NCT.A-W-010:
August 1997
Tl '
ic
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Guidance for NCHA-W.
Risk Assessors
National Cer
ter for Imvironmental Assessment-Washington Office
Office of Research and Development
U.S. Environmental Protection Agency
"!. DC
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NCEA-I-0105
August 1997
Risk Characterization: A Practical
Guidance for NCEA-Washington
Risk Assessors
National Center for Environmental Assessment-Washington Office
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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DISCLAIMER
This document is intended primarily for internal use by NCEA-W risk assessors. It has
not been subjected to external peer or administrative review and does not constitute U.S.
Environmental Protection Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
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CONTENTS
FOREWORD . vi
PREFACE .
AUTHORS AND CONTRIBUTORS ix
1. INTRODUCTION AND PURPOSE 1
2. WHAT IS RISK CHARACTERIZATION7 4
3. Is THE CHARACTERIZATION CLEAR, TRANSPARENT, REASONABLE,
AND CONSISTENT
3.1. CLARITY
3.2. TRANSPARENCY
3.3. REASONABLENESS
3.4. CONSISTENCY
4. COMMUNICATION AS PART OF RISK CHARACTERIZATION 11
5. WHAT QUESTIONS DO RISK MANAGERS ASK 15
6. SAMPLE CHECKLISTS FOR CHARACTERIZATIONS 18
6.1. CHECKLIST FOR RISK CHARACTERIZATION SUMMARY 19
6.1.1. Scope and Background 19
6.1.2. Risk Conclusions 20
6.1.3. Risk Context 21
6.1.4. Other Information 22
6.2. CHECKLIST FOR SUMMARY OF CHARACTERIZATION OF HAZARD
IDENTIFICATION 22
6.3. CHECKLIST FOR SUMMARY OF DOSE-RESPONSE CHARACTERIZATION . .23
6.4. CHECKLIST FOR SUMMARY OF CHARACTERIZATION OF EXPOSURE 25
6.5. CHECKLIST FOR INTEGRATIVE ANALYSIS 26
7. ABOUT THE APPENDICES
Appendix A. Characterization of Ecological Effects and Exposures
Appendix B. Characterization of Reproductive Toxicity
Appendix C. Characterization of Cancer Risk
Appendix D. Characterization for Exposure Assessments
Appendix E. Risk Characterization Framework for Asbestos
Appendix F. Hazard Identification for Brominated Alkane (BA)
Appendix G. Summary Figures Describing Risks Associated With Dioxin and
Dioxinlike Compounds in North America G- 1
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A-i
B-i
C-i
D-1
E-1
F-i
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CONTENTS (continued)
Appendix H. Example of Comparative Risks for Lung Cancer Associated
With Radon Exposure H-i
Appendix I. Hazard Identification Summary for “Substance 4” I-i
Appendix J. For Dioxinlike Compounds, Summary of Exposure Findings and
Uncertainties for North America J- 1
Appendix K. Characterization of Human Health and Wildlife Risks From
Anthropogemc Mercury Emissions in the United States K-i
Appendix L. Workers, EMFs, and Cancer L-1
Appendix M. Nitrate and Nitrite in Drinking Water M-1
Appendix N. Questions Used to Develop NCEA’s Dioxin Risk Characterization N-i
Appendix 0. Questions Used to Develop NCEA’s Trichioroethylene Risk
Characterization 0-1
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LIST OF TABLES
1. Comparison of Agency, ORD, and NCEA risk characterization guidance documents 2
2. Guide for cross-referencing examples in the appendices with the
Administrator’s four values and the checklists in chapter 6 32
LIST OF FIGURE
1. Components of a risk assessment 5
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FOREWORD
The National Center for Environmental Assessment (NCEA) of the U.S. Environmental
Protection Agency’s (EPA’s) Office of Research and Development (ORD) has three main
functions: (1) providing research into risk assessment methods to advance the state of the art in
the field; (2) performing health and ecological assessments, particularly when they illustrate a
new method or are cross-program assessments of high Agency priority; and (3) helping our client
organizations do better risk assessments by providing guidelines, training, and consulting
assistance. The activities under each of these functions respond to the needs of the various EPA
Program Offices, Regional Offices, and others.
In March 1995, the Administrator issued a Policy for Risk Characterization to improve
the way we characterize and communicate information about environmental risks. The
Administrator also directed each Program and Regional Office to develop its own policies and
procedures for risk characterization, consistent with EPA’s policy guidance. In response, the
Washington Office of NCEA (NCEA-W) developed this guidance document to provide our own
risk assessors with the information they need to develop risk characterizations consistent with the
Administrator’s 1995 policy. This document relates most closely to the third function noted
above for NCEA, by providing guidance for preparing risk characterizations. Although it is
intended primarily for use by NCEA-W risk assessors, this guidance should be relevant to risk
assessment efforts in other organizations as well.
