Harmonization Projec t Document No.

WHO Human Health

Risk Assessment Toolkit
CHEMICAL HAZARDS
Second Edition

1
 Harmonization Projec t Document No. 8

WHO Human Health

Risk Assessment Toolkit
CHEMICAL HAZARDS
Second Edition

This project was conducted within the WHO/IPCS project

on the Harmonization of Approaches to the Assessment
of Risk from Exposure to Chemicals.
WHO human health risk assessment toolkit: chemical hazards, second edition
(IPCS harmonization project document, no. 8)
ISBN 978-92-4-003572-0 (electronic version)
ISBN 978-92-4-003573-7 (print version)

© World Health Organization 2021

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CONTENTS
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Process for development of the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Purpose and intended audience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Scope of the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Description of human health risk assessment of chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2.1 Definition of risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Uses of human health risk assessments of chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3. Description of the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

3.1 The toolkit as a roadmap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2 Tiered assessments in the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.3 Generic roadmaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.1 Problem formulation: chemical identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.2 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.3.3 Hazard characterization/guidance or guideline value identification . . . . . . . . . . . . . . . . . . . . 18
3.3.3.1 Health-based guidance values derived by international organizations . . . . . . . . . . 20
3.3.3.2 
Media-specific guideline values (quality guideline values) derived by
international organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.3.3.3 
Evaluating the appropriateness of available guidance or guideline values for
a specific problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.3.4 Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.3.4.1 Routes and pathways of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.3.4.2 Estimating exposures: modelling or measurement approaches . . . . . . . . . . . . . . . 31
3.3.4.3 Duration and frequency of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.3.4.4 Concentration and rate of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.3.4.5 Biomonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.3.5 Risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.3.5.1 Comparison with a guidance or guideline value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.3.5.2 Margin of exposure approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.3.5.3 Estimation of cancer risk using the slope factor approach . . . . . . . . . . . . . . . . . . . . 37
WHO human health risk assessment toolkit: chemical hazards

4. International risk assessment resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.2 Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.3 Directories of resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
4.4 General resources on risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.4.1 Resources on risk assessment methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.4.2 Resources on susceptible populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.4.3 Risk assessment for chemical incidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.5 Chemical-specific resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.5.1 JMPR monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.5.2 JECFA monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.5.3 EHC monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.5.4 CICADs
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.5.5 Drinking-water quality background documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.5.6 Air quality guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.6 Hazard identification resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.6.1 International Chemical Safety Cards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
4.6.2 Screening Information Dataset for High Production Volume Chemicals . . . . . . . . . . . . . . . . 46
4.6.3 WHO Recommended Classification of Pesticides by Hazard . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.6.4 United Nations Recommendations on the Transport of Dangerous Goods . . . . . . . . . . . . . 47
4.6.5 IARC monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.6.6 Hazardous Substances Data Bank . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.6.7 European Union (EU) Classification and Labelling System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.8 ECHA substance evaluation reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.9 ECHA Infocards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.10 EU risk assessment reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.11 International Chemical Control Toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.12 EFSA OpenFoodTox chemical hazards database . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.7 Hazard characterization/guidance or guideline value resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.7.1 Guidance values for exposure rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.7.1.1 Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.7.1.2 
Food additives and contaminants, naturally occurring toxicants and residues
of veterinary drugs in food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.7.2 Guideline values for exposure concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.7.2.1 WHO drinking-water guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.7.2.2 WHO air quality guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.7.3 Guidance and guideline values from chemical-specific monographs . . . . . . . . . . . . . . . . . . . 51
4.7.4 Integrated Risk Information System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.7.5 Occupational exposure limits (OELs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

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 Contents

4.8 Exposure assessment resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

4.8.1 General guidance on exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.8.2 Exposure factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
4.8.3 Emission sources and scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.8.4 Emission rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.8.5 Transport and fate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.8.6 Exposure concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4.8.7 Exposure from products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.9 Risk characterization resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

5. Evolving approaches and methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

5.1 Evidence-based methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
5.2 Chemical grouping and read-across . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
5.3 Threshold of toxicological concern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
5.4 Adverse Outcome Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
5.5 New approach methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
5.6 Use of in vitro data to characterize dose–response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
5.7 Strategies for assessing and testing multiple chemical exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Annex 1. Drinking-water case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

A1.1 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
A1.2 Statement of the problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
A1.3 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
A1.4 Hazard characterization/guidance or guideline value identification . . . . . . . . . . . . . . . . . . . . . . . . . . 83
A1.5 Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
A1.6 Risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
A1.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
References: Annex 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Annex 2. Respirable particulate matter (PM10) case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

A2.1 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
A2.2 Statement of the problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
A2.3 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
A2.4 Hazard characterization/guidance or guideline value identification . . . . . . . . . . . . . . . . . . . . . . . . . . 94
A2.5 Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
A2.6 Risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
A2.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
References: Annex 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

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WHO human health risk assessment toolkit: chemical hazards

Annex 3. Pesticide case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

A3.1 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
A3.2 Statement of the problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
A3.3 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
A3.4 Hazard characterization/guidance or guideline value identification . . . . . . . . . . . . . . . . . . . . . . . . . 104
A3.5 Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
A3.6 Risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
A3.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
References: Annex 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

vi
FIGURES
Figure 1. An environmental health paradigm and its relationship to the human health risk
assessment framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. Generic roadmap for chemical risk assessment in the context of the toolkit following the
conventional risk assessment paradigm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 3. Generic roadmap for chemical and hazard identification in the context of the toolkit . . . . . . . 16
Figure 4. Generic roadmap for hazard characterization/guidance or guideline value identification
in the context of the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 5. Mode of Action roadmap illustrating the use of mode of action knowledge in human health
risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 6. Tiered approach in risk assessment including uncertainty analysis with reference to
pertinent WHO/IPCS guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure 7. Generic roadmap for exposure assessment in the context of the toolkit . . . . . . . . . . . . . . . . . 29
Figure 8. Possible exposure media and corresponding means of contact . . . . . . . . . . . . . . . . . . . . . . . . . 30
Figure 9. Generic roadmap for risk characterization in the context of the toolkit . . . . . . . . . . . . . . . . . . . 35
Figure 10. Schematic diagram of exposure pathways, factors and routes . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Figure 11. Framework of modifying factors for exposure associated with geography and culture . . . . . 58
Figure 12. The GRADE approach to rating quality of evidence for each outcome . . . . . . . . . . . . . . . . . . . . 64
Figure 13. Schematic representation of the AOP illustrated with reference to a number of pathways . . 65
Figure 14. Illustration of the relationship between Mode of Action and AOP . . . . . . . . . . . . . . . . . . . . . . . . 66
Figure 15. Conceptual representation of the IPCS framework for the risk assessment of combined
exposure to multiple chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Figure A1.1 Case-specific roadmap for hazard identification: drinking-water case study . . . . . . . . . . . . . . 83
Figure A1.2 Case-specific roadmap for hazard characterization/guidance or guideline value
identification: drinking-water case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Figure A1.3 Case-specific roadmap for exposure assessment: drinking-water case study . . . . . . . . . . . . . 88
Figure A1.4 Case-specific roadmap for risk characterization: drinking-water case study . . . . . . . . . . . . . . . 90
Figure A2.1 Case-specific roadmap for hazard identification: particulate matter case study . . . . . . . . . . . 94
Figure A2.2 Case-specific roadmap for hazard characterization/guidance or guideline value
identification: particulate matter case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Figure A2.3 Case-specific roadmap for exposure assessment: particulate matter case study . . . . . . . . . . 98
Figure A3.1 Case-specific roadmap for hazard identification: pesticide case study . . . . . . . . . . . . . . . . . . 103
Figure A3.2 Case-specific roadmap for hazard characterization/guidance or guideline value
identification: pesticide case study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Figure A3.3 Case-specific roadmap for exposure assessment: pesticide case study . . . . . . . . . . . . . . . . . 108
Figure A3.4 Case-specific roadmap for risk characterization: pesticide case study . . . . . . . . . . . . . . . . . . . . 110

vii
WHO human health risk assessment toolkit: chemical hazards

TABLES
Table 1. Paradigm for risk assessment, including problem formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Table 2. Output from the framework for chemical risk assessment in the context of the toolkit . . . . . . 11
Table 3. Tiers of risk assessment included in the toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Table 4. Human health effects included in the Globally Harmonized System of Classification and
Labelling of Chemicals (GHS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Table 5. Guidance and other values commonly used in chemical evaluations . . . . . . . . . . . . . . . . . . . . . . 21
Table 6. Sources of guidance values for chemicals developed by international organizations . . . . . . . . 24
Table 7. Sources of media-specific guideline values for chemicals developed by international
organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Table 8. Two compilations of hazard identification, hazard characterization, exposure assessment
and risk characterization information for chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Table 9. WHO documents on principles of human health risk assessment for chemicals . . . . . . . . . . . 40
Table 10. International sources of information on harmonization of risk assessment methodology . . . 41
Table 11. International sources of information on susceptible populations . . . . . . . . . . . . . . . . . . . . . . . . . 42
Table 12. WHO resources on identification of chemical hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Table 13. General content of international hazard identification resources . . . . . . . . . . . . . . . . . . . . . . . . 46
Table 14. International resources on hazard characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Table 15. International sources of information on media and routes of exposure . . . . . . . . . . . . . . . . . . . 52
Table 16. International sources of guidance on exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Table 17. Summary of selected exposure factors published by WHO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Table 18. Summary of additional resources on exposure factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Table 19. Widely accepted resources on emissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Table A1.1 GHS classification for cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Table A1.2 International guidance and guideline values for cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Table A1.3 Cadmium concentrations in five samples of water obtained from each of three locations
in the vicinity of Rivertown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Table A2.1 WHO air quality guideline values for PM10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Table A2.2 WHO interim targets for PM10: annual mean concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Table A3.1 Relevance of study findings to an African country: template . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

viii
PREFACE
The production and use of chemicals are increasing worldwide. According to the UNEP publication
“Global Chemicals Outlook II” (UNEP 2019) the production capacity of the global chemical industry almost
doubled between 2000 and 2017, from about 1.2 to 2.3 billion tonnes. It was also noted in that report that
production of chemicals was projected to continue growing rapidly in emerging economies.

The World Health Organization (WHO) has estimated that 24% of global deaths are due to modifiable
environmental factors, including exposure to toxic chemicals (Preventing disease through healthy
environments, WHO 2019). The estimated burden of disease attributable to chemicals (from a limited
selection of chemicals where sufficient data are available and hence an underestimate of the total) was
1.6 million lives and 45 million disability-adjusted life years lost based on 2016 data. Lead exposure,
for example, accounts for 2.5% of cardiovascular diseases, 1.7% of chronic kidney diseases and 30%
of idiopathic intellectual disability. Unintentional poisonings kill an estimated 78,000 people per year,
in particular children and young adults, and cancer and lung disease attributable to exposure to
occupational carcinogens were responsible for more than 300,000 deaths (The public health impact of
chemicals: knowns and unknowns – data addendum for 2016, WHO 2018).

Despite what has been known for many years about the potential public health risks that can be posed by
chemicals, these problems have not been fully addressed. They persist especially in developing countries,
which typically have fewer resources for chemical risk management. This, together with the projected
growth in the production and use of chemicals in the developing world, is likely to result in an increase in
adverse effects on health if sound chemical management is not put in place.

In contrast, many countries have recognized the need for action and have signed a number of
international instruments, including multilateral environmental agreements, such as the Rotterdam
Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in
International Trade, the Stockholm Convention on Persistent Organic Pollutants and the Basel Convention
on the Control of Transboundary Movements of Hazardous Wastes and Their Disposal; the Strategic
Approach to International Chemicals Management; International Labour Organization Conventions; and
the International Health Regulations of 2005. All these instruments place requirements on countries to
develop capacities for chemical management, including capacities allowing them to assess health and
environmental risks associated with the use of chemicals in order to make informed decisions on whether
to take action to manage these risks. However, many countries are still lacking competencies to assess
risks to human health from exposure to chemicals, especially developing countries and countries with
economies in transition.

The purpose of the WHO human health risk assessment toolkit: chemical hazards is to provide its users with
guidance to identify, acquire and use the information needed to assess chemical hazards, exposures and
the corresponding health risks in their given health risk assessment contexts at local and national levels.
The toolkit provides roadmaps for conducting a human health risk assessment, identifies information that
must be gathered to complete an assessment and provides electronic links to international resources

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WHO human health risk assessment toolkit: chemical hazards

from which the user can obtain information and methods essential for conducting the human health risk
assessment.

By doing so, the toolkit also aims to raise awareness and promote the use of globally accepted risk
assessment information that has been developed by international organizations such as WHO, the Food
and Agriculture Organization of the United Nations, the United Nations Environment Programme, the
Codex Alimentarius Commission and the Organisation for Economic Co-operation and Development
(OECD) for use in countries.

The toolkit has been developed for public health and environmental professionals, regulators, industrial
managers and other decision-makers with at least some training in the principles of risk assessment who
are responsible for conducting human health risk assessments and making decisions on whether to take
action to manage human health risks associated with exposure to chemicals.

Since the publication of the first edition in 2010, the toolkit has been acknowledged for the role it has
played in providing assistance with chemical risk assessments (UNEP, 2019). In the period since 2010 there
have been a number of new developments in chemical risk assessment methodologies, new tools and
new WHO publications. This revised edition of the toolkit is intended to incorporate information about
these new developments in methodologies, and to keep references and links to the information sources
up to date.

WHO continues to hope that the toolkit will have wide application, especially in developing countries and
countries with economies in transition. It is hoped that, in all countries, the identification of human health
risks related to chemicals as well as related management decisions and mitigation measures, including
those related to international agreements, will be based on best evidence through the application of best
risk assessment methodology and use of available authoritative risk assessment information developed by
international organizations in combination with locally relevant information.

UNEP (2019) – Global Chemicals Outlook II. Nairobi: United Nations Environment Programme; 2019 https://wedocs.unep.org/handle/20.500.11822/28113
WHO (2018) – The public health impact of chemicals: knowns and unknowns – data addendum for 2016. Geneva: World Health Organization; 2018
https://apps.who.int/iris/rest/bitstreams/916484/retrieve
WHO (2019) – Preventing disease through healthy environments – updated 2016 data tables. Geneva: World Health Organization; 2019
https://www.who.int/quantifying_ehimpacts/publications/Updated-2016-data-tables_Preventing_disease_Deaths_DALYs_PAFs_Sept_2019_rev.xlsx

x
PROCESS FOR DEVELOPMENT
OF THE TOOLKIT
The WHO human health risk assessment toolkit: chemical hazards was developed under the auspices of the
International Programme on Chemical Safety (IPCS) Harmonization Project (https://www.who.int/activities/
harmonizing-global-approaches-to-chemical-risk-assessment). The goal of the IPCS project is to globally
harmonize approaches to risk assessment by increasing understanding and developing basic principles
and guidance on specific chemical risk assessment issues.

Dr K. Gutschmidt and Ms C. Vickers, Team Leader, Chemical Safety, WHO Secretariat, served as the
responsible officers for the development of this toolkit, including its scientific content.

An initial expert meeting was convened to provide guidance for the development of the toolkit on 5–7
March 2008 in Montreux, Switzerland. The meeting was chaired by Professor B. Chen (School of Public
Health, Fudan University, China) and co-chaired by Dr P. Preuss (National Center for Environmental
Assessment, Environmental Protection Agency, United States of America (USA)). The meeting was
also attended by Dr C. Alonzo (Chemical Safety Unit, Department of Environmental Health, Ministry of
Public Health, Uruguay), Dr A. Dawson (South Asian Clinical Toxicology Research Collaboration, Faculty
of Medicine, University of Peradeniya, Sri Lanka), Dr J.F.M. de Kom (Senior Policy Advisor, Toxicology
Focal Point, Secretariat Director, Ministry of Health, Suriname), Dr I. Dobrev (Fraunhofer Institute
for Toxicology and Experimental Medicine, Germany), Dr S.H. Inayat-Hussain (Associate Professor of
Toxicology, Environmental Health Program, Faculty of Allied Health Sciences, Universiti Kebangsaan
Malaysia, Malaysia), Dr M.E. Meek (Associate Director, Chemical Risk Assessment, McLaughlin Centre for
Population Health Risk Assessment, Canada), Dr K. Olokun (Deputy Director, Chemical Safety Management
Programme, Food and Drug Services Department, Federal Ministry of Health, Nigeria) and Dr M.
Ruchirawat (Office of Academic Affairs, Chulabhorn Research Institute, Thailand). Representatives of the
International Life Sciences Institute (Dr S.S. Olin, ILSI Research Foundation, USA), OECD (Mr R. Diderich,
Environment, Health and Safety Division, Environment Directorate, OECD, France) and the United Nations
Environment Programme (Ms A. Sundén Byléhn, Senior Scientific Affairs Officer, Chemicals Branch, Division
of Technology, Industry and Economics, UNEP, Switzerland) were also in attendance. WHO provided the
Secretariat (Ms C. Vickers and Ms S. Kunz, IPCS, WHO, Switzerland).

Initial draft material was developed by Professor B. Chen (China) and Dr P. Preuss (USA). A teleconference
was held on 23 September 2008, attended by Dr B. Chen (Chair), Dr P. Preuss (Co-chair), Dr I. Dobrev
(Germany), Dr S.H. Inayat-Hussain (Malaysia), Dr M.E. Meek (Canada), Dr K. Olokun (Nigeria) and Dr M.
Ruchirawat (Thailand). Representatives from ILSI (Dr S.S. Olin) and UNEP (Mr C. Siewe and Ms A. Sundén
Byléhn) also participated. The Secretariat consisted of Ms C. Vickers and Dr K. Walker (consultant,
USA). Further initial draft material was developed by Dr K. Walker (USA) until February 2009. The first
comprehensive toolkit was drafted by Dr D.L. MacIntosh (Harvard School of Public Health, USA), taking into
account previously developed material.

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WHO human health risk assessment toolkit: chemical hazards

The draft toolkit was pilot-tested from August to October 2009 in three Asian countries: China, Malaysia
and Thailand. A meeting was held to lead into the pilot phase on 30–31 July 2009 at the Chulabhorn
Research Institute in Bangkok, Thailand. The meeting was organized in close collaboration with the
Rotterdam Convention Secretariat, who identified participants from designated national authorities
for the Rotterdam Convention in pilot countries. The meeting was attended by Ms P. Chareonsong
(Director of Hazardous Substance Section, Waste and Hazardous Substance Management Bureau,
Pollution Control Department, Thailand), Mr C. Goh Choo Ta (Research Fellow, Institute for Environment
and Development, Universiti Kebangsaan Malaysia, Malaysia), Ms P. Klaimala (Pesticide Risk Assessment
Programme, Pesticide Research Group, Office of Agricultural Production, Science Research and
Development, Department of Agriculture, Thailand), Ms H.H. Mohd (Assistant Director, Pesticides
Control Division, Department of Agriculture, Ministry of Agriculture and Agro-based Industry, Malaysia),
Mr S. Ruengrotvriya (Designated National Agency, Rotterdam Convention, Thailand), Dr M. Ruchirawat
(Chulabhorn Research Institute, Thailand), Ms W. Thangnipon (Senior Research Scientist, Pesticide Risk
Assessment Programme, Pesticide Research Group, Office of Agricultural Production, Science Research
and Development, Department of Agriculture, Thailand), Dr Z. Shan (Professor, Nanjing Institute of
Environmental Sciences, Ministry of Environmental Protection, China), Ms S. Sirichuaychoo (Senior
Agricultural Scientist, Pesticide Regulatory Subdivision, Office of Agricultural Regulation, Department of
Agriculture, Thailand), Ms P. Tarin (Environmental Scientist, Waste and Hazardous Substance Management
Bureau, Pollution Control Department, Thailand) and Dr J. Zhang (Professor, Department of Environmental
Pollution and Health, Chinese Research Academy of Environmental Sciences, Ministry of Environmental
Protection, China). The Rotterdam Convention Secretariat was represented by Ms N. Grasser (Scientific
Affairs Officer, Rotterdam Convention Secretariat, UNEP, Switzerland). WHO was represented by Dr K.
Gutschmidt (Department for Public Health and Environment, Health Security and Environment, WHO,
Switzerland) and Dr D.L. MacIntosh (Harvard School of Public Health, USA).

In parallel to the pilot-testing in the three countries, the draft toolkit underwent international peer review
from August to October 2009. A final review meeting was held to provide recommendations to finalize
the WHO toolkit by taking into account the lessons learned from the pilot phase and comments from the
peer review. The final review meeting was held on 29–30 October 2009 at the WHO Office in Lyon, France.
The meeting was co-chaired by Professor B. Chen (China) and Dr P. Preuss (USA). The meeting was further
attended by Mr S. Adu-Kumi (Chemicals Control and Management Centre, Environmental Protection
Agency, Ghana), Dr I. Dobrev (Germany), Mr J. Fawell (consultant, United Kingdom of Great Britain and
Northern Ireland), Mr C. Goh Choo Ta (Malaysia), Dr S.H. Inayat-Hussain (Malaysia), Dr M. Ruchirawat
(Thailand), Dr D. Russell (Head of Unit, Chemical Hazards and Poisons Division, Deputy Director, WHO
Collaborating Centre, The Health Protection Agency, United Kingdom) and Dr J. Satayavivad (Chulabhorn
Research Institute, Thailand). Representatives of OECD (Mr M. Oi, Environment, Health and Safety Division,
Environment Directorate, OECD, France), the Rotterdam Convention Secretariat (Ms N. Grasser, UNEP)
and UNEP (Ms A. Sundén Byléhn, UNEP) were also in attendance. WHO provided the Secretariat (Dr K.
Gutschmidt, WHO; Dr J. Thomas-Crusells, Department for Public Health and Environment, Health Security
and Environment, WHO, Switzerland; and Dr D.L. MacIntosh, Harvard School of Public Health, USA).

The final toolkit was prepared by Dr D.L. MacIntosh (USA) and Dr K. Gutschmidt (WHO), with technical and
linguistic editing by Ms M. Sheffer (Ottawa, Canada).

xii
 Process for development of the toolkit

Update for the second edition

The toolkit was updated during 2019–2020 to incorporate new developments in chemical risk assessment
methodologies and tools since the first edition was published in 2010. This included an update of the
references and links in the main body text of the toolkit. The case studies published in the first edition in
2010 were not updated but were moved to annexes in the document along with separate reference lists.

The update of the toolkit was prepared by Ms K. Hughes (consultant, Canada). The draft updated toolkit
underwent invited peer review from international experts during June and July 2020. Comments were
received from the following: Dr A. Beronius (Karolinska Institutet, Sweden), Dr R. Fitzgerald (University of
Basel, Switzerland), Dr A. Hanberg (Karolinska Institutet, Sweden), Dr Y. Hirabayashi (National Institute of
Health Sciences, Japan), Dr A. Hirose (National Institute of Health Sciences, Japan), Dr G. Kass (European
Food Safety Authority, Italy), Dr G. Kowalczyk (consultant, United Kingdom), Dr B. Meek (University of
Ottawa, Canada), Dr J. Nicolas (Ministry for Primary Industries, New Zealand), Dr L. Perharič (National
Institute of Public Health, Slovenia), Dr T. Vermeire (RIVM, Netherlands), Dr M. Wilks (University of Basel,
Switzerland) and Dr J. Zilliacus (Karolinska Institutet, Sweden).

Following peer review, the draft toolkit was finalized by Ms K. Hughes taking into account comments
received during peer review.

The updated toolkit was edited by Mr J. Dawson (Nairobi, Kenya).

Dr R. Brown (Chemical Safety and Health Unit, Department of Environment, Climate Change and Health,
WHO) served as the responsible officer for the update of the toolkit.

Acknowledgements
The contributions of all who participated in the preparation and finalization of the WHO human health
risk assessment toolkit: chemical hazards, including those who provided their comments during the peer
review process, are gratefully acknowledged. Special thanks go to those who pilot-tested the toolkit in
China, Malaysia and Thailand and provided invaluable comments from their experience to further the
development of the toolkit.

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WHO human health risk assessment toolkit: chemical hazards

ABBREVIATIONS
ADI acceptable daily intake
ALOHA Areal Locations of Hazardous Atmospheres
AOP Adverse Outcome Pathway
ARfD acute reference dose
BE biomonitoring equivalent
BMD benchmark dose
BMDL benchmark dose lower confidence limit
CAS Chemical Abstracts Service
CICAD Concise International Chemical Assessment Document
CSAF chemical-specific adjustment factor
DDE p,p-dichlorodiphenyldichloroethane
DDT p,p-dichlorodiphenyltrichloroethane
ECHA European Chemicals Agency
EFSA European Food Safety Authority
EHC Environmental Health Criteria
EPA Environmental Protection Agency
EU European Union
EuroMix European Test and Risk Assessment Strategies for Mixtures
EUSES European Union System for the Evaluation of Substances
FAO Food and Agriculture Organization of the United Nations
GHS Globally Harmonized System of Classification and Labelling of Chemicals
GRADE Grading of Recommendations Assessment, Development and Evaluation
HSDB Hazardous Substances Data Bank
IARC International Agency for Research on Cancer
ICSC International Chemical Safety Card
ILO International Labour Organization
IPCHEM Information Platform for Chemical Monitoring
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System

xiv
 Abbreviations

JECFA Joint FAO/WHO Expert Committee on Food Additives

JMPR Joint FAO/WHO Meeting on Pesticide Residues
LOAEL lowest observed adverse effect level
LOEL lowest observed effect level
MOA Mode of Action
NOAEL no observed adverse effect level
NOEL no observed effect level
OECD Organisation for Economic Co-operation and Development
OEL occupational exposure limit
PBTK physiologically based toxicokinetic model
PM particulate matter
POD Point of Departure
PPE personal protective equipment
PTMI provisional tolerable monthly intake
PTWI provisional tolerable weekly intake
QSAR quantitative structure–activity relationship
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
RfD reference dose
RIVM National Institute for Public Health and the Environment (Netherlands)
SF slope factor
SIDS Screening Information Dataset for High Production Volume Chemicals
TC tolerable concentration
TDI tolerable daily intake
TRA Targeted Risk Assessment
TTC threshold of toxicological concern
UN United Nations
UNEP United Nations Environment Programme
WHO World Health Organization

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WHO human health risk assessment toolkit: chemical hazards

xvi
1. INTRODUCTION
Risk analysis is a process that incorporates three components: risk assessment, risk management and
risk communication. The first component, risk assessment, consists of scientific analyses, the results of
which are quantitative or qualitative expressions of the likelihood of harm associated with exposure to a
chemical substance (henceforth generally referred to as a “chemical” in this toolkit).

The assessment of human health risk requires identification, compilation and integration of information
on the health hazards of a chemical, human exposure to the chemical, and the relationships between
exposure, dose and adverse effects. Acquisition of information appropriate to an exposure scenario of
interest is a fundamental challenge in risk assessment. Numerous sources of such information can be
readily found through literature searches facilitated by electronic tools. Compilations of relevant data
prepared by international and other organizations also provide rapid access to information on chemical
hazards, exposures and risks.

1.1 Purpose and intended audience

This World Health Organization (WHO) human health risk assessment toolkit was developed to help people
make decisions about chemicals by assessing the magnitude of potential risks to human health associated
with exposure to the chemicals. In so doing, the toolkit helps its users to (a) identify and acquire the
information needed to assess chemical hazards, exposures and risks; and (b) use that information to
estimate potential exposure to hazardous chemicals and the corresponding health risks.

It is envisioned that the toolkit will be used to address a wide range of situations that are relevant to the
management of risks for public health. For example, the principles, approaches and resources described
in the toolkit can aid risk assessments of chemical incidents; retrospective evaluations conducted in
support of information on the incidence of illness or related concerns; and prospective analyses of
potential impacts of a proposed policy or management decision. Specific examples of risk assessment
are described in the case studies presented in the annexes. Users of the toolkit may also find it helpful
to consult a glossary of key terminology used in chemical risk assessment published by the International
Programme on Chemical Safety (1).

Although the toolkit alone cannot answer all of the questions regarding risks from chemical exposures,
it will provide important information to public health and environmental specialists, regulators, industrial
managers and other decision-makers involved with chemical safety and protection. The toolkit has been
developed particularly for people with at least some training in the principles of risk assessment who
are responsible for conducting health risk assessments (for example, public health and environmental,
scientific or engineering professionals) and making decisions on whether to take action to manage
environmental risks (for example, officials in health or environmental regulatory bodies or in private
businesses).

1
WHO human health risk assessment toolkit: chemical hazards

The toolkit was developed in recognition that complementary initiatives are under way within WHO and
other international organizations. For example, a conceptual framework for a preventive, risk-based
approach to managing water quality is presented in the WHO Guidelines for drinking-water quality (2),
along with a range of supporting information. In addition, the Organisation for Economic Co-operation
and Development (OECD) has developed Internet-based resources for environmental risk assessment in
parallel with the toolkit (3). Similarly, the World Bank has established internet-based training modules and
interactive tools that are intended to enable use of risk-based approaches to prioritize and manage land
sites contaminated with persistent organic pollutants and other hazardous chemicals (4).

