DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
This report contains the collective views of an international group of experts and does not
necessarily represent the decisions or the stated policy of the World Health Organization, the
International Labour Organization or the United Nations Environment Programme.
Harmonization Project DRAFT Document for Public and Peer Review
12
13
14
RISK ASSESSMENT OF COMBINED EXPOSURES TO
MULTIPLE CHEMICALS: A WHO/IPCS FRAMEWORK
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
This project was conducted within the IPCS project on the Harmonization of Approaches to
the Assessment of Risk from Exposure to Chemicals.
Published under the joint sponsorship of the World Health Organization, the International
Labour Organization and the United Nations Environment Programme, and produced within
the framework of the Inter-Organization Programme for the Sound Management of
Chemicals.
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture
of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO)
and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the
scientific basis for assessment of the risk to human health and the environment from exposure to
chemicals, through international peer review processes, as a prerequisite for the promotion of
chemical safety, and to provide technical assistance in strengthening national capacities for the sound
management of chemicals.
The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was
established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations,
WHO, the United Nations Industrial Development Organization, the United Nations Institute for
Training and Research and the Organisation for Economic Co-operation and Development
(Participating Organizations), following recommendations made by the 1992 UN Conference on
Environment and Development to strengthen cooperation and increase coordination in the field of
chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities
pursued by the Participating Organizations, jointly or separately, to achieve the sound management of
chemicals in relation to human health and the environment.
CIP Data to be inserted on publication of the final document
© World Health Organization 2009
All rights reserved. Publications of the World Health Organization can be obtained from WHO
Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791
2476; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or
translate WHO publications—whether for sale or for non-commercial distribution—should be
addressed to WHO Press at the above address (fax: +41 22 791 4806; e-mail: [email protected]).
The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the
delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for
which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they
are endorsed or recommended by the World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are
distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the
information contained in this publication. However, the published material is being distributed
without warranty of any kind, either express or implied. The responsibility for the interpretation and
use of the material lies with the reader. In no event shall the World Health Organization be liable for
damages arising from its use.
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
TABLE OF CONTENTS
FOREWORD .............................................................................................................................1
ACKNOWLEDGEMENTS.......................................................................................................2
WHO/IPCS COMBINED EXPOSURES PLANNING GROUP ..............................................3
LIST OF ACRONYMS AND ABBREVIATIONS ..................................................................4
1. INTRODUCTION .................................................................................................................5
2. TERMINOLOGY ..................................................................................................................5
3. PURPOSE AND FOCUS OF THE ASSESSMENT .............................................................6
4. CONSIDERING THE NEED FOR A FRAMEWORK ANALYSIS FOR AN
ASSESSMENT GROUP ...........................................................................................................6
5. THE FRAMEWORK.............................................................................................................8
5.1 Example Tier 0.................................................................................................................8
5.1.2 Exposure assessment.................................................................................................8
5.1.2 Hazard assessment ....................................................................................................9
5.2 Example Tier 1...............................................................................................................10
5.2.1 Exposure assessment...............................................................................................10
5.2.2 Hazard assessment ..................................................................................................10
5.2.3 Risk characterization...............................................................................................10
5.3 Example Tier 2...............................................................................................................10
5.3.1 Exposure assessment...............................................................................................10
5.3.2 Hazard assessment ..................................................................................................11
5.3.3 Risk characterization...............................................................................................11
5.4 Example Tier 3...............................................................................................................11
5.4.1 Exposure assessment...............................................................................................11
5.4.2 Hazard assessment ..................................................................................................11
5.4.3 Risk characterization...............................................................................................11
6. CASE-STUDIES..................................................................................................................12
7. REFERENCES ....................................................................................................................12
iii
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
FOREWORD
Harmonization Project Documents are a family of publications by the World Health
Organization (WHO) under the umbrella of the International Programme on Chemical Safety
(IPCS) (WHO/ILO/UNEP). Harmonization Project Documents complement the
Environmental Health Criteria (EHC) methodology (yellow cover) series of documents as
authoritative documents on methods for the risk assessment of chemicals.
