation 220
7.3 Hazard identification 221
7.3.1 End-points and critical periods of exposure 223
7.3.2 Human studies 224
7.3.3 Relevance of animal studies for assessing
potential hazards to children 225
7.3.4 Reversibility and latency 229
7.3.5 Characterization of the health-related
database 230
7.4 Dose–response assessment 230
7.4.1 Application of health outcome data 232
EHC 237: Principles for Evaluating Health Risks in Children
ix
7.4.2 Quantitative evaluation 233
7.4.2.1 Tolerable daily intake (TDI) and
reference dose (RfD)/reference
concentration (RfC) approaches 233
7.4.2.2 Benchmark dose (BMD)/benchmark
concentration (BMC) approach 236
7.4.2.3 Biologically based dose–response
models 236
7.4.2.4 Duration adjustment 237
7.4.2.5 Toxicokinetics 237
7.5 Exposure assessment 238
7.5.1 Age-specific exposures 238
7.5.2 Assessment methods 240

7.6 Risk characterization 242
7.7 Summary and conclusions 244
REFERENCES 247
ANNEX 1: WORKING DEFINITIONS OF KEY TERMS 310
RESUME, CONCLUSIONS ET RECOMMANDATIONS 315
RESUMEN, CONCLUSIONES Y RECOMENDACIONES 323
Contents
x
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are requested to communicate any
errors that may have occurred to the Director of the International
Programme on Chemical Safety, World Health Organization,
Geneva, Switzerland, in order that they may be included in corri-
genda.
xi
Environmental Health Criteria
PREAMBLE
Objectives
In 1973, the WHO Environmental Health Criteria Programme
was initiated with the following objectives:
(i) to assess information on the relationship between exposure to
environmental pollutants and human health, and to provide
guidelines for setting exposure limits;
(ii) to identify new or potential pollutants;
(iii) to identify gaps in knowledge concerning the health effects of
pollutants;
(iv) to promote the harmonization of toxicological and epidemio-

logical methods in order to have internationally comparable
results.
The first Environmental Health Criteria (EHC) monograph, on
mercury, was published in 1976, and since that time an ever-
increasing number of assessments of chemicals and of physical
effects have been produced. In addition, many EHC monographs
have been devoted to evaluating toxicological methodology, e.g. for
genetic, neurotoxic, teratogenic, and nephrotoxic effects. Other
publications have been concerned with epidemiological guidelines,
evaluation of short-term tests for carcinogens, biomarkers, effects on
the elderly, and so forth.
Since its inauguration, the EHC Programme has widened its
scope, and the importance of environmental effects, in addition to
health effects, has been increasingly emphasized in the total
evaluation of chemicals.
The original impetus for the Programme came from World
Health Assembly resolutions and the recommendations of the 1972
UN Conference on the Human Environment. Subsequently, the work
became an integral part of the International Programme on Chemical
Safety (IPCS), a cooperative programme of WHO, ILO, and UNEP.
In this manner, with the strong support of the new partners, the
EHC 237: Principles for Evaluating Health Risks in Children
x
ii
importance of occupational health and environmental effects was
fully recognized. The EHC monographs have become widely
established, used, and recognized throughout the world.
The recommendations of the 1992 UN Conference on Environ-
ment and Development and the subsequent establishment of the
Intergovernmental Forum on Chemical Safety with the priorities for