1.2 Scope of the toolkit

The toolkit is a manual on how to identify and characterize chemical hazards, assess exposures to
these chemicals and determine whether these exposures are dangerous to public health. The toolkit
also provides references, including electronic links to risk assessment information and data published
by international organizations. Where there are gaps in the information available from international
organizations, generally accepted scientific guidance or methods from national resources were selected,
based upon expert judgement, for presentation in the toolkit. Finally, the toolkit focuses on assessment
of health risk for human populations and therefore does not encompass environmental risk assessment.
As mentioned above, the toolkit is complementary to the Environmental risk assessment toolkit developed
by OECD (3). Characterization of health risks is the end-point of the methodology described in the WHO
toolkit. Therefore, both risk management and risk communication, the two components of risk analysis
that follow risk assessment, are outside the scope of the toolkit.

To assist with performance of a risk assessment, this toolkit:

― provides roadmaps for conducting chemical risk assessments;

― identifies information that must be gathered to complete an assessment;
― provides references, including internet URLs, for international resources from which an assessor can
obtain information and methods essential to a risk assessment.

The description of chemical risk assessment in the context of the toolkit depicts the starting and ending
points of an assessment and the pathways that connect various types of information. In this way, the
toolkit is analogous to a roadmap that describes how to conduct a chemical risk assessment and interpret
its results using publicly available resources from international organizations. The roadmap concept is
illustrated in case studies of risk assessments for a chemical in drinking-water, respirable particulate
matter in air and a pesticide. The general description of the toolkit in section 3 and the case studies in the
annexes walk the user through the components of a chemical risk assessment, linking each component
to relevant international sources of information. While international sources of information are referenced
in the toolkit, an understanding of the local situation is also needed. In this regard, it is important to note
that valuable knowledge may also be gained from national and local authorities, academia and research
institutions, employees, plant managers or members of the community. These institutions and individuals
may have useful and important information about the history of a site, process or problem, chemical
usage, human activities, and past, current and future land uses that can be used to identify chemical
hazards or to assess chemical exposures.

This document also presents a tiered approach to chemical risk assessment in that the methods used
to assess risk reflect the problem and resources at hand. For example, a relatively low-level tier of risk
assessment may consist of comparing existing information on exposure with an applicable guidance
or guideline value for an environmental medium (such as air) or food published by an international

2
 1. Introduction

organization. This toolkit focuses on lower tiers of chemical risk assessment that involve similar practical
applications of existing information to assess potential health risks of chemical exposure. Therefore, the
toolkit is focused on chemicals and exposure scenarios that are reasonably well described in the scientific
literature and publications of international organizations such as WHO.

The toolkit also provides links to and some brief descriptions of more resource-intensive methodologies,
such as hazard characterization of new chemicals or new health outcomes associated with an existing
chemical, to provide additional or background information on tools and approaches incorporated into
higher-tiered assessments, such as derivation of existing guidance or guideline values. In those cases, a
quantitative evaluation of toxicity based on laboratory animal models or epidemiological studies may be
required. This type of assessment often requires new laboratory or observational studies to characterize
the physical and toxicological properties of a chemical, all of which may take months or years to complete.
The hazard information required for a chemical risk assessment of this type is described in documents
published by various international organizations, including the OECD Guidelines for the testing of chemicals
(5).

It is recognized that humans are usually exposed to several different chemicals at the same time. While
methodologies for assessing combined exposures to multiple chemicals have been developed and
continue to evolve (see section 5.7), this toolkit focuses on approaches to assessing risks associated with
exposure to individual chemicals.

The toolkit is organized into sections that provide:

― an introduction to the purpose and scope of the document (section 1);

― a description of human health risk assessment of chemicals (section 2);
― a detailed description of the toolkit (section 3);
― references to international sources (and regional and national sources, where these may also be
helpful or where there are gaps in international sources) of information useful for conducting
chemical risk assessments (section 4);
― information about evolving approaches and methodologies and anticipated future developments in
chemical risk assessment methodology (section 5).

The annexes contain case studies that illustrate how the toolkit can be used to address a human health
risk assessment question.

Reference lists, including URLs for most of the information resources, are also provided.

3
WHO human health risk assessment toolkit: chemical hazards

2. DESCRIPTION OF HUMAN
HEALTH RISK ASSESSMENT OF
CHEMICALS

2.1 Definition of risk assessment

Human health risk assessment is a process intended to estimate the risk to a given target organism,
system or (sub)population, including the identification of attendant uncertainties, following exposure to
a particular agent, taking into account the inherent characteristics of the agent of concern as well as the
characteristics of the specific target system (1). It is the first component in a risk analysis process that also
includes risk management and risk communication. Human health risk assessment of chemicals refers
to methods and techniques that apply to the evaluation of hazards, exposure and harm associated with
chemicals, which in some cases may differ from approaches used to assess risks associated with biological
and physical agents.

The risk assessment process begins with problem formulation and includes four additional steps: (a)
hazard identification, (b) hazard characterization, (c) exposure assessment and (d) risk characterization
(1). The risk assessment paradigm, incorporating problem formulation, is summarized in Table 1. A full
description of the concepts presented in the table may be found in Chapter 3 of WHO Environmental
Health Criteria (EHC) 239 (6). A detailed description of risk assessment can also be found in Chapter 2 of
EHC 240 (7) and in a number of general publications on this topic.

4
 2. Description of human health risk assessment of chemicals

Table 1.  Paradigm for risk assessment, including problem formulation

Step Description Content

Problem Establishes the scope and objective of the Defining the question
formulation assessment and the degree of uncertainty Prior knowledge
acceptable Time and resources required
Nature of desired assessment output
Analysis plan

Hazard Identifies the type and nature of adverse health Human studies
identification effects Animal-based toxicology studies
In vitro toxicology studies
Structure–activity studies
Other predictive technologies

Hazard Qualitative or quantitative description of Selection of critical data sets

characterization inherent properties of an agent having the Modes/mechanisms of action
potential to cause adverse health effects Kinetic variability
Dynamic variability
Dose/exposure–response for critical effects

Exposure Evaluation of the exposure situation of the (sub) Characteristics of population exposed
assessment population identified in problem formulation Sources
to a particular agent (e.g. concentration or Magnitude
amount) Frequency
Duration
Route

Risk Advice for decision-making Qualitative statements or recommendations

characterization or quantitative guidance or risk estimates
Nature and severity of effects
Probability of effects
Health-based guidance
Populations of concern
Uncertainties

Source: Adapted from EHC 239 (6).

Risk assessors should be aware that their outputs will often be incorporated into risk management
and policy decisions. This use of risk assessments is appropriate, in that environmental health policy
decisions should be based on established links among exposure sources, human exposures and adverse
health effects. A modified version of the environmental health chain published originally in EHC 214 (8)
is illustrated in Figure 1. The chain of events depicted in Figure 1 is an “environmental health paradigm”:
a simplified representation of the key steps between exposure to toxic agents and the final outcome as
potential disease or dysfunction in humans. This sequential series of events serves as a useful framework
for understanding and evaluating human health risks. It is directly related to the risk assessment process.
Human health risk assessment for chemical hazards is a means of integrating the components of the
environmental health chain in a manner that is useful for analysis and management of chemical-mediated
risks. In addition to risk assessment, effective chemical risk management also includes other aspects
such as risk perception and socioeconomic considerations; all of these components should be reflected in
effective risk communication.

5
WHO human health risk assessment toolkit: chemical hazards

2.2 Uses of human health risk assessments of chemicals

Human health risk assessments of chemicals can be performed to evaluate exposures to any chemical
found in air, soil, water, food, consumer or other products (henceforth referred to more generally as
“products” in this toolkit), or other materials. These assessments could relate to past or current exposures
(retrospective) or potential future exposures (prospective). They can be quantitative or qualitative in
nature. Risk assessments are often limited by a lack of complete information. To be protective of public
health, risk assessments are typically performed in a manner that is unlikely to underestimate the actual
risk. Chemical risk assessments rely on scientific understanding of chemical behaviour, exposure, dose
and toxicity. In general terms, risk depends on the following factors:

― the amount of a chemical present in an environmental medium (such as soil, water or air), food and/
or a product;
― the amount of contact (exposure) a person has with the chemical in the medium;
― how the body processes the chemical (toxicokinetics);
― the toxicity of the chemical.

Obtaining information on these factors is the basis or foundation of most chemical risk assessments. As
these data are not always available, estimates or judgements may be necessary for some data inputs or
characterizations. Consequently, risk assessment results have associated uncertainties, which should be
characterized as much as possible.

Despite these uncertainties, human health risk assessment of chemicals can help to answer basic
questions about potential dangers from exposure to chemicals, such as:

― What chemical exposures pose the greatest risks? Can the risks be ranked to allow a country to
spend its resources in the most efficient way?
― What are the risks of drinking this water? Should drinking-water be provided from a different, safer
source?
― Is this chemical spill dangerous? What is the appropriate emergency response?
― Is it “safe” to build homes on this old hazardous waste site? Should we clean up this contaminated
soil?
― Should this chemical be authorized for the proposed use(s)?
― What, if any, limits on chemical exposure should be established in occupational settings, in
products, in environmental media and in food?
― Should limits be set for chemical emissions from industrial, agricultural or other human activities?

6
 2. Description of human health risk assessment of chemicals

Figure 1.  An environmental health paradigm and its relationship to the human health risk
assessment framework

Sequence of events
in the environmental Environmental Risk assessment
health paradigm health paradigm framework

Emission Exposure
source(s) and assessment
presence in food What
and products environmental,
food and product
Chemical use, exposures are
environmental expected to
transport, Concentrations occur for human
Biological, transformation and in environmental populations, and
chemical, fate processes media, food and what is the resulting
physical products dose to target
and social tissue?
determinants
Risk
of the critical
Demographic, Hazard characterization
events leading
geographical and characterization What is the
from release
lifestyle attributes Human exposure What is the estimated human
of toxic agents
relationship health risk from
into the
between dose or anticipated
environment
concentration to the exposure?
or release
from products Toxicokineticsa target tissue and
Internal adverse effects in
to resulting
exposure humans?
disease or
injury in people

Toxicodynamicsb Hazard
identification
Is the chemical
Adverse effect(s)
capable of causing
an adverse effect in
humans?

a. Toxicokinetics: what the body does to the agent. The process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the
distribution of the substances and their metabolites in the tissues and the elimination of the substances and their metabolites from the body (9).
b. Toxicodynamics: what the agent does to the body. The process of interaction of chemical substances with the target sites and the subsequent reactions leading to
adverse effects (9).
Source: Adapted from Sexton et al. (10); IPCS (8).

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WHO human health risk assessment toolkit: chemical hazards

3. DESCRIPTION OF THE TOOLKIT

The WHO human health risk assessment toolkit: chemical hazards follows the traditional risk assessment
paradigm and guides the reader through the various components of the paradigm in an applied manner.
The toolkit does not contain detailed discussion of the inputs to a human health risk assessment, but
instead focuses on the interpretation and assembly of those inputs for characterizing risk. Three practical
aspects of the toolkit that are intended to facilitate its use – (a) the presentation of the risk paradigm as
a roadmap, (b) the introduction of a tiered approach based on the attributes of the assessment question
and the available data, and (c) the provision of sources of information on aspects on risk assessment –
are described below. These brief descriptions are followed by generic roadmaps for components of risk
assessment: hazard identification, hazard characterization (including guidance value and guideline value
identification), exposure assessment, and risk characterization.

The terminology used in the toolkit is generally in line with the definitions and practice established
through the WHO/International Programme on Chemical Safety (IPCS) in numerous publications.
Throughout this document, frequent reference is made to guidance values and guideline values. The
reader should note that WHO is not entirely consistent in the usage of these terms and that, for the
purpose of the toolkit, guidance values refers to those values developed entirely from health-based
toxicological and epidemiological information, such as the acceptable daily intake (ADI) and tolerable daily
intake (TDI) (or reference dose (RfD), the term used by some institutions), whereas guideline values, such
as those for concentrations in air or water, are derived after allocation of the guidance value or reference
dose among the different possible media (routes) of exposure. The reader is referred to subsection 3.3.3
for further information on guidance and guideline values.

3.1 The toolkit as a roadmap

As described more fully below, the risk posed by chemicals can be determined based on the toxicity of the
chemicals and on who is exposed to the chemicals, in what amount and through what route. Ultimately,
each of these considerations will be critical to a determination of health risk or a risk management
decision. Risk managers and other toolkit users will draw on this information to help decide how to protect
people from these chemicals.

For the purposes of the toolkit, the risk assessment paradigm is presented as a roadmap that extends
from problem formulation to risk characterization (Figure 2). Each step in the roadmap is represented by a
set of questions that an assessor can follow to identify information and resources that are appropriate for
estimating risk. A generic roadmap that an assessor can follow to answer these questions is presented for
each step in section 3.3. As noted above, the data gathering and analysis associated with these steps for
the purposes of the toolkit may differ somewhat from a higher-tier de novo assessment of risk conducted
for a new chemical, proposed use or health end-point, or for full reassessment of a previously assessed
chemical. However, information on some of the tools and approaches applied in higher-tier assessments
are included herein for additional information.

8
 3. Description of the toolkit

Figure 2.  Generic roadmap for chemical risk assessment in the context of the toolkit
following the conventional risk assessment paradigm

Problem formulation
What is the objective, approach and scope of the risk assessment?
What is the risk management goal and the acceptable degree of uncertainty?
Is the identity of the chemical known?

Hazard identification
Are the potential hazards to human health caused by the
chemical known?

Hazard characterization and Exposure assessment

guidance/guideline value Do those assumptions reflect
identification conditions specific to the population
Do guidance or guideline values from of interest for this assessment?
international organizations exist for
In what ways could people come into
the chemical?
contact with the chemical?
What assumptions about exposure
How much exposure is likely to
scenarios are incorporated into
occur?
guidance/guideline values for the
chemical? For how long is exposure likely to
occur?
What metric of exposure is
appropriate for characterizing health
risks?

Risk characterization
How does the estimated exposure compare with guidance/guideline values or
hazard Points of Departure for the chemical?
What are the uncertainties in the assessment?

9
WHO human health risk assessment toolkit: chemical hazards

As shown in Figure 2, a chemical risk assessment starts with the problem formulation. Problem
formulation is a process that considers the need for and the purpose of the assessment, the scope and
the depth of assessment that is needed, the time and resources available and the overall risk management
goal (7, 11). Problem formulation identifies the focus of the assessment (for example, a single chemical or a
group of chemicals1 and the identity of the chemical(s)) and what degree of uncertainty is acceptable (that
is, what degree of certainty is needed to meet the overall goal), and guides adoption of an approach that
is appropriate to the situation (for example, whether there a need to provide guidance to risk managers in
an emergency situation such as a spill, or whether a more comprehensive assessment is desired). Problem
formulation is iterative and should be revisited as more knowledge is acquired and the focus refined as
required. Communication between risk assessors and risk managers, along with other interested parties,
is an important aspect of problem formulation, to ensure that a risk assessment meets the needs and
expectations of risk managers and stakeholders.

The purpose of the hazard identification step (subsection 3.3.2) is to determine the hazardous
properties of the chemical. In the context of the toolkit, hazard identification is followed by the hazard
characterization/guidance or guideline value identification and exposure assessment steps, which
are complementary and connected efforts, though it is recognized that exposure assessment may
occur prior to or concurrent with hazard identification. Hazard characterization/guidance or guideline
value identification (subsection 3.3.3) is used to obtain a guidance or guideline value for the chemical
that matches the anticipated route and duration of exposure (for example, inhalation and long-term
exposure). Guidance and guideline values are normally the result or output of hazard characterizations
and involve dose–response assessment. Exposure assessment (subsection 3.3.4) is used to determine
the most likely routes, pathways, duration, frequency and intensity of exposure to the identified chemical.
Information obtained in these two steps must be compared during the risk assessment process to
ensure that the exposure and hazard characterization metrics are aligned appropriately. In the final step
– risk characterization – the hazard identification, hazard characterization and exposure information are
combined to yield a statement of risk. As described in subsection 3.3.5, the quantitative form of the risk
characterization will vary depending upon the type of information available on hazard characterization
and exposure. In some cases, the available information is sufficient to support only a qualitative
characterization of risk, the results of which can nonetheless be an important contribution to risk
management decisions (see the pesticide case study in Annex 3 for an example).

The questions posed in Figure 2 provide a structure for chemical risk assessment in the context of the
toolkit. By answering the questions, an assessor obtains the information needed to formulate the risk
assessment problem, identify the hazard, characterize the hazard, assess the exposure and characterize
the risk. Output anticipated from answering the questions is shown in Table 2.

1 Although the descriptions of the various steps of the risk assessment process included in this toolkit generally refer to
assessment of individual chemicals, assessments of groups or classes of substances follow the same basic process.

10
 3. Description of the toolkit

Table 2.  Output from the framework for chemical risk assessment in the context of the
toolkit

Question Output

Problem formulation

What is the objective, approach and scope of the risk Clear idea of the objective and scope of the assessment,
assessment? the resources available and the approach to be followed

What is the risk management goal and the acceptable Clear vision of what is needed to achieve the risk
degree of uncertainty? management goal

Is the identity of the chemical known? Clear identification of chemical in question through
Chemical Abstracts Service (CAS) registry number

Hazard identification

Are the potential hazards to human health caused by the Description of health hazards obtained from
chemical known? internationally available information

Hazard characterization/guidance or guideline value identification

Do guidance or guideline values from international List of guidance or guideline values (rates or
organizations exist for the chemical? concentrations) for the chemical obtained from
internationally available resources

What assumptions about exposure scenarios are List of assumptions about contact rates, absorption and
incorporated into guidance/guideline values for the other factors incorporated into the guidance or guideline
chemical? values

Do those assumptions reflect conditions specific to the A reference value that reflects exposure and dose
population of interest for this assessment? parameters specific to the local culture and demographics

Exposure assessment

In what ways could people come into contact with the Qualitative and quantitative description of the relevant
chemical? media, exposure conditions and exposure routes

What metric of exposure is appropriate for characterizing Determination from the guidance or guideline value of
health risks? whether an exposure concentration or exposure rate is
needed to perform the risk characterization

Risk characterization

How does the estimated exposure compare with A quantitative or qualitative statement of non-cancer or
guidance/guideline values or hazard Points of Departure cancer risk and a description of uncertainties
(PODs) for the chemical?
What are the uncertainties in the assessment?

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WHO human health risk assessment toolkit: chemical hazards

3.2 Tiered assessments in the toolkit

In practical terms, the user of the risk assessment toolkit must consider the apparent magnitude of the
issue at hand, the resources that can be allocated, and societal acceptability of risk. Depending upon
the nature of the problem as well as time, cost and human and technical resource considerations, the
amount of information applied to each step may differ, with some steps requiring more detailed and some
requiring less detailed information gathering.

As shown in Table 3, the toolkit includes four tiers of analysis and information gathering. These tiers are
characterized by the amount of quantitative or qualitative data required or obtained to answer a question
posed in any given step of the risk paradigm.

Tier 1 (screening level) refers to screening-level risk assessments that rely solely upon existing guidance
and guideline values and other information and make no adjustments to the hazard characterization for
local conditions or other considerations. Consider an example where there is strong anecdotal information
that use of a certain chemical is associated with a significant or specific health outcome among workers
of a certain industry. Further, hazard identification information on toxicological properties of the chemical
and experiences in other countries are consistent with the anecdotal reports. Faced with this situation, a
public health official may conclude that the occupational health risks of using the chemical under current
conditions are unacceptable. In a move intended to protect health, the official may seek to ban the
chemical from that particular use or from the country at large based on generalizing risk information from
international sources to the local uses and conditions. The pesticide case study described in Annex 3 of
this document is an example of a Tier 1 risk assessment.

Tier 2 (adaptive level) refers to risk assessments that reflect local exposure conditions, which can be
incorporated through the exposure assessment or hazard characterization stages (as applied in this
toolkit). In a Tier 2 assessment, local exposure conditions are derived from existing information. Such
information may be the result of routine monitoring conducted for regulatory or other purposes, the
application of a model to a known or suspected source of pollutant emissions or some other metric that
was generated for a purpose other than the current assessment. The respirable particulate matter case
study presented in Annex 2 is an example of a Tier 2 risk assessment that yields a qualitative result. In that
case study, the risk assessor evaluates the relationship between concentrations of respirable particles
in ambient air (particulate matter less than 10 micrometres (µm) in aerodynamic diameter, or PM102) and
personal exposure to PM10 in the assessor’s own country and compares it with the same relationship in
the studies from which the WHO air quality guideline for PM10 was derived (12). The evaluation is qualitative
in this example, but nonetheless involves a more rigorous analysis than a Tier 1 risk assessment.

2 Whereas WHO defines PM10 as particulate matter less than 10 µm in aerodynamic diameter, most jurisdictions define PM10
as particulate matter less than or equal to 10 µm in aerodynamic diameter.

12
 3. Description of the toolkit

Table 3.  Tiers of risk assessment included in the toolkit

Hazard
characterization/
guidance or
Hazard guideline value Exposure Risk
Tiera Description identification identification assessment characterization

1. Screening Existing Identify the Apply appropriate Existing Qualitative or

hazard and chemical; existing guidance qualitative or quantitative
exposure obtain hazard or guideline values quantitative
data from information from from international estimates;
international international organizations local exposure
sources resources conditions

2. Adaptive Existing Identify the Adjust guidance or Existing Qualitative or

hazard chemical; guideline values quantitative quantitative
data from obtain hazard from international estimates;
international information from organizations for local exposure
sources international local conditions conditions
reflecting resources
local
conditions;
existing local
exposure data

3. Modelling Existing Identify the Adjust guidance or Conduct Qualitative or

or field- hazard chemical; guideline values measurement quantitative
based data from obtain hazard from international or modelling
international information from organizations for campaign
sources; new international local conditions
local exposure resources
data

4. De novo Locally Independent Establish new Estimate from Qualitative or

conducted review of original guidance or measurements quantitative
hazard and hazard data guideline value or models
exposure or controlled
assessments experimental
trials,
gather local
observations
a
Some organizations have defined the tiers differently using different terminology. For example, OECD considers three tiers, calling them preliminary, refined and
comprehensive assessments. It should also be noted that, for Tiers 1 to 3, existing hazard data evaluations developed by international sources can be updated in
order to include more recent available information.

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WHO human health risk assessment toolkit: chemical hazards

Tier 3 (modelling or field-based level) risk assessments involve quantitative characterization of exposure
conditions through a measurement or modelling campaign, but are otherwise similar to a Tier 2
assessment. Tier 3 assessments require the design and execution of a quantitative exposure assessment.
In many situations, the exposure assessment will consist of a survey; in others, the assessment may be
hypothesis driven. A field campaign would require a plan for collection and analysis of samples as well
as management and interpretation of the data. Similarly, a modelling campaign would require selection
of an appropriate modelling tool, identification of values needed to parameterize the model, resources
to execute the model, and data management and analysis skills to manage and interpret the model
results. Tier 3 risk assessments are distinct from Tier 2 assessments, in that Tier 3 requires generation
or gathering of new exposure information, whereas Tier 2 does not. The drinking-water case study
presented in Annex 1 is an example of a Tier 3 risk assessment.

Tier 4 (de novo) risk assessments apply to chemicals or chemical forms whose toxicological properties
have not been evaluated previously, as well as to consideration of new routes of exposure to existing
chemicals. They are unique in that they may involve the review of original data or the generation of new
information concerning the hazardous properties of a chemical, as well as measurement or modelling
approaches for the quantitative assessment of exposure that is specific to local conditions. Tier 4
assessments are generally beyond the scope of the toolkit. Nonetheless, guidance from international
organizations on approaches and considerations for filling the data gaps presented by these situations is
identified in section 4. Readers are referred to these documents for assessments that require techniques
that are more advanced than the methods addressed in the toolkit.

3.3 Generic roadmaps

3.3.1 Problem formulation: chemical identification
Given sufficient time and resources, the surest way to identify chemicals that are the focus of the risk
assessment is sample collection and chemical analysis. However, this generally requires preliminary
identification of the chemical of interest, as the appropriate collection and laboratory analysis methods
will depend on the specific chemical. Thus, even when chemical analyses are planned, some preliminary
identification of the chemical is needed. In cases where chemical analyses are not possible, this
preliminary identification may compromise the entire chemical identification step.

In some cases, it may be important to identify the specific form or nature of the chemical of interest, as
the health risks of the different forms may vary. Examples could include individual isomers of the chemical,
its physical state (which could influence routes of exposure), or whether the assessment might focus on a
commercial formulation or its active ingredient.

Chemicals can be identified from a number of internal and external information sources (see Figure 3). For
workplace settings, internal sources include company documents and people who work with the chemical,
such as a plant manager or operator. Generally, in cases where the source of the chemical is easily
identified, the chemical is listed as an ingredient on the chemical or product packaging, on the associated
chemical safety card or material safety data sheet or on a list of chemicals used in the industrial process.
For general population exposures, the chemical may also be listed as an ingredient in the packaging
of products or have been included in local air or water quality measurement programmes. The same
information sources can be relied upon for cases in which the chemicals of concern come from multiple
sources; however, this identification may also involve additional determinations of whether any identified
chemicals will behave differently or will form different chemicals when mixed together.

14
 3. Description of the toolkit

If the identity of the chemical is not known, the assessor should gather information from various
resources to infer the types of chemicals of concern. In situations where an industrial process or operation
is of interest, the assessor should search the emission scenario documents referred to in subsection
4.8.3 for information relevant to the current situation. Emission scenario documents published by OECD
(13) contain descriptions of sources, production processes, pathways and use patterns of numerous
commercial industrial operations with the aim of quantifying the releases of chemicals into water, air, soil
or solid waste. Emission scenario documents can be used to generate hypotheses about chemicals of
concern that may be associated with a particular source, such as a manufacturing operation, laboratory,
disposal area or waste site. In addition to OECD’s work in this area, the European Chemicals Agency
publishes emission scenario documents in support of risk assessments for new and existing substances
(14). The emission scenario documents describe environmental releases for different industrial categories
and biocidal products.

With respect to identification of chemicals in products, where product ingredient lists may not be
available, a potential source of information may be EHC 242 on dermal exposure (15), which provides
examples of some chemicals that may be present in a range of occupational scenarios or products. A
comprehensive source of information on chemicals present in a wide range of products is the Chemicals
and Products Database of the United States Environmental Protection Agency (EPA), which is searchable
online using the CompTox Chemicals Dashboard (16).

A full-text search feature of the INCHEM database (17) (see section 4.3 for further information on INCHEM)
can also help to identify a chemical. In addition to these international resources, permits or building plans
that may have been filed with local or provincial authorities may contain useful information on operations
and emissions from a particular type of operation. Finally, initiating dialogues with representatives of the
facility and other members of the community may also be helpful for identifying chemicals of concern.

3.3.2 Hazard identification

Hazard identification is generally the first step in a risk assessment following problem formulation
(possibly at the same time as exposure assessment) and is the process used to determine whether
exposure to this chemical has the potential to harm human health. For the purposes of the toolkit, hazard
identification involves determining whether the chemical has been considered hazardous by international
organizations and, if so, to what degree. A process for gathering information in support of hazard
identification is illustrated in Figure 3.

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 WHO human health risk assessment toolkit: chemical hazards

Figure 3.  Generic roadmap for chemical and hazard identification in the context of the
toolkit

Has the identity of the chemical been clearly identified in

Yes problem formulation? No

Gather information on presence of chemical in

environmental media associated with industrial, natural
or other sources or processes and/or its presence in food
Are the potential hazards to human health and products of interest
caused by the chemical known?

Yes No
Search emission scenario information on the sources,
processes or products of interest
Stop

Full-text search of INCHEM database

Examine information provided by
international and other organizations
(see sections 4.5 and 4.6) Review any available public documentation on the specific
source, site or products

Proceed to hazard characterization/

guidance or guideline value identification Communicate with parties who may have knowledge of
and exposure assessment the source, site or products

Local officials and International

stakeholders organizations

For Tier 1 to 3 assessments, once a chemical is identified, the potential hazards of the chemical can be
determined from international reviews of the available scientific data on the chemical, generally data
from toxicological or epidemiological studies. A chemical may be associated with one or more hazards to
human health. Several schemes for classification of hazard information have been developed. In general,
chemicals are classified according to the human health hazards that they pose, such as irritation and
sensitization, or neurological, developmental, reproductive, cardiovascular and carcinogenic effects. There
are many international sources of this information, as noted in sections 4.5, 4.6 and 4.7.

In the case of Tier 4 risk assessments (see section 3.2), where the health hazards of a chemical have
not yet been identified, the reader is referred to the Globally Harmonized System of Classification and
Labelling of Chemicals (GHS) (18). The GHS was initiated by international organizations in recognition of the
varying criteria for determination of hazardous chemicals among countries and the extensive global trade
of chemicals. The GHS includes (a) harmonized criteria for classifying chemicals and mixtures 3 according
to their health, environmental and physical hazards; and (b) harmonized hazard communication elements,

3 The term “mixtures” in the context of GHS relates primarily to chemicals in products, whereas “mixtures” toxicology is
more concerned with co-exposures to multiple chemicals.

16
 3. Description of the toolkit

including requirements for labelling and safety data sheets. The human health hazard classification
scheme is detailed and includes a broad range of potential health effects (Table 4). For some of these
effects, the hazards of individual chemicals or mixtures of chemicals are further categorized by their
toxicological potency, the extent of evidence for effects in humans and related considerations.