The main impetus for the current coordinated international, regional and national efforts on
the assessment and management of hazardous chemicals arose from the 1992 United Nations
Conference on Environment and Development (UNCED). UNCED Agenda 21, Chapter 19,
provides the “blueprint” for the environmentally sound management of toxic chemicals. This
commitment by governments was reconfirmed at the 2002 World Summit on Sustainable
Development and in 2006 in the Strategic Approach to International Chemicals Management
(SAICM). The IPCS project on the Harmonization of Approaches to the Assessment of Risk
from Exposure to Chemicals (Harmonization Project) is conducted under Agenda 21, Chapter
19, and contributes to the implementation of SAICM. In particular, the project addresses the
SAICM objective on Risk Reduction and the SAICM Global Plan of Action activity to
“Develop and use new and harmonized methods for risk assessment”.
The IPCS Harmonization Project goal is to improve chemical risk assessment globally,
through the pursuit of common principles and approaches, and, hence, strengthen national
and international management practices that deliver better protection of human health and
the environment within the framework of sustainability. The Harmonization Project aims to
harmonize global approaches to chemical risk assessment, including by developing
international guidance documents on specific issues. The guidance is intended for adoption
and use in countries and by international bodies in the performance of chemical risk
assessments. The guidance is developed by engaging experts worldwide. The project has
been implemented using a step-wise approach, first sharing information and increasing
understanding of methods and practices used by various countries, identifying areas where
convergence of different approaches would be beneficial and then developing guidance that
enables implementation of harmonized approaches. The project uses a building block
approach, focusing at any one time on the aspects of risk assessment that are particularly
important for harmonization.
The project enables risk assessments (or components thereof) to be performed using
internationally accepted methods, and these assessments can then be shared to avoid
duplication and optimize use of valuable resources for risk management. It also promotes
sound science as a basis for risk management decisions, promotes transparency in risk
assessment and reduces unnecessary testing of chemicals. Advances in scientific knowledge
can be translated into new harmonized methods.
This ongoing project is overseen by a geographically representative Harmonization Project
Steering Committee and a number of ad hoc Working Groups that manage the detailed work.
Finalization of documents includes a rigorous process of international peer review and public
comment.
1
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
ACKNOWLEDGEMENTS
This Harmonization Project Document was prepared by a Drafting Group under the guidance
of the Combined Exposures Planning Group.
2
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
WHO/IPCS COMBINED EXPOSURES PLANNING GROUP
(*DRAFTING GROUP MEMBERS)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Alan R. Boobis*
Department of Experimental Medicine and Toxicology, Division of Investigative Science,
Imperial College London, Hammersmith Campus, London, England
Kevin M. Crofton*
National Health and Environmental Effects Research Laboratory, Office of Research and
Development, Environmental Protection Agency, Research Triangle Park, NC, United States
of America (USA)
Gerhard Heinemeyer*
Federal Institute for Risk Assessment (BfR), Berlin, Germany
M.E. (Bette) Meek* (Chair)
Existing Substances Division, Safe Environments Programme, Health Canada, Ottawa,
Ontario, Canada
Stephen Olin
International Life Sciences Institute Research Foundation, Washington, DC, USA
Carlos Rodriguez
European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium
Marcel Van Raaij*
National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands
Carolyn Vickers*
International Programme on Chemical Safety, World Health Organization, Geneva,
Switzerland
3
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
LIST OF ACRONYMS AND ABBREVIATIONS
BBDR
BMC10
BMD10
IPCS
LD50
LOAEL
MOA
MOE
NOAEL
PBDE
PBPK
POD
QSAR
RPF
SAR
WHO
biologically based dose–response
benchmark concentration for 10% risk
benchmark dose for 10% risk
International Programme on Chemical Safety
median lethal dose
lowest-observed-adverse-effect level
mode of action
margin of exposure
no-observed-adverse-effect level
polybrominated diphenyl ether
pharmacologically based pharmacokinetic
point of departure
quantitative structure–activity relationship
relative potency factor
structure–activity relationship
World Health Organization
3
4
4
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
1. INTRODUCTION
A World Health Organization (WHO)/International Programme on Chemical Safety (IPCS)
Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple
Chemicals) was held in Washington, DC, United States of America (USA), on 19–21 March
2007. The principal objective of the workshop was to initiate development of a framework
for the risk assessment of combined exposures to multiple chemicals. The workshop report
comprised an overview and a series of extended abstracts to describe the state of the art in
this area and delineation of next steps. In addition to recommendations relevant to subsequent
development and review of the draft framework, terminology was considered in order to
facilitate communication internationally in this area (WHO, 2009). This Harmonization
Project Document describes the framework developed subsequent to the WHO/IPCS
workshop.