action in the six programme areas of Chapter 19, Agenda 21, all
lend further weight to the need for EHC assessments of the risks of
chemicals.
Scope
Two different types of EHC documents are available: 1) on
specific chemicals or groups of related chemicals; and 2) on risk
assessment methodologies. The criteria monographs are intended to
provide critical reviews on the effect on human health and the
environment of chemicals and of combinations of chemicals and
physical and biological agents and risk assessment methodologies.
As such, they include and review studies that are of direct relevance
for evaluations. However, they do not describe every study carried
out. Worldwide data are used and are quoted from original studies,
not from abstracts or reviews. Both published and unpublished
reports are considered, and it is incumbent on the authors to assess
all the articles cited in the references. Preference is always given to
published data. Unpublished data are used only when relevant
published data are absent or when they are pivotal to the risk
assessment. A detailed policy statement is available that describes
the procedures used for unpublished proprietary data so that this
information can be used in the evaluation without compromising its
confidential nature (WHO (1990) Revised Guidelines for the
Preparation of Environmental Health Criteria Monographs.
PCS/90.69, Geneva, World Health Organization).
In the evaluation of human health risks, sound human data,
whenever available, are preferred to animal data. Animal and in
vitro studies provide support and are used mainly to supply evidence
missing from human studies. It is mandatory that research on human
subjects is conducted in full accord with ethical principles, including
the provisions of the Helsinki Declaration.

xiii
The EHC monographs are intended to assist national and
international authorities in making risk assessments and subsequent
risk management decisions. They represent a thorough evaluation of
risks and are not, in any sense, recommendations for regulation or
standard setting. These latter are the exclusive purview of national
and regional governments.
Procedures
The following procedures were followed in the development
and publication of this EHC. A designated IPCS Staff Member (Dr
T. Damstra), responsible for the scientific content of the document,
serves as the Responsible Officer (RO). The IPCS editor is
responsible for layout and language.
An advisory group of scientific experts was convened by the
RO to provide oversight, expertise, and guidance for the project and
to ensure its scientific accuracy and objectivity. This advisory group
met in Gex, France (22–23 October 2002), to develop and evaluate
the structure and content of this EHC document and designate
chapter coordinators and contributors of text. Initial drafts of the
document were prepared by chapter coordinators (Dr Germaine
Buck Louis, Bethesda, Maryland, USA; Dr Terri Damstra, Research
Triangle Park, North Carolina, USA; Dr Fernando Díaz-Barriga,
San Luis Potosi, Mexico; Dr Elaine Faustman, Washington, D.C.,
USA; Dr Ulla Hass, Soborg, Denmark; Dr Robert Kavlock,
Research Triangle Park, North Carolina, USA; Dr Carole Kimmel,
Washington, D.C., USA; Dr Gary Kimmel, Silver Spring, Maryland,
USA; Dr Kannan Krishnan, Montreal, Quebec, Canada; Dr Ulrike
Luderer, Irvine, California, USA; Dr Linda Sheldon, Research
Triangle Park, North Carolina, USA) with input from the following
experts who contributed text for various sections of the document:

Tom Burbacher, Department of Environmental and Occupational
Health Sciences, University of Washington, Seattle, Washington,
USA; George Daston, Procter & Gamble Company, Cincinnati,
Ohio, USA; Rodney Dietert, Department of Microbiology and
Immunology, College of Veterinary Medicine, Cornell University,
Ithaca, New York, USA; Agneta Falk-Filipsson, Karolinska
Institutet, Stockholm, Sweden; Fernando Froes, USP School of
Medicine, Sao Paulo, Brazil; Gonzalo Gerardo Garcia Vargas,
Universidad Juárez del Estado de Durango, Gómez Palacio, Mexico;
Preamble
EHC 237: Principles for Evaluating Health Risks in Children
x
iv
Kimberly Grant, University of Washington, Seattle, Washington,
USA; Tony Myres, Ottawa, Ontario, Canada; Asher Ornoy, Hebrew
University, Jerusalem, Israel; Susan Ozanne, University of
Cambridge, Cambridge, United Kingdom; Jerry Rice, Washington,
D.C., USA; Peter Sly, Department of Pediatrics and Physiology,
Telethon Institute; and Jorma Toppari, University of Turku, Turku,
Finland.
The advisory group members, chapter coordinators, and con-
tributors of text serve as individual scientists, not as representatives
of any organization, government, or industry. All individuals who as
authors, consultants, or advisers participating in the preparation of
EHC monographs must, in addition to serving in their personal
capacity as scientists, inform the RO if at any time a conflict of
interest, whether actual or potential, could be perceived in their
work. They are required to sign a conflict of interest statement. Such
a procedure ensures the transparency of the process. The composi-
tion of the advisory group is dictated by the range of expertise