Table 4.  Human health effects included in the Globally Harmonized System of
Classification and Labelling of Chemicals (GHS)

Health effect GHS categories or subcategoriesa

Acute toxicity 1 to 5

Skin corrosion or irritation 1 to 3

Serious eye damage or irritation 1, 2A, 2B

Respiratory sensitizer 1A, 1B

Skin sensitizer 1A, 1B

Germ cell mutagenicity 1A, 1B, 2

Carcinogenicity 1A, 1B, 2

Toxic to reproduction 1A, 1B, 2

Effects on or via lactation 1

Specific organ toxicity (acute exposure) 1 to 3

Specific organ toxicity (repeated exposure) 1, 2

Aspiration hazard 1, 2
a
Note that use of subcategories is not obligatory in application of the GHS system.

The weight of evidence for carcinogenic effects of a chemical in humans is another important feature of
hazard identification. In addition to the GHS system of classification for carcinogenicity, the International
Agency for Research on Cancer (IARC) (19) categorizes chemicals and other agents into one of five
categories based on the strength of evidence of carcinogenicity:

― Group 1: the agent is carcinogenic to humans

― Group 2A: the agent is probably carcinogenic to humans
― Group 2B: the agent is possibly carcinogenic to humans
― Group 3: the agent is not classifiable as to its carcinogenicity to humans
― Group 4: the agent is probably not carcinogenic to humans.

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WHO human health risk assessment toolkit: chemical hazards

A cancer hazard in the context of the IARC classification system is an agent that is capable of causing
cancer under some circumstances. A thorough description of the IARC cancer hazard classifications
and other fundamental aspects of the assessment objectives and methods of the IARC can be found in
the Preamble that is included in each monograph published by the agency. The Preamble is periodically
updated (20).

3.3.3 Hazard characterization/guidance or guideline value identification

The objective of hazard characterization/guidance or guideline value identification is to obtain a qualitative
or quantitative description of the potential of the chemical to cause adverse health effects as a result of
exposure. An adverse effect is defined as a change in the morphology, physiology, growth, development,
reproduction or lifespan of an organism, system or (sub)population (or their progeny) that results in an
impairment of functional capacity, an impairment of the capacity to compensate for additional stress or
an increase in susceptibility to other influences (definition adapted from reference (1)). To discriminate
between adverse and non-adverse effects, consideration should be given to whether the observed effect
is an adaptive or trivial response, transient or reversible, of minor magnitude or frequency, a specific
response of an organ or system, or secondary to general toxicity (21).

Note, however, that for chemicals that are essential to the human body, adverse health effects can be
observed if exposure to these is below a required level as well as above an upper tolerable level (for
example, vitamin A).

Quantitative hazard characterization often consists of a dose–response assessment, including

identification of a Point of Departure for health effects in critical studies, such as:

― no observed adverse effect level (NOAEL);

― no observed effect level (NOEL);
― lowest observed adverse effect level (LOAEL);
― lowest observed effect level (LOEL);
― benchmark dose lower confidence limit (BMDL), which is the lower confidence limit of the
benchmark dose (BMD), the dose associated with a predefined degree of adverse response;
― cancer potency factor (slope factor from the dose–response curve).

With the application of uncertainty factors to account for interspecies and intraspecies (interindividual)
variability, data quality and other uncertainties (see subsection 3.3.3.1), this information is used to develop
guidance values, such as the TDI, ADI and acute reference dose (ARfD) (see subsection 3.3.3.1 and Tables
5 and 6). Human exposure factors, such as intake rates (see subsection 4.8.2 and Table 17), are then
considered to develop guideline values for chemicals in specific media such as air, water and food (see
subsection 3.3.3.2 and Table 7).

In the context of the toolkit, the user identifies available guidance and guideline values (the output of
traditional hazard characterization) and discusses the applicability of the assumptions embedded within
them to the situation of interest (such as exposure duration and allocation of total exposure among routes
of exposure). Therefore, users of the toolkit should identify a guidance or guideline value for the chemical
under investigation that matches the anticipated route and duration of exposure (such as inhalation
and long-term exposure). Figure 4 illustrates considerations that are key to determining whether an
international guidance or guideline value is appropriate for a specific situation (the concepts in Figure 4
(such as contact rate) are described in detail in subsection 3.3.3.3).

18
 3. Description of the toolkit

Hazard characterization in the context of the toolkit requires an understanding of how the guidance or
guideline values were derived by international organizations, in particular:

― guidance values developed entirely from toxicological and epidemiological information (“health-
based guidance values”), such as the ADI and TDI, which provide an estimate of the amount of a
chemical that can be taken in orally (mainly by food and drinking-water) or by inhalation or dermal
contact by a person without appreciable health risk, or a tolerable concentration (TC), which relates
to a concentration in air similarly considered to be without appreciable health risk (see also Tables 5
and 6 in subsection 3.3.3.1 below);

― media-specific guideline values (“quality guideline values”) for chemical concentrations in drinking-
water, air and food (the exposure medium). Based on ADIs and TDIs, these values usually take into
account multimedia exposure scenarios (for example, the WHO Guidelines for drinking-water quality).
Alternatively, they may be based on agricultural practices and climate scenarios, as in the case of
maximum residue limits (MRLs) of pesticide residues in food.

The development of these guidance or guideline values by international organizations is described in

the next subsections. That information is followed by a discussion of factors that a risk assessor should
consider to evaluate the extent to which a guidance or guideline value applies to a specific situation or
assessment question. Additional information is presented in section 4.7 as well as in the case studies (see
annexes).

In addition to guidance or guideline values developed by international organizations, many countries

have developed national quality standards for chemicals in media (for example, food, water, air and soil).
Usually, the development of national standards follows two stages. The first stage is a scientific process
that either determines the exposure levels for a chemical that are unlikely to produce adverse effects or
characterizes the potency of carcinogens (for example, by establishing BMDLs or cancer slope factors).
This stage is similar to the derivation of health-based guidance values or quality guideline values by
international organizations. The second stage is an administrative process to determine acceptable risk
in consideration of scientific uncertainty, risk management options, economic benefits and costs, relevant
laws and social norms. The identification and use of national standards are beyond the scope of the
toolkit. In the event, however, that a risk assessor decided to use a national standard from another country
(such as a national air quality standard), consideration must be given to the relevant socioeconomic
factors. A national air quality standard, for example, might be numerically higher than the relevant WHO
air quality guideline value because it takes into account the feasibility of air pollution control measures in a
particular country.

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WHO human health risk assessment toolkit: chemical hazards

Figure 4.  Generic roadmap for hazard characterization/guidance or guideline value

identification in the context of the toolkit

Identify available guidance/

guideline values and determine if
the assumptions of the values are
appropriate for the population of
interest

Is the assumed contact rate

appropriate for the population of
Yes interest? No

Determine the appropriate contact

rate

Is the allocation of exposure rate No

Determine the appropriate allocation
appropriate for the population of
of exposure rate
interest?

Yes Determine the situation-appropriate

exposure rate based on contact rate
and/or allocation

Proceed to risk characterization

3.3.3.1 Health-based guidance values derived by international organizations

Development of health-based guidance values (Table 5) requires the assessment of the toxicological
effect of a chemical in relation to exposure. The relationship between exposure and effect is frequently
derived from standardized tests of laboratory animals conducted under controlled conditions. A range of
increasingly complex tools and approaches and higher-tiered assessments may be used by international
organizations to derive health-based guidance values based on the results of these studies. The WHO
Harmonization Project Document No. 2 on chemical-specific adjustment factors (CSAF) provides a detailed
description of the extrapolation of the results from laboratory-based toxicology studies from experimental
animals to humans (22). The use of CSAF was reviewed by WHO after ten years (23). Extrapolation
across studies, species, routes and dose levels may also be aided by the use of physiologically based
pharmacokinetic (PBPK) modelling (24). The relevance of the effects observed in experimental species
to humans can be evaluated with the WHO/IPCS Framework on Mode of Action/Species Concordance
Analysis, which lays out a biologically plausible series of key events that lead to an adverse effect (11),
as shown in Figure 5. (Mode of Action analyses can, in turn, be informed by existing Adverse Outcome
Pathways – see section 5.4.) In other cases, observations of effects in human populations characterized
with epidemiological methods are the basis of guidance value development. Even if the human data are
insufficient to be used to quantitatively assess risk, they may support the evaluation of the relevance of
observations in animal studies or identify important data gaps not addressed by the animal data.

20
 3. Description of the toolkit

Table 5.  Guidance and other values commonly used in chemical evaluations

Type of
outcome Term (units)a Abbreviation Definition

Non-cancer, Tolerable concentration (mg/m3) TC An estimate of the amount of a chemical

including in air, food, soil or drinking-water that can
laboratory Tolerable daily intake TDI be taken in daily, weekly or monthly per
animal (mg/kg body weight per day) unit body weight over a lifetime without
carcinogens appreciable health risk
determined For products, these values would be
to not be Provisionalb tolerable weekly intake PTWI estimates of the dermal, oral or inhalation
relevant to (mg/kg body weight per week) exposure to a chemical from products
humans over a specified duration without
Provisionalb tolerable monthly intake PTMI appreciable health risk
(mg/kg body weight per month)

Acceptable daily intake ADI

(mg/kg body weight per day)

Acute reference dose ARfD Amount of a chemical, normally in food

(mg/kg body weight per day) or drinking-water, that can be ingested in
a period of 24 hours or less per unit body
weight without appreciable health risk to
the consumer

Cancer Oral slope factor SF An estimate of the cancer risk associated

potentially ([mg/kg body weight per day]−1) with a unit dose of a chemical through
relevant to ingestion or inhalation per unit body
humans weight over a lifetime

Slope factor in relation to a An estimate of cancer risk associated with

concentration of a chemical in air a unit concentration of a chemical in air
([µg/m3]−1) or water

Slope factor in relation to a

concentration of a chemical in water
([µg/L]−1)

Cancer and Benchmark dose BMD Amount of contaminant derived from

non-cancer (mg/kg body weight per day) epidemiological studies or studies in
effects experimental animals associated with a
predefined incidence of adverse effect
(e.g. 5% or 10%). This value is usually
expressed as the lower confidence limit of
the BMD, or BMDL
a
The terms ADI and TDI as used by international organizations are equivalent to the term reference dose (but not acute reference dose) that is used by some national
agencies.
b
Note that it is being considered that the term “provisional” be phased out (25).

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WHO human health risk assessment toolkit: chemical hazards

Figure 5.  Mode of Action roadmap illustrating the use of mode of action knowledge in
human health risk assessment

Mode of Action roadmap

Utility of Mode of Action knowledge in human health risk assessment

Problem Formulation (purpose-oriented)

What is the decision context (e.g. priority setting, quantitative risk
assessment)?
Can Mode of Action help inform the decision?

Mode of Action Framework

• Hypothesis based
• Evidence in support of key events based on modified Bradford Hill
considerations
• Qualitative and quantitative species concordance

Mode of Action Knowledge Informs

Risk Assessment Assessment-specific Research

Data Generation
Human relevance Diagnostic biomarkers
Targeted testing
Human variation Expert systems
(in vivo and in vitro)
Species extrapolation New test methods
Non-test methods
Life stage effects (QSAR, read-across, Non-test methods
modelling) (QSAR, read-across, modelling)
Dose-response extrapolation
Therapeutic intervention to treat
Combined exposures
intoxication

Note: The extent of analysis is tailored to the issue under consideration through iterative analysis and consultation among the assessment, management and
research communities.
Source: From Meek el al. (11).

Health-based guidance values are derived and used according to a number of widely accepted principles
and conventions. Four important conventions are listed here and discussed below.

1. The dose of some known or suspected genotoxic human carcinogenic chemicals is assumed to have
a relationship with risk of cancer, and some level of risk is assumed to occur at any level of exposure
(so-called non-threshold carcinogens). However, for some other carcinogens, sufficient information
may be available to confidently determine that the Mode of Action involves a non-genotoxic key
event for which a threshold of exposure can be characterized (so-called threshold carcinogens).

22
 3. Description of the toolkit

2. For adverse effects other than non-threshold cancer, there is a threshold level of exposure below
which adverse effects are unlikely to occur (that is, the probability is considered to be very low or
negligible).

3. The risk of adverse effects from exposure to a given chemical may vary depending upon the route
of exposure as a result of differential absorption, metabolism or elimination following intake by
inhalation, ingestion or dermal absorption.

4. Populations sensitive to the health effects of chemical exposure or exposure scenarios that are
not reflected in experimental animal toxicological or human epidemiological studies are accounted
for through the use of factors or procedures intended to reduce the likelihood that actual risks to
humans will be underestimated.

As noted above, for chemicals positive in experimental animal carcinogenicity studies, available
information on Mode of Action is assessed in order to consider human relevance (11). For chemicals
that are treated as potential non-threshold human carcinogens, the risk of cancer is characterized
as the response (for example, incidence of tumours) in relation to the dose. Dose–response data
from epidemiological studies may also be used for hazard characterization if exposure is adequately
characterized; this avoids the need for interspecies comparisons and extrapolation over many orders of
magnitude from the high doses usually employed in animal studies to more human-relevant exposures.

Two methods for characterizing carcinogenic potency of a chemical are available: (a) calculation of the
slope of the line fit to the dose–response data to derive the increase in cancer risk per unit dose (the slope
factor approach); and (b) modelling of the dose–response relationship to identify a predefined level of
carcinogenic response (the BMD approach).

In the slope factor approach, the carcinogenic potency of a chemical is characterized as the slope of a
line fitted to the relationship between exposure to the chemical and prevalence of cancer in populations.
As described in EHC 239, a polynomial equation that contains a linear term is frequently fitted to
dose–response data from cancer bioassay studies in laboratory animals (6). Analogous approaches are
applied to the analysis of epidemiological data that inform chemical-mediated risks of cancer in human
populations. In both cases, the coefficient estimated for the linear term of an equation fit to the dose–
response data is taken as an estimate of the carcinogenic potency of the chemical. In practice, an upper-
bound estimate of the coefficient, such as the 95th percentile, is selected to account for uncertainty in
model fit and to provide a conservative estimate of the carcinogenic potency.

Carcinogenic potencies determined from laboratory or epidemiological studies are often termed cancer
slope factors, which have units of inverse dose or exposure. The units of a slope factor therefore depend
upon the route of exposure and the extent of information about dose that is available to the toxicologist
or epidemiologist. In laboratory studies, animals may receive a known dose of a chemical for a given
period of time, expressed as milligrams per kilogram of body weight per day. The slope factor derived
from such a study would therefore have units of (mg/kg body weight per day) −1. In an epidemiological
study, the risk of cancer may be quantified in relation to the concentration of a chemical in air or water. In
those cases, slope factors may be expressed as (µg/m3) −1 or (µg/L) −1, respectively. These slope factors can
be used to derive health-based guidance values or guideline values for a given level of risk (see subsection
3.3.5).

In the BMD approach, a suite of dose–response models is used to calculate the dose for a biologically
relevant predetermined level of response, called the benchmark response (BMR), such as a 5% or 10%

23
WHO human health risk assessment toolkit: chemical hazards

cancer incidence in animal studies. Information about where to obtain BMD models (software packages)
and instructions for their use are provided in Chapter 5 of EHC 240 (25). BMDs or, more typically,
their lower confidence limits (BMDLs) are used to determine the margin of exposure (MOE) at the risk
characterization stage in the risk assessment process (see also subsection 3.3.5.2). This approach is
currently preferred by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint FAO/
WHO Meeting on Pesticide Residues (JMPR) where possible and appropriate, because all of the dose–
response data are taken into account (25).

For effects other than cancer, where a cancer effect in laboratory animals is considered not relevant
to humans or where a non-genotoxic mechanism is suggested (that is, there is sufficient support for a
threshold of exposure for carcinogenicity), health-based guidance values are characterized as thresholds
of exposure below which adverse effects are considered unlikely to occur. Reference doses for non-cancer
effects are most frequently expressed as rates of exposure with the units of milligrams per kilogram of
body weight per day. As summarized in Table 5, common terms for these values are ADI (for example, ADIs
have been developed for pesticides by JMPR and for food additives by JECFA), TDI, PTWI, PTMI (developed
for food contaminants by JECFA) and ARfD (for example, developed for pesticides by JMPR) (see also
subsections 4.5.1 and 4.5.2). These reference values are estimates of the amount of a chemical in air, food,
soil or drinking-water that can be taken in daily, weekly or monthly over a lifetime or other specified period
without appreciable health risk (Table 6). For airborne chemicals, the guidance value is often expressed as
a tolerable concentration (TC), with units of milligrams or micrograms per cubic metre of air.

Table 6.  Sources of guidance values for chemicals developed by international organizations

Guidance values Sources/references

Acceptable daily intake (ADI)

Acute reference dose (ARfD)

INCHEM (17)
WHO food safety databases (26)
Tolerable daily intake (TDI)
OECD eChemPortal (27)

Provisional tolerable weekly intake (PTWI)

Provisional tolerable monthly intake (PTMI)

To account for the fact that humans may be exposed to hazardous chemicals through multiple routes
of contact with differing health consequences, health-based guidance values are frequently determined
separately for exposure by inhalation and ingestion, and sometimes dermal absorption, depending upon
the route of exposure that is relevant to the population and chemical of interest.

For both cancer and non-cancer effects, results from laboratory animals or humans are extrapolated
to the general human population using one or more uncertainty factors (the term generally used in
this toolkit, though these factors are sometimes referred to as safety factors, assessment factors or
adjustment factors) or procedures that are intended to reduce the likelihood that actual risks to humans
will be underestimated. Separate uncertainty factors may be applied to account for:

24
 3. Description of the toolkit

― differences between experimental animal species and humans (interspecies differences) and the
application of laboratory animal test results to humans;4
― susceptible members of human populations (intraspecies or interindividual variability);
― extrapolation of laboratory animal bioassay tests conducted over short periods of time (for
example, weeks or months) to exposures of interest over longer periods of time (for example, years)
or to adjust for experimental frequency to human-relevant frequency (for example, intermittent to
continuous exposure); these concepts are separate from the time course of adverse effects that can
immediately follow exposure or result from cumulative or continuous exposure;
― other aspects, such as insufficiency of the database or steepness of the dose–response curve.

Hazard characterization will involve uncertainties associated with extrapolating results from studies to the
population of interest. Though it adds an element of complexity, addressing the uncertainty quantitatively
where possible can lead to a more complete risk assessment, improved risk communication and more
informed decision-making.

Guidance on how to quantitatively address uncertainty in hazard characterization is also available in the
WHO Harmonization Project Document No. 11 (9) and supporting documentation (28). The framework
outlined in this guidance involves characterization of individual sources of uncertainty (associated with
Point of Departure, study population or study design versus target population, and human variability) and
combining these uncertainties using increasingly complex approaches (Figure 6):

― a non-probabilistic approach (where the individual lower and upper bounds for each hazard
characterization aspect are combined by multiplication);
― an approximate probabilistic approach (where uncertainty distributions are combined
probabilistically, assuming that all uncertainties can be described as independent lognormal
probability distributions);
― a full probabilistic approach (where uncertainty distributions are combined probabilistically,
generally through Monte Carlo simulations, and are not restricted to independent log-normal
probability distributions).

4 Note that some institutions do not apply uncertainty factors for inter- and intraspecies differences for genotoxic
carcinogens, assuming that linear extrapolation is already a conservative approach.

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WHO human health risk assessment toolkit: chemical hazards

Figure 6.  Tiered approach in risk assessment including uncertainty analysis with reference
to pertinent WHO/IPCS guidance

Problem formulation

Initial tier “fit Exposure Outcome with Hazard Initial tier “fit
for purpose” assessment uncertainty characterized assessment for purpose”

Lower tier Lower tier

Yes

Refined Exposure Do we Hazard Refined

Increasing refinement

Increasing refinement
scenarios, uncertainty know uncertainty MOA,
refined analysis enough? analysis develop
parameters, CSAF,
refined More precise More precise develop
models, new uncertainty No uncertainty PBTK, new
data, etc. analysis analysis data, etc.
needed needed

Higher tier Refinement needed to Higher tier

reduce uncertainty

What is the best option for refinement

given available resources and potential to
reduce uncertainty?

Source: IPCS (9)

A simple, easy-to-use spreadsheet tool, APROBA, is provided with WHO Harmonization Project Document
No. 11 (9) for the application of the approximate probabilistic approach. The outcome is expressed in
terms of ranges or probability distributions rather than as single (often considered to be conservative)
values as developed using a deterministic approach. Estimates of the relative contributions from the
various aspects to the overall uncertainties are useful for identifying the greatest sources of uncertainty
and showing for which aspects additional information would be most effective in reducing the overall
uncertainty. The APROBA tool can also assist in the application of a non-probabilistic approach.

Some of the authors of the APROBA tool extended the tool further (APROBA-Plus) to combine the output
from the probabilistic hazard characterization with probabilistic exposure estimates to rapidly characterize
risk and its uncertainty, adding balanced transparency in regard to uncertainties. APROBA-Plus can inform
risk management measures or assist in prioritizing refinements in a higher-tier assessment (29). Several
case studies are presented in supplementary materials to this publication.

26
 3. Description of the toolkit

3.3.3.2 Media-specific guideline values (“quality guideline values”) derived by international

organizations
The ADI and TDI are estimates of exposure rate (sometimes called administered dose) and, as described
above, are derived from toxicological and epidemiological information. For this reason, they consider
the total (or aggregate) exposure to a chemical from all routes and pathways (see subsection 3.3.4).
In contrast, the media-specific guideline values take into account conditions specific to the medium of
interest and also vary in the extent to which aggregate exposure is considered. For instance, the WHO
drinking-water guidelines are primarily health-based and do attempt to account for exposure through
other media. However, the FAO/WHO maximum residue limits (MRLs) and maximum limits (MLs) are not
direct public health limits, but instead reflect agricultural or veterinary practices, climate scenarios, and
technical and economic feasibility, and they are normally set at levels well below amounts that might lead
to an adverse health effect.

Guideline values developed by international organizations and links to further information are listed
in Table 7. The use of these guideline values is described in subsection 3.3.5 and illustrated in the case
studies presented in the annexes.

Table 7.  Sources of media-specific guideline values for chemicals developed by

international organizations

Guidelines Organization and reference

Drinking-water quality guideline values WHO (2)

Air quality guidelines WHO Regional Office for Europe (12, 30-32)

WHO (33)
Indoor air quality guidelines
WHO Regional Office for Europe (12, 34)

Maximum residue limits (MRLs) of pesticides in food FAO/WHO (35)

Maximum limits (MLs) of contaminants in food FAO/WHO (26)

Media-specific guideline values (for example, drinking-water quality guideline values, air quality guidelines,
maximum limits in food) are available for many chemicals. Whether these guideline values are applicable
to a specific case depends on the information used to establish these levels, the comparability of human
populations with regard to their activity and dietary patterns and demographics, and the exposure
averaging times, among other considerations.

More specifically, media-specific guideline values typically incorporate a number of assumptions about
exposure, including contact rate, body weight, absorption fraction and allocation of total intake (see also
subsection 4.8.2 and Table 17).

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WHO human health risk assessment toolkit: chemical hazards

3.3.3.3 Evaluating the appropriateness of available guidance or guideline values for a specific
problem
The flow chart shown in Figure 4 above illustrates considerations that are key to whether an international
guidance or guideline value is appropriate for a specific situation. These factors are discussed briefly
here; additional information is presented in both subsection 3.3.5 and the case studies that appear in the
annexes. Contact rates related to different means of contact, as shown in Figure 8 in subsection 3.3.4.1,
refer to assumptions about rates of water consumption, inhalation, food consumption and other forms of
contact with environmental media, food and products. Default values are typically used for those contact
rates (see Table 17 in subsection 4.8.2). For example, health-based guideline values for contaminants
in water may assume that an average adult consumes 2 litres of water per day. Yet it is recognized that
population average water consumption rates can vary significantly, perhaps by a factor of 2–4, in different
parts of the world, particularly where consumers are engaged in manual labour in hot climates. This
example illustrates that an assessor should consider whether the default values incorporated into a
health-based guideline value are appropriate for the specific population and time period of interest.

Guidance or guideline values for a given medium (such as drinking-water, air or food) may also assume
that total exposure to a chemical occurs via multiple routes or media. For example, guideline values for
a chemical in water may assume that a certain amount of exposure to that chemical also occurs through
ingestion of food. Variation in natural resources, culture and lifestyle among populations may invalidate
some assumptions about allocation of total intake. For example, in areas where the intake of a particular
contaminant in drinking-water is known to be much greater than that from other sources (such as food
and air), it may be appropriate to allocate a greater proportion of the ADI or TDI, for example, to drinking-
water to derive a guideline value more suited to the local conditions. Where relevant exposure data are
available, authorities are encouraged to develop context-specific guideline values that are tailored to local
circumstances and conditions.

Cases in which a guideline value for a chemical has yet to be established by an international or other
organization (Tier 4 risk assessment) are generally outside the scope of the toolkit. For more information
on some of the methods used by these organizations in establishing guidelines, readers are referred to:

― Assessing human health risks of chemicals: derivation of guidance values for health-based exposure
limits (EHC 170) (36);
― Principles for modelling dose–response for the risk assessment of chemicals (EHC 239) (6);
― Principles and methods for the risk assessment of chemicals in food (EHC 240) (7).

Other sources of helpful information are described in section 4.

3.3.4 Exposure assessment

Exposure assessment is used to determine whether people are in contact with a potentially hazardous
chemical and, if so, to how much, by what route, through what media and for how long. Because hazard
characterization and risk characterization are dependent upon the route (oral, inhalation or dermal)
and duration (short-term, medium-term or long-term) of exposure, knowledge of how and when people
may be exposed is relevant to the determination of an appropriate guidance or guideline value. When
combined with information on hazard characterization or a guidance or guideline value, exposure
information is used to characterize health risks.

The exposure concentration is the concentration of a chemical in a medium with which a person is
in contact. These media include air, water and soil in outdoor and indoor locations frequented by a
population. Other media include food and products with which people come in contact. Ideally, exposure

28
 3. Description of the toolkit

concentrations will be obtained for media, locations and durations that are representative of potential
human contact with a chemical of concern.

As indicated in Figure 7, the assessor must determine the following parameters to initiate the exposure
assessment portion of the risk evaluation:

― the relevant routes and pathways of exposure

― the media expected to contain the chemical
― the appropriate duration and frequency of exposure.

Figure 7.  Generic roadmap for exposure assessment in the context of the toolkit

In what ways could people come into

contact with the chemical?

Draw upon output from the problem formulation, hazard

identification and hazard characterization stages to
identify:
— pathways of exposure
— routes of exposure
— exposure media

How much exposure is likely to

occur?

Estimate the concentration in the exposure media using:

— measurement approaches
— modelling approaches
— generalizations from other studies

For how long is exposure likely to

occur?

Is the guidance/guideline
value expressed as a Exposure rate or Estimate the rate of contact with the
concentration, exposure rate or cancer slope factor medium
cancer slope factor?

Concentration
Estimate the rate of exposure

Proceed to risk characterization

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WHO human health risk assessment toolkit: chemical hazards

3.3.4.1 Routes and pathways of exposure

The medium of exposure refers to air, water, soil, food or products (consumer, commercial or industrial)
that are thought to contain the chemical of interest (Figure 8). These exposures may occur in occupational
or community (that is, non-occupational) settings or while using products. Ingestion exposure is
associated with chemicals in food, water and soil, both indoors and outdoors. Inhalation exposure
requires that chemicals be present in air, although it is important to recognize that chemicals with
moderate to high vapour pressures and low solubilities can volatilize from water, soil or products and then
be inhaled. Trichloroethene, an organic solvent, is one example of a chemical that readily volatilizes from
potable water. Inhalation can also be an important route of exposure to less volatile chemicals, such as
polychlorinated biphenyls, when present at elevated concentrations in soil, dusts, particulates or fibres.
Finally, dermal absorption requires contact between a chemical and skin, which can occur in water, during
contact with soil, in the presence of high concentrations in air and during occupational or consumer use of
the chemical or products in which it is present.

Figure 8.  Possible exposure media and corresponding means of contact

— Inhalation ­— Ingestion
— Dermal — Dermal

Air Soil and water

Humans

Consumer Food and

products beverages

— Ingestion
— Inhalation — Ingestion
— Dermal

The scope of an exposure assessment can be narrowed with information about the chemical and its
properties, from which the important exposure media and routes can be inferred. For example, health-
relevant exposures to some chemicals, such as ozone, occur through only one medium, in this case air.
For chemicals that can be found in several media, such as lead, pesticides or chloroform, information
about the chemical properties and behaviour can point to environmental media, locations, foodstuffs or
products where the highest levels of the chemicals are likely. In addition, this information can suggest
relevant pathways and routes of exposure. Pathway of exposure refers to the physical course taken
by a chemical as it moves from a source to a point of contact with a person (for example, through the
environment to humans via food). Route of exposure refers to intake through ingestion, inhalation or
dermal absorption. The exposure routes may have important implications in the hazard characterization
step, as the danger posed by a chemical may differ by route.

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 3. Description of the toolkit

3.3.4.2 Estimating exposures: modelling or measurement approaches

While data on exposure concentrations in personal air, ingested media such as drinking-water and food,
and media contacting the skin (including products) should be among the most accurate estimates of
actual exposure to a chemical, in practice, they can be difficult, expensive or impractical to determine. In
light of this limitation, risk assessments, especially screening-level risk assessments, are often based upon
incomplete data on chemical concentrations in media that are relatively easy to access, such as outdoor
air, indoor air, surface water, outdoor soil and commonly used products. Chemical concentration data can
be determined from measurement campaigns or modelling efforts.