2. TERMINOLOGY
At the WHO/IPCS Workshop on Aggregate/Cumulative Risk Assessment (Combined
Exposures to Multiple Chemicals), it was recommended that terminology to describe various
aspects of exposure to and effects of multiple chemicals be as precisely descriptive as
possible. Working definitions for key terms and concepts developed at the workshop are
included here, as background to the framework. For clarity, it is recommended that the terms
in bolded text be used when applying this framework for the risk assessment of combined
exposures to multiple chemicals.
Exposure to the same substance from multiple sources and by multiple pathways and routes is
likely best described as “single chemical, all routes” (referenced in some jurisdictions as
“aggregate” exposure). Similarly, it is recommended that exposure to “multiple chemicals
by a single route” be distinguished from exposure to “multiple chemicals by multiple
routes” (referenced in some jurisdictions as “cumulative” exposure). To this end, this
framework addresses “combined exposures to multiple chemicals”—i.e. exposure to
multiple chemicals by a single route and exposure to multiple chemicals by multiple routes.
Substances grouped together for assessment in this context are referenced as an “assessment
group”.
Chemicals that act by the same mode of action and/or at the same target cell or tissue often
act in a potency-corrected “dose additive” manner. Where chemicals act independently, by
discrete modes of action or at different target cells or tissues, the effects may be additive
(“effects additive” or “response additive”). Alternatively, chemicals may interact to produce
an effect, such that their combined effect “departs from dose additivity”. Such departures
comprise synergy, where the effect is greater than that predicted on the basis of additivity,
and antagonism, where the effect is less than that predicted on the basis of additivity.
Relevant also to the framework for risk assessment of combined exposures to multiple
chemicals is a common understanding of “mode of action”, which has been defined
previously by IPCS, as it figures prominently in approaches to grouping of chemicals for
assessment of combined effects. A postulated mode of action is a biologically plausible
5
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
sequence of key events leading to an observed effect supported by robust experimental
observations and mechanistic data. It describes key cytological and biochemical events—i.e.
those that are both measurable and necessary to the observed effect. Notably, mode of action
contrasts with mechanism of action, which generally involves a sufficient understanding of
the molecular basis for an effect so that causation can be established (Sonich-Mullin et al.,
2001).
Combined exposure to multiple chemicals is also defined in the context of whether or not the
components act by similar or different modes of action (i.e. “single mode of action” or
“multiple modes of action”). This is a critically important distinction in the context of the
framework. The terms “simple mixtures” and “complex mixtures” are often used by some
authors to refer to combined exposures to multiple chemicals that act by similar and different
modes of action, respectively. Other authors use the very same terms (“simple mixtures” and
“complex mixtures”) to distinguish mixtures with limited numbers of substances from those
with large numbers of substances or to distinguish mixtures of known composition from
those of unknown or variable composition. To avoid confusion, these terms are not used in
this framework.
3. PURPOSE AND FOCUS OF THE ASSESSMENT
The extent of consideration of an assessment group is dependent not only upon potential risk
but also on the purpose (e.g. priority setting, screening and/or full risk assessment) and focus
(e.g. local, national) of the assessment.
The framework for the risk assessment of combined exposure to multiple chemicals has been
developed, therefore, to maximize efficiency in the consideration and generation of available
information, depending on potential risks and the objective of the assessment (e.g. priority
setting or screening for additional focus or risk management). Iterative consideration of
available data should be helpful not only in conserving resources in assessment but in
ensuring that research is focused in critical areas (see, for example, United Kingdom
Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment,
2008).
Use of the framework requires integrated consideration of exposure and hazard at all phases.
This phased approach ensures that no more resources are invested than are necessary to make
a decision for the purpose at hand. For this reason, the framework incorporates a hierarchical
structure and iterative and integrated consideration of exposure and hazard.
4. CONSIDERING THE NEED FOR A FRAMEWORK
ANALYSIS FOR AN ASSESSMENT GROUP
Initially, the need for embarking on a framework analysis for an assessment group should be
assessed. This should include consideration of the following sequential questions:
•
What is the nature of exposure? Are the key components known? Are there data available
on the hazard of the mixture itself?
6
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Lack of information on these aspects precludes a framework analysis. This does not,
however, obviate the need potentially to introduce risk management measures to reduce
exposure, although recognizably in the absence of a robust science basis to inform the
process.
•
Is exposure unlikely or very low, taking into account the context?