NCEA-W produces a variety of risk assessment products, ranging from those covering
just exposure assessment or hazard identification to complete assessments containing all of the
components of a risk assessment. I believe that the principles of risk characterization (clarity,
transparency, reasonableness, and consistency) apply to all of these products and that this
guidance should be considered in the preparation of not only full risk assessments, but also in
assessments of hazard, dose response, and exposure even if risk per se is not estimated.
Specifically, I am directing the NCEA-W risk assessors responsible for preparing these risk
assessment products to use this guidance document in the following ways:
• Review chapters 1 through 5 to understand what a risk characterization is and the
four values that the Administrator believes are important in risk characterization;
• Identify the checklist(s) in chapter 6 most relevant to the risk assessment product
you are preparing, and use this as a guide to what should be covered in the
characterization(s);
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• Review the risk characterization guidance contained in the NCEA risk assessment
guidelines most relevant to the risk assessment product you are preparing
(appendices A through D contain the risk characterization guidance excerpted
from NCEA risk assessment guidelines on ecological effects and exposures,
reproductive toxicity, cancer risk, and exposure assessments, respectively);
• Review the case studies in appendices E through M to get ideas (e.g., how to
summarize and present characterization infonnation) that may help you with the
development of your risk assessment product; and
• Review the list of questions contained in appendices N and 0 for relevance to
your risk assessment product. (These questions were developed to help NCEA-W
risk assessors focus on the key issues that needed to be covered in the risk
characterizations for the dioxin and trichioroethylene assessments.)
I would like risk assessors to pay particular attention to chapter 5 of this guidance, which
concerns questions that risk managers ask about risk assessments. By keeping these questions in
mind and by following the four principles of risk characterization, we can make progress toward
lifting risk assessment from an obscure, arcane, esoteric field to make it a scientific tool that is
widely understood and highly prized for the insights it brings to our own and our clients’ real-
world problems.
Michael A. Callahan
Director
National Center for Environmental Assessment
Washington Office
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PREFACE
This document provides some practical tools for NCEA-W risk assessors to use to
develop risk characterizations that are consistent with the Administrator’s 1995 Policy for Risk
Characterization. This document is to be used in conjunction with the Administrator’s policy
memorandum and guidance documents and ORD’s 1995 draft Risk Characterization Guidance.
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AUTHORS AND CONTRIBUTORS
This document was developed by the NCEA-Washington Risk Characterization Team:
Authors:
Susan Perlin, Lead Author
Michael Dellarco
John Schaum
Contributors:
Thomas L. Baugh
Margaret Chu
Manuel Gomez
Aparna Koppikar
Robert McGaughy
Jean Parker
Lawrence Valcovic
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1. INTRODUCTION AND PURPOSE
In March 1995, the EPA Administrator issued a Policy for Risk Characterization to
“improve the way in which we characterize and communicate environmental risks” (Browner,
1995). That policy statement, with its supporting documentation (Science Policy Council,
1995a, b), defines the basic principles and values that need to be addressed in all risk
characterization activities in the Agency. The Administrator’s policy also directed each Program
and Regional Office to “develop office-specific policies and procedures for risk characterization
that are consistent with this policy and associated guidance” (Browner, 1995). In response, the
Office of Research and Development (ORD) prepared a document (U.S. EPA, 1995) that defines
the policies and procedures to guide ORD in the implementation of the Administrator’s policy.
The purpose of Risk Characterization: A Practical Guidance for NCEA-Washington Risk
Assessors is to provide the staff of the National Center for Environmental Assessment (NCEA)
who will be involved in the development, review, and evaluation of risk assessments with
practical tools to assist them in the implementation of the overall Agency policy and the specific
policies and procedures of ORD and NCEA. Table 1 summarizes the purpose, content, and
status of these three complementary guidance documents. In addition to these three documents,
the individual EPA risk assessment guidelines (developed by ORD) contain specific risk
characterization guidance (see appendices A through D). Taken together, all these documents are
intended to facilitate the understanding and application of the principles and practices of effective
risk characterization. The users of Risk Characterization: A Practical Guidance for NCEA-
Washington Risk Assessors already should be well acquainted with both the 1995 Agency policy
and the ORD guidance documents.