Exposures can be measured directly, estimated using models or generalized from existing data. Each
requires that exposures be determined for time periods relevant to possible adverse health outcomes. For
example, if the relevant health hazard is chronic in nature, exposure should be long term as well. Of the
three methods, estimating exposures from existing data can often be the simplest approach; however,
such data are not often available or not entirely representative of the exposure scenario of interest.
Measurements, on the other hand, generally provide the most accurate and relevant data, but are the
most time and resource intensive, precluding their use for many risk assessments. Exposure models may
be used to provide estimates of exposure from a range of sources. A summary of exposure measurement
and generalization methods is given in EHC 214 (8). Other sources of helpful information are described in
section 4.

(a) Exposure models

Exposure models generally require information about the concentration of a chemical in a medium or
product, the period of time over which individuals are in contact with the chemical and the route of
the contact (dermal, inhalation and/or ingestion). Chemical concentrations can be measured or can be
estimated from chemical usage, data from previous investigations or product composition information.
As described in section 4.8, concentrations in specific environmental media can be estimated using
several publicly available models that have been recommended by international organizations or have
been vetted in the scientific literature and are widely adopted in the field of environmental health. These
models may be used to estimate, for example, chemical releases to the atmosphere, fate and transport of
chemicals in aquifers or groundwater, or distribution of chemicals among multiple environmental media.
Similarly, models have been developed to estimate exposures to chemicals through use of products. Given
the complexity of many of these models, some may require specialized training on running the models,
while for many models, extensive information on how to use them is available online; see, for example,
the United States EPA ExpoBox (37) and ConsExpo Web from the National Institute for Public Health and
the Environment (RIVM) of the Netherlands (38, 39). In order to select the appropriate model, information
about the geographical and temporal extent of the chemical exposures of interest or the nature and
intended use of the products in which the chemicals are present, and the exposed populations of interest,
should be obtained or otherwise determined.

To estimate exposures, concentration estimates in media provided by models can be used, together with
information about chemical contact, including who is exposed and the frequency and duration of their
exposure. Depending on the route of contact, information on physiological parameters such as body
surface area, area of the exposed skin, degree of dermal or gastrointestinal absorption, inhalation rate
and inhalation volume for various populations and circumstances (rest or activity) may also be required.
Models that estimate direct exposure to chemicals in products incorporate information on product use
patterns and product composition. Information about chemical contact can be obtained using a variety
of techniques, including questionnaires or enquiries with affected individuals, demographic data, survey
statistics, behaviour observation, activity diaries, activity models or, in the absence of more substantive
information, assumptions about behaviour. Using this information, exposures for air, water, food, soil or

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WHO human health risk assessment toolkit: chemical hazards

products can be estimated using mathematical equations. A summary of principles for characterizing
and applying human exposure models is given in IPCS Harmonization Project Document No. 3 (40). Other
helpful information on conducting exposure assessments is indicated in section 4.8. Guidance on how to
address uncertainty and data quality in exposure assessments is also available from WHO Harmonization
Project Document No. 6 (41). A range of publications on exposure assessment is also available through
OECD (42).

(b) Exposure measurements

Exposure concentrations in media can also be obtained from measurements, whether they be historical,
current or planned for the future. For these concentrations to be truly representative of exposures, they
must measure the concentration of the chemical of interest in relevant environmental media (such as
air, water or soil), food or products. Exposure measurements are intended to match the actual media,
location, duration and use that represent the human exposure to the chemical of concern, although this is
often not possible to achieve.

To evaluate the representativeness of prior exposure measurements or to plan future measurements,

many factors that are specific to the chemical of interest need to be considered. These factors include
the availability, performance and sensitivity of appropriate exposure measurement devices, the size
and activity patterns of the potentially exposed population, the contact rate and duration of exposures,
and the media through which exposures generally occur. Information about exposure measurement
devices can be obtained through review of the scientific literature, with specific attention paid to their
performance, as measured by their sensitivity, accuracy and precision. A complete description of these
concepts is contained in EHC 214 on human exposure assessment (8). Often, the cost of the measurement
method is proportional to its performance, which may result in trade-offs between cost and sample size
in any measurement plan. Information about activity patterns, contact rates and exposure durations, as
well as other information about the potentially exposed population, can be obtained through surveys
and questionnaires. Together, this information can be used to determine whether the past exposure
measurements apply to the current situation or can help in the design of a measurement campaign that is
efficient while providing data relevant to the risk assessment.

Further, some consideration should be given to the heterogeneity of exposures within the relevant
population. For example, if the exposures are similar for all individuals, then measurements made for a
relatively small subset of individuals can be generalized to a larger population. By contrast, if exposures
vary within a population by age, sex or residential location, it is possible that exposure measurements
should be made for subsets within each of these groups and generalized to the larger group. The problem
formulation stage in the risk assessment process can serve to identify which particular subpopulation
is the focus of the exposure assessment. An example of a measurement-based approach to determine
exposure concentrations is included in the drinking water case study in Annex 1. With respect to
exposures to chemicals in products, exposure measurements would apply specifically to the subgroup of
the population using the products.

3.3.4.3 Duration and frequency of exposure

The duration of exposure is a critical element in assessment and estimation of health risks, as the
relevant period of exposure is defined by knowledge or theory of the mechanisms of injury or
disease. Consequently, the duration of exposure is an explicit component of the design of exposure
assessments as well as toxicological studies conducted for purposes of hazard identification and hazard
characterization.

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 3. Description of the toolkit

Single and short-term exposures over minutes, hours or a day are relevant for chemicals that have an
immediate or rapid adverse effect on the body at certain concentrations. Examples of chemicals for which
assessment of single and short-term exposure is important include water-soluble gases such as sulfur
dioxide and asphyxiants such as carbon monoxide.

Medium-term or intermediate exposure is important for chemicals that are thought to exert adverse
effects over a period of contact that ranges from weeks to months in duration. Respiratory irritants
such as hydrogen sulfide are a class of chemicals for which some public health agencies have developed
guidelines for intermediate exposure.

For chemicals that pose a hazard as a result of cumulative or long-term low-dose exposure, long-
term average exposures are most relevant for characterization of adverse effects. Chemicals such as
polychlorinated biphenyls, which have been associated with learning deficits and diabetes (as well as
cancer), are in this category. Assessments of cancer risk are a special case of long-term exposure for
which lifetime average exposure is generally of interest.

Exposure to chemicals may be of shorter duration on an intermittent basis, such as during use of
products or application of pesticides. In these situations, it is important to consider the frequency of
exposure as well as duration. The ConsExpo models developed by RIVM incorporate frequency of event in
estimating exposure and provide default values for a range of product uses (39). Likewise, information on
incorporation of frequency is provided in the generic scenarios for estimating exposure to vector control
agents (43).

3.3.4.4 Concentration and rate of exposure

In practice, exposures are generally expressed as either a concentration of the chemical in the exposure
medium or a rate of contact with a chemical over a specific duration. Therefore, this step of the toolkit
must produce an estimate of exposure that is in the same form as the guidance or guideline value – that
is, either a rate or a concentration, respectively (see subsection 3.3.3).

For example, concentrations in contact media are usually expressed in units of micrograms per cubic
metre (µg/m3) for air, micrograms per litre (µg/L) for water, and milligrams per kilogram (mg/kg) for solids
such as soil, dust, food and products. Rate of exposure for a chemical is typically referred to as average
daily dose, with units of milligrams of chemical per kilogram of body weight per day (mg/kg body weight
per day); a shorter period of time may be considered for situations where the exposure may be infrequent
or occurs over only a limited duration (for example, a brief exposure to a chemical in a household cleaning
product). Approaches to assessment for shorter-term exposures to chemicals are illustrated in the generic
risk assessment models developed by WHO for insecticides (43). In general, exposure rate is calculated as
the concentration of a chemical in an exposure medium multiplied by the rate at which a person inhales,
ingests or has dermal contact with that medium, divided by a representative body weight. For dermal
exposures, the area of skin contact is also considered.

As shown in Equation 1, the period of exposure and averaging time of exposure are considered explicitly
as well:

Exposure concentration × contact rate × exposure duration

= [1]
rate body weight × averaging time

where:

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WHO human health risk assessment toolkit: chemical hazards

― concentration is the amount of chemical per mass or volume of the medium;

― contact rate is the mass or volume of the medium in contact with the body;
― exposure duration is the period of time over which the person is in contact with the chemical;
― body weight is the body weight over the averaging time;
― averaging time is the period of time over which the exposure is relevant for health risk
characterization and is related to the situation identified in problem formulation.

However, for some chemicals in products, such as for volatile substances migrating from toys, the air
concentration in the room in which the product is used is determined by the concentration in the product,
the migration rate and the breathing space or room volume.

The averaging time used in calculation of average daily dose is typically different for estimation of non-
cancer and cancer risks. For chemicals that pose a non-cancer hazard, the average exposure during the
period of contact with a chemical is generally the relevant duration of exposure for risk assessment. For
cancer risk assessment, however, the averaging time is fixed at a lifetime, which is commonly assumed to
be 70 years in risk assessments.

3.3.4.5 Biomonitoring
Besides the above-described traditional exposure assessment, the use of biological monitoring (generally
referred to as biomonitoring) is another method with which to evaluate human exposure to a chemical.
Biological monitoring of exposure is considered a measure of internal dose, whereas exposure describes
the contact with a chemical at the boundary between an individual (for example, skin, mouth or nostrils)
and the environment, food or product.

Numerous biological media are available for use in exposure assessment. Selection of sampling media
depends on the contaminant of interest, the pattern of exposure, the timing of exposure, the population
studied, ease of collection and storage, and participant burden. Biological monitoring is frequently
considered invasive; however, several media that can be collected in a non-invasive manner are available
for exposure assessment. Blood and urine, as well as exhaled breath and saliva, can be used to document
recent exposures; past exposure can be evaluated using blood and urine, as well as keratinized tissues
(hair and nails), ossified tissue (teeth and bone), adipose tissue and breast milk. Adipose tissue and bone
can also represent future sources of internal exposure. Other media available for biomonitoring studies
include faeces, nasal lavage, tears, sputum, semen, cord blood and buccal cells, which can be feasible
means for population exposure characterization. For some chemicals, biomonitoring has been conducted
over periods of several years, permitting a better understanding of geographical and temporal trends,
such as those for mercury (44). Further information on biomonitoring is available in various IPCS and WHO
publications (8, 45–47) (see also Table 16 in section 4.8).

To assist in interpreting the results of biomonitoring in a public health context, biomonitoring equivalents
(BEs) have been developed for several chemicals. BEs are estimates of the concentration of a chemical or
its metabolite in a biological medium that is consistent with an existing exposure guidance value such as
a tolerable daily intake or reference dose. BEs for various chemicals are available in Human biomonitoring:
facts and figures (47), as well as in the open scientific literature.

3.3.5 Risk characterization

The last step of a chemical risk assessment – the risk characterization – is typically a quantitative
statement about the comparison of estimated exposure to the most appropriate health-based guidance
value, media-specific quality guideline value or other hazard characterization value, such as the cancer
slope factor or a Point of Departure (for example, a NOAEL/LOAEL or BMDL) (Figure 9).

34
 3. Description of the toolkit

Figure 9.  Generic roadmap for risk characterization in the context of the toolkit

Review the objective and scope of the assessment

(problem formulation)

Does the assessment require comparison with a

guidance/guideline value or with a hazard Point of Departure
(i.e., a NOAEL/LOAEL for non-cancer effects or a BMDL for non-cancer
effects or cancer) or a calculation of a slope factor
for cancer risk?

Obtain the guidance/guideline Obtain the hazard Point of Obtain the cancer slope factor for
value Departure the chemical

Obtain the exposure concentration or rate

derived from the exposure assessment

Calculate the ratio: exposure rate Calculate the Margin of Calculate excess lifetime cancer
divided by guidance value OR Exposure: divide the hazard risk as the product of exposure
exposure concentration divided by Point of Departure by the concentration or rate and the
guideline value exposure metric cancer slope factor

How does the estimated exposure What is the margin between the Is the excess lifetime cancer risk
compare with the guidance/ hazard Point of Departure and high or low (e.g., greater than 1 in
guideline value? the exposure metric? 10 000 or less than 1 in a million)?

Report results to risk

management team

3.3.5.1 Comparison with a guidance or guideline value

Health-based guidance values or guideline values have been established for a number of chemicals
by international organizations. For chemicals that are considered to be “threshold chemicals” (that is,
chemicals for which there is believed to be a threshold of exposure or dose for induction of effects;
see subsections 3.3.3.1 and 3.3.3.2), the guidance or guideline value may be based on an exposure
concentration or rate below which adverse effects are considered to be unlikely.

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WHO human health risk assessment toolkit: chemical hazards

For chemicals that have the potential to result in non-cancer effects, risk is frequently characterized as
the ratio of the appropriate exposure rate (for example, the average daily, weekly or monthly intake) to
the health-based guidance value: ADI, TDI, PTWI, PTMI or ARfD (often used for pesticide residues and
contaminants in food). For exposure to non-cancer chemical hazards in media such as air and drinking-
water, the ratio of the chemical concentration in that medium to a reference concentration (such as
the WHO air quality guideline or the WHO drinking-water quality guideline value) may also be used to
assess risk. The ratio is obtained by dividing the exposure rate or concentration by the guidance value
or reference concentration. A ratio of less than 1 indicates that the chemical exposure is less than the
reference concentration and that the exposure is unlikely to result in an adverse effect. For example,
an evaluation of chemical concentrations in exposure media and rates of contact with those media may
conclude that the exposure to a chemical is 15 times less than the ADI established by an authoritative
organization as a reference concentration for risk of an adverse effect. Conversely, a ratio of greater than
1 indicates that the exposure is greater than the reference concentration and that the sources, pathways
and routes of chemical exposure should be evaluated further.

In some cases, public health organizations account for exposure to a chemical in multiple other media
when setting quality guidelines or standards for a particular medium. For example, drinking-water quality
guideline values established by WHO allocate only a portion of the ADI or TDI to intake through water
for some chemicals. In order to account for the variations in exposure from different sources in different
parts of the world, a certain proportion, generally between 1% and 80%, of the ADI or TDI is allocated
to drinking-water in setting guideline values for many chemicals. Where relevant exposure data are
available, authorities are encouraged to develop context-specific guideline values that are tailored to
local circumstances and conditions. For example, in areas where the intake of a particular contaminant in
drinking-water is known to be much greater than that from other sources (such as air and food), it may be
appropriate to allocate a greater proportion of the ADI or TDI to drinking-water to derive a guideline value
more suited to the local conditions.

Guidance or guideline values are also sometimes established for chemical exposures that are thought to
have a continuous hazard characterization relationship, and there is a theoretical risk of an effect at any
level of exposure (non-threshold chemical). Carcinogens and some air pollutants, such as fine particulate
matter, are examples of stressors that are considered to pose risk of an adverse health outcome at all
levels of exposure. For these chemicals, guidance or guideline values are often exposure concentrations
or rates that correspond to levels of risk that have been determined to be very low and may be tolerable.
For instance, the WHO drinking-water guideline for benzene was based on extrapolation of modelled
excess lifetime risk for leukaemia of 1 in 100 000 estimated from epidemiological studies involving
inhalation exposure (48, 49) (see subsection 3.3.5.2 for more on estimation of cancer risk). Further, in
some cases, a level of exposure associated with low levels of risk may not be achievable using control
measures available at the time. For example, the WHO drinking-water guideline for arsenic is considered
provisional in light of practical difficulties in removing it from drinking-water (50).

3.3.5.2 Margin of exposure approach

The margin of exposure approach involves the comparison of a metric of exposure to a Point of Departure
for adverse effects (such as a NOAEL or BMDL). This approach can be used for both cancer and non-
cancer effects. The margin of exposure (often abbreviated as MOE) is unitless and is not an absolute
value but provides guidance to risk managers of how close human exposures are to those anticipated to
produce a measurable effect in experimental animals or humans. For example, the NOAEL for a non-
cancer effect such as reproductive toxicity can be compared to an estimate of exposure to a chemical in
a medium or during use of a product; similarly, the BMDL for a defined incidence of tumours in a cancer
bioassay can be compared to a metric of exposure. JMPR and JECFA use the margin of exposure approach

36
 3. Description of the toolkit

when assessing presumed genotoxic carcinogens and sometimes in cases where data are inadequate
for establishing guidance or guideline values. JECFA also applies the margin of exposure approach in the
evaluation of additives used in infant formulas. The margin of exposure approach can be used to prioritize
different contaminants, providing that a consistent approach has been adopted (51).

In interpretation of a margin of exposure (such as in determination of whether the margin is adequately

protective of the population), considerations that need to be taken into account are similar to those used
in selection of appropriate uncertainty factors in the establishment of a guidance or guideline value,
including human variability, interspecies differences, the nature and severity of the effect that is the basis
of the Point of Departure and the steepness of the dose–response curve, and database uncertainties (for
example, have all potentially relevant end-points been assessed). In general, a higher margin of exposure
is desirable for more serious effects such as cancer, or for when there are more uncertainties in the risk
assessment.

3.3.5.3 Estimation of cancer risk using the slope factor approach

For chemicals that may exert a carcinogenic effect, the risk characterization is sometimes expressed as
the excess lifetime cancer risk. Characterization of cancer risk over a lifetime has become a convention
primarily because cancer is thought to be a function of long-term rather than short-term exposure.
Excess lifetime cancer risk is an estimate of the likelihood of excess cancer associated with a given level
of exposure averaged over a lifetime. To estimate cancer risk in environmental media, the slope factor
determined from dose–response modelling, expressed in the appropriate units for relevant media (the
“unit risk” or the estimated number of cases of a cancer associated with a unit of exposure), is compared
to measured or estimated concentrations in those media, with the risk increasing proportionately with
exposure (for example, a twofold increase in exposure would be estimated to be associated with a
doubling in the number of projected cases in a population). Slope factors can be used to provide guidance
for risk management. For example, a target concentration of a chemical in drinking-water that would be
associated with a 1 in 100 000 (1x10 –5) excess risk for a chemical with a unit risk of 5x10 –5 (µg/L) –1 would be
0.2 µg/L, while the target for an excess risk of 1 in 1 000 000 (1x10 –6) would be 0.02 µg/L.

37
WHO human health risk assessment toolkit: chemical hazards

4. INTERNATIONAL RISK
ASSESSMENT RESOURCES

4.1 Introduction
This section provides a guide to information, data and tools that are useful for conducting human
health risk assessments. While the previous sections of the toolkit and the case studies described in the
annexes of this document are intended to raise the reader’s level of knowledge about human health risk
assessments, this section directs the reader to sources of information that can inform a risk assessment.

The resources included in this section reflect an emphasis on information developed by international
organizations, including WHO (including IARC), the Food and Agriculture Organization of the United
Nations (FAO) and OECD. Gaps in key risk assessment information available from international
organizations were filled with widely accepted approaches described in the peer-reviewed scientific
literature or codified in regional- and country-specific resources.

In addition to the resources noted here, readers are encouraged to seek sources of information developed
within their own countries or regions that may contain risk assessment guidance or data that are more
specific to the populations and geographical areas of interest. Organizations within countries that may
be sources of this information include universities, water resource management authorities, land use
management authorities, customs and security authorities, poison control centres and health care
institutions.

4.2 Organization
The resources described in the remainder of this section are organized according to their content in the
following manner:

― directories of resources
― general resources on risk assessment
― chemical-specific resources
― hazard identification resources
― hazard characterization and guidance or guideline value resources
― exposure assessment resources
― risk characterization resources.

The directories of resources presented in section 4.3 are portals to technical summaries and scientific
data that are relevant to risk assessment. The directories included here are maintained by international
organizations. They can be accessed through the internet and are available at no cost to the user. The
portals provide access to information on all aspects of the risk assessment process that are described in
section 3.

38
 4. International risk assessment resources

Section 4.4 is a listing of documents on risk assessment in general prepared by WHO as well as other
international and national institutions. These resources are included in the toolkit to provide information
to readers who are interested in gaining a deeper understanding of the principles and methods that
contribute to the theoretical and scientific foundation of human health risk assessment for chemical
agents.

The chemical-specific resources identified in section 4.5 contain detailed summaries on numerous aspects
of hundreds of chemicals that are widespread in commerce and have hazardous properties. In addition to
information on hazard characterization, exposure assessment and risk characterization, these resources
also provide information on the contributions of both anthropogenic and natural background sources to
levels in the environment as well as body burdens in human populations.

Sources of information specific to the fundamental steps of a risk assessment, including hazard
identification, hazard characterization, exposure assessment and risk characterization, are identified in
sections 4.6, 4.7, 4.8 and 4.9.

4.3 Directories of resources

Comprehensive and detailed summaries of information essential to risk assessment for a wide variety of
chemicals have been compiled by numerous organizations. Notable among them are the online resources
INCHEM and eChemPortal, which are gateways to some sources of internationally peer-reviewed
chemical risk assessment information (Table 8). Databases within INCHEM and eChemPortal that contain
information specific to the principal components of a human health risk assessment (see section 2) are
described in the remainder of section 4.

Table 8.  Two compilations of hazard identification, hazard characterization, exposure

assessment and risk characterization information for chemicals

INCHEM eChemPortal

Sponsor WHO/IPCS (17) OECD (27)

Description A compilation of internationally peer OECD, United Nations Environment Programme (UNEP),
reviewed information from a number WHO, European Chemicals Agency (ECHA) and national
of international organizations databases on physical-chemical properties, ecotoxicity,
whose goal is to assist in the sound environmental fate and behaviour and toxicity; also GHS
management of chemicals classifications

URL http://www.inchem.org/ https://www.oecd.org/env/ehs/risk-assessment/echempo

rtalglobalportaltoinformationonchemicalsubstances.htm

Portal page

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WHO human health risk assessment toolkit: chemical hazards

4.4 General resources on risk assessment

The resources listed below provide information about the principles of risk assessment. In addition, they
address populations that are susceptible to the effects of exposure to chemicals, as well as chemical
incidents.

4.4.1 Resources on risk assessment methodology

Principles and fundamentals of approaches to chemical risk assessment are described in several WHO
reports, as shown in Table 9. These documents elaborate on the basic components of a risk assessment
that are summarized in section 3 above. They also contain information specific to trace elements and risk-
related considerations of elemental speciation.

Table 9.  WHO documents on principles of human health risk assessment for chemicals

Document title Reference

Principles for the assessment of risks to human health from exposure to chemicals (EHC 210) IPCS (52)

Human exposure assessment (EHC 214) IPCS (8)

Principles and methods for the risk assessment of chemicals in food (EHC 240) IPCS (7)

Principles and methods for the assessment of risk from essential trace elements (EHC 228) IPCS (53)

Elemental speciation in human health risk assessment (EHC 234) IPCS (54)

The European Food Safety Authority (EFSA) has also published several guidance and other assessment
methodology documents that define the scientific rationale for evaluations and important scientific
considerations such as data needs and formats, study design requirements and reporting standards.
These offer cross-cutting guidance on broader assessment principles and other methodologies, including
approaches and procedures, “state-of-the-science” reviews of international assessment best practices,
and reviews of new and developing assessment tools (55). Similarly, ECHA has published guidance on
conducting human health risk assessments for registrants (56).

The United States EPA has also developed numerous guidance materials on a range of risk assessment
topics, including assessment of cancer and several non-cancer end-points (such as developmental toxicity,
neurotoxicity and mutagenicity), for individual chemicals and groups of chemicals that are made available
through the Integrated Risk Information System (IRIS) (see United States EPA (57) for basic information
about IRIS and links to the range of guidance and tools therein). Other helpful guidance documents in IRIS
relate to quantitative characterization of hazard and interspecies extrapolation.

The IRIS assessments have increasingly applied the concept of systematic review in consideration of
scientific information, using an objective and transparent approach for analysing and synthesizing data,
with the aim of minimizing bias. WHO is in the process of developing a framework for application of
systematic review methods in chemical risk assessment (see section 5.1). Likewise, WHO has published
the WHO Handbook for guideline development, which provides guidance on the process behind

40
 4. International risk assessment resources

establishment of WHO guidelines (see section 4.7) (58). It is anticipated that such methodologies will be
further developed and elaborated in future efforts to assess chemical risks to health in a transparent and
consistent manner.

This toolkit is a contribution to the WHO project to harmonize approaches to the Harmonization Projec t Document No. 8

assessment of risk from exposure to chemicals. The goal of this project is to globally WHO Human Health
Risk Assessment Toolkit

harmonize approaches to risk assessment by increasing understanding of and

CHEMICAL HAZARDS
Second Edition

developing basic principles and guidance on specific chemical risk assessment

issues. Harmonization enables efficient use of resources and consistency among
assessments. Relevant technical documents developed by this project, along with
key publications where the original authors have extended the tools further, are
provided in Table 10 (this toolkit was originally published as No. 8 in that series). 1

Table 10.  International sources of information on harmonization of risk assessment

methodology

Document title Reference

IPCS risk assessment terminology. Part 1: IPCS/OECD key generic terms used in chemical hazard/risk IPCS (1)
assessment. Part 2: IPCS glossary of key exposure assessment terminology (Harmonization Project
Document No. 1)

Chemical-specific adjustment factors for interspecies differences and human variability: guidance IPCS (22)
document for use of data in dose/concentration–response assessment (Harmonization Project
Document No. 2)

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; Bhat et al. (23)
increasing utility and facilitating regulatory acceptance

Principles of characterizing and applying human exposure models (Harmonization Project IPCS (40)
Document No. 3)

New developments in the evolution and application of the WHO/IPCS framework on mode of action/ Meek et al. (11)
species concordance analysis (update to Harmonization Project Document No. 4, Parts 1 and 2) (59)

Skin sensitization in chemical risk assessment (Harmonization Project Document No. 5) IPCS (60)

Uncertainty and data quality in exposure assessment. Part 1: Guidance document on characterizing IPCS (41)
and communicating uncertainty in exposure assessment. Part 2: Hallmarks of data quality in
chemical exposure assessment (Harmonization Project Document No. 6)

Assessment of combined exposures to multiple chemicals: report of a WHO/IPCS international IPCS (61)
workshop on aggregate/cumulative risk assessment (Harmonization Project Document No.7)

Risk assessment of combined exposures to multiple chemicals: a WHO/IPCS framework Meek et al. (62)

Chemical mixtures in source water and drinking-water WHO (63)

Characterization and application of physiologically based pharmacokinetic models in risk IPCS (24)
assessment (Harmonization Project Document No. 9)

41
WHO human health risk assessment toolkit: chemical hazards

Document title Reference

Case study illustrating the WHO/IPCS guidance on characterization and application of Meek et al. (64)
physiologically based pharmacokinetic models in risk assessment

Guidance for immunotoxicity risk assessment for chemicals (Harmonization Project Document No. IPCS (65)
10)

Guidance document on evaluating and expressing uncertainty in hazard characterization, second IPCS (9)
edition (Harmonization Project Document No. 11)

A unified probabilistic framework for dose–response assessment of human health effects Chiu and Slob
(28)

APROBA-Plus: a probabilistic tool to evaluate and express uncertainty in hazard characterization and Bokkers et al.
exposure assessment of substances (29)

4.4.2 Resources on susceptible populations

Young children and the elderly are generally more susceptible than non-elderly adults to chemical
exposure for reasons that relate to both exposure and effect. Children, for example, take in more
water, food and air per unit body weight than do adults. In addition, some organ systems (such as the
nervous system) continue to develop in the first several years of life, which adds another dimension to
the vulnerabilities experienced by children. Likewise, aged populations may be less mobile than younger
adults and children and therefore can have greater time-weighted average exposure to pollutants in and
around their residences. Importantly, elderly persons may have pre-existing illness, such as respiratory
or cardiovascular conditions, that can make them more likely to experience adverse effects of pollutant
exposure. Further information is available from the sources listed in Table 11.

Table 11. International sources of information on susceptible populations

Document title Reference

Principles for evaluating health risks to progeny associated with exposure to chemicals during IPCS (66)
pregnancy (EHC 30)

Principles for evaluating health risks from chemicals during infancy and early childhood: the need IPCS (67)
for a special approach (EHC 59)

Principles for evaluating chemical effects on the aged population (EHC 144) IPCS (68)

Principles for evaluating health risks in children associated with exposure to chemicals (EHC 237) IPCS (69)

Summary of principles for evaluating health risks in children associated with exposure to chemicals WHO (70)

Identifying important life stages for monitoring and assessing risks from exposures to Cohen Hubal et
environmental contaminants: results of a World Health Organization review al. (71)

42
 4. International risk assessment resources

4.4.3 Risk assessment for chemical incidents Department of Public Health and Environment

Manual FOR THE PuBlIC HEalTH ManaGEMEnT OF CHIEMICal InCIDEnTS

World Health Organization
20, Avenue Appia

Risk assessment also plays a crucial role in managing chemical incidents such risk
CH-1211 Geneva 27
Switzerland
www.who.int/environmental_health_emergencies/

assessment
as accidental industrial releases, natural events or deliberate mass poisonings.
The WHO Manual for the public health management of chemical incidents (72)
provides a comprehensive overview of the principles and roles of public health in
preparedness
the management of chemical incidents and emergencies, including prevention,
crisis communication
Manual
for the Public Health
planning and preparedness, detection and alert, response and recovery. The risk Management of
Chemical Incidents

assessment component of this type of incident is necessarily conducted over a hazard emergency
ISBN 9 789241 598149

very short period of time (usually hours), referred to as “rapid risk assessment”. planning
WHO guidance is available on rapid risk assessment of acute public health risks from all types of hazard,
including multisectoral links in these types of incidents (73). The key steps of a rapid risk assessment
are the same as those included in the toolkit, namely problem formulation, hazard identification, hazard
characterization, exposure assessment and risk characterization. Many of the resources mentioned in the
toolkit can be consulted for a rapid risk assessment, along with predictive exposure modelling tools such
as the Areal Locations of Hazardous Atmospheres (ALOHA®), a programme designed by the United States
EPA specifically for use in responding to chemical releases that result in toxic gas dispersions, fires, and
explosions (74).