Is the use profile of the substance such that exposure is not expected? For example, is the
substance used only as an industrial intermediate and not expected to be released to the
general environment? Is it diluted or degraded in the environment, or is absorption precluded
because the molecular weight is large? Alternatively, is the combined exposure less than a
threshold of toxicological concern? If the response to these questions is yes, then further
assessment in a framework analysis for combined exposure is not required.
•
Is there a likelihood of co-exposure within a relevant timeframe ?
Do the temporal aspects of external exposure, toxicokinetics and toxicodynamics preclude
co-exposure to the compounds of interest? If, based on consideration of these aspects, the
likelihood of co-exposure is low, a framework analysis of an assessment group is
unnecessary.
•
What is the rationale for considering compounds in an assessment group?
This is commonly based on information indicating that the components are believed to act
similarly or interact. Normally, it would be based on predictive information on chemical
structure, such as structure–activity relationships (SARs), quantitative structure–activity
relationship (QSAR) modelling, structural alerts or, alternatively, data on hazard or other
biological data (toxicity or efficacy) that lead to the conclusion that effects are likely to be
similar with a potentially common mode of action. For example, are effects observed in the
same target organs? Is the biological outcome the same? Are the chemicals used for similar
application (e.g. anti-oxidants, moulting inhibitors), which might potentially imply similar
modes of action?
7
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
5. THE FRAMEWORK
2
3
A conceptual representation of the framework is included in Figure 1.
Sample Tiered Exposure and Hazard Considerations
Mixture or Component Based
Tiered Exposure
Assessments
Simple semiquantitative
estimates of
exposure
Tier 1
Generic exposure
scenarios using
conservative point
estimates
Tier 2
Refined exposure
assessment, increased
use of actual measured
data
Tiered Hazard
Assessments
Tier 0
Dose addition for all
components
Input from
exposure or hazard
assessments
(iterative process)
Is the margin of
exposure adequate
?
Tier 1
Refined potency
based on individual
POD, refinement of
POD
Tier 2
More refined potency
(RPF) and grouping
based on MOA
Tier 3
PBPK or BBDR; probabilistic
estimates of risk
Tier 3
Probabilistic Exposure Estimates
Increasing refinement of hazard models (MOA)
Increasing refinement of exposure models
Tier 0
Yes, no further
action required
No, continue
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Figure 1: A conceptual representation of the framework (see text for details).
The point of departure (POD) is a selected measure of effect. It may be a no- or lowestobserved-(adverse-)effect level (NO(A)EL or LO(A)EL) or a dose or concentration
associated with a specified increase in the incidence of an effect (e.g. a benchmark dose
[BMD10] or concentration [BMC10] associated with a 10% increase in incidence of an effect).
Mode of action (MOA) is a biologically plausible sequence of key events leading to an
observed effect, supported by robust experimental observations and mechanistic data.
The margin of exposure (MOE) is the ratio of the selected measure of effect to the estimated
exposure dose or concentration.
Components of the framework are described in more detail below. However, in considering
the content of both the figure and the supporting text, it is important to understand that
included tiers are provided principally as examples. They are not fixed and will vary,
depending on available data. There may also be additional iterations of the tiers; for some
compounds, for example, earlier iterations of Tier 0 may be sufficient. Mixtures containing
components with different modes of action require separate analyses for each.
5.1 Example Tier 0
5.1.2 Exposure assessment
Where the margins between very crude and conservative estimates of exposure and points of
departure for hazard are large, simple semiquantitative estimates of summed exposure for the
8
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
various components of an assessment group may be sufficient as a basis for an early-tier
analysis. Semiquantitative estimates are based on limited data and a few very simple
assumptions. Information on indicators of potential exposure, such as volume, use and/or
physicochemical properties, is often combined to enable measures of relative ranking, which
can then be quantified crudely based on comparison with more robust quantitative estimates
for chemicals with similar profiles.
For example, in the categorization of the Canadian Domestic Substances List, each of the
23 000 substances on the list was relatively ranked (from 1 to 23 000) based on its volume of
production, the numbers of producing and/or using companies and the sum of “expert ranked
uses”. Expert ranking for the latter was based on the extent to which the uses were considered
to contribute to potential exposure of the general population, derived from several workshops
involving relevant experts (Health Canada, 2006).
Another example of semiquantitative estimates is the budget method for food additives. In
this method, the theoretical exposure to food additives is based on assumptions regarding
physiological requirements for energy and liquid and on the energy density of food, rather
than on specific food consumption survey data (Douglass et al., 1997).
Alternatively, such estimates can also be based on information on sales, contribution of
compound in a product and the number of users, providing rough worst-case estimates.