Chapter 2 of this guidance document briefly reviews the basic principles of risk
characterization, guiding the reader to the more detailed descriptions of these principles as
presented in the Agency (Browner, 1995; Science Policy Council, 1995 a, b) and ORI) (U.S.
EPA, 1995) guidance documents. The remainder of this document contains the practical tools
for use by NCEA-W risk assessors. These are not intended to be rigid instructions but flexible
tools to assist in the development of effective risk characterizations.
Chapter 3 provides a series of criteria that can be applied by risk assessors to evaluate
whether their work satisfies the Administrator’s key requirements of clarity, transparency,
reasonableness, and consistency that form the basis for the overall Agency policy. Chapter 4
discusses the need for communication between the risk assessor and the end users of the risk
assessment. Chapter 5 summarizes the kinds of questions risk managers ask of the risk
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Table 1. Comparison of Agency, ORD, and NCEA risk characterization guidance documents
Agency
ORD
NCEA
Purpose
Ensure Agency risk documents
adequately describe degree of risk,
basis, and uncertainties.
Provide ORD-specific policies and
procedures to implement
Administrator’s policy,
Provide practical tools for NCEA -W
risk assessors to implement Agency
and ORD policies.
Contents
-General policy memorandum
-Guidance and general principles
-Elements to consider
-Management responsibilities in ORD
-Application to ORD products and
activities
-General principles
-Goals
-Elements to consider
Practical tools:
-Criteria for evaluating
Administrator’s four values
-Questions risk managers want
answered
-Sample characterization checklists
-Sample excerpts from
characterizations (case studies)
-Risk characterization sections from
current ORD risk assessment
guidelines
Status
1995 Final
1995 Final Draft
1997 Final Report
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characterization to support their decisions. Chapter 6 provides checklists that can be used by
NCEA-W risk assessors during the preparation of risk characterizations and characterizations of
risk assessment components. These checklists focus on the kinds of issues that should be
addressed and information that should be included when characterizing human health risks.
Chapter 7 provides information about the content and organization of the appendices and
includes a table that is a guide for cross-referencing examples in the appendices with the
Administrator’s four values and the checklists in chapter 6.
Appendices A through D contain the risk characterization guidance sections from the
ORD risk assessment guidelines for ecological effects and exposures, reproductive toxicity,
cancer risk, and exposure assessments, respectively.
Appendices E through M present excerpts of documents that illustrate various ways to
characterize risk or risk assessment components (e.g., hazard, dose response, exposure). These
appendices are provided simply as examples that NCEA-W risk assessors may want to follow or
modify to suit their own needs. Each example is accompanied by a short critique to highlight
some of its strengths and weaknesses.
Appendices N and 0 present lists of questions used to develop the risk characterizations
for the dioxin and trichioroethylene assessments, respectively.
REFERENCES
Browner, C. (1995) Policy for risk characterization. Policy memorandum from the U.S.
Environmental Protection Agency Administrator Carol Browner. U.S. Environmental Protection
Agency, Washington, DC.
Science Policy Council. (1995a) Guidance for risk characterization. U.S. Environmental
Protection Agency, Washington, DC.
Science Policy Council. (1995b) Elements to consider when drafting EPA risk characterizations.
U.S. Environmental Protection Agency, Washington, DC.
U.S. Environmental Protection Agency. (1995) Risk characterization guidance (draft). Prepared
by the Office of Research and Development, Washington, DC.
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2. WHAT IS RISK CHARACTERIZATION?
Consistent with the Administrator’s policy (Browner, 1995), and its supporting
documentation (Science Policy Council, 1995a, b), ORD’s 1995 draft guidance document
describes a risk characterization as “a summary, integration, and evaluation of the major
scientific evidence, reasoning and conclusions of a risk assessment. It is a concise description of
the estimates of potential risk and the strengths and weaknesses of those estimates” (U.S. EPA,
1995).
A risk characterization is the final step in a risk assessment and is always part of an
assessment. A risk characterization is designed to support risk managers by providing, in plain
language, the essential scientific evidence and rationale about risk that they need for
environmental decision making. Because it combines information concerning dose response (or
stressor response) and exposure, a risk characterization provides an estimate of the risk to human
health (or to ecological endpoints) under relevant exposure scenarios. Thus, a risk
characterization is an evaluation and integration of the available scientific evidence used to
estimate the nature, importance, and often the magnitude of human and/or environmental risk,
including attendant uncertainty, that can reasonably be estimated to result from exposure to a
particular environmental agent under particular circumstances.
For the risk manager, a risk characterization answers the question, “What is the impact (in
terms of potential occurrence of adverse effects, or increased risk) from exposure to the agent?”