4.5 Chemical-specific resources

This section identifies cross-cutting sources of comprehensive risk assessment information for specific
chemicals that have been prepared by WHO and FAO. These resources include summary and in-depth
reports of sources, uses, hazards, exposures and toxicities of chemicals that are either common in
commerce or known to be hazardous to human health.

4.5.1 JMPR monographs

The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) is an international expert scientific group that is
administered jointly by FAO and WHO (75). The values set by JMPR are published in a searchable database
(26). JMPR consists of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the
WHO Core Assessment Group on Pesticide Residues, and has been meeting regularly since 1963.

During the meetings, the WHO Core Assessment Group is responsible for reviewing toxicological and
related data and for estimating, where possible, the ADIs and ARfDs of the pesticides under consideration
(see also subsection 3.3.3.1).

WHO and FAO have jointly developed an International Code of Conduct on Pesticide Management (76).
The Code provides standards of conduct and serves as a point of reference in relation to sound pesticide
life cycle management practices, in particular for government authorities and the pesticide industry.

4.5.2 JECFA monographs

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is an international
WHO FOOD ADDITIVES SERIES: 77
Prepared by the eighty-sixth meeting of the
Joint FAO/WHO Expert Committee
on Food Additives (JECFA)

expert scientific committee that is administered jointly by FAO and WHO. It has
been meeting since 1956 to evaluate the safety of food additives, contaminants, Safety
evaluation

naturally occurring toxicants and residues of veterinary drugs in food. JECFA has
of certain
food additives

evaluated more than 2600 food additives, approximately 50 contaminants and

naturally occurring toxicants, and the residues of approximately 75 veterinary drugs
(as of 2016) (77). A searchable database is maintained that contains summaries of
all evaluations (26). Each summary provides links to the most recent reports and

43
WHO human health risk assessment toolkit: chemical hazards

monographs and to the specification database, and provides a history of previous JECFA evaluations (see
also subsections 3.3.3.1 and 4.7.1.2).

4.5.3 EHC monographs

WHO has published EHC monographs on over 220 chemicals, each of which
contains a detailed summary of the sources, pathways and routes of exposure
to each chemical (78). Ranges of exposure reported in the scientific literature for
multiple exposure sources are also presented in the monographs. As such, the EHC
monographs are valuable for helping investigators prioritize exposure media and
routes as part of a risk assessment.

4.5.4 CICADs
The Concise International Chemical Assessment Documents (CICADs), published IPCS
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

by WHO, join the EHC monographs as authoritative sources of information on risk Concise International Chemical Assessment Document

50
assessment of chemicals (79). In addition to hazard characterization of a chemical,
CICADs contain information on sources of human exposure; environmental
transport, distribution and transformation; environmental levels and human
exposure; and information on guidance or guideline values. The section on human
exposure includes numerous environmental media, such as ambient air, indoor air,
IOMC
INTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALS
A cooperative agreement among UNEP, ILO, FAO, WHO, UNIDO, UNITAR and OECD

drinking-water, surface water, sediment, soil, food and products, where relevant to World Health Organization

the chemical of concern.

Geneva, 2003

4.5.5 Drinking-water quality background documents

The WHO Guidelines for drinking-water quality include fact sheets and comprehensive
review documents for many individual chemicals (see also subsection 4.7.2.1). For
many of these, guideline values are derived. All of these can be accessed through
WHO publications (2) and also via an online resource (80)

WHO INDOOR AIR

QUALITY GUIDELINES:
HOUSEHOLD FUEL
COMBUSTION
4.5.6 Air quality guidelines
WHO GUIDELINES FOR INDOOR AIR QUALITY

WHO sets recommended limits for concentrations of key harmful air pollutants both
WHO GUIDELINES FOR INDOOR AIR QUALITY
HOUSEHOLD FUEL COMBUSTION
WHO GUIDELINES FOR INDOOR AIR QUALITY: HOUSEHOLD FUEL COMBUSTION

Well into the 21st century, almost 3 billion of the world’s poorest

outdoors and inside buildings and homes, based on a global synthesis of scientific
people still rely on solid fuels (wood, animal dung, charcoal, crop
wastes and coal) burned in inefficient and highly polluting stoves for
cooking and heating, resulting in some 4 million premature deaths
among children and adults. Together with widespread use of kerosene
stoves and lamps, these household energy practices also cause many
deaths and serious injuries from scalds, burns and poisoning. Use of
HOUSEHOLD FUEL
solid fuel stoves for heating in more developed countries is also
COMBUSTION
evidence (see also subsection 4.7.2.2). WHO guidelines cover annual and daily
common and contributes significantly to air pollution exposure. Air
pollution from household fuel combustion is the most important
global environmental health risk today.

Building on existing WHO indoor air quality guidelines for specific

pollutants, these guidelines bring together the most recent evidence
on fuel use, emission and exposure levels, health risks, intervention

concentrations of fine particulates, nitrogen dioxide, sulfur dioxide, carbon monoxide

impacts and policy considerations, to provide practical recommendations
to reduce this health burden. Implementation of these recommendations
will also help secure additional benefits to society, development and
the environment – including climate benefits that will result from wider
access to clean, safe and efficient household energy.

The guidelines are targeted at public health policy-makers and specialists

working with the energy, environment and other sectors to develop and

and ozone (12). Guidelines also cover indoor mould and dampness (34). Most
implement policy to reduce the adverse health impacts of household
fuel combustion. This publication is linked to ongoing work by WHO
and its partners to provide technical support for implementation of the
recommendations, monitoring progress and evaluating programme
impacts.

recently, WHO Guidelines for indoor air quality: household fuel combustion set limits on
emissions from cooking and heating stoves, as well as recommendations regarding
World Health Organization (WHO)
Department of Public Health, Environmental and
Social Determinants of Health (PHE)
Family, Women's and Children's Health (FWC)

clean fuel use (33).

ISBN 978 92 4 154887 8
Avenue Appia 20
CH-1211 Geneva 27
Switzerland
http://www.who.int

44
 4. International risk assessment resources

4.6 Hazard identification resources

The OECD Guidelines for the testing of chemicals are a collection of the most relevant internationally agreed
testing methods used by government, industry and independent laboratories to identify chemical hazards
(5).

Detailed information on the principles of the identification of a variety of human health effects is
contained in a number of reports published by WHO as a part of the EHC series and other sources (Table
12). Likewise, OECD has published a series of guidance documents and case studies on how to test for and
assess different kinds of toxic effects (81), such as endocrine disruption (82).

Table 12.  WHO resources on identification of chemical hazards

Document title Reference

Principles and methods for the assessment of neurotoxicity associated with exposure to chemicals (EHC IPCS (83)
60)

Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals (EHC IPCS (84)
119)

Principles and methods for assessing direct immunotoxicity associated with exposure to chemicals (EHC IPCS (85)
180)

Principles and methods for assessing allergic hypersensitization associated with exposure to chemicals IPCS (86)
(EHC 212)

Principles for evaluating health risks to reproduction associated with exposure to chemicals (EHC 225) IPCS (87)

Principles and methods for assessing autoimmunity associated with exposure to chemicals (EHC 236) IPCS (88)

Guidance for immunotoxicity risk assessment for chemicals (Harmonization Project Document No. 10) IPCS (65)

The WHO recommended classification of pesticides by hazard and guidelines to classification 2019 WHO (89)

Pesticide registration toolkit: identification of HHPs FAO (90)

The resources listed below contain detailed information on the identities, hazardous properties and
toxicities of thousands of chemicals in commerce, provided by international organizations and others. A
brief description of each database is provided in the subsections below, together with references that
include the internet addresses. As shown in Table 13, most of these resources contain detailed information
specific to either chemical hazards identified through scientific investigations or the classification of
chemicals according to regulatory schemes developed by international organizations.

45
WHO human health risk assessment toolkit: chemical hazards

Table 13.  General content of international hazard identification resources

Resource Summary or Classification

detailed content scheme

International Chemical Safety Cards Summary Yes

Screening Information Dataset for High Production Volume Chemicals Detailed No

WHO Recommended Classification of Pesticides by Hazard Summary Yes

United Nations Recommendations on the Transport of Dangerous Goods Summary Yes

IARC monographs Detailed Yes

Hazardous Substances Data Bank Detailed No

European Union Classification and Labelling System Detailed Yes

ECHA substance evaluation reports Detailed Yes

ECHA Infocards Summary Yes

European Union risk assessment reports Detailed No

International Chemical Control Toolkit Detailed Yes

EFSA OpenFoodTox chemical hazards database Summary No

4.6.1 International Chemical Safety Cards

International Chemical Safety Cards (ICSCs) contain a brief summary of
essential information on chemicals that was developed cooperatively by IPCS
and the International Labour Organization (91). In addition to potential health
and environmental hazards, each ICSC also contains a description of fire and
explosion hazards and preventive measures, as well as appropriate responses
to a spill, packaging and labelling information, guidance on personal protection,
and storage conditions. Basic physical, chemical and hazardous properties
of chemicals are also summarized in a standard format on each ICSC. GHS
classifications (18) are also indicated on many ICSCs. The ICSCs are available in
multiple languages.

4.6.2 Screening Information Dataset for High Production Volume Chemicals

The OECD Screening Information Dataset for High Production Volume Chemicals (SIDS) is an extensive
compilation of data on physicochemical properties and toxicity values for the most common chemicals
in commerce, along with the major conclusions of the hazard assessment (92). In contrast to the ICSCs
described above, which are brief summaries of these chemical characteristics, the SIDS includes results for

46
 4. International risk assessment resources

a variety of environmental conditions and species. As a result, this resource can be useful for considering
potential risks in unique climates and exposure scenarios.

4.6.3 WHO Recommended Classification of Pesticides by Hazard

The WHO Recommended Classification of Pesticides by Hazard and Guidelines to Classification 2019
The WHO Recommended
The WHO Recommended Classification of Pesticides by Hazard distinguishes Classification of Pesticides
by Hazard

between the more and less hazardous forms of selected pesticides based on acute
and Guidelines to
Classification
2019

risk to human health (that is, the risk of a single exposure or multiple exposures
over a relatively short period of time) (89). The classification system takes into
consideration the toxicity of the technical compound and its common formulations.
It lists common technical-grade pesticides and recommended classifications,
together with active ingredients believed to be obsolete or discontinued for
use as pesticides, pesticides subject to the prior informed consent procedure
under the Rotterdam Convention, limitations to trade because of the Stockholm
Convention on Persistent Organic Pollutants, and gaseous or volatile fumigants not classified under these
recommendations. Since 2009, the acute toxicity hazard categories from the GHS have been used as
the starting point for determining a revised classification scheme, replacing the guide points originally
proposed in 1975.

4.6.4 United Nations Recommendations on the Transport of Dangerous Goods

The United Nations Recommendations on the Transport of Dangerous Goods have been developed by the
United Nations Economic Commission for Europe’s Committee of Experts on the Transport of Dangerous
Goods in the light of technical progress, the advent of new chemicals and materials, the exigencies of
modern transport systems and, above all, the requirement to ensure the safety of people, property
and the environment (93). Goods, including chemicals, are classified according to hazard class. The
recommendations are harmonized with the GHS (18).

4.6.5 IARC monographs

IARC has published summaries and evaluations of the evidence of carcinogenicity of
chemicals since its inception in 1969 (19). The monographs include single chemicals
as well as chemical mixtures. The objective of the programme is to prepare, with
the help of international working groups of experts, and to publish, in the form of
monographs, critical reviews and evaluations of evidence on the carcinogenicity of a
wide range of chemicals to which humans may be exposed. The IARC monographs
represent the first step in carcinogen risk assessment, which involves examination
of all relevant information in order to assess the strength of the available evidence that an agent could
alter the age-specific incidence of cancer in humans. The monographs may also indicate where additional
research efforts are needed, specifically when data immediately relevant to an evaluation are not available.

4.6.6 Hazardous Substances Data Bank

The Hazardous Substances Data Bank (HSDB), which is maintained by the United States National Library
of Medicine, is a detailed listing of peer-reviewed toxicological data for over 5800 chemicals, including
information on human health effects, emergency medical treatment, physicochemical properties,
metabolism, toxicology and laboratory methods. It is accessed by searching for the chemical in the United
States National Institutes of Health PubChem database (94). Unlike the ICSCs (see subsection 4.6.1), the
toxicity information is presented in narrative form rather than tables. The HSDB also contains excerpts

47
WHO human health risk assessment toolkit: chemical hazards

from case reports of humans exposed to the chemical of interest, in addition to summaries of laboratory
animal studies.

4.6.7 European Union (EU) Classification and Labelling System

Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures of the EU
(commonly referred to as the “CLP Regulation) entered into force on 20 January 2009 and is based on the
GHS (18). Since 2015, the regulation is the only legislation in force in the EU for classification and labelling
of substances and mixtures.

An online version of the Classification and Labelling Inventory of the European Chemicals Agency (ECHA)
is available (95). This “C&L Inventory” is a database that contains classification and labelling information
on notified and registered chemicals on the EU market according to their toxicological properties, as
well as harmonized classifications where they have been established in the EU for health hazards of
highest concern (carcinogenicity, mutagenicity and reproductive toxicity). It should be noted that the C&L
Inventory shows information that has been submitted to ECHA by manufacturers and importers but, apart
from EU harmonized classifications, ECHA does not review or verify the accuracy of the information.

4.6.8 ECHA substance evaluation reports

As part of the implementation of the regulation on Registration, Evaluation, Authorisation and Restriction
of Chemicals (REACH), comprehensive substance evaluations are prepared by EU Member States under
the coordination of ECHA. Substance evaluation aims to clarify whether a chemical that has been identified
as being of potential concern poses an actual risk to human health and/or the environment, based on
information submitted by registrants and any additional clarifying information requested (96). These
reports contain information related to clarifying the risk of particular concern but also include information
on other aspects. The ECHA REACH database (97) provides comprehensive information on chemicals.

4.6.9 ECHA Infocards

ECHA Infocards provide a first-tier tool for disseminating information on chemicals from ECHA’s database.
Infocards present key information on chemical identification, hazard classification and labelling, properties
of concern, a summary of the most relevant regulatory activities in the EU, how to safely use the chemical,
and where and how the chemical is used, along with other helpful information such as guidance on where
to find more detailed information (97). Information is displayed automatically on Infocards based on data
submitted to ECHA by manufacturers and importers, and does not undergo review or verification by
ECHA. The quality and correctness of the information is the responsibility of the data submitter, not ECHA.

4.6.10 EU risk assessment reports

Before REACH came into force, comprehensive risk assessment reports were prepared by Member States
and published by the Joint Research Centre of the European Commission. Several of these assessments
are now available on the ECHA website (98) and on the EU Publications Office website (99). These reports
evaluated environmental risks as well as risks to human health from occupational, consumer and
environmental exposures to chemicals.

4.6.11 International Chemical Control Toolkit

Another source of hazard information is provided by the International Chemical Control toolkit of
the International Labour Organization (100), which outlines a scheme for protection against harmful
and dangerous chemicals in the workplace. It is designed for small and medium-sized enterprises in
developing countries.

48
 4. International risk assessment resources

4.6.12 EFSA OpenFoodTox chemical hazards database

The EFSA OpenFoodTox (101) is a structured database that summarizes the outcomes of hazard
identification and characterization for human health (all regulated products, including substances
used in feed and food, and contaminants), as well as for animal health (feed additives, pesticides and
contaminants) and the environment (feed additives and pesticides). The database provides open-source
information on the substance characterization, links to EFSA’s related output, background European
legislation, and a summary of the critical toxicological end-points and reference values.

4.7 Hazard characterization/guidance or guideline value resources

As mentioned in subsection 3.3.3, hazard characterization typically consists of a qualitative or quantitative
description of the inherent properties of an agent having the potential to cause adverse health effects.
This information is then often used to develop guidance values or, if human exposure factors are
considered, guideline values. In other words, guidance or guideline values provide a measure of the
hazardous characteristics of the chemical. The challenging part of applying guidance or guideline values
is to review the hazard characterization step and to assess the applicability of the assumptions embedded
within it to the situation of interest (for example, exposure duration and allocation of total exposure
among routes of exposure).

WHO has published a Handbook for guideline development (58), which provides step-by-step guidance
on how to plan, develop and publish a WHO guideline. The handbook covers the methods, processes
and procedures for producing a document that meets WHO standards for guidelines (WHO publications
containing recommendations for clinical practice or public health policy). It does not provide detailed
technical guidance on many of the steps; this can be obtained from the references in the handbook. The
principles of the methods underlying WHO guidelines are that they should be based on a review of all
the relevant evidence in a systematic process that evaluates the evidence in ways that minimize the risk
of bias and evaluate the quality of the evidence using a framework such as Grading of Recommendations
Assessment, Development and Evaluation (GRADE) (see section 5.1). Evaluations of the health effects of
chemicals are increasingly adopting systematic review principles, a trend that is likely to continue in the
future (see section 5.1).

The resources noted in subsections 4.7.1–4.7.3 are compilations of guidance values, such as TDIs and ADIs,
and guideline values, such as air and water quality guidelines, established by WHO. The guidance values
are thresholds of exposure for non-cancer effects and slope factors for cancer risks, and the guideline
values are concentrations of chemicals in environmental media. As described in subsection 3.3.5, these
values can be combined with estimates of exposure to calculate the hazard or risk quotient or the excess
lifetime cancer risk, indicators of non-cancer and cancer risks, respectively. Points of Departure (such
as BMDLs or NOAELs) presented in some of these resources can also be used to derive margins of
exposure (MOEs) to provide guidance to risk managers. In addition, this section provides an example of a
national resource that provides similar information from national assessments (the United States EPA IRIS
database). Finally, the section provides examples of national resources of occupational exposure limits
(OELs).

In addition, WHO has published several EHC documents on principles and methods for the hazard
characterization component of human health risk assessments for chemicals (Table 14).

49
WHO human health risk assessment toolkit: chemical hazards

Table 14.  International resources on hazard characterization

Document title Reference

Principles of studies on diseases of suspected chemical etiology and their prevention (EHC 72) IPCS (102)

Assessing human health risks of chemicals: derivation of guidance values for health-based exposure IPCS (36)
limits (EHC 170)

Principles for modelling dose–response for the risk assessment of chemicals (EHC 239) IPCS (6)

Principles and methods for the risk assessment of chemicals in food (EHC 240) IPCS (7)

Chemical-specific adjustment factors for interspecies differences and human variability: guidance IPCS (22)
document for use of data in dose/concentration–response assessment (Harmonization Project
Document No. 2)

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience: Bhat et al. (23)
increasing utility and facilitating regulatory acceptance

New developments in the evolution and application of the WHO/IPCS framework on mode of action/ Meek et al.
species concordance analysis (update to Harmonization Project Document No. 4, Parts 1 and 2 (59)) (11)

OECD also coordinates projects to help identify the health hazards associated with exposure to chemicals
or groups of chemicals using predictive technologies such as the quantitative structure–activity
relationship (QSAR) through the OECD QSAR Toolbox (103) and gain better understanding of the biological
pathways by which they are induced (Adverse Outcome Pathways) (104), which can be useful in a higher-
tier assessment.

4.7.1 Guidance values for exposure rates

4.7.1.1 Pesticides
A summary of ADIs and ARfDs that have been established by JMPR is available in the WHO food safety
databases (26). Additional information is available in Tables 5 and 6 and subsection 3.3.3.1.

4.7.1.2 Food additives and contaminants, naturally occurring toxicants and residues of veterinary
drugs in food
TDIs, ADIs and other guidance values for food additives and contaminants, naturally occurring toxicants
and residues of veterinary drugs in food have been established by JECFA (see also Tables 5 and 6 and
subsection 3.3.3.1). These values are also available on the WHO food safety databases (26).

4.7.2 Guideline values for exposure concentrations

4.7.2.1 WHO drinking-water guidelines
WHO has developed guidelines for concentrations of chemicals and other contaminants in drinking-
water. The guideline values, as well as supporting information and the methodology employed to derive
the guideline values, are published (2). The guideline values are expressed in units of mass concentration
in drinking-water (mg/L) and assume a water consumption rate of 2 litres per day and a body weight of
60 kg. For risk of cancer, the guideline values are equivalent to lifetime exposure that yields an excess

50
 4. International risk assessment resources

lifetime cancer risk of 10 −5 (or 1 in 100 000). For chemicals that are likely to be present in multiple media,
the guideline values account for intake through air, food and soil. In this case, the guideline value is
determined based on the fraction of total or aggregate intake expected to occur as a result of a chemical’s
presence in drinking-water. Consider a case where drinking-water is thought, a priori, to account for one
half of all intake of a chemical. Then, the guideline value would be set such that consumption of drinking-
water at the prescribed value would account for half of the ADI or TDI for that chemical. Variation in the
allocation of the ADI or TDI to water can be an important factor when considering whether the WHO
drinking-water guidelines should be adapted for country use.

The methodology used to develop WHO drinking-water guidelines is being adapted to systematically
review the evidence available for the health effects of chemicals, in line with the WHO Handbook for
guideline development (58).

While the WHO drinking-water guidelines are based on the hazard characterization, it should be noted
that other factors may also be taken into consideration in derivation of the guidelines, including treatment
technologies, analytical capabilities and feasibility.

4.7.2.2 WHO air quality guidelines

Air pollution from both outdoor and indoor sources represents the single largest environmental risk to
health globally (32). WHO publishes air quality guidelines for ubiquitous pollutants in ambient (outdoor)
air – particulate matter, ozone, nitrogen dioxide and sulfur dioxide (12) – and other commonly encountered
pollutants. Separate guidelines are included for particulate matter less than 2.5 µm (PM2.5) and less than
10 µm (PM10) in aerodynamic diameter.1 The WHO guidelines are intended for worldwide use but have
been developed to support actions to achieve air quality that protects public health in different contexts.
Notably, the air quality guidelines are derived from an extensive body of epidemiological studies relating
air pollution to its health consequences in human populations. The air quality guidelines for these air
pollutants are not based directly upon assumptions about intake rates, body weight and other factors,
unlike the drinking-water guidelines described in subsection 4.7.2.1. Instead, the relationships between
ambient air pollution and personal exposure to air pollutants in those studies should be considered in
comparison with local circumstances before adopting the guidelines as air quality standards in a country.

WHO has also developed guidelines for indoor air quality for a number of indoor pollutants, including
chemicals, biological contaminants and those derived from household fuel consumption (31, 33, 34).

WHO has recently undertaken an update of the air quality guidelines, a process that will involve systematic
review of the enormous amount of new relevant scientific evidence. The process will apply the procedures
outlined in the WHO Handbook for guideline development (58) and will use evidence-based methods for
assessing the quality of the body of evidence.

4.7.3 Guidance and guideline values from chemical-specific monographs

Media-specific guidelines, as well as ADIs, TDIs and other guidance and guideline values for specific
chemicals, are available from the internationally developed comprehensive risk assessment monographs
mentioned in section 4.5, including EHCs, CICADs and other documents.

1 Whereas WHO defines PM10 and PM2.5 as particulate matter less than 10 µm or 2.5 µm in aerodynamic diameter, most
jurisdictions define PM10 and PM2.5 as particulate matter less than or equal to 10 µm or 2.5 µm in aerodynamic diameter.

51
WHO human health risk assessment toolkit: chemical hazards

4.7.4 Integrated Risk Information System

The United States EPA maintains an online database that contains chronic toxicity values for more than
500 chemicals, groups of chemicals or mixtures (105). The database contains reference concentrations
(RfC) or reference doses (RfD), which are derived from a NOAEL, LOAEL, or benchmark concentration or
dose, with uncertainty factors generally applied to reflect limitations of the data used. For cancer, the IRIS
database contains qualitative descriptors as well as oral slope factors and inhalation unit risks. This source
contains national information provided by the United States Government. Other sources of national
information may also be available and should be consulted where applicable.

4.7.5 Occupational exposure limits (OELs)

OELs are intended for use in the practice of industrial hygiene as standards, guidelines or
recommendations in the control of potential workplace health hazards. The EU provides OELs for a
range of workplace chemicals, based on scientific advice from ECHA (previously provided by the Scientific
Committee for Occupational Exposure Limits to Chemical Agents (SCOEL)). The EU OELs, along with
several available national OELs, are available on the free GESTIS Substance Database, hosted by the
Institute for Occupational Safety and Health of the German Social Accident Insurance (106). Not freely
available OELs include, for example, the threshold limit values (TLVs) of the American Conference of
Governmental Industrial Hygienists (107).

4.8 Exposure assessment resources

The resources noted in this section include general guidance on exposure assessment as well as detailed
information on exposure to a wide variety of specific chemicals. The general guidance resources listed
here discuss in detail the concepts that were only briefly summarized in subsection 3.3.4. The resources
on specific chemicals are compendia of chemical profiles that feature information on sources, pathways,
routes and typical levels of exposure. A description of each of these resources is provided below, with
references that include the internet address as of the drafting of this document.

Fundamental principles and approaches for chemicals in specific environmental media and routes of
exposure such as food, water and air are set out in several guidance and EHC documents available from
WHO. Key examples of these materials are listed in Table 15.

Table 15.  International sources of information on media and routes of exposure

Topic Document title Reference

Food additives and Principles and methods for the risk assessment of chemicals IPCS (7)
contaminants in food (EHC 240)

Pesticide residues in food Principles and methods for the risk assessment of chemicals IPCS (7)
in food (EHC 240)

Dermal absorption Dermal absorption (EHC 235) IPCS (108)

Drinking-water quality Guidelines for drinking-water quality: fourth edition, WHO (2)
guidelines incorporating the first addendum

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 4. International risk assessment resources

Topic Document title Reference

Air quality guidelines Air quality guidelines for Europe, second edition WHO Regional Office
for Europe (30)

Air quality guidelines Air quality guidelines – global update 2005: particulate WHO Regional Office
matter, ozone, nitrogen dioxide and sulfur dioxide for Europe (12)

Indoor air quality guidelines WHO guidelines for indoor air quality: selected pollutants WHO Regional Office
for Europe (31)

4.8.1 General guidance on exposure assessment

General guidance on exposure assessment is provided in the international resources listed in Table 16.
Information about some examples of other tools that are available from sources other than international
organizations are shown in the following list.

Other tools available for exposure assessment (not international resources)

― The United States EPA provides a list of a range of tools and databases to assist in conducting
exposure assessments for human health risk assessment and ecological assessment, pulled from
the EPA ExpoBox and EPA EcoBox websites, respectively (109). The EPA ExpoBox provides links
to guidance documents, databases, models, reference materials, and other related resources for
exposure assessment for six “tool sets”, including approaches, media, routes, tiers and types, life
stages and populations, and chemical classes (37).

― The Environmental Modeling Community of Practice of the United States EPA has developed
several exposure assessment methods, databases and predictive models to help in evaluating what
happens to chemicals when they are used and released to the environment, and how workers, the
general public and consumers may be exposed to chemicals (110).

― The National Institute for Public Health and the Environment of the Netherlands (RIVM) has
developed a suite of helpful models called ConsExpo (39) to assist in assessing exposure to
chemicals in products, in particular for spray products, with an emphasis on consumer products
(see subsection 4.8.2 for further details).

― Institutions in the United Kingdom have developed a range of models to estimate exposure to
chemicals, including for contaminated soil (Contaminated Land Exposure Assessment tool) (111) and
for registration of pesticides (112).

― The European Centre for Ecotoxicology and Toxicology of Chemicals (113) has developed a Targeted
Risk Assessment (TRA) tool to calculate exposures for workers, consumers and the environment.
The TRA tool is used extensively in the European Union to prepare chemical safety reports
submitted under the REACH regulations.