required for the subject of the meeting and, where possible, by the
need for a balanced geographical distribution.
The chapter coordinators met over a three-year period to
evaluate and revise various drafts of the document. Once the RO
found the unedited final draft acceptable, it was sent to over 100
contact points throughout the world for review and comment. The
unedited draft was also made available on the IPCS web site for
external review and comment for a period of two months. These
comments were peer-reviewed by the RO and chapter coordinators,
and additions and revisions to the draft document were made if
necessary. A file of all comments received and revisions made on
the draft is available from the RO. When the RO was satisfied as to
the scientific correctness and completeness of the document, it was
forwarded to an IPCS editor for language editing, reference
checking, and preparation of camera-ready copy. After approval by
the Director, IPCS, the manuscript was submitted to the WHO
Office of Publications for printing. It will also be available on the
IPCS web site.
xv
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA ON PRINCIPLES FOR EVALUATING
HEALTH RISKS IN CHILDREN ASSOCIATED WITH
EXPOSURE TO CHEMICALS
Dr T. Damstra, IPCS, served as the Responsible Officer and
was responsible for the preparation of the final document and for its
overall scientific content. Marla Sheffer, Ottawa, Canada, was the
IPCS editor responsible for layout and language.
* * *
Risk assessment activities of IPCS are supported financially by
the Department of Health and Department for Environment, Food &

Rural Affairs, United Kingdom; Environmental Protection Agency,
Food and Drug Administration, and National Institute of
Environmental Health Sciences, USA; European Commission;
German Federal Ministry of Environment, Nature Conservation and
Nuclear Safety; Health Canada; Japanese Ministry of Health, Labour
and Welfare; and Swiss Agency for Environment, Forests and
Landscape.
* * *
Advisory group members
Dr Patric Amcoff, Organisation for Economic Co-operation and
Development, Paris, France
Dr Bingheng Chen, Environmental Health, Fudan University School
of Public Health, Shanghai, People’s Republic of China
Dr Thea De Wet, Department of Anthropology and Developmental
Studies, Rand Afrikaans University, Auckland Park, South Africa
Dr Agneta Falk-Filipsson, Utredningssekretariatet,
Karolinska Institutet, Stockholm, Sweden
Dr Elaine Faustman, Pediatric Environmental Health Research
Center, University of Washington, Seattle, Washington, USA
Institutet för
miljömedicin (IMM)
,
EHC 237: Principles for Evaluating Health Risks in Children
x
v
i
Dr Ryuichi Hasegawa, Division of Medicinal Safety Science,
National Institute of Health Sciences, Tokyo, Japan
Dr Carole Kimmel, Office of Research and Development, National
Center for Environmental Assessment, Environmental Protection

Agency, Washington, D.C., USA
Dr Kannan Krishnan, University of Montreal, Montreal, Quebec,
Canada
Dr Irma Makalinao, National Poisons Control & Information
Service, Philippines General Hospital, Manila, Philippines
Dr Mathuros Ruchirawat, Chulabhorn Research Institute, Bangkok,
Thailand
Dr Radim J. Srám, Institute of Experimental Medicine, Academy of
Sciences of the Czech Republic, Prague, Czech Republic
Dr William Suk, Division of Extramural Research and Training,
National Institute of Environmental Health Sciences, Department of
Health and Human Services, Research Triangle Park, North
Carolina, USA
Dr Jan E. Zejda, Department of Epidemiology, Medical University
of Silesia, Katowice, Poland
Secretariat
Dr Terri Damstra, International Programme on Chemical Safety,
World Health Organization, Research Triangle Park, North
Carolina, USA
xvii
PREFACE
The International Programme on Chemical Safety (IPCS) was
initiated in 1980 as a collaborative programme of the United Nations
Environment Programme (UNEP), the International Labour Organi-
zation (ILO), and the World Health Organization (WHO). One of
the major objectives of IPCS is to improve scientific methodologies
for assessing the effects of chemicals on human health and the
environment. As part of this effort, IPCS publishes a series of
monographs, called Environmental Health Criteria (EHC) docu-
ments, that evaluate the scientific principles underlying method-