Along with the concise description of risk, a characterization addresses the uncertainty in the
underlying data and models. The characterization provides a sense of the degree of confidence in
the risk estimates and a sense of where the supporting data lie on the continuum between strong
evidence that is based on or is highly relevant to humans (or to ecological entities of concern)
and weak evidence that is based on less relevant species or systems (e.g., in vitro experiments).
The ORD guidance (U.S. EPA, 1995) describes risk characterization as being conducted
in two steps. The first step involves a detailed integrative analysis that is an integration of the
major findings of the components of the assessment and a description of its major conclusions
and limitations. The second step involves developing a concise summary that is a synopsis of
those conclusions and limitations. Figure 1 shows all the components of a detailed risk
assessment and how the characterization discussions fit into these components. The risk
characterization portion, composed of the integrative analysis and summary, is illustrated as one
large triangle on the right side of the figure. Each of the smaller triangles on the left illustrate
how each of the components of the assessment also contains a characterization piece with an
appropriate summary.
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Exposure Exposure [ -
Assessment J y(a)>
r -- -
I
IdenWication ••i __• _•_•_ Afla S(d) L Summary(e) >
Dose- Dose-Response
Response Assessment Summary (c) -’
Assessment Chamcter zat0n
Risk Chare er zaUofl
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Audiences:
Scientificallyversed_— General Public
A,RA,RD -± . __ —--- D ___ P
Scientific Complexity:
Sc enttficallycompiex!aflgUage _
Figure 1. Components of a risk assessment.
A=Risk Assessors, R=Peer Reviewers, D=Decision Makers, P =Genera1 Public. Peer review may take place anywhere along this continuum. It may be advantageous to have
different reviewers for different documents.
Chapter 6 contains sample checklists of information that should be considered for inclusion when preparing any of the above summaries. The checklists for the specific
summaries are as follows:
(a) Checklist for Summary of Exposure Assessment Characterization is in section 6,4.
(b) Checklist for Summary of Hazard Identification Characterization is in section 6.2.
(c) Checklist for Summary of Dose-Response Assessment Characterization is in section 6.3.
(d) Checklist for Integrative Analysis is in section 6.5.
(e)Checklist for Summary of Risk Characterization is in section 6.1.
During the preparation of a complete risk assessment, there is a great deal of interaction between the groups preparing the exposure assessment and the hazard identification and
dose-response assessment. We have chosen to not show all the possible pathways of interaction and iteration schematically because the figure would become too cluttered.
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The reduction in the size of the triangles as one moves from the assessment to the
characterization to the summary is intended to symbolize the reduction in the amount of
information presented in each of these pieces. The figure also indicates that, in general, as one
moves from assessment to summary, the audience changes from being more technically versed to
less technically versed. For example, a detailed exposure assessment characterization would be a
very technical document, appropriate for individuals with expertise in this field (e.g., risk
assessors and peer reviewers). In contrast, the summary of the exposure assessment
characterization would be more simplified, using fewer technical terms and written in a manner
that a decision maker or educated lay person could understand. The summaries would then be
simplified even more to produce information appropriate for risk communication activities and
understandable by the general public.
The current guidance document is intended for application not only to complete risk
assessments but also to other risk-related tools and documents, including hazard identifications,
dose-response and exposure assessments, as well as models, databases, and other tools that
support risk assessments. All of these typesof documents should contain a separate
characterization and summary covering the major conclusions, supporting evidence, and
assumptions.
It is important to remember that numerous science policy choices are made by the risk
assessor during preparation of all phases of a risk assessment, and particularly during the risk
characterization. These choices (e.g., which dose response model to use, which default value to
select to estimate a model parameter) often are dependent less on rigorous scientific knowledge
and more on policy assumptions. Nevertheless, the sum of all these science policy choices may
heavily influence the result of the risk assessment. For this reason, it is essential to describe the
approach used to estimate the risk, identify and explain the science policy choices that are made
in each step of the assessment, carry this information through the summaries, and indicate how
these choices affect the final risk estimate. To the extent possible, the risk characterization
should indicate how the sum of all these choices affects the result of the assessment.
REFERENCES
Browner, C. (1995) Policy for risk characterization. Policy memorandum from the U.S.
Environmental Protection Agency Administrator Carol Browner. U.S. Environmental Protection
Agency, Washington, DC.
Science Policy Council (1995a) Guidance for risk characterization. U.S. Environmental
Protection Agency, Washington, DC.