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WHO human health risk assessment toolkit: chemical hazards

Table 16.  International sources of guidance on exposure assessment

Document title Reference

Human exposure assessment (EHC 214) IPCS (8)

Human exposure assessment: an introduction Berglund, Elinder and

Järup (114)

Dietary exposure assessment of chemicals in food: report of a joint FAO/WHO consultation, FAO/WHO (115)
Annapolis, MD, 2–6 May 2005

Towards a harmonised total diet study approach: a guidance document EFSA/FAO/WHO (116)

Occupational and consumer exposure assessments OECD (117)

Principles of characterizing and applying human exposure models (Harmonization Project IPCS (40)
Document No. 3)

Dermal exposure (EHC 242) IPCS (15)

Considerations when assessing children’s exposure to chemicals from products OECD (118)

Biomarkers and risk assessment: concepts and principles (EHC 155) IPCS (45)

Biomarkers in risk assessment: validity and validation (EHC 222) IPCS (46)

A state-of-the-science review of mercury biomarkers in human populations worldwide Basu et al. (44)
between 2000 and 2018

Human biomonitoring: facts and figures WHO (47)

Review of the state of the art of human biomonitoring for chemical substances and its Choi et al. (119)
application to human exposure assessment for food safety

Generic risk assessment model for insecticide-treated nets, second edition WHO (120)

Generic risk assessment model for indoor and outdoor space spraying of insecticides, second WHO (121)
edition

4.8.2 Exposure factors

In order to characterize human exposure to chemicals, generic or default exposure factors are often
incorporated. Exposure factors are values that describe contact rates with media, including inhalation
rate, drinking-water consumption and food consumption. Exposure factors also include anthropometric
features of people, such as body weight and body surface area. A schematic diagram of exposure
pathways, exposure factors and exposure routes is presented in Figure 10.

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 4. International risk assessment resources

Figure 10.  Schematic diagram of exposure pathways, factors and routes

Environmental Pathways Exposure Factors Exposure Route

Time Indoors
Volume of Residence
Indoor Air Building Characteristics
Air Exchange Rates Inhalation
Inhalation Rate

Outdoor Air Time Outdoors

Non-Dietary Ingestion
Ingestion
Soil and Dust Ingestion
Time Playing on Sand/
Soil/Dust
Gravel, Grass, and Dirt
Dermal Contact
Body Surface Area
Soil Adherence

Ground Surface Time Swimming Ingestion Inhalation Dermal

Water Water Body Surface Area Dermal Contact
Household Inhalation Rate Inhalation
Water Time Showering/Bathing Inhalation Dermal Contact
Human Milk Intake
Ingestion of Water and Ingestion
other Select Liquids

Intake of Fruits and

Plants
Vegetables
Intake of Grain Products
Total Food Intake
Intake of Home Produced Ingestion
Meat, Foods
Animals Dairy, Human Milk Intake
Eggs Intake of Meats, Dairy
Products and Fats

Intake of Fish and Shellfish

Fish Human Milk Intake Ingestion
Total Food Intake

Note: The pathways presented are selected pathways. This diagram is not meant to be comprehensive. Products are not shown; humans can be exposed to products
through all pathways and routes.
Source: United States EPA, ExpoBox (122).

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WHO human health risk assessment toolkit: chemical hazards

Default exposure factors for adults published by WHO are summarized in Table 17.

Table 17.  Summary of selected exposure factors published by WHO

Exposure factor Value Reference

Drinking-water consumption 2 litres/day WHO (2)

Body weight 60 kg IPCS (52)

Food consumption Diets for clusters of countries WHO (123)

Other helpful resources for exposure factors are summarized in Table 18 and are discussed further below.

Table 18.  Summary of additional resources on exposure factors

Document title Reference

EPA ExpoBox: about the exposure factors handbook United States EPA (122)

Neglected tropical diseases: guidelines and risk assessment models WHO (43)

Generic risk assessment model for insecticide-treated nets, second edition WHO (120)

Generic risk assessment model for indoor and outdoor space spraying of insecticides, WHO (121)
second edition

Exposure Factors Interactive Resource for Scenarios Tool (ExpoFIRST), Version 2.1 United States EPA (124)

Current fact sheets RIVM (125)

Identifying important life stages for monitoring and assessing risks from exposures to Cohen Hubal et al. (71)
environmental contaminants: results of a World Health Organization review

Guidance on selecting age groups for monitoring and assessing childhood exposures to United States EPA (126)
environmental contaminants

Child-specific exposure factors handbook United States EPA (127)

Highlights of the child-specific exposure factors handbook (final report) United States EPA (128)

Child-specific exposure scenarios examples (final report) United States EPA (129)

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 4. International risk assessment resources

The United States EPA (122) has published an extensive Exposure factors handbook for assessing human
exposure, including drinking-water consumption, soil ingestion, inhalation rates, dermal factors,
consumption of various foodstuffs (including human breast milk), activity factors, product use and
building characteristics. These exposure factors have been used by WHO in the development of guidelines
and risk assessment models for neglected tropical diseases (43). Recommended values are presented for
the general population and also for various segments of the population who may have characteristics
different from the general population. Values for a particular segment of the United States population that
is closer in terms of size parameters to the population of interest may be selected in preference to the
values for the general population; for example, the 25th percentile values for females aged 30–40 years
(with a bodyweight of 60 kg) have been used to represent the population of interest in areas where vector
control is undertaken (for example, where malaria is endemic) in some WHO generic exposure models for
use of insecticides (120, 121). To facilitate use of the Exposure factors handbook in conducting an exposure
assessment, the United States EPA provides an interactive online tool, ExpoFIRST (124), which allows
users to draw on data found in the handbook to develop user-defined scenarios; the user can modify
parameters to develop deterministic exposure estimates to suit the assessment situation.

The RIVM ConsExpo suite of models for estimating consumer exposures from products incorporate
numerous default exposure factors, such as values for the room in which the exposure takes place (for
example, room size), for the person that is exposed (such as body weight and the surface areas of different
parts of the body), as well as information on ventilation in houses (38, 39). Information is also provided
on inhalation rates for adults and children while at rest and during exercise, along with data on activity
patterns. These default factors are available in a series of fact sheets (125).

However, chemical exposures can change throughout stages of life related to changes in anatomy,
physiology, metabolism and behaviour. It may therefore be important to identify the ages or life stages
most vulnerable to chemicals. To address this need, a group of experts convened by WHO developed a
two-tier, fit-for-purpose approach for monitoring and assessing risks from exposures to chemicals for
global use with a focus principally on early life stages, from preconception through adolescence (71). The
first tier involves the adoption of guidance similar to the childhood age groups recommended by the
United States EPA (126), while the second tier consolidates some of those age groups to reduce the burden
of developing age-specific exposure factors for different regions. The harmonized age groups allow for
greater consistency and better comparison across time, place and culture. The numerous factors that
modify exposures to different age groups are also described (Figure 11).

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WHO human health risk assessment toolkit: chemical hazards

Figure 11.  Framework of modifying factors for exposure associated with geography and
culture

GEOGRAPHIC CULTURAL

Climate General milieu

Immediate
Disease community
profile Food
behaviors/
Household Household
food culture
chemicals
used
Toxic Primary
substance caregiver Manufactured toys and consumer
profile Access to
products
(i.e. vector and quality
control, of food
agriculture, Body/ Child-care arrangements/
Genetic
industry) baby care practices/allowing of
profile
products crawling and mouthing

Individual child Occupation/labor

Substance use/abuse

Medicines/
Primary Access to medical
treatments and
industries services
remedies

Access to water and Physical activity

sanitation patterns

Housing quality

Level of
urbanization

Source: Cohen Hubal et al. (71).

Also helpful in assessing exposure in young children is the Child-specific exposure factors handbook
published by the United States EPA (127, 128). Factors include drinking-water consumption, soil ingestion
and non-dietary factors, inhalation rates, dermal factors including skin area and soil adherence factors,
consumption of fruits and vegetables, fish, meats, dairy products, homegrown foods, human milk, activity
patterns, body weight and products. A range of example scenarios specifically for children is available
from the United States EPA (129).

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4.8.3 Emission sources and scenarios

Chemicals can be released to the environment from a variety of sources. These sources include emissions
from discrete points, areas or volumes, and large geographical areas that may not be possible to quantify
precisely. Numerous comprehensive descriptions of different types of sources of chemical emissions to air
and water have been published in the scientific literature.

Emission scenario documents contain descriptions of sources, production processes, pathways and
use patterns of numerous commercial industrial operations with the aim of quantifying the releases of
chemicals into water, air, soil or solid waste. They can be used to generate hypotheses about contaminants
of concern that may be associated with a particular source, such as a manufacturing operation, laboratory,
disposal area or waste site. In addition to contaminants of concern, emission scenario documents
frequently provide descriptions of industrial processes and the corresponding points and types of by-
product discharges to air, water and land.

OECD has prepared emission scenario documents for more than 60 industry categories or use categories,
including wood preservatives, plastic additives, leather processing, paper mills, flame retardants and many
others (130). ECHA (14) has also made available emission scenario documents that describe environmental
releases for different industrial categories and biocidal products. These documents are useful for
understanding processes that may contribute to emissions of contaminants and support the hazard
identification process.

4.8.4 Emission rates

Emission rates are chemical releases from a source expressed as amount per time – for example, grams
per second or tonnes per year. As such, emission rates are useful for characterizing the magnitude or
strength of emissions associated with a source. In some cases, the emission rate of a chemical from
a source may be known, perhaps from monitoring or estimates conducted previously. In most cases,
however, emission rates are not known. In those situations, an assessor may be able to estimate emission
rates from information about the process employed by the source and process-related emission factors
published in various reference books and databases.

Peer-reviewed and generally accepted emission factors for numerous processes and sources have been
compiled by several organizations (Table 19). The European Monitoring and Evaluation Programme and
the European Environment Agency publish emission factors and related information for the evaluation of
long-range transboundary air pollutants. Other examples are provided in Table 19.

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WHO human health risk assessment toolkit: chemical hazards

Table 19.  Widely accepted resources on emissions

Source Topic Reference

European Monitoring and Evaluation Programme Emission data for long-range transboundary air EMEP (131)
pollutants

European Environment Agency Pollutant emission inventories for stationary and EEA (132)
mobile sources

National Atmospheric Emissions Inventory Emission factors database NAEI (133)

Intergovernmental Panel on Climate Change Emission factors for greenhouse gases IPCC (134)
(IPCC) Emission Factors Database

Clearinghouse for Inventories and Emission Pollutant emission inventories for stationary and United States
Factors mobile sources EPA (135)

Default emission factors generally are not applicable to releases from chemical waste sites, storage
sites with leaking containers of chemicals and other sources that are not process oriented. Instead,
measurements or models can be used to estimate emission rates in those situations. Measurement
approaches are detailed and modelling approaches are introduced in EHC 214 (8).

Chemical emissions from waste sites and related scenarios occur primarily as a result of diffusive
processes in which chemicals move from locations of high concentration to locations of low concentration.
The rate at which a chemical will diffuse is determined by the physicochemical properties of the chemical
and environmental conditions, such as temperature. Consider the potential for a semivolatile organic
chemical, such as p,p-dichlorodiphenyldichloroethene, or DDE (a degradation product of p,p-dichlorodip
henyltrichloroethane, or DDT), to volatilize from surface soil to air. Among other factors, volatilization will
depend principally upon the vapour pressure of the chemical and the strength of the bond between the
chemical and soil. While the details of these techniques are beyond the scope of the toolkit, readers are
referred to some of the primary literature and guidance on this topic.

4.8.5 Transport and fate

Chemicals can move through water, air and soil following their release from a source in accordance with
their properties and those of the transport media. Numerous tools are available to aid with the transport
and fate component of exposure assessment.

For releases to the atmosphere, a number of preferred and recommended models have been identified
by international and national organizations. Some of these models are available in the public domain and
thus can be accessed by risk assessors around the world. Specialized training, either formal or informal,
is possibly required to use these models. Thus, a risk assessor may choose to enlist assistance from
a specialist if one of these tools will be used to assess exposure. An example of a dispersion model is
AERMOD (136).

For releases to water, MODFLOW is a public access model that is commonly used to assess the transport
and fate of chemicals in aquifers or groundwater (137). MODFLOW can simulate the flow of groundwater

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 4. International risk assessment resources

and contaminants therein, including the effects of wells, rivers, streams, drains, evaporation and recharge.
Like the air models mentioned above, this tool also requires training and practice in order to be applied
successfully. A wide range of tools is available for estimating contaminant transport and fate in surface
waters. Risk assessors are directed to the WHO Guidelines for drinking-water quality for an introduction to
those assessment techniques (2).

In contrast to the tools for assessing exposure in a single medium, such as air or water, some tools can
be used for characterizing the distribution of chemical pollutants among multiple environmental media,
including surface water, soil, sediment and air, as well as partitioning between the gas, aqueous and
solid phases in each of those media. Rather than simulating transport and fate based on atmospheric
turbulence, flows of water and other advective processes, these models rely upon physicochemical
properties of a chemical to predict its distribution among environmental media based on diffusive
processes. As a result, the geographical extent of the assessment domain and the initial pollutant
concentrations at the boundaries of the domain are important characteristics of the assessment. For
these and other reasons, multimedia models of this type typically operate on a regional rather than local
scale. Environmental fate models continue to evolve; discussion of developments in this area can be found
in the scientific literature.

The European Union System for the Evaluation of Substances (EUSES) includes a multimedia
environmental transport and fate model that was developed specifically for chemical risk assessment.
The EUSES model, supporting documentation and training materials are available from the ECHA website
(138). EUSES is intended mainly for initial and refined risk assessments rather than for comprehensive
assessments.

4.8.6 Exposure concentrations

Exposure concentration is the concentration of a chemical in an environmental medium with which a
person is in contact. These media include air, water and soil in outdoor and indoor locations frequented by
a population, as well as food and products.

Ideally, exposure concentrations will be obtained for media, locations and durations that are
representative of potential human contact with a chemical of concern. Therefore, the amount of a
chemical in environmental media, food or products that is truly inhaled, ingested or in contact with skin
is of primary interest. For example, the concentration of a chemical in the breathing zone of an individual
is an example of an ideal exposure concentration, in contrast to the chemical concentration in outdoor or
indoor air. With respect to water, chemical concentrations in the actual water used for drinking, bathing
and cooking represent ideal exposure concentrations, in contrast to levels in sources of potable water,
such as a reservoir or river.

Examples of measurement-based approaches to determination of exposure concentrations are included

in the case studies in the annexes. Frequently used modelling approaches for estimating exposure
concentrations are introduced in subsections 4.8.4 and 4.8.5. In reference to subsection 4.8.5, exposure
assessment features in the EUSES model cover the entire life cycle of chemicals as well as their fate in all
environmental compartments at three spatial scales: the personal scale for consumers and workers, the
local scale for humans near point sources and the regional scale for humans exposed as a result of all
releases in a larger region. Detailed information on both types of approaches is provided in EHC 214 (8).
Finally, comprehensive summaries of exposure information for specific chemicals are available in many
of the directories of resources and cross-cutting resources identified in sections 4.4 and 4.5. Those
resources include exposure concentrations and rates of exposure that are reported in the scientific
literature for both occupational and environmental exposure scenarios in various countries and regions

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WHO human health risk assessment toolkit: chemical hazards

of the world. For example, the Joint Research Centre of the European Commission hosts the online
Information Platform for Chemical Monitoring (IPCHEM), which collates data on chemical occurrences,
mostly in Europe. IPCHEM is structured into four modules for environmental monitoring, human
biomonitoring, food and feed, and products and indoor air (139).

4.8.7 Exposure from products

In addition to exposure to chemicals in environmental media and food, the general population is also
exposed on a daily basis to chemicals present in products, such as household cleaners, insecticide
products, paints and personal care products. Awareness of products as an important source of exposure
to chemicals has increased in recent years, and much attention has been focused on assessing exposures
from products. Information on the presence of chemicals in products can be obtained from listings
of product ingredients, the scientific literature and Safety Data Sheets (for products also used in the
workplace), as well as from available databases such as the CompTox Chemicals Dashboard (16).

Several models have been developed by agencies to estimate exposure to chemicals from products, such
as the ConsExpo suite of models (see subsection 4.8.2) developed by the National Institute for Public
Health and the Environment of the Netherlands (RIVM). ConsExpo is recommended for use as a higher-
tier consumer exposure assessment model within the scope of the EU REACH (38, 39). Numerous other
models and tools are described in EHC 242 on dermal exposure (15).

WHO has developed generic models for estimating exposure to insecticides used for space spraying
(indoors and outdoors), as indoor residual sprays, for treatment of sleeping nets and for products used as
larvicides and molluscicides (43).

4.9 Risk characterization resources

Information on risk characterization, the last step of risk assessment, is usually addressed by the
documents listed in Tables 9 and 10 of subsection 4.4.1.

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5. EVOLVING APPROACHES AND
METHODOLOGIES
Methodologies for chemical risk assessment continue to evolve over time as more knowledge and
experience are gained, and with the increasing pace of technological advancements as a means of
generating and analysing relevant data. International collaborative activities, such as those undertaken
under the WHO Chemical Risk Assessment Network (140) and other initiatives, contribute significantly
to the development of forward-looking and harmonized approaches to risk assessment. Some evolving
developments in chemical risk assessment methodology, which may be incorporated into international
evaluations that could be consulted by users of this toolkit, are described briefly below.

5.1 Evidence-based methodologies

The widespread adoption of evidence-based medicine has prompted scientists to apply the principles
of evidence-based quality assessment and systematic review to toxicology and human health risk
assessment. To assess the quality of a body of evidence and to develop and report recommendations
when developing guidelines, WHO has adopted the widely used Grading of Recommendations
Assessment, Development and Evaluation (GRADE) approach (141). This is a structured framework for
assessing the quality of evidence using processes that are explicit and transparent (58). The GRADE
approach to rating quality of evidence is illustrated in Figure 12.

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WHO human health risk assessment toolkit: chemical hazards

Figure 12.  The GRADE approach to rating quality of evidence for each outcome

1 2 3
Establish initial level of Consider lowering or raising level of Final level of quality
quality or confidence quality or confidence (confidence rating)

Study Initial Reasons for considering lowering or Confidence in

design confidence in raising confidence an estimate of
an estimate effect across all
of effect Lower if Higher if# considerations

Randomized High Risk of bias Large effect High

controlled confidence
Inconsistency Dose response
trials
Indirectness All plausible
confounding and bias Moderate
Imprecision
— would reduce a
Publication
demonstrated effect
bias
Observational Low or Low
studies confidence
— would suggest a
spurious effect if no effect
Very low
was observed

# Note: Criteria for upgrading the quality are only applicable to observational studies without any reason for downgrading.
Source: WHO (58).

As noted above in subsection 4.4.1, WHO is developing a high-level framework document on the use of
systematic review in chemical risk assessment. Systematic review refers to a structured and documented
process for consideration of relevant information with the goals of minimizing error and bias and the
production of a transparent literature review. Other institutions, including the United States National
Toxicology Program and EFSA, have developed detailed guidance for the use of systematic reviews and
evidence integration in human health risk assessment (142, 143).

5.2 Chemical grouping and read-across

To facilitate the assessment of multiple related chemicals simultaneously, including those for which
limited information is available, OECD has published guidance on analogue and category approaches
(144). In the analogue approach, data gaps for a specific chemical are filled using data from one or
more similar chemical(s) (“the analogue(s)”) or “source” chemicals to predict the same end-point for
the “target” chemical. In the category approach, chemicals whose physical-chemical and toxicological
properties are likely to be similar or follow a regular pattern as a result of structural similarity may be
considered as a group. This approach differs from the analogue approach, in which each chemical is
assessed on an individual basis, in that the properties of the individual chemicals within a category are
assessed on the basis of the evaluation of the category as a whole, rather than based on measured
data for any one particular chemical alone. Data gaps can be filled in a number of ways, including by
read-across (qualitatively or quantitatively) from one or more other chemicals in the category. Within a
chemical category, the members are often related by a trend in an effect for a given end-point, and a
trend analysis can be carried out through deriving a model based on the data for the members of the

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 5. Evolving approaches and methodologies

category. Grouping and read-across approaches can reduce the need for experimental testing since every
substance does not need to be tested if these approaches can be applied instead.

5.3 Threshold of toxicological concern

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that may be used to
assess potential human health concerns for a chemical based on its structural similarities to other
chemicals and estimated exposure when chemical-specific toxicity data are scarce or absent. The TTC
approach is a fit-for-purpose methodology that can be used as a screening tool, to assess low-dose
chemical exposures and to identify those for which further data are necessary to assess the human health
risk. It can be used where evaluation of a large number of compounds with low exposure is required,
in prioritization of large numbers of compounds where resources are limited, or when a rapid safety
assessment is needed. This approach has evolved over the years and was expanded by EFSA and WHO
to develop a tiered approach and accompanying decision tree, recognizing that the TTC approach is not
suitable for some types of chemicals, such as high-potency carcinogens, inorganics, metals and various
others (145). EFSA has published guidance on the use of the TTC approach in food safety assessment (146).

5.4 Adverse Outcome Pathways

OECD, through engagement of its member countries, has been leading the ongoing development of
Adverse Outcome Pathways (AOPs) to support development of testing strategies and hazard assessment
based on mechanistic reasoning (104). Based on the same principles as the WHO/IPCS Mode of Action
framework (11), an AOP describes a plausible sequence of causally linked key events (KEs) and key event
relationships (KERs) at different levels of biological organization, from the molecular initiating event (MIE)
resulting from exposure to a chemical stressor to an adverse outcome (health effect) in humans or wildlife.
AOPs are available in the OECD AOP Wiki, an interactive and virtual encyclopaedia for AOP development.
Following their development and review, endorsed AOPs are published in the OECD series on Adverse
Outcome Pathways (147). A guidance document for developing and assessing AOPs and a users’ handbook
are also available through OECD (148). A schematic representation of the AOP is illustrated in Figure 13.

Figure 13.  Schematic representation of the AOP illustrated with reference to a number of
pathways

Macro-
Cellular Organ Organism Population
Toxicant molecular
responses responses responses responses
interactions

Chemical Receptor/ligand Gene activation Altered Lethality Structure

properties interaction physiology Extinction
Protein Impaired
DNA binding production Disrupted development
homeostasis
Protein Altered Impaired
oxidation signalling Altered tissue reproduction
development/
function

Source: Figure reproduced from OECD (104)

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While AOPs and Mode of Action (MOA) analyses are conceptually identical in that they both describe a
sequence of causally linked events leading to toxicity, AOPs do not apply to specific chemicals whereas
MOA analyses are constructed for specific chemicals and therefore require incorporation of chemical-
specific information, such as metabolism and toxicokinetics, in consideration of species concordance (149).
Therefore, a MOA could be considered an extension of an AOP (Figure 14).

Figure 14. Illustration of the relationship between MOA and AOP

Mode of Action

Adverse Outcome Pathway

Molecular
Adverse
Initiating KER Key Event KER Key Event KER Key Event KER
Outcome
Event

Macro- Cellular Organ Organism Regulatory-

Molecular Responses Responses Responses Relevant
Interactions Population
Responses

Chemical ADME

Target tissue

Absorption,
Distribution,
Metabolism, Excretion

Exposure

Source: Edwards et al. (149).

5.5 New approach methodologies

Extensive work continues to be undertaken by numerous national and international institutions (such as
ECHA, OECD, and the Joint Research Centre of the European Community) to enhance the incorporation
of new approach methodologies (often referred to as “NAMs”) in human health risk assessment. New
approach methodologies include a range of non-animal testing approaches including in silico tools, in
chemico and in vitro assays, and high-throughput screening and high-content methods such as genomics,
proteomics and metabolomics (150). New approach methodologies are important in informing integrated
approaches to testing and assessment (151), providing guidance for targeted testing strategies. In addition
to providing valuable information on the toxicity of chemicals, new approach methodologies are also
being developed for application in exposure assessment, complementary to measurement data (152).

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 5. Evolving approaches and methodologies

5.6 Use of in vitro data to characterize dose–response

In light of initiatives to reduce animal testing and to be more efficient and human relevant in toxicological
assessment, dose–response data from in vitro studies are increasingly being considered in risk
assessment. There are a number of challenges to be addressed in this area, including establishment of
the qualitative and quantitative relationships between in vitro observations and adverse in vivo effects. An
extensive ongoing area of research, referred to as quantitative in vitro to in vivo extrapolation (QIVIVE),
addresses these challenges, facilitating greater quantitative use of in vitro data in human health risk
assessment. For example, a workflow tool for conducting in vitro to in vivo extrapolation (IVIVE) analyses
is available in the Integrated Chemical Environment (ICE) of the United States National Toxicology Program
(153).

5.7 Strategies for assessing and testing multiple chemical exposures

Since humans are usually exposed to several chemicals concurrently, WHO has also developed a
framework to assess coexposures to multiple chemicals (Figure 15). The framework involves a tiered
approach of increasing levels of refinement for integrated and iterative consideration of exposure and
hazard at all phases (61–63).

Figure 15. Conceptual representation of the IPCS framework for the risk assessment of
combined exposure to multiple chemicals

Example tiered exposure and hazard considerations:

Mixture or component based

Tiered exposure Tiered hazard assessments

assessments

Tier 0 Yes, no further action Tier 0

Simple semi-quantitative required Default dose addition for all
Increasing refinement of exposure models

Increasing refinement of hazard models

estimates of exposure components

Tier 1 Tier 1
Generic exposure scenarios using Refined potency based on
conservative point estimates Is the margin of individual POD, refinement of
exposure adequate? POD
Tier 2
Refined exposure assessment, Tier 2
increased use of actual measured More refined potency and
data No, continue with grouping based on mode of
iterative refinement action
Tier 3 as needed (i.e. more
Probabilistic exposure estimates complex exposure and Tier 3
hazard models) PBPK or BBDR, probabilistic
estimates of risk

Source: Meek et al. (62).

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WHO human health risk assessment toolkit: chemical hazards

OECD has published an overview of the technical aspects of the various approaches and methodologies
available with respect to the assessment of risks from combined exposures to multiple chemicals that
draws from approaches applied and experience gained in a regulatory context (154). While the document
does not provide guidance, it outlines key scientific considerations to be taken into account in assessing
such exposure situations and the application of risk characterization through a tiered approach.

The EuroMix project (155) was initiated to support development of a harmonized tiered strategy for risk
assessment of combined exposures to multiple chemicals from multiple sources as well as development
of efficient strategies for testing to generate data for refining risk assessment of mixtures. Outputs of the
EuroMix project include a Toolbox of models and data to support chemical mixture risk assessment (156)
and the EuroMix handbook (157).

The development of methodologies to assess risks from multiple chemicals is recognized as an important
issue by all stakeholders, and this is a topic where methodologies are anticipated to continue to evolve
over time.

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80
ANNEX 1. DRINKING-WATER
CASE STUDY

A1.1 Objective
The objective of this fictional case study is to demonstrate how the principles and roadmaps that comprise
the toolkit can be used by a public health or related professional to evaluate potential risks of chemical
contaminants in drinking-water as a result of emissions from a discrete or point source. The specific
roadmaps for this scenario are shown in Figures A1.1, A1.2, A1.3 and A1.4.1

While the aim of the case study is to demonstrate the thinking behind all stages of human health
risk assessment, including hazard identification, hazard characterization/guidance or guideline value
identification, exposure assessment, and risk characterization, the user of the toolkit should be aware that
measuring substances in drinking-water for which drinking-water guidelines exist allows a quick initial
assessment of the potential scale of the problem and whether there is a need to take action.

A1.2 Statement of the problem

A metal finishing facility is located on the bank of the fictional Flowing River in the fictional Country X
in Asia. Liquid waste from the plating operations pours from a discharge pipe directly into the river in
conjunction with the 24 hours per day, seven days per week operating schedule of the facility. Additional
information on the plant operations, such as the rate of production and the content of the liquid waste,
is not available. The Flowing River flows directly through the community of Rivertown, which is a short
distance downstream of the plating facility. Water from the river is used by the residents of Rivertown
for drinking, cooking and bathing. Preliminary research by the official Rivertown Department of
Environmental Health has identified cadmium as a by-product of chrome plating operations. To address
public health concerns, the Department of Environmental Health undertakes an evaluation of the potential
health risks of cadmium releases into the Flowing River.

The questions to be asked are as follows (see also Figure 2 in section 3.1 in the main toolkit document):

― What is the identity of the chemical of concern?

― Is the chemical potentially hazardous to humans?
― What properties of the chemical have the potential to cause adverse health effects?
― Do guidance or guideline values from international organizations exist for the chemical?
― What assumptions about exposure and dose are incorporated into guidance or guideline values for
the chemical?
― Do those assumptions reflect conditions specific to the local situation?
― In what ways could people come into contact with the chemical?

1 Note: The case studies presented here were developed for illustrative purposes in the application of the toolkit to
different scenarios and may not represent the most recent evaluations of the chemicals discussed.

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WHO human health risk assessment toolkit: chemical hazards

― How much exposure is likely to occur?

― For how long is exposure likely to occur?
― What metric of exposure is appropriate for characterizing health risks?
― How does the estimated exposure compare with the health-based guidance or guideline values?

A1.3 Hazard identification

What is the identity of the chemical of concern?
It is probable that cadmium is one of the hazards and may be the only hazard. However, while carrying out
an investigation on cadmium, it is important to seek further information from the company and other local
authorities as to what else (for example, cyanide) might be in the effluent.

In situations where an industrial process or operation is of interest, the assessor should search the
emission scenario documents described in subsection 4.8.3 of the main toolkit document for information
relevant to the current situation. The full-text search feature of the INCHEM database (1) can also be
helpful. In addition to these international resources, permits or building plans that may have been filed
with local or provincial authorities may contain useful information about health hazards associated
with the metal finishing operation. Also, initiating dialogue with representatives of the facility and other
members of the community is an essential step in identifying all contaminants of concern. Finally,
collection and analyses of wastewater should be considered in identifying contaminants.

Output: Cadmium is identified as the chemical of immediate concern. Other chemicals might also be of
concern, including cyanide, and action should be taken to identify these.

Is cadmium potentially hazardous to humans?