Semiquantitative estimates may be additionally refined through inclusion of information on
physicochemical properties (e.g. information on vapour pressure provides an indication of
whether or not particular uses are likely to lead to emissions to air).
5.1.2 Hazard assessment
In a Tier 0 analysis in relation to hazard, dose addition is normally assumed.
For example, as a conservative early assumption, based on an indication that components of
an assessment group should be grouped together (e.g. target organs are similar or mode of
action might be similar, based on predictive hazard tools such as SAR or QSAR) and where
reference doses or concentrations for components are available, a hazard index may be
developed. A hazard index is the sum of exposures divided by the reference value for each of
the individual components of an assessment group and, as such, represents risk-based
summation of exposures to individual components, adjusted by their relative hazard
For this hazard index, there is the likelihood that reference doses are not strictly comparable,
being based on reviews of varying datasets in different periods, for different critical effects
and with inconsistent application of uncertainty factors by different regulatory agencies.
However, it is considered to be conservative and protective, given the common underlying
premise of being based on critical effects occurring at lowest dose.
9
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
5.2 Example Tier 1
5.2.1 Exposure assessment
For a Tier 1 assessment, summation of deterministic estimates of exposure for all components
of the assessment group may suffice as a basis for comparison with a measure of hazard to
determine whether further assessment is necessary. These estimates are commonly based on
broad, conservative scenarios addressing a range of somewhat similar uses with limited
numbers of parameters being included. For example, for the evaluation of cosmetics in the
European Union, a default exposure to 17.8 g of all cosmetic products per day (without
distinction) is used as a very early generic estimate (European Commission, 2006).
5.2.2 Hazard assessment
For conservative consideration of hazard in a Tier 1 assessment, particularly in the absence of
information on individual components, it is often assumed that all components have the same
potency as the most toxic compound known.
In more refined analyses, additional information on the potency of individual components
and more accurate measures of points of departure for hazard are incorporated. For example,
for substances where the critical effects occur following acute exposure, the measure of
relative potency (i.e. the point of departure) could be a median lethal dose (LD50). For chronic
effects, rather than reference values for which the timeframe of development, critical effects
and uncertainty factors may not be comparable, LOAELs or NOAELs for critical effects may
be used. Use of benchmark doses for critical effects increases precision somewhat
additionally for the measure of potency or point of departure.
Alternatively, a point of departure index is calculated. A point of departure index is the sum
of exposures divided by the point of departure for each of the individual components of an
assessment group and, as such, represents risk-based summation of exposures to individual
components, adjusted by a hazard measure of greater accuracy than that used for the hazard
index.
5.2.3 Risk characterization
The margin between estimated exposure and hazard is considered in the context of associated
uncertainties as a basis to consider whether or not a higher-tier assessment is required. The
nature of considerations that constituted the basis for determining that a higher-tier
assessment is required (i.e. adequacy of the margin of exposure in the context of uncertainty
associated with both estimated exposure and hazard) is explicitly stated.
5.3 Example Tier 2
5.3.1 Exposure assessment
In middle-tier assessments, deterministic estimation of exposure is refined, with incorporation
of increasing amounts of measured data. Scenarios are better defined (i.e. more tailored to the
specific situation under consideration). Models may incorporate additional parameters, and,
although estimates are still considered conservative, they are believed to be more realistic,
10
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
incorporating more data. Multiple sources are often taken into account by summation (this
approach introducing additional conservatism).
5.3.2 Hazard assessment
In middle-tier assessments, the definition of an assessment group may be additionally refined
through consideration of increasingly more specific information on mode of action. For some
substances (e.g. cholinesterase inhibitors), this may be at the level of molecular target. In
addition, availability of measures of potency for each of the components of the assessment
group permits derivation of relative potency factors (RPFs). The potency of each component
is expressed as an equivalent of that for an index compound, with the latter often selected on
the basis of being the most potent member of the group (i.e. the point of departure of an index
compound divided by the point of departure of the compound of interest).
5.3.3 Risk characterization
The margin between estimated exposure and hazard is considered in the context of associated
uncertainties as a basis to consider whether or not a higher-tier assessment is required. The
nature of considerations that constituted the basis for determining that a higher-tier
assessment is required (i.e. adequacy of the margin of exposure in the context of uncertainty
associated with both estimated exposure and hazard) is explicitly stated.