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Science Policy Council. (1995b) Elements to consider when drafting EPA risk characterizations.
U.S. Environmental Protection Agency, Washington, DC.
U.S. Environmental Protection Agency. (1995) Risk characterization guidance (draft). Prepared
by the Office of Research and Development, Washington, DC.
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3. Is THE CHARACTERIZATION CLEAR, TRANSPARENT,
REASONABLE, AND CONSISTENT?
The Administrator’s 1995 policy (Browner, 1995) calls for risk characterizations and
characterizations of risk assessment components to be clear, transparent, reasonable, and
consistent. Although the policy emphasizes the need to adhere to these four values, neither the
Administrator nor the Science Policy Council actually provides a definition for these values.
Rather than try to defme these values here, we have provided the following criteria to serve as a
guide to help NCEA-W risk assessors determine if a characterization meets these four values.
Because some of the following criteria are relevant to more than one of the Administrator’s four
values, there are unavoidable redundancies across some of the categories.
3.1. CLARITY
Clarity of the characterizations can be judged by the extent to which:
The purpose of the risk assessment is defined and explained (e.g., regulatory
purpose, policy analysis, priority setting, public health concern, ecological
concern).
• The text is clear, concise, and understandable to informed lay readers.
• The description and organization of the issues are understandable to EPA risk
managers and informed lay readers.
• The level of effort (e.g., quick screen, extensive evaluation, qualitative versus
quantitative assessment) put into the assessment is described, accompanied by the
reason(s) why this level of effort was selected.
• The strengths and limitations of the assessment are described in simple terms that
can be understood without knowing all of the technical details of the assessment.
Technical terms are defined.
• Key scientific information and analytical procedures, including assumptions (e.g.,
to err on the side of safety), used in the assessment are clearly described. Science
policy choices made throughout the risk assessment are identified and explained.
The effect of the sum of all these policy choices on the final product of the risk
assessment is explained.
• Unusual or unique issues are fully discussed and explained.
• There is complete documentation of the data sources and analytical methods used
to interpret the dz t i , to allow the reader to obtain more detailed information.
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• All components are well integrated into an overall conclusion of risk that is
complete, informative, and useful in decision making.
• Science policy choices are identified.
3.2. TRANSPARENCY
Transparency of the characterization process can be judged by the extent to which:
• Conclusions drawn from the scientific and technical information are identified
separately from policy judgments.
• The strengths, limitations, and uncertainties of the assessment are addressed in a
balanced manner. This includes a discussion of the quality of the data and
analytic methods and important issues that could bias or skew the conclusions.
• Assumptions, and the rationale for using them, are described for key science
policy decisions (e.g., use of default assumptions, use of nonthreshold rather than
threshold cancer risk model). The justification, be it scientific or policy, for using
these assumptions and the implications for the reported risk estimate(s) are clearly
indicated.
• Reasonable, alternative approaches to interpretation of the data that could result in
significantly different risk estimates are identified and summarized. These
include alternative assumptions and default values and their implications for the
conclusions reached in the assessment.
• The results of scientific arid public peer review of the associated risk assessment
(or risk assessment components) are summarized, and key scientific controversies
surrounding the assessment (or components) are discussed.
3.3. REASONABLENESS
The extent to which characterizations are reasonable can be judged by whether:
• They use common sense to assess risk in a forthright manner, acknowledging
scientific and technical uncertainty. While it is EPA’s mission to protect public
health and the environment in the face of scientific uncertainty, common sense
and reasonable application of assumptions and policies are used to avoid
unrealistic risk estimates.
• They are based on the best available, current scientific information and judgment,
documenting sources appropriately.
• Analyses are based on accepted scientific principles, to the extent possible.
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3.4. CONSISTENCY
Criteria for judging if characterizations produced by NCEA are consistent with
characterizations produced by other parts of the Agency are as follows:
The supporting NCEA risk assessment or risk assessment components are
consistent with existing Agencywide guidelines, such as those for exposure
analyses and health risk assessment. Reasons for any discrepancies are clearly
explained and justified.
• The supporting NCEA risk assessment uses Agency-accepted indicators of risk,
such as the cancer slope factor (q* 1 value), the reference concentration (RfC), and
the reference dose (R.fl)).
• Whenever appropriate, standard language and format are used.
REFERENCE
Browner, C. (1995) Policy for risk characterization. Policy memorandum from the U.S.
Environmental Protection Agency Administrator Carol Browner. U.S. Environmental Protection
Agency, Washington, DC.