ologies and strategies to assess risks from exposure to chemicals.
Since its inception, IPCS has been concerned about the effects
of chemical exposures on susceptible populations, including chil-
dren. Past EHC publications addressing methodologies for risk
assessment in children include EHC 30, Principles for Evaluating
Health Risks to Progeny Associated with Exposure to Chemicals
during Pregnancy (IPCS, 1984), and EHC 59, Principles for
Evaluating Health Risks from Chemicals during Infancy and Early
Childhood: The Need for a Special Approach (IPCS, 1986b). EHC
30 focused on the use of short-term tests and in vivo animal tests to
assess prenatal toxicity and postnatal alterations in reproduction,
development, and behaviour following chemical exposure during
gestation, and EHC 59 focused on methods to detect impaired
reproductive and neurobehavioural development in infants and
children who were exposed during the prenatal and early postnatal
periods. Since these monographs were published in the 1980s, new
data and methodologies have emerged, indicating that children are a
vulnerable population subgroup with special susceptibilities and
unique exposures to environmental factors that have important
implications for public health practices and risk assessment
approaches. In recognition of this new scientific knowledge, IPCS
was asked to provide an up-to-date EHC on scientific principles and
approaches to assessing risks in children associated with exposures
to environmental chemicals.
IPCS is producing this monograph as a tool for use by public
health officials, research and regulatory scientists, and risk asses-
sors. It is intended to complement the monographs, reviews, and test
guidelines on reproductive and developmental toxicity currently
EHC 237: Principles for Evaluating Health Risks in Children
xviii

available. However, this document does not provide specific guide-
lines or protocols for the application of risk assessment strategies or
the conduct of specific tests. Specific testing guidelines for assessing
reproductive toxicity from exposure to chemicals have been devel-
oped by the Organisation for Economic Co-operation and Develop-
ment (OECD) and national governments.
The efforts of all who helped in the preparation, review, and
finalization of the monograph are gratefully acknowledged. Special
thanks are due to the United States Environmental Protection
Agency (USEPA) and the United States National Institute of Envi-
ronmental Health Sciences/National Institutes of Health for their
financial support of the planning and review group meetings.
xix
ACRONYMS AND ABBREVIATIONS
ACE angiotensin converting enzyme
ACTH adrenocorticotropic hormone
AGD anogenital distance
AIDS acquired immunodeficiency syndrome
APEX Air Pollutants Exposure
AT
2
angiotensin II
BMC benchmark concentration
BMCL a statistical lower confidence limit on the BMC
BMD benchmark dose
BMDL a statistical lower confidence limit on the BMD
CI confidence interval
CNS central nervous system
CYP cytochrome P450
DDE dichlorodiphenyldichloroethene

DDT dichlorodiphenyltrichloroethane
DEPM Dietary Exposure Potential Model
DES diethylstilbestrol
DHEA dehydroepiandrosterone
DHT dihydrotestosterone
DNA deoxyribonucleic acid
EDSTAC Endocrine Disruptor Screening and Testing
Advisory Committee
EHC Environmental Health Criteria
EPA Environmental Protection Agency (USA)
ETS environmental tobacco smoke
EU European Union
FEF forced expiratory flow
FEV forced expiratory volume
FSH follicle stimulating hormone
EHC 237: Principles for Evaluating Health Risks in Children
xx
GD gestation day
GH growth hormone
GnRH gonadotropin releasing hormone
GST glutathione-S-transferase
HAPEM Hazardous Air Pollutant Exposure Model
hCG human chorionic gonadotropin
HIV human immunodeficiency virus
HPG hypothalamic–pituitary–gonadal
IAQX Indoor Air Quality and Inhalation Exposure
IEUBK Integrated Exposure Uptake Biokinetic
IGF insulin-like growth factor
ILO International Labour Organization
IPCS International Programme on Chemical Safety