Data on the effects of cadmium can be found by looking in the INCHEM database (1). Selecting the entry
for cadmium brings the user to the International Chemical Safety Card (ICSC) for that chemical (2). The
Chemical Abstracts Service (CAS) number is found in the first row of the card: CAS No. 7440-43-9. Other
information contained on the card includes a brief list of acute hazards and symptoms as well as how
cadmium is identified in the United Nations (UN) classification scheme known as the Globally Harmonized
System of Classification and Labelling of Chemicals (GHS) (3). The health hazards for cadmium according to
the GHS classification scheme are shown in Table A1.1.

Table A1.1  GHS classification for cadmium

Hazard class and categorya Hazard statement

Acute toxicity (category 2) H330: Fatal if inhaled

Germ cell mutagenicity category 2 H341: Suspected of causing genetic defects

Carcinogenicity category (1A) H350: May cause cancer (route of exposure, if applicable)

Reproductive toxicity category 2 H361: Suspected of damaging fertility or the unborn child

Specific target organ toxicity (single exposure) H372: Causes damage to organs (or affected organs) through
Category 1 prolonged or repeated exposure
a
Some older reference sources may also make reference to the former EU system for classification (with risk phrases such as R26 (very toxic by inhalation)). Guidance
on the transition from that system to a system aligned with the GHS is available (4).

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 Annex 1. Drinking-water case study

Review of the IARC monographs (5) confirms that cadmium has been classified in Group 1: carcinogenic to
humans.

Output: Knowledge that cadmium is a hazardous chemical and that it has been classified to be very
toxic and carcinogenic to humans.

A roadmap for the hazard identification step of the drinking-water case study is shown in Figure A1.1.

Figure A1.1  Case-specific roadmap for hazard identification: drinking-water case study

No 
One of the chemicals of (Note: Chemicals other than
cadmium that have not yet been
concern is cadmium identified might also be of concern;
not considered in this case study)

Cadmium is very toxic and Gather information on chemical by-products and waste
carcinogenic streams associated with the source or process
No

Stop Search emission scenario documents for the industry or

process of interest

Key references include the International Full-text search of INCHEM database

Chemical Safety Card (ICSC) no. 20 and
IARC monograph volume 100C

Review any available public documents on the specific

source or site

Communicate with parties who may have knowledge of

the source or site

Proceed to exposure assessment and Local officials and International

hazard characterization stakeholders organizations

Bold lines indicate the flow of information gathering and analysis described in the text.

A1.4 Hazard characterization/guidance or guideline value identification

What properties of the chemical have the potential to cause adverse health effects?
Searching the INCHEM database in the previous step brought the user also to the WHO Food Additives
Series No. 52: Cadmium (addendum) (6) and other documents, including an EHC monograph (7), that
describe the toxicological properties of cadmium.

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WHO human health risk assessment toolkit: chemical hazards

Output: Knowledge about the principal toxic end-points of cadmium, considered to be kidney
dysfunction, lung damage, hepatic injury, bone deficiencies, hypertension and cancer, depending on
route, dose and duration of exposure, as well as knowledge that cadmium accumulates in the kidney.

Do health-based guidance or guideline values from international organizations exist for cadmium?
Sources mentioned in section 4.7 provide information on existing guidance and guideline values. JECFA
recommended a provisional tolerable weekly intake (PTWI) for cadmium of 0.007 mg/kg body weight. The
WHO Guidelines for drinking-water quality contain a guideline value for cadmium of 0.003 mg/L (Table A1.2).
WHO has not published a relevant health-based air quality guideline for cadmium (see also Tables 6 and 7
in the main toolkit document).

Table A1.2  International guidance and guideline values for cadmium

Type of value Guidance or guideline value Reference

Food guidance value 0.007 mg/kg body weight (PTWI)a WHO (8)

Drinking-water guideline value 0.003 mg/L WHO (9)

a
The PTWI included for the purposes of this case study was published by JECFA in 2005. However, it should be noted that JECFA subsequently published, in 2010, a
provisional tolerable monthly intake (PTMI) of 0.025 mg/kg body weight (8).

Output: Knowledge about international guidance and guideline values for cadmium in drinking-water
and food.

What assumptions about exposure and dose are incorporated into the WHO drinking-water guideline value for
cadmium?
Water is the most important pathway of exposure (see section A1.5); therefore, the WHO drinking-water
guideline for cadmium is of main interest. The WHO drinking-water guideline for cadmium is described
in section 12.1 of the current edition of the WHO Guidelines for drinking-water quality (9). According to
the table of key items presented for cadmium in that section, the guideline value is based on a default
water consumption rate of 2 litres per day, a body weight of 60 kg and an allocation to water of 10% of
the provisional tolerable weekly intake PTWI. It is recognized that population average water consumption
rates can vary significantly, perhaps by a factor of 2–4, in different parts of the world, particularly where
consumers are engaged in manual labour in hot climates. Similarly, typical body weights can also vary
among countries or regions, although the range of uncertainty is likely to be less than ± 25%. Overall,
the range of uncertainty about water consumption rates and body weights is quite small in comparison
with the much larger range in toxicological uncertainty that exists for the vast majority of chemicals.
Consequently, the default assumptions for those parameters are likely to be adequate in nearly all
situations.

In order to account for the variations in exposure from different sources in different parts of the world, a
certain proportion of the acceptable daily intake (ADI), tolerable daily intake (TDI), PTWI, and similar values,
generally between 1% and 80%, is allocated to drinking-water in setting drinking-water guideline values
for many chemicals. Where relevant exposure data are available, authorities are encouraged to develop
context-specific guideline values that are tailored to local circumstances and conditions. For example, in
areas where the intake of a particular contaminant in drinking-water is known to be much greater than
that from other sources (such as food and air), it may be appropriate to allocate a greater proportion of

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 Annex 1. Drinking-water case study

the ADI, TDI, PTWI, and other similar parameters to drinking-water to derive a guideline value more suited
to the local conditions.

Output: The WHO drinking-water guideline value for cadmium is based on a default water consumption
rate of 2 litres per day, a body weight of 60 kg and an allocation to water of 10% of the PTWI.

Do those assumptions reflect conditions specific to the local situation?

In the case of Rivertown, the Rivertown Department of Environmental Health would require detailed
information on food consumption patterns, cadmium levels in specific foods, and levels of cadmium
in air and soil to consider deriving a context-specific drinking-water guideline value for cadmium. The
water is not used for irrigation of crops, so, in the absence of information on contact rates, body weight,
absorption fraction and total exposure to cadmium from the general diet specific to local conditions, the
Rivertown Department of Environmental Health elects to rely upon the WHO drinking-water guideline
value for cadmium of 0.003 mg/L in the risk assessment. This is an appropriate decision, as the WHO
drinking-water guideline values account for ingestion through food and are considered, in most cases,
sufficient to account for intake of contaminants through inhalation and dermal absorption.

Output: The WHO drinking-water guideline value for cadmium of 0.003 mg/L is appropriate to be used
under the given local conditions.

A roadmap for the hazard characterization step of the drinking-water case study is shown in Figure A1.2.

Figure A1.2  Case-specific roadmap for hazard characterization/guidance or guideline

value identification: drinking-water case study

Toxic end-points of cadmium include kidney dysfunction,

lung damage, hepatic injury, bone deficiencies,
hypertension and cancer

Relevant guidance/guideline values are:

— JECFA PTWI for food of 0.007 mg/kg body weight, and
— WHO drinking-water guideline value of 0.003 mg/l

The default contact rates of 2 l/day and

60 kg body weight considered appropriate. No

Determine the appropriate contact rate

No
A default value of 10% for allocation of Determine the appropriate allocation of exposure rate
PTWI is considered appropriate

Determine the situation-appropriate exposure rate based

on contact rate and/or allocation

Proceed to exposure assessment

Bold lines indicate the flow of information gathering and analysis described in the text.

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A1.5 Exposure assessment

In the context of the risk assessment toolkit, the goal of the exposure assessment is to obtain an estimate
of exposure concentration or rate that can be compared with the appropriate guidance or guideline value.
As described in section 3 of the main toolkit document, several combinations of guidance or guideline
values and exposure metrics are possible, depending upon the medium (or media) and exposure routes
that are most appropriate for the situation.

In what ways could people come into contact with the chemical?
The river forms the basis of the water supply to the town, so exposure through drinking-water is
likely. Water is also used for cooking and bathing. It is important to consider whether drinking-water
consumption is likely to be significantly greater than the 2 litres a day for adults used by WHO to derive the
drinking-water guideline. The water is not used for irrigation, and therefore it is unlikely that food crops
are contaminated.

Output: People come into contact with the chemical through water. Ingestion of drinking-water and
water used for cooking and dermal absorption through bathing are the most relevant routes of
exposure.

How much exposure is likely to occur?

It is important to obtain further information on the concentration of cadmium (and any other identified
contaminants of concern) in order to more accurately assess exposure. Where there is water treatment, it
would be appropriate to measure the concentration in water at the water treatment plant after treatment.
However, cadmium can also leach from galvanized water supply pipes (usually in buildings), so if such
pipes are in use, a sample at a tap in a building using such pipes would be important in judging overall
exposure from drinking-water. Crops have not been irrigated, and therefore crop samples are not needed
to judge the total exposure to cadmium.

Measurements require that the assessor has access to appropriate protocols and supplies for sampling,
storage, transport and analysis of water samples obtained from the river and drinking-water. This also
means that there must be access to suitable analytical facilities with an adequate level of expertise
and quality assurance, as incorrect analytical data are highly misleading and have led to inappropriate
decisions in a number of circumstances. In some cases, it may be appropriate to use models to determine
how much of a contaminant will reach a point downstream from a discharge. Models require information
on the discharge rate of cadmium through the effluent pipe that extends from the facility to the river.

Guidance on appropriate measurement and modelling methods is provided in several documents

and other materials produced by international organizations and countries. In particular, Guidance on
information requirements and chemical safety assessment, prepared in conjunction with the Registration,
Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation in the EU, provides a detailed
discussion of measurement and modelling approaches (10). Measurement and modelling approaches both
require a study design that will allow the assessment question to be answered. General guidance on the
design and implementation of exposure investigations is provided in EHC 214 (11).

Unable to obtain information needed to model the concentration of cadmium in water drawn from the
river, the Rivertown Department of Environmental Health makes the decision to estimate long-term
average exposure concentrations from direct measurements. Information on sampling and analysis
methods is available in EHCs and CICADs prepared for specific chemicals. EHC 134 on cadmium
(7) contains introductory information on analytical methods for cadmium, including collection and

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preparation of samples, separation and concentration, methods for quantitative determination and quality
control. Specific methods for sampling water and analysis of cadmium and other metals are available from
country resources, such as the United States EPA’s Method 1669: sampling ambient water for trace metals at
EPA water quality criteria levels (12).

The Rivertown Department of Environmental Health collects water samples from three locations on five
separate days: upstream of the metal finishing facility, downstream of the metal finishing facility and from
the tap of the town hall building. The average concentrations of cadmium in the samples obtained from
those locations are shown in Table A1.3.

Table A1.3  Cadmium concentrations in five samples of water obtained from each of three
locations in the vicinity of Rivertown

Location Average concentration (µg/L) Concentration range (µg/L)

Upstream of facility < LOD < LOD–0.2

Downstream of facility 0.4 0.1–1.0

Town hall water 0.3 0.2–0.8

LOD = limit of detection (0.1 µg/L).

The results of the water sampling indicate that concentrations of cadmium downstream of the metal
finishing facility are greater than concentrations upstream of the facility. The results also indicate that
cadmium concentrations in potable water received from the Flowing River are approximately equal to the
levels in the river downstream of the facility.

Output: A quantitative estimate of cadmium exposure, with levels greater downstream of the facility
compared with upstream, and with concentrations in drinking-water approximately equal to the
downstream levels.

For how long is exposure likely to occur?

The assessor has knowledge that the facility routinely operates 24 hours per day, seven days per week.
Therefore, long-term average conditions and long-term exposure are of primary interest. The assessor
should also consider variation in operations of the facility or flow of the river that could result in transient
increases in exposure concentrations.

Output: Knowledge that long-term exposure is of concern, with exposure levels that can vary over time
as a result of the operations of the facility.

What metric of exposure is appropriate for characterizing health risks?

Having selected the environmental medium (water), exposure route (mainly ingestion) and exposure
duration (long-term) of interest, the next step is to determine if an international guidance or guideline
value exists that corresponds to those criteria. In this case, data gathering conducted in support of the
hazard characterization step revealed that WHO has established a guideline value of 0.003 mg/L for long-
term average concentrations of cadmium in drinking-water. The form of the guideline value dictates the
form of the exposure estimate required for the risk characterization step. Thus, the risk assessor in this

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WHO human health risk assessment toolkit: chemical hazards

case study requires an estimate of long-term average concentrations of cadmium in water drawn from the
Flowing River in order to proceed to the risk characterization step.

Output: Knowledge that a long-term average exposure concentration is needed to perform the risk
characterization.

A roadmap for the exposure assessment step of the drinking-water case study is shown in Figure A1.3.

Figure A1.3  Case-specific roadmap for exposure assessment: drinking-water case study

— The source is a local point source (metal finishing

company)
— The pathway of exposure is river water
— The exposure medium is drinking-water

Measurements show concentrations of:

— 0.0004 mg/l cadmium in river water;
and
— 0.0003 mg/l at community water supply.

Exposure is considered to be long term and

continuous with levels that might vary.

The guideline value is expressed as a Exposure rate or Estimate the rate of contact
concentration in drinking-water in mg/l cancer slope factor with the medium

Estimate the rate of exposure

Proceed to risk characterization

Bold lines indicate the flow of information gathering and analysis described in the text.

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 Annex 1. Drinking-water case study

A1.6 Risk characterization

How does the estimated exposure compare with the guidance or guideline values?
The objective of the risk characterization step is to address the risk assessment question by combining the
information gathered on exposure and hazard characterization. As noted in subsection 3.3.5 of the main
toolkit document, health risk can be characterized in various ways. In many cases, risk characterization
consists of comparing an estimate of chemical exposure with a guidance or guideline value. The exposure
and guidance or guideline value can be expressed as either a concentration or an exposure rate. The
exposure and guidance or guideline values should reflect the same averaging time; if not, the assessor
should be cognizant of any differences when interpreting the results of the risk characterization.
Where exposure is short term and the guidance or guideline value long term, this provides a more
conservative assessment. If the long-term guidance or guideline value is exceeded in short-term
exposure, it would be necessary to consider other questions. For example, is exposure from food such
that the allocation of the PTWI to water can be increased without exceeding the PTWI? If the exposure of
interest is still greater than the PTWI, it is appropriate to examine the derivation of the PTWI to determine
if the uncertainty factors are excessively conservative for the situation. For example, an additional factor
to allow for extrapolation from medium-term to long-term exposure would not be appropriate if exposure
was actually short term.

Referring to the first step in the flow chart shown in Figure A1.4, the objective of the Rivertown
Department of Environmental Health was to evaluate potential health risks associated with cadmium
releases into the Flowing River. Based upon the available risk-based criteria for cadmium in drinking-water,
it is apparent that the assessment involves comparing estimated exposures with a health-based guideline
value. In this case, the value is 0.003 mg/L, the WHO guideline value for cadmium in drinking-water.
Turning to the exposure metrics, at least two are available: (a) the average concentration of cadmium in
drinking-water downstream of the metal finishing facility (0.0004 mg/L); and (b) the average concentration
of cadmium in water drawn from the community water supply (0.0003 mg/L). Taking the ratio of the
exposure to the guideline value, the hazard quotient is calculated to be approximately 0.1 in this case.
Exposures are therefore estimated to be less than the guideline value.

If the concentration in the river was below but close to the guideline value, it would still be appropriate to
determine whether there was potential exposure from the plumbing system.

Output: The hazard quotient is approximately 0.1 for cadmium in drinking-water. As a result, the
cadmium exposures are unlikely to result in any adverse health effects.

In terms of actions, there is no immediate cause for concern. However, it would be appropriate to consider
whether it was feasible to reduce concentrations in the effluent to prevent accumulation of cadmium in
sediment that could be mobilized at a later time if conditions change.

A roadmap for the risk characterization step of the drinking-water case study is shown in Figure A1.4.

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WHO human health risk assessment toolkit: chemical hazards

Figure A1.4  Case-specific roadmap for risk characterization: drinking-water case study

The objective is to evaluate if the consumption of drinking-water drawn from

the Flowing River is likely to cause a health risk

The assessment requires comparison with a guideline value

Calculate
cancer risk

The WHO drinking-water guideline Obtain the cancer slope factor for the
value for cadmium is 0.003 mg/l chemical

The exposure concentrations are:

— 0.0003 mg/l in river water; and
— 0.0004 mg/l in the community water supply

The hazard/risk quotient is approximately 0.1 Calculate excess lifetime cancer risk as the
for river and community supply water product of exposure concentration or rate and
the cancer slope factor

Cadmium exposure through drinking-water is Is the excess lifetime cancer risk high or low
10 times lower than the WHO drinking-water (e.g. greater than 1 in 10 000 or less than 1 in a
guideline value million)?

Report results to risk management team

Bold lines indicate the flow of information gathering and analysis described in the text.

A1.7 Summary
An assessment was conducted of potential health risks associated with ingestion of cadmium introduced
into a community water supply as a result of emissions to surface water from a metal finishing facility.
Cadmium is reported to accumulate in the kidney, which is also the main target for cadmium toxicity.
Consequently, potential health risks of long-term average exposure to cadmium in drinking-water are
the primary concern of local authorities. The WHO guideline value for cadmium in drinking-water was
selected as the most appropriate guidance or guideline value for evaluation of potential risk. The exposure
assessment was based on measurements of cadmium in drinking-water on five separate days. Average
concentrations of cadmium in river water and drinking-water samples were consistent with contributions
from the metal finishing facility, yet were approximately 10 times below the WHO guideline value. This
evaluation indicates that risks of adverse health effects from cadmium exposure associated with the
facility are relatively low. Authorities should consider obtaining additional plant information and sampling
data needed to confirm these findings with exposure periods representative of longer-term average
conditions.

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REFERENCES: ANNEX 1
1. INCHEM internationally peer reviewed chemical safety information. Geneva: World Health
Organization, International Programme on Chemical Safety (http://www.inchem.org/pages/icsc.html,
accessed 14 November 2020).
2. International Chemical Safety Cards (ICSCs). Cadmium ICSC #0020. Geneva: International Labour
Organization and World Health Organization (https://www.ilo.org/dyn/icsc/showcard.display?p_
lang=en&p_card_id=0020&p_version=2, accessed 7 February 2021).
3. Globally Harmonized System of Classification and Labelling of Chemicals (GHS, Rev.8). Geneva:
United Nations Economic Commission for Europe; 2019 (https://www.unece.org/index.php?id=51896,
accessed 14 November 2020).
4. European Union. Chemicals at work – a new labelling system. Guidance to help employers and
workers to manage the transition to the new classification, labelling and packaging system.
European Commission 2013 (https://osha.europa.eu/en/file/40573/, accessed 7 February 2021).
5. Arsenic, Metals, Fibres, and Dusts. IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans Volume 100C. International Agency for Research on Cancer; 2012 (https://publications.iarc.
fr/120, accessed 7 February 2021).
6. International Programme on Chemical Safety. Safety evaluation of certain food additives and
contaminants: prepared by the sixty-first meeting of the Joint FAO/WHO Expert Committee on Food
Additives (JECFA). WHO Food Additives Series No. 52. Geneva: World Health Organization; 2004
(https://apps.who.int/iris/handle/10665/43038, accessed 28 December 2020).
7. International Programme on Chemical Safety. Cadmium. Environmental Health Criteria 134. Geneva:
World Health Organization; 1992 (http://www.inchem.org/documents/ehc/ehc/ehc134.htm, accessed
28 December 2020).
8. Food safety databases. Geneva: World Health Organization (https://www.who.int/teams/nutrition-
and-food-safety/databases, accessed 28 December 2020).
9. Guidelines for drinking-water quality: fourth edition, incorporating the first addendum. Geneva:
World Health Organization; 2017 (https://apps.who.int/iris/handle/10665/254637, accessed 11
November 2020).
10. Guidance on information requirements and chemical safety assessment. Helsinki: European
Chemicals Agency (https://echa.europa.eu/guidance-documents/guidance-on-information-
requirements-and-chemical-safety-assessment, accessed 10 December 2020).
11. International Programme on Chemical Safety. Human exposure assessment. Environmental Health
Criteria 214. Geneva: United Nations Environment Programme, International Labour Organization
and World Health Organization (within the framework of the Inter-Organization Programme for the
Sound Management of Chemicals); 2000 (http://www.inchem.org/documents/ehc/ehc/ehc214.htm,
accessed 14 November 2020).
12. Method 1669: sampling ambient water for trace metals at EPA water quality criteria levels.
Washington (DC): United States Environmental Protection Agency; 1996 (https://www.epa.gov/sites/
production/files/2015-10/documents/method_1669_1996.pdf, accessed 28 December 2020).

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WHO human health risk assessment toolkit: chemical hazards

ANNEX 2. RESPIRABLE
PARTICULATE MATTER (PM10)
CASE STUDY

A2.1 Objective
The objective of this case study is to demonstrate how the principles and roadmaps of the toolkit can be
used to guide a review of the scientific factors that should be considered in the adoption or amendment
of national air quality standards for respirable particulate matter, defined by WHO as aerosols with
aerodynamic diameter less than 10 µm (PM10) (see also section 3.2 of the main toolkit document) (1, 2).
Specific roadmaps are shown in Figures A2.1, A2.2 and A2.3.1

The questions to be asked are as follows (see also Figure 2 in section 3.1 of the main toolkit document):

― What is the identity of the chemical of concern?

― Is the chemical potentially hazardous to humans?
― What properties of the chemical have the potential to cause adverse health effects?
― Do guidance or guideline values from international organizations exist for the chemical?
― What assumptions about exposure and dose are incorporated into guidance or guideline values for
the chemical?
― Do those assumptions reflect conditions specific to the local situation?
― In what ways could people come into contact with the chemical?
― For how long is exposure likely to occur?
― What metric of exposure is appropriate for characterizing health risks?

Questions not addressed in this case study are:

― How much exposure is likely to occur?

― How does the estimated exposure compare with the health-based guidance or guideline values?

PM10 was selected for a case study because of the unique attributes of this ubiquitous and well studied
air pollutant. PM10 is a mixture of chemical species, water and biological components and therefore
differs from the individual chemical substances considered elsewhere in this document. In addition,
epidemiological studies provide strong evidence that health effects occur in human populations at current
levels of respirable particulate matter.

1 Note: The case studies presented here were developed for illustrative purposes in the application of the toolkit to
different scenarios and may not represent the most recent evaluations of the chemicals discussed.

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 Annex 2. Respirable particulate matter case study

A2.2 Statement of the problem

Given findings from epidemiological studies and a growing concern about the impacts of ambient
respirable particles (or PM10) on health, Country A is interested in setting a national standard to regulate
ambient PM10 concentrations. The situation is that only limited PM10 monitoring data are available in the
country and in surrounding countries. Further, there is limited evidence from Country A of associations
between increased ambient PM10 concentrations and daily mortality, with supporting evidence from other
countries in the region.

At this time, the pollutant of interest to Country A is limited to respirable particles (PM10), not its individual
components, 2 and the default governmental standard is the WHO air quality guidelines for PM10.

The WHO air quality guidelines were developed based on scientific evidence of the risks posed by PM10
pollution to human health. It is important to note that these guidelines are not intended to be fully
protective of public health, as there is no identified “safe” concentration of ambient PM10. The guidelines
differ from PM10 standards set by individual countries, as they were developed for a wide variety of
situations across the world and do not take into account individual country characteristics and needs. For
individual countries, the WHO guidelines may need to be amended in light of scientific factors, such as
PM10 sources, populations at risk and geography, as well as policy-related factors, such as technological
feasibility and economic considerations.

A2.3 Hazard identification

What is the identity of the chemical of concern?
The hazard identification process for this example is relatively straightforward and follows the flow chart
in Figure A2.1. As shown in this figure, determining the identity of the chemical of interest is the first step
in the hazard identification process. In this case, the identity of the chemical is known to be ambient PM10.

Output: Identification of PM10 as the pollutant of interest.

Is PM10 potentially hazardous to humans?

WHO has evaluated the health effects of particulate matter (PM), including PM10. The evidence on airborne
PM and its public health impact is consistent in showing adverse health effects at exposures that are
currently experienced by urban populations in both developed and developing countries (1,2,3).

Output: Knowledge that PM, including PM10, is hazardous to humans at concentrations experienced by
urban populations worldwide.

2 Information about the specific components of PM10 may be important to consider for standard-setting purposes, as
scientific studies show individual PM10 components to have different health risks. Further, for regulatory purposes, the
PM10 components may provide important information, as they can help to establish appropriate source control strategies.

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WHO human health risk assessment toolkit: chemical hazards

Figure A2.1  Case-specific roadmap for hazard identification: particulate matter case study

The agent is PM10

No

PM10 is considered hazardous to No Gather information on chemical by-products and

humans at all concentrations waste streams associated with the source or process

Stop Search emission scenario documents for the

industry or process of interest

Key references include the WHO Air Full-text search of INCHEM database
Quality Guidelines and WHO publication
“Public Health Impact of Chemicals,
Knowns and Unknowns”
Review any available public documents on the
specific source or site

Communicate with parties who may have

knowledge of the source or site

Proceed to exposure assessment and Local officials and International

hazard characterization stakeholders organizations

Bold lines indicate the flow of information gathering and analysis described in the text.

A2.4 Hazard characterization/guidance or guideline value identification

What properties of PM10 have the potential to cause adverse health effects?
Air quality guidelines of the WHO Regional Office for Europe (1, 2) indicate that the range of health
effects caused by PM10 is broad, but that effects associated with short-term and long-term exposures
are predominantly to the respiratory and cardiovascular systems, with recent scientific studies finding
adverse health impacts at short exposures, in the order of 1–4 hours. All populations are affected, but
susceptibility to the pollutant may vary with health status or age. The risk for various outcomes has been
shown to increase with exposure, and there is little evidence to suggest a threshold below which no
adverse health effects would be anticipated.

Output: Description of health hazards for PM10 based on results from epidemiological studies.

Do health-based guidance or guideline values from international organizations exist for PM10?
WHO has set international guidelines for ambient PM10 of 20 µg/m3 averaged over a year and 50 µg/m3
averaged over 24 hours (Table A2.1). These are the lowest levels at which total, cardiopulmonary and lung
cancer mortality has been shown to increase in response to long-term exposure to PM.

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Table A2.1  WHO air quality guideline values for PM10

Type of value Guideline value Reference

Annual mean 20 µg/m3 WHO Regional Office for Europe (1, 2)

24-hour mean 50 µg/m3 WHO Regional Office for Europe (1, 2)

Besides the guideline values, three interim targets are defined for PM10. These have been shown to be
achievable with successive and sustained abatement measures. Countries may find these interim targets
particularly helpful in gauging progress over time in the difficult process of steadily reducing population
exposure to PM, including PM10 (Table A2.2) (1, 2).

Table A2.2  WHO interim targets for PM10: annual mean concentrations

Interim target PM10 concentration Basis for the selected level

1 70 µg/m3 This level is associated with about a 15% higher long-term mortality risk
relative to the annual air quality guideline mentioned in Table A2.1.

2 50 µg/m3 In addition to other health benefits, this level lowers the risk of premature
mortality by approximately 6% (2–11%) relative to the interim target 1
level.

3 30 µg/m3 In addition to other health benefits, this level reduces the mortality risk by
approximately 6% (2–11%) relative to the interim target 2 level.

Other countries have set their own PM10 standards. For example, the EU has established an annual limit
of 40 µg/m3, with this issue to be revisited in subsequent years (4). Interestingly, standards and guidelines
for PM10 are somewhat unique, in that they have been established primarily based on findings from
epidemiological studies and not toxicological studies.

Output: List of guideline values or standards for PM10.

What assumptions about exposure and dose are incorporated into guideline values for PM10?
As discussed in section A2.5, air quality standards for PM10 are expressed as concentrations in ambient air,
given a specific averaging time, and often also specifying the location of compliance monitors. The WHO
air quality guidelines and standards set by the EU, the United States of America and other countries reflect
assumptions about the relative importance of observed health outcomes (for example, mortality being
more important than asthma incidence), population characteristics and activity patterns of the population
(for example, number of potentially susceptible individuals, time spent outside, indoor PM10 sources), and
source characteristics and locations (for example, local versus regional sources, location of major PM10
sources relative to populations).

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WHO human health risk assessment toolkit: chemical hazards

Output: Knowledge about the health outcomes, population characteristics, activity patterns of the
population, pollution source characteristics and locations reflected in the guideline values or standards
for PM10.

Do those assumptions reflect conditions specific to the local conditions?

The relative importance of the assumptions is likely to be subjective, as are their relevance and
applicability to the standard-setting country. If, however, the assumptions are found to be appropriate
for the standard-setting country as well, then risk assessors may decide to adopt the PM10 guideline set
by WHO or standard set by another governmental group or country. Otherwise, risk assessors may want
to seek additional information to identify hazard characterization information applicable to their country.
This information can be obtained from a variety of sources, including (a) a review of the scientific literature
for PM10, with specific emphasis on studies from Country A or surrounding countries; (b) PM10 standards
for Country A or other countries; and (c) measurements or estimates of background PM10 concentrations,
which can include PM10 that originates from anthropogenic sources outside Country A. A roadmap for the
hazard characterization step is shown in Figure A2.2.