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4. COMMUNICATION AS PART OF RISK CHARACTERIZATION
In 1983, the National Research Council (NRC) recommended that “regulatory agencies
take steps to establish and maintain a clear conceptual distinction between assessment of risks
and consideration of risk management alternatives; that is, the scientific findings and policy
judgments embodied in risk assessments should be explicitly distinguished from the political,
economic, and technical considerations that influence the design and choice of regulatoiy
strategies” (NRC, 1983). The NRC report further states, “even the perception that risk
management considerations are influencing the conduct of risk assessment in an important way
will cause the assessment and the regulatory decisions based on them to lack credibility.”
However, this same report notes that the “importance of distinguishing between risk assessment
and risk management does not imply that they should be isolated from each other; in practice
they interact, and communication in both directions is desirable and should not be interrupted.”
Thus, the process by which agencies reach decisions is iterative, so that risk assessors are often
called on repeatedly for analysis and advice as risk managers identify and consider various
options in attempting to reach a decision. Equally important is the need for risk assessors to
interact with risk managers to ensure that the latter understand the assessment, interpret the risk
estimates correctly, and use the information appropriately to support their decisions.
It is important to recognize that the face of risk characterization is changing. NRC
recently published new risk characterization guidance, in which the authors modify the 1983
precautions and now stress the need for interaction between not only risk assessors and risk
managers but also relevant at-risk and interested parties throughout the entire preparation of the
assessment and characterization, starting with the problem formulation phase (NRC, 1996). This
recent guidance also indicates that risk characterizations can no longer be thought of as merely a
summary or translation of the results of a technical analysis for use by a decision maker. In a
departure from the guidance contained in its 1983 report, NRC now defmes risk characterization
as a “synthesis and summary of information about a potentially hazardous situation that
addresses the needs and interests of decision makers and of interested and affected parties. Risk
characterization is a prelude to decision making and depends on an iterative, analytic-deliberative
process” (NRC, 1996). The 1996 report further states, “The aim of risk characterization, and
therefore also of the analytic-deliberative process on which it is based, is to describe a potentially
hazardous situation in as accurate, thorough, and decision-relevant manner as possible,
addressing the significant concerns of the interested and affected parties, and to make this
information understandable and accessible to the parties and public officials. If the underlying
process is unsatisfactory to some or all of the interested and affected parties, the risk
characterization will be unsatisfactory as well. A risk characterization can be only as good as the
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analytic-deliberative process that produces it.” The NRC report goes on to say, “Agencies
should recognize from the start that a risk characterization should be useful to multiple parties
with different interests, concerns, and information needs.”
The1996 NRC guidance maintains that risk characterization “cannot succeed as an
activity added at the end of a risk analysis, but must result from a recursive process that includes
problem formulation, analysis, and deliberation. Two essential aspects of that process are
appropriately broad participation by the interested and affected parties and appropriate
incorporation of science.” The NRC guidance deals more with the process of how to develop a
risk characterization rather than what should be contained in a risk characterization. To that end,
the guidance provides a set of seven principles for organizing the process (note that the following
italicized emphases are used in the NRC guidance):
1. “Risk characterization should be a decision-driven activity, directed toward
informing choices and solving problems.”
2. “Coping with a risk situation requires a broad understanding of the relevant losses,
harms, or consequences to the interested and affected parties.”
3. “Risk characterization is the outcome of an analytic-deliberative process. Its success
depends critically on systematic analysis that is appropriate to the problem, responds
to the needs of the interested and affected parties, and treats uncertainties of
importance to the decision problem in a comprehensive way. Success also depends
on deliberations that formulate the decision problem, guide analysis to improve the
decision participants’ understanding, seek the meaning of analytic findings and
uncertainties, and improve the ability of interested and affected parties to participate
effectively in the risk decision process. The analytic-deliberative process must have
an appropriately diverse participation or representation of the spectrum of interested
and affected parties, of decision makers, and of specialists in risk analysis, at each
step.”
4. “Those responsible for a risk characterization should begin by developing a
provisional diagnosis of the decision situation so that they can better match the
analytic-deliberative process leading to the characterization to the needs of the
decision, particularly in terms of level and intensity of effort and representation of
parties.”
5. “The analytic-deliberative process leading to a risk characterization should include
early and explicit attention to problem formulation; representation of the spectrum of
interested and affected parties at this stage is imperative.”
6. “The analytic-deliberative process should be mutual and recursive. Analysis and
deliberation are complementary and must be integrated throughout the process
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leading to risk characterization: deliberation frames analysis, analysis informs
deliberation, and the process benefits from feedback between the two.”