5.4 Example Tier 3
5.4.1 Exposure assessment
In highest-tier assessments, estimates of exposure are probabilistic in nature, taking into
account distributions of exposure factors or exposure data. This approach requires
representative information on exposure for the scenarios of interest for the relevant
populations for different uses and across populations. Models at this level of complexity often
include multiple source exposures.
5.4.2 Hazard assessment
Highest-tier assessments of hazard incorporate increasingly refined information on mode of
action, including both kinetic and dynamic aspects. These can include both physiologically
based pharmacokinetic (PBPK) and biologically based dose–response (BBDR) models,
which may permit probabilistic estimates of hazard and characterization of some aspects of
kinetic and dynamic variability and uncertainty. These models, which incorporate both
chemical-specific and more generic information on comparative physiology, biochemistry,
etc., improve the characterization of interspecies differences and human variability (i.e. as a
basis for extrapolation across species and within humans).
5.4.3 Risk characterization
The margin between estimated exposure and hazard is considered in the context of associated
uncertainties as a basis to consider whether or not a higher-tier assessment is required. The
nature of considerations that constituted the basis for determining that a higher-tier
assessment is required (i.e. adequacy of the margin of exposure in the context of uncertainty
associated with both estimated exposure and hazard) is explicitly stated.
11
DRAFT FOR PUBLIC REVIEW: DO NOT CITE OR QUOTE
1
6. CASE-STUDIES
2
3
4
5
6
7
8
Two example case-studies have been prepared to illustrate the application of this framework
for the risk assessment of combined exposures to multiple chemicals. The first case-study
(case-study A) is on polybrominated diphenyl ethers (PBDEs), and the second (case-study B)
is on carbamates. These case-studies appear in separate documents, to which the interested
reader can refer.
9
7. REFERENCES
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Douglass JS, Barraj LM, Tennant DR, Long WR, Chaisson CF (1997) Evaluation of the
budget method for screening food additive intakes. Food Additives and Contaminants, 14(8):
791–802.
European Commission (2006) The SCCNFP’s notes of guidance for the testing of cosmetic
ingredients and their safety evaluation, 6th rev. Luxembourg, European Commission,
Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers
(SCCNFP/0690/03
Final;
http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_03j.pdf).
Health Canada (2006) The health-related components of categorization of the Domestic
Substances List (DSL): Approach, results, and next steps. Ottawa, Ontario, Health Canada
(http://www.hc-sc.gc.ca/ewh-semt/contaminants/existsub/categor/approachapproche_e.html).
Sonich-Mullin C, Fielder R, Wiltse J, Baetcke K, Dempsey J, Fenner-Crisp P, Grant D,
Hartley M, Knaap A, Kroese D, Mangelsdorf I, Meek E, Rice J, Younes M (2001) IPCS
conceptual framework for evaluating a mode of action for chemical carcinogenesis.
Regulatory Toxicology and Pharmacology, 34: 146–152.
United Kingdom Committee on Mutagenicity of Chemicals in Food, Consumer Products and
the Environment (2008) Statement on mutagenicity assessment of chemical mixtures
(COM/08/S1; http://www.advisorybodies.doh.gov.uk/com).
WHO (2009) Assessment of combined exposures to multiple chemicals: Report of a
WHO/IPCS international workshop on aggregate/cumulative risk assessment. Geneva, World
Health Organization (in press).
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
THE HARMONIZATION PROJECT DOCUMENT SERIES
IPCS risk assessment terminology (No. 1, 2004)
Chemical-specific adjustment factors for interspecies differences and human variability:
Guidance document for use of data in dose/concentration–response assessment (No. 2, 2005)
Principles of characterizing and applying human exposure models (No. 3, 2005)
Part 1: IPCS framework for analysing the relevance of a cancer mode of action for humans
and case-studies; Part 2: IPCS framework for analysing the relevance of a non-cancer mode
of action for humans (No. 4, 2007)
Skin sensitization in chemical risk assessment (No. 5, 2008)
Part 1: Guidance document on characterizing and communicating uncertainty in exposure
assessment; Part 2: Hallmarks of data quality in chemical exposure assessment (No. 6, 2008)
Combined exposures to multiple chemicals: an IPCS framework and sample case-studies
(No. X, 2009)
To order further copies of monographs in this series, please contact WHO Press,
World Health Organization, 1211 Geneva 27, Switzerland
(Fax No.: +41 22 791 4857; E-mail: [email protected]).
The Harmonization Project Documents are also available on the web at http://www.who.int/ipcs/en/.