Output: Selection of the appropriate PM10 guideline value or standard for specific exposure averaging
times.

Figure A2.2  Case-specific roadmap for hazard characterization/guidance or guideline

value identification: particulate matter case study

Toxic end-points of PM10 include respiratory and cardiovascular effects.

Relevant WHO air quality guideline values are the:

— annual mean of 20 µg/m3; and
— 24 hour mean of 50 µg/m3.
In addition, WHO has established interim targets for PM10.

The contact rate is unknown.

In order to establish the contact rate, more weight
Yes should be given to studies conducted on populations and
pollution profiles most similar to those in Country A.

Characterize activity patterns and housing

characteristics that influence exposure to
ambient PM10

The allocation of exposure rate for the Evaluate the amount of personal PM10
local population is unknown exposure per unit of PM10 in outdoor air

Determine the situation-appropriate

exposure rate based on contact rate and/
or allocation

Proceed to exposure assessment

Bold lines indicate the flow of information gathering and analysis described in the text.

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 Annex 2. Respirable particulate matter case study

A2.5 Exposure assessment

In what ways could people come into contact with PM10?
In this case study, the assessor knows that PM10 is present in ambient air. Therefore, air is the
environmental medium of interest, with inhalation being the only route of exposure. The frequency of
exposure is likely to be constant: people may be exposed to ambient PM10 even when inside, as ambient
PM10 can readily enter homes and other buildings. Although the level of exposure may differ inside
compared with outside, epidemiological studies are generally based on ambient concentrations. As
a result, risks estimated by these studies intrinsically take into account the building types and activity
patterns of their study populations. As these factors can differ substantially by country and even city,
Country A should consider giving more weight to risk estimates obtained from epidemiological studies
conducted in populations with activity patterns and housing stock that are similar to those in Country A.

Output: Identification of air as the relevant environmental medium, inhalation as the exposure route
and exposure frequency as constant. Also, qualitative determination of the importance of housing stock
and activity patterns in evaluating PM10 exposures.

For how long is exposure likely to occur?

Decisions about the appropriate averaging time for the PM10 standard are more complicated, as
consideration should be paid not only to the exposure averaging time (year, day, hour or minute), but
also to how concentrations for this averaging time will be calculated and from which measurements and
monitoring sites. Exposure averaging times will generally be based on findings from epidemiological
studies, as these studies are the basis of existing PM10 standards and guidelines. As reflected in the WHO
annual and daily air quality guidelines, health effect studies conducted in countries across the world have
shown both acute and chronic adverse effects to be associated with exposure to PM10 in ambient air,
suggesting that both a short-term and a long-term standard are appropriate. To address acute adverse
effects, WHO set air quality guidelines based on a 24-hour averaging time, whereas WHO addressed
chronic effects using an annual average guideline. To determine the appropriate averaging time for a PM10
standard, countries can rely on the WHO air quality guidelines or on standards set by other countries
with similar populations, source profiles and topography. In addition, a variety of other resources may
be useful, including (a) PM10 monitoring data that show the relationship between annual and daily
concentrations; and (b) findings from health studies that identify the exposure windows of concern, taking
into account country-specific factors such as geography, sources and their location, and the country’s
inhabitants.

Output: Determination of the appropriate averaging times for an ambient PM10 standard, including an
evaluation of the importance of separate standards for daily and yearly mean PM10 concentrations.

What metric of exposure is appropriate for characterizing health risks?

Once the appropriate averaging time is selected, the method used to calculate the exposure averaging
time and the location of the compliance monitors must be determined. In terms of exposure averaging
time, the WHO guidelines average data across one year for the annual concentration limit for PM10 and
across one day for the 24-hour limit. In contrast, the annual PM10 standard in the United States is based
on the three-year average of the weighted annual mean PM10 concentrations from single or multiple
monitors representing population exposure. Similarly, the daily standard in the United States is based on
the three-year average of the 98th percentile of 24-hour concentrations at each monitor representing
population exposure. The calculations for the United States are intended to de-emphasize years or days
with unusually high concentrations (5).

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WHO human health risk assessment toolkit: chemical hazards

The final component of a PM10 standard is generally the location of the compliance monitors, which are
the monitors from which concentrations will be obtained to determine whether the PM10 standard is met
or violated. Specification of the compliance monitor locations is generally a key component of a PM10
standard, as it will help determine the stringency of the PM10 standard and may cause emissions from
certain PM10 sources to have more impact on standard compliance than others. Possible locations for
compliance monitors could include urban settings where people live, rural areas, or near roadways or
sources; alternatively, concentrations from monitors located across the country could be averaged.

Output: Specification of (a) the calculation used to estimate PM10 concentrations for the specified
exposure averaging times to allow comparisons with the PM10 standard; and (b) the location and
number of compliance monitors.

The question on How much exposure is likely to occur? has not been addressed in this case study because
of a lack of monitoring data. A roadmap for the exposure assessment step, as applied in this case study, is
shown in Figure A2.3.

Figure A2.3  Case-specific roadmap for exposure assessment: particulate matter case
study

Numerous sources contribute to air pollution.

The pathway of exposure is atmospheric transport.
The exposure medium is ambient air.

When measuring exposure concentrations, decisions

have to be made as to where to place monitors, with
considerations including source proximity, population
densities and urban versus rural locations.

Duration of the exposure is short term and long term.

For compliance monitoring, the number of years
appropriate for an annual standard and the number of
hours or days appropriate for a short-term standard need
to be determined.

The guideline value is expressed as a Exposure rate or Estimate the rate of contact with the
concentration in air in µg/m3. cancer slope factor medium

Estimate the rate of exposure

Stop here. Exposure data are not available in order to

proceed to the risk characterization step.

Bold lines indicate the flow of information gathering and analysis described in the text.

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 Annex 2. Respirable particulate matter case study

A2.6 Risk characterization

Because of the fact that exposure information is not available, the question on How does the estimated
exposure compare with the health-based guidance or guideline values? – and therefore the risk
characterization step – is not necessary for this example.

A2.7 Summary
Principles and roadmaps of the toolkit were used to guide the review of scientific factors to be considered
when adopting or amending international available guidance or guideline values or national standards
for respirable particulate matter (PM10) for local or national conditions. The range of health effects of PM10
is broad, but the effects associated with short-term and long-term exposures are predominantly to the
respiratory and cardiovascular systems, with recent scientific studies finding adverse health impacts at
short exposures, in the order of 1–4 hours. All populations are affected, but susceptibility to the pollutant
may vary with health status or age. WHO has set international air quality guidelines for ambient PM10
of 20 µg/m3 averaged over a year and 50 µg/m3 averaged over 24 hours. Knowledge about the health
outcomes, population characteristics, activity patterns of the population, pollution source characteristics
and locations is needed to adopt or amend existing international guidelines or national standards. In
addition, the case study discussed averaging time of a local standard and the method used to calculate
the exposure averaging time and the location of the compliance monitors.

99
REFERENCES: ANNEX 2
1. Air quality guidelines – global update 2005: particulate matter, ozone, nitrogen dioxide and sulfur
dioxide. Copenhagen: World Health Organization Regional Office for Europe; 2006 (https://apps.who.
int/iris/handle/10665/107823, accessed 14 November 2020).
2. WHO air quality guidelines for particulate matter, ozone, nitrogen dioxide and sulfur dioxide: global
update 2005: summary of risk assessment. Copenhagen: World Health Organization Regional Office
for Europe; 2006 (https://apps.who.int/iris/handle/10665/69477, accessed 28 December 2020).
3. International Programme on Chemical Safety. Public Health Impact, Knowns and Unknowns
publication. Geneva: World Health Organization; 2016 (https://www.who.int/publications/i/item/
WHO-FWC-PHE-EPE-16.01-eng).
4. Environment: air quality standards. Brussels: European Commission (https://ec.europa.eu/
environment/air/quality/standards.htm, accessed 28 December 2020).
5. United States of America. Revised air quality standards for particle pollution and updates to the air
quality index (AQI). https://www.epa.gov/sites/production/files/2020-04/documents/fact_sheet_pm_
naaqs_proposal.pdf (accessed 13 January 2021).

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ANNEX 3. PESTICIDE CASE STUDY

A3.1 Objective
In making decisions on the use of chemicals, many countries take into account risk assessments completed
by other countries or by international organizations. In doing so, these countries are faced with several
challenges, one of the most difficult of which is the assessment of whether and how the original risk evaluation,
including the exposure assessment, is relevant to their own conditions and situations. This assessment must
be made before a prior risk evaluation can be used as the basis for national decision-making.1

The objective of this fictional case study is to illustrate how the toolkit can be used to guide a review of the
factors that would need to be considered in using a risk evaluation conducted in one country as the basis
for regulatory decision-making in a second country.

A3.2 Statement of the problem

In a central African country (Country B) with a population of approximately 12 million, public health officials
have observed cases of poisoning in workers using a methyl parathion formulation to control insects in
vegetable fields. In order to protect human health, the country considers a regulatory action to severely
restrict uses of methyl parathion and conducts a risk assessment of methyl parathion to support such an
action. Because risk assessment data specific for their country are not available, risk assessors decide to
rely on international data and observations to evaluate the health risks from methyl parathion use in their
country and, from this evaluation, to decide whether methyl parathion use should be restricted.

The questions to be asked are as follows (see also Figure 2 in section 3.1 of the main toolkit document):

― What is the identity of the chemical of concern?

― Is the chemical potentially hazardous to humans?
― What properties of the chemical have the potential to cause adverse health effects?
― Do guidance or guideline values from international organizations exist for the chemical?
― What assumptions about exposure and dose are incorporated into guidance or guideline values for
the chemical?
― Do those assumptions reflect conditions specific to the local situation?
― In what ways could people come into contact with the chemical?
― How much exposure is likely to occur?
― For how long is exposure likely to occur?
― What metric of exposure is appropriate for characterizing health risks?
― How does the estimated exposure compare with the health-based guidance or guideline values?

1 Note: The case studies presented here were developed for illustrative purposes in the application of the toolkit to
different scenarios and may not represent the most recent evaluations of the chemicals discussed.

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A3.3 Hazard identification

What is the identity of the chemical (or formulation) of concern?
A primary source of information on methyl parathion formulations could be a pesticide registry within
the country, if, in fact, a registration process existed. In the absence of a registry, information on
methyl parathion formulations may be obtained from a variety of sources, such as industrial permits,
import and export records, survey results administered by the ministry of agriculture or ministry of the
interior, surveys of wholesale or retail agricultural supply companies and, finally, owners or managers of
agricultural properties.

Information on formulations of methyl parathion is also available from sources outside the country. The
Hazardous Substances Data Bank (HSDB) (1) (see subsection 4.6.6 of the main toolkit document), for
example, provides information on the presence of methyl parathion in technical-grade products and
numerous ready-to-use products. The technical-grade products include pure methyl parathion as a
solid and an 80% solution of methyl parathion in xylene. Ready-to-use products appear to be 2% methyl
parathion available as dusts, emulsifiable concentrates, ultra-low-volume liquids and wettable powders.

In addition to the codified chemical identity information available from the HSDB, interviews with
insecticide applicators and observations of application procedures made by personnel of the Department
of Environmental Health in Country B indicate that wettable powders and emulsifiable concentrates of
methyl parathion are the primary forms of methyl parathion used in the country. The Department of
Environmental Health noted the product names Kilex Parathion and Metaphos during their inspections
and recorded that the labels indicated 2% methyl parathion concentrations.

Output: Wettable powders and emulsifiable concentrates are the primary forms of methyl parathion
used in the country. Applied products contain a 2% methyl parathion concentration.

Is the chemical (or formulation) potentially hazardous to humans?

The toxicological properties of methyl parathion have been classified by numerous international and
national agencies, including WHO, the UN and the EU:

― WHO recommended classification of pesticides by hazard. Class Ia (extremely hazardous) (2).

― IARC list of classifications. Group 3 (not classifiable as to its carcinogenicity to humans) (3).
― UN Globally Harmonized System of Classification and Labelling of Chemicals 2 (GHS) (4)
» Acute toxicity 2: H300 Fatal if swallowed; H330 Fatal if inhaled
» Acute toxicity 3: H311 Toxic in contact with skin
» Specific target organ toxicity RE2: H373 May cause damage to organs (or affected organs) through
prolonged or repeated exposure

Output: Methyl parathion is very toxic to humans when inhaled and ingested and when in contact with
skin.

What properties of the chemical (or formulation) have the potential to cause adverse health effects?
Toxicological information is available from EHC 145 on methyl parathion (5), the Joint FAO/WHO Meeting
on Pesticide Residues (JMPR) monograph on the toxicological evaluation of methyl parathion (listed there
as parathion-methyl) (6) and the HSDB (1). As noted in these documents, exposure to methyl parathion at

2 Some older reference sources may also make reference to the former EU system for classification (with risk phrases
such as R26 (very toxic by inhalation)). Guidance on the transition from that system to a system aligned with the GHS is
available (7).

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 Annex 3. Pesticide case study

sufficiently high concentrations can result in severe or fatal poisoning, primarily through damage to the
peripheral and central nervous systems. Symptoms of poisoning may appear almost immediately (a few
minutes) after exposure. When exposure occurs through skin contact, the severity of poisoning symptoms
may increase over more than one day and may last several days. Exposure to methyl parathion may also
cause eye or skin irritation and may adversely affect health in ways that are not clinically apparent – for
example, by decreasing blood cholinesterase activities or by increasing chromosomal aberrations. Methyl
parathion is readily absorbed via all routes of exposure (oral, dermal, inhalation). Once absorbed, methyl
parathion is rapidly distributed to the tissues, with the liver being the primary organ of metabolism and
detoxification. Methyl parathion and its metabolic products are eliminated primarily through urine.

Output: Exposure can result in severe or fatal poisoning, primarily through damage to the peripheral
and central nervous systems. Symptoms of poisoning may appear almost immediately (a few minutes)
after exposure.

A roadmap for the hazard identification step of the pesticide case study is shown in Figure A3.1.

Figure A3.1  Case-specific roadmap for hazard identification: pesticide case study

The chemical of concern is methyl parathion

Methyl parathion is very toxic when No Gather information on chemical by-products and waste
inhaled and ingested and when in streams associated with the source or process
contact with skin.

Stop Search emission scenario documents for the industry or

process of interest

Key references include the “WHO Full-text search of INCHEM database

Recommended Classification of
Pesticides” and the IARC evaluations.
Review any available public documents on the specific
source or site

Communicate with parties who may have knowledge of

the source or site

Proceed to exposure assessment and Local officials and International

hazard characterization stakeholders organizations

Bold lines indicate the flow of information gathering and analysis described in the text.

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WHO human health risk assessment toolkit: chemical hazards

A3.4 Hazard characterization/guidance or guideline value identification

Do guidance or guideline values from international organizations exist for the chemical?
Health-based guidance values available from international resources are listed below:

― In 1995, JMPR re-evaluated methyl parathion and set an acceptable daily intake (ADI) of 0–0.003 mg/
kg body weight and an acute reference dose (ARfD) of 0.03 mg/kg body weight (6).

― The Codex Alimentarius Commission established maximum residue limits (MRLs) for methyl
parathion for a variety of food commodities (in milligrams of methyl parathion per kilogram of food
item), including apples (0.2 mg/kg), dry beans (0.05 mg/kg), head cabbages (0.05 mg/kg), dried
grapes (1 mg/kg), grapes (0.5 mg/kg), nectarines (0.3 mg/kg), peaches (0.3 mg/kg), dry peas (0.3
mg/kg), potatoes (0.05 mg/kg) and sugar beets (0.05 mg/kg) (8).

As a note, a formal WHO drinking-water guideline value for methyl parathion has not been established. In
fact, a health-based value of 0.009 mg/L was derived (for guidance purposes), and as this value is much
greater than concentrations likely to be found in water, no formal guideline value was deemed necessary
(9). WHO has not published an air quality guideline for methyl parathion.

Output: JMPR established an ADI (0–0.003 mg/kg body weight) and an ARfD (0.03 mg/kg body weight)
for oral intake (considering mainly food intake). In addition, the Codex Alimentarius Commission
established maximum residue limits for a variety of food commodities. A health-based value of 0.009
mg/L for methyl parathion in drinking-water was derived by WHO for guidance purposes only.

What assumptions about exposure and dose are incorporated into guidance or guideline values for the
chemical, and do those assumptions reflect conditions specific to the local situation?
As described in section A3.5, applicators of methyl parathion are anticipated to have the greatest
exposure among the population of the country. In the absence of information on contact rates, body
weight, absorption fraction and total exposure to methyl parathion specific to local conditions, the
Department of Environmental Health elects to rely upon the guidance/guideline values provided above in
this section.

A roadmap for the hazard characterization step of the pesticide case study is shown in Figure A3.2.

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 Annex 3. Pesticide case study

Figure A3.2  Case-specific roadmap for hazard characterization/guidance or guideline

value identification: pesticide case study

Toxic end-points include damage to the peripheral and

central nervous systems.

Relevant guidance/guideline values are:

— JMPR ADI for food of 0-0.003 mg/kg body weight;
— JMPR ARfD for food of 0.03 mg/kg body weight;
— MRLs for food commodities;
— WHO 0.009 mg/l in drinking-water (for guidance only).

The default contact rates are assumed to be appropriate

in the absence of further information. No

Determine the appropriate contact rate

Other assumptions incorporated in the No Determine the appropriate allocation of

guidance/guideline values are assumed to exposure rate
be appropriate.

Determine the situation-appropriate

exposure rate based on contact rate and/
or allocation

Proceed to exposure assessment

Bold lines indicate the flow of information gathering and analysis described in the text.

A3.5 Exposure assessment

In what ways could people come into contact with the chemical?
The risk assessor gathers information from within the country that shows that the methyl parathion in the
country is primarily applied to vegetable fields using rotary disc sprayers carried on the backs of workers.
Through field visits and interviews with agricultural workers, the Department of Environmental Health
finds that workers have not been informed about the health risks of methyl parathion and its formulations,
nor do they wear personal protective equipment (PPE) during the preparation of the formulation or during
the spraying campaigns. The corresponding routes of exposure of workers are expected to be dermal
absorption, inhalation and ingestion. Short-term exposures of workers are expected to occur during
application, whereas short-term, medium-term and long-term exposures may occur after application until
the commodity is harvested. Further, interviews with medical professionals at local health facilities reveal
that an increasing number of patients show neurological symptoms during spraying campaigns. As an
official disease surveillance system is not in place, the exact number, distribution and cause of poisonings
are not known.

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WHO human health risk assessment toolkit: chemical hazards

From international information sources – EHC 145 on methyl parathion (5) and the HSDB (1) – the risk
assessor learns that methyl parathion is thermally unstable, relatively insoluble in water, poorly soluble in
petroleum ether and mineral oils, but soluble in most organic solvents. Important exposure routes include
skin contact and, to a lesser degree, inhalation for workers and inhalation and ingestion of contaminated
food for the general public. Methyl parathion exposures of workers generally result from both proper use
and misuse (or misapplication) of the pesticide during agricultural or forestry practices.

Although occupational exposure studies have not been conducted in the country, information from other
countries demonstrates the potential for elevated exposure to methyl parathion among applicators.
The HSDB provides information that can be used in support of an exposure assessment. For example,
as noted above, the HSDB provides information about critical methyl parathion exposure pathways.
Of these critical pathways, the greatest danger to workers exposed to methyl parathion is from skin
contact, which may occur during or after its application or where it is formulated. Occupational exposure
to methyl parathion may also occur through other pathways, such as inhalation of spray mists. As
listed in the HSDB, occupations with potential exposure to methyl parathion include aerial application
personnel, area clean-up crews, bagging machine operators, basic manufacturing employees, laundry
haulers, drum fillers, drum reconditioning personnel, dump personnel, field checkers, fieldworkers (who
are exposed to residues on crops and foliage), flag persons, ground applicator vehicle drivers, janitorial
personnel, laundry workers, maintenance personnel, mixer and blender operators, refuse haulers, tractor
tank loaders, truck loaders and warehouse personnel. Based on information presented in the HSDB, in
production plants, average air levels are less than 0.1 mg/m3, with maximum levels of 0.2 mg/m3. For
workers checking cotton for insect damage, dermal exposure is estimated to be 0.7 mg per hour. For
formulators, median levels of methyl parathion on their non-washed body parts range between 510 and
9200 nanograms (ng), compared with a range of 74–345 ng for formulators who wash after work.

For the general population, exposure to methyl parathion may occur via inhalation of ambient air and
ingestion of contaminated food. The general population is not expected to be exposed to meaningful
levels of methyl parathion in drinking-water. Inhalation exposure of the general population is likely to be
greatest for populations living near agricultural applications.

Output: Methyl parathion is applied to vegetable fields using rotary disc sprayers carried on the backs
of workers. Workers are not aware of the health risks of methyl parathion, nor do they wear PPE when
preparing formulations and during spraying campaigns. Therefore, the greatest danger to workers
exposed to methyl parathion is from skin contact, which may occur during or after its application or
where it is formulated. Suspected cases of poisoning during spraying campaigns confirm possible
exposure to methyl parathion. The international literature confirms these exposure pathways and
routes for workers working with methyl parathion. General population exposure is possible through
food, but not confirmed.

How much exposure is likely to occur?

In the absence of exposure information from Country B, the Department of Environmental Health
conducts a literature search that reveals that a non-African country recently assessed the health risks of
methyl parathion in order to support regulatory action. The Department of Environmental Health in the
African country convenes a small, multidisciplinary workshop (involving health, occupational, pesticide,
agricultural, environmental and other experts) to evaluate and discuss the relevance of the other country’s
findings for the African country. Discussions are organized along a template. The template and results are
presented in Table A3.1.

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Table A3.1  Relevance of study findings to an African country: template

Study element Local condition Other country

1. Is the form in which the pesticide was used at the local level similar to those in the exposure assessment
undertaken at the international level or in another country?

(i) Has the same formulation been used (e.g. liquid, powder, 2% ready-to-use Wettable powder
granule; concentration of active ingredient(s))? product

(ii) What are the contaminants that should be considered? Unknown None

2. Is the pesticide/formulation(s) applied in the same way? Do similar environmental conditions apply?

Are the use patterns the same, including:

— Type of use (e.g. agriculture, non-agriculture, public Agriculture, vegetables Agriculture, vegetables
health, disinfectant)?

— Environment of use (e.g. greenhouse, field, indoor)? Open field Open field

— Environmental conditions (e.g. temperature, type of soil)? Tropical climate Moderate climate

— Rate, frequency and period of application? Six times a year Twice a year

— Application equipment (e.g. backpack sprayer, air blast Rotary disc sprayer Different back sprayers
sprayer)?

— Transportation, dissemination and storage? Uncontrolled Very controlled (e.g. follow

GHS, trained drivers, controlled
dissemination)

3. Are similar pesticide management measures in place?

(i) Are workers trained? Do they know about risks? Generally not Yes, training programmes are
in place

(ii) Is PPE available and used? Usually not Yes

(iii) Are occupational standards in place? No Yes

4. Are similar health impacts observed?

(i) Are workers poisoned, and what are the signs and Believed to be Seldom; surveillance system in
symptoms? common; neurological place
symptoms

(ii) Has the pesticide been detected in environmental media Unknown Low levels in some crops; not
or food? detected in air or surface water

(iii) Is the public exposed to the pesticide? Unknown Little via food

(iv) Are there signs of intoxication in the general population? Unknown No; surveillance system in place

5. Others

Not applicable Not applicable Not applicable 107

WHO human health risk assessment toolkit: chemical hazards

The meeting concludes that the exposure conditions as described in the study of the other country
are very different to those identified in the situation in Africa. Striking differences include the literacy
of workers about the health risks of methyl parathion and the use of PPE, as well as the pesticide
management system, which is functioning in the non-African country, and the small number of poisoned
worker cases reported in the other country by the existing disease surveillance system and local poison
centres.

Output: Compared with another country that has management measures in place, the African country
seems to experience much higher exposure.

A roadmap for the exposure assessment step of the pesticide case study is shown in Figure A3.3.

Figure A3.3  Case-specific roadmap for exposure assessment: pesticide case study

The source is agricultural applications.

The pathway of exposure is multiple.
The exposure media include surfaces and soil.

Exposure has been generalized from other studies and

is qualitative in nature. It is concluded that agricultural
exposure is likely and general population exposure is
possible.

Exposure can be short term, medium term and long term

for workers and the general population.

Guideline and guidance values are expressed as Estimate the rate of contact with
concentrations (e.g. MRLs) and exposure rates (ADI, the exposure media for the general
ARfD). population.

Exposure information is qualitative in

nature, and rates of exposure for the
general population cannot be calculated
in this case-study.

Proceed to risk characterization

(Comment: Risks are estimated qualitatively because of
lack of local exposure data).

Bold lines indicate the flow of information gathering and analysis described in the text.

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For how long is exposure likely to occur?

Short-term exposures of workers are expected to occur during application, whereas short-term,
medium-term and long-term exposures may occur mainly through skin contact after application until the
commodity is harvested. For the general population, short-term, medium-term and long-term exposures
to methyl parathion may occur via ingestion of contaminated food and by inhalation of ambient air. The
general population is not expected to be exposed to meaningful levels of methyl parathion in drinking-
water. Inhalation exposures of the general population are likely to be greatest for populations living near
agricultural applications.

Output: Knowledge that exposure can be short term, medium term and long term for workers as well as
the general population.

What metric of exposure is appropriate for characterizing health risks?

As described in section A3.4, guidance/guideline values are expressed in mg/kg body weight (ADI and
ARfD), mg/kg of food item (maximum residue limits) and mg/L for drinking-water

Output: Knowledge that if exposure has been modelled or measured, it should be expressed as an
exposure rate (mg/kg body weight) and/or as an exposure concentration (mg/kg of food item or mg/L
in drinking-water).

A3.6 Risk characterization

How does the estimated exposure compare with the health-based guidance or guideline values?
The above question cannot be answered, because the Department of Environmental Health has not
come up with a measure of exposure, either exposure rate or exposure concentration. However, the
Department of Environmental Health believes that the potential for exposure to workers is high, based on
studies in other areas, as summarized in section A3.5. Upon initial consideration, the absence of exposure
information could be interpreted as precluding a risk assessment. However, a qualitative assessment is
possible by generalizing from empirical information available from other locations. To minimize exposure
among occupational populations, other countries recommend that workers use PPE, including respirators,
gloves, tight fabric or polyvinyl chloride overalls, rubber gloves, rubber boots and goggles, as discussed in
the HSDB. Further, the signallers for aerial dusting operations must wear a hat and cape made of polyvinyl
chloride or a fabric impregnated with a water repellent.

Information compiled in the HSDB also includes other necessary protective equipment, including eyewash
fountains and showers or other facilities to quickly drench the body in the immediate work areas where
exposure may occur. Additional protective measures include segregation of contaminated protective
clothing to prevent personal contact by personnel who handle, dispose of or clean the clothing. Quality
assurance procedures must be implemented to ascertain the completeness of the cleaning procedures
before the decontaminated protective clothing is returned for reuse by the workers. Contaminated
clothing should not be taken home at end of shift, but should remain at the employee’s place of work for
cleaning.

The African country does not have the infrastructure needed to ensure appropriate training and
implementation of occupational health and safety measures in agricultural operations. Without
a management system for protecting workers from excessive exposure to methyl parathion, the
Department of Environmental Health concludes that risks to human health are likely to be unacceptable
under current conditions and considers restricting methyl parathion use.

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A roadmap for the risk characterization step of the pesticide case study is shown in Figure A3.4.

Figure A3.4  Case-specific roadmap for risk characterization: pesticide case study

The objective is to evaluate the potential health risks of

methyl parathion use in the country and decice whether
its use should be restricted

In principle, assessment requires comparison with

guidance and guideline values. However, the assessment
is qualitative in nature by comparing the local situation Calculate
with situations in other countries. cancer risk

ADI, ARID, MRLs, OEL, drinking- Obtain the cancer slope factor for the
water guideline value chemical

In qualitative terms, exposure is

estimated to be comparable to the
elevated exposures reported to occur
in other locations with similar use
patterns, jobs and tasks.

The hazard/risk quotient can only be Calculate excess lifetime cancer

estimated qualitatively in this case- risk as the product of exposure
study and is considered to be high concentration or rate and the cancer
based on the available information. slope factor.

The lack of infrastructure and

training makes it likely that use
of methyl parathion under these
conditions results in health risks
that should be mitigated through Is the excess lifetime cancer risk high
appropriate risk management or low (e.g. greater than 1 in 10 000
strategies. or less than in a million)?

Report results to risk management

team

Bold lines indicate the flow of information gathering and analysis described in the text.

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 Annex 3. Pesticide case study

A3.7 Summary
A case study of methyl parathion was used to illustrate how principles, roadmaps and resources contained
in the toolkit can be used to facilitate the use of risk assessments and information available in international
sources and their extrapolation to the conditions prevailing at the national level as a basis for national
decision-making on chemicals. References to online databases compiled in the toolkit were provided, and
the electronic links contained in those references provide direct access to information.

The case study demonstrated how qualitative information on chemical use in a country can be related to
empirical information on exposures and risks developed in other countries or settings through the use of
bridging principles that consider use patterns, formulations and risk mitigation measures.

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