7. “Each organization responsible for making risk decisions should work to build
organizational capability to conform to the principles of sound risk characterization.
At a minimum, it should pay attention to organizational changes and staff training
efforts that might be required, to ways of improving practice by learning from
experience, and to both cost and benefits in terms of the organization’s mission and
budget.”
As NCEA-W risk assessors prepare their characterizations, they may want to keep the
following precautions in mind: “Risk characterizations have been needed for a much wider
range of policy questions, including many in which the nature of the problem and the identity of
the available choices is not at all obvious; articulate and scientifically informed public opposition
to risk decisions has revealed gaps in many risk analyses; experiences with risk communication
have demonstrated that official summaries of risk are often incomprehensible, confusing, or
irrelevant to many of the affected parties; and public trust in many of the organizations that
conduct risk assessments has declined” (NRC, 1996).
As noted above, the updated NRC guidance deals more with the process of how to
develop a risk characterization, so the reader may want to refer to that document for some
interesting approaches. Moreover, much of the NRC guidance may be more relevant to the
preparation of a complete risk assessment having high visibility. In contrast, the current
guidance developed for NCEA-W risk assessors deals more with the suggested content of both
risk characterizations and characterizations of risk assessment components.
In view of the guidance offered in both the 1983 and 1996 NRC documents, it is
important to stress the need for ongoing communication between the risk assessor, risk manager,
and other appropriate stakeholders. Such interaction could help to (1) formulate the problem to
be addressed by the assessment, (2) determine the scope of the assessment (this could be
particularly useful in site-specific assessments), (3) identify questions and concerns that develop
during the assessment process, and (4) educate the end user on how to properly interpret and use
the information in the risk assessment or risk assessment components. It may be particularly
important to educate the end user on the issue of uncertainty (i.e., understanding the nature and
magnitude of the uncertainty in a specific assessment and how it can potentially affect the
decision-making process).
To the extent possible during the early planning phases of an assessment, the potential
end users (e.g., risk managers, other stakeholders, at-risk groups) of the risk information should
be identified. The information needs of these users should be kept in mind during all phases of
the assessment. It is particularly important to consider the needs of the users when planning and
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conducting the characterization phase of the assessment to help ensure that characterizations and
summaries of the characterizations are applicable to the decisions that need to be made.
As part of the planning phase, the assessor should not only identify the end users, but also
lay out a plan for the type and level of communication that is appropriate. The purpose and
conduct of the communication should be clearly understood by all parties to avoid the pitfalls
noted by NRC in its 1983 report yet ensure that the relevant concerns and needs of the end users
are addressed.
REFERENCES
National Research Council. (1983) Risk assessment in the federal government: managing the
process. Washington, DC: National Academy Press.
National Research Council. (1996) Understanding risk, informing decisions in a democratic
society. Washington, DC: National Academy Press.
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5. WHAT QUESTIONS DO RISK MANAGERS ASK?
To help deal with the issue of communication between risk assessors and risk managers,
it would be helpful to understand what kind of information risk managers are looking for in a risk
characterization.
In March 1993, the Office of Air Quality Planning and Standards (OAQPS) conducted a
focus group session with 11 senior EPA headquarters decision makers selected from various
Program Offices (U.S. EPA, 1993). The purpose of this effort was to directly ask risk managers
about their risk assessment information needs and preferences. OAQPS recognized that although
it had been charged with presenting risk assessment information to decision makers, it had never
asked the risk managers how well this information suited their needs. The intent was to solicit
ideas and insights from the people who actually use risk assessment information to provide a
better understanding of how risk managers use risk information in making regulatory decisions
and what level of detail they want concerning assumptions and uncertainties in the data.
During the preparation of a risk characterization or characterization of risk assessment
components, it would be useful to keep in mind the kind of information risk managers actually
want. The following is an edited sample of questions that the managers asked and that appear to
be relevant to the preparation of the various characterizations:
• What is the bottom line of the risk assessment?
• Does the risk assessment provide sufficient information to support a regulatory
decision?
• What is the range of uncertainty around the estimated exposure level and the
projected number of people who may be exposed to the chemical? Do we know if
people are actually being exposed to the levels identified in the risk assessment? Are
these levels of public health concern?
• What data gaps are likely to elicit criticism of the risk estimate andlor selected risk
management options? There will always be data gaps, but which are the ones that
may lead to criticism of the risk assessment or of the risk management options and
decision(s)?
• Are studies being conducted that will “soon” provide new information that could fill
a critical data gap(s)? If so, is it worth delaying a decision while waiting for this
information?
• Has the risk assessment been peer reviewed? If so, by whom, and what was the
outcome of the review?