IQ intelligence quotient
IUGR intrauterine growth restriction
LH luteinizing hormone
LOAEL lowest-observed-adverse-effect level
MOE margin of exposure
NDMA N-nitrosodimethylamine
NOAEL no-observed-adverse-effect level
OECD Organisation for Economic Co-operation and
Development
OR odds ratio
PAH polycyclic aromatic hydrocarbon
PBB polybrominated biphenyl
PBPK physiologically based pharmacokinetic
PCB polychlorinated biphenyl
PCDD polychlorinated dibenzo-p-dioxin
PCDF polychlorinated dibenzofuran
pH relative hydrogen ion concentration
PM
2.5
particulate matter less than 2.5 μm in diameter
xxi
PM
10
particulate matter less than 10 μm in diameter
PND postnatal day
PNS peripheral nervous system
p.o. per oral (by mouth)
POP persistent organic pollutant
PRL prolactin
RfC reference concentration

RfD reference dose
RNA ribonucleic acid
RO Responsible Officer
s.c. subcutaneous
SCALE
Science, Children, Awareness, EU Legislation, and
Continuous Evaluation
SF-1 steroidogenic factor 1
SHEDS Stochastic Human Exposure and Dose Simulation
T3 triiodothyronine
T4 thyroxine (tetraiodothyronine)
TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin
TCP 3,5,6-trichloro-2-pyridinol
TDI tolerable daily intake
TERIS Teratogen Information System
TG Test Guideline
TGF-Į transforming growth factor-alpha
TGF-ȕ transforming growth factor-beta
Th1 T helper 1
Th2 T helper 2
TSH thyroid stimulating hormone
UN United Nations
UNEP United Nations Environment Programme
USA United States of America
Acronyms and Abbreviations
EHC 237: Principles for Evaluating Health Risks in Children
xxii
USEPA United States Environmental Protection Agency
VOC volatile organic compound
WHO World Health Organization

1
1. SUMMARY, CONCLUSIONS, AND
RECOMMENDATIONS
1.1 Summary
Environmental factors play a major role in determining the
health and well-being of children.
1
Accumulating evidence indicates
that children, who comprise over one third of the world’s popula-
tion, are among the most vulnerable of the world’s population and
that environmental factors can affect children’s health quite differ-
ently from adults’ health. Poor, neglected, and malnourished chil-
dren suffer the most. These children often live in unhealthy housing,
lack clean water and sanitation services, and have limited access to
health care and education. One in five children in the poorest parts
of the world will not live to their fifth birthday, mainly because of
environment-related diseases. The World Health Organization
(WHO) estimates that over 30% of the global burden of disease in
children can be attributed to environmental factors.
Health is determined by a variety of factors. In addition to the
physical environment, genetics, and biology, social, economic, and
cultural factors play major roles. Although it is critical to understand
the various driving forces during childhood that shape health and
behaviour throughout life, the emphasis of this document is
specifically on exposure to environmental chemicals. This document
evaluates the scientific principles to be considered in assessing
health risks in children from exposures to environmental chemicals
during distinct developmental stages and provides information for
public health officials, research and regulatory scientists, and other
experts responsible for protecting children’s health. The central

focus of this document is on the developmental stage rather than on
a specific environmental chemical or a specific disease or outcome.
Developmental stage–specific periods of susceptibility have been
referred to as “critical windows for exposure” or “critical windows
of development”. These distinct life stages are defined by relevant
dynamic processes occurring at the molecular, cellular, organ