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• Indicate how likely, or if, there is a chance of zero risk. Has zero risk actually been
ruled out?
• What is the key parameter(s) that drives the analysis? Is there research on the
horizon that will address this key parameter and reduce its uncertainty? How much
interest is there in issues surrounding this parameter?
• If certain studies were excluded, what would be the consequence to the risk
assessment results? What was the rationale for excluding these studies?
Other questions have been identified informally within ORD as being of interest to risk
managers and relevant to the risk characterization process. These questions primarily concern
the issue of uncertainty:
• What are the specific conditions of exposure believed to cause or contribute to the
risk? Have exposures and/or dose been measured in the population of interest? If
so, has it been possible to relate exposure to actual body burden? If exposures have
been calculated through analogy, modeling, or other estimation techniques, what
evidence is there that the estimates are realistic?
• What is the degree of confidence in the existence of the risk and the magnitude of the
risk estimate? If the risk is based on animal models, is there an observable parallel
between humans and the positively responding animal species in terms of the
absorption,, metabolism, distribution, and excretion of the chemical of interest? If
not, what is the basis for thinking such a parallel exists? Is there epidemiologic
evidence indicating that comparable effects seen in the animal model have been seen
in human populations (e.g., heavily exposed occupational or environmental settings,
accidents)?
• Can population subgroups be identified who are at increased risk of exposure and/or
especially sensitive to such exposures? At a given exposure or dose level, are there
observable differences in the range of responses among different human subgroups
(e.g., infants, children, healthy adults, elderly)? If so, have these differences been
evaluated and employed in the models used to calculate specific risks? If not, what
evidence provides the basis for conclusions drawn about differences in sensitivity
among subpopulations and their (potential) risks?
EPA risk managers have raised other issues that they want risk assessors to address in
their risk assessments and characterizations:
• What part(s) of this assessment can be challenged? What would be the basis of the
challenge? How can I defend against such a challenge?
• Provide a “road map” that identifies all the issues brought out in the assessment and
then leads me to the really important issues that I have to be concerned about. Can
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you provide me with a means of comparison across chemicals so I can get a feel for
whether what we know about the subject chemical is “typical” or “way out of line”
compared with the chemicals we usually deal with in this office? For example, does
this chemical have many more data gaps than the typical chemical we deal with?
• How valid are the opposing views?
• If this is a reassessment, how do the results in the new assessment compare with the
results in the old assessment? Has the level of concern changed? If so, why? Is
there a “real” difference between the two assessments, and is this difference
something to be concerned about?
REFERENCE
U.S. Environmental Protection Agency. (1993, March) Communicating risk to senior EPA policy
makers: a focus group study. Prepared by the Office of Air Quality Planning and Standards,
Research Triangle Park, NC.
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6. SAMPLE CHECKLISTS FOR CHARACTERIZATIONS
This chapter presents checklists of information that should be considered when
characterizing the components of a risk assessment. These checklists are intended to be
examples that users can follow to any extent they wish. Risk assessments vary considerably in
terms of the amount and quality of the supporting data, the use of qualitative versus quantitative
evaluations, the level of detail, etc. Many, if not most, of the assessments conducted by NCEA
are not complete assessments because they lack one or more of the three components (hazard
identification, dose-response assessment, and exposure assessment). For these reasons, NCEA-
W risk assessors need to practice professional judgment when deciding which elements of the
following checklists are appropriate for characterizing their particular assessments. In any case,
the level of complexity of the characterizations should be consistent with the level of complexity
of the supporting risk assessments.
The following checklists refer to both “screening” and “full” assessments. A screening
assessment may contain all the risk assessment components (hazard identification, dose-response
assessment, and exposure assessment); however, one or more of these components would be very
limited in scope, making the screening assessment less rigorous than a full assessment.
Alternatively, the screening assessment may be incomplete, in which case one or more of the
assessment components is missing. A screening assessment may or may not present a quantified
estimate of the risk to exposed populations. In contrast, a full assessment always contains all the
risk assessment components, with each component supported by a fairly extensive database that
allows for the quantification of risk to exposed individuals.
Whenever possible, summarize the characterization information in a table or checklist for
easy comparison across risk factors, exposure scenarios, etc. Provide appropriate supporting
narratives.
The checklists in this chapter are organized as follows:
6.1. Checklist for Risk Characterization Summary. (The Risk Characterization Summary
can be duplicative of the Executive Summary in some assessment documents and thus may
eliminate the need for a separate Executive Summary.)
I. Scope and Background
II. Risk