1
The terms “children” and “child” as used in this document include the
stages of development from conception through adolescence.
EHC 237: Principles for Evaluating Health Risks in Children
2
system, and organism level. It is the differences in these life stages
along with exposures that will define the nature and severity of
environmental impacts.
Children have different susceptibilities during different life
stages owing to their dynamic growth and developmental processes
as well as physiological, metabolic, and behavioural differences.
From conception through adolescence, rapid growth and develop-
mental processes occur that can be disrupted by exposures to
environmental chemicals. These include anatomical, physiological,
metabolic, functional, toxicokinetic, and toxicodynamic processes.
Exposure pathways and exposure patterns may also be different in
different stages of childhood. Exposure can occur in utero through
transplacental transfer of environmental agents from mother to fetus
or in nursing infants via breast milk. Children consume more food
and beverages per kilogram of body weight than do adults, and their
dietary patterns are different and often less variable during different
developmental stages. They have a higher inhalation rate and a
higher body surface area to body weight ratio, which may lead to

increased exposures. Children’s normal behaviours, such as crawling
on the ground and putting their hands in their mouths, can result in
exposures not faced by adults. Children’s metabolic pathways may
differ from those of adults. Children have more years of future life
and thus more time to develop chronic diseases that take decades to
appear and that may be triggered by early environmental exposures.
They are often unaware of environmental risks and generally have
no voice in decision-making.
The accumulating knowledge that children may be at increased
risk at different developmental stages, with respect to both biologi-
cal susceptibility and exposure, has raised awareness that new risk
assessment approaches may be necessary in order to adequately pro-
tect children. Traditional risk assessment approaches and environ-
mental health policies have focused mainly on adults and adult
exposure patterns, utilizing data from adult humans or adult animals.
There is a need to expand risk assessment paradigms to evaluate
exposures relevant to children from preconception to adolescence,
taking into account the specific susceptibilities at each develop-
mental stage. The full spectrum of effects from childhood exposures
cannot be predicted from adult data. Risk assessment approaches for
exposures in children must be linked to life stages.
Summary, Conclusions, and Recommendations
3
A broad spectrum of diseases in children are known (or sus-
pected) to be associated with unhealthy environments. For much of
the world, traditional environmental health hazards continue to
remain the primary source of ill-health. These include lack of ade-
quate nutrition, poor sanitation, contaminated water, rampant disease
vectors (e.g. mosquitoes and malaria), and unsafe waste disposal. In
addition, rapid globalization and industrialization coupled with

unsustainable patterns of production and consumption have released
large quantities of chemical substances into the environment.
Although the term “environmental exposure” can encompass a vari-
ety of factors, the focus of this document is specifically on environ-
mental chemical exposures. Most of these substances have not been
assessed for potential toxicity to children, nor have the most
vulnerable subpopulations of children been identified. The incidence
of a number of important paediatric diseases and disorders (e.g.
asthma, neurobehavioural impairment) is increasing in several parts
of the world. Although a variety of factors are likely to be involved,
this may be due, in part, to the quality of the environment in which
children live, grow, and play.
Establishing causal links between specific environmental expo-
sures and complex, multifactorial health outcomes is difficult and
challenging, particularly in children. For children, the stage in their
development when the exposure occurs may be just as important as
the magnitude of exposure. Very few studies have characterized
exposures during different developmental stages. Examples have
shown that exposures to the same environmental chemical can result
in very different health outcomes in children compared with adults.
Some of these outcomes have been shown to be irreversible and
persist throughout life. Furthermore, different organ systems mature
at different rates, and the same dose of an agent during different
periods of development can have very different consequences. There
may also be a long latency period between exposure and effects,
with some outcomes not apparent until later in life. Some examples
of health effects resulting from developmental exposures include
those observed prenatally and at birth (e.g. miscarriage, stillbirth,
low birth weight, birth defects), in young children (e.g. infant mor-
tality, asthma, neurobehavioural and immune impairment), and in

adolescents (e.g. precocious or delayed puberty). Emerging evidence
suggests that an increased risk of certain diseases in adults (e.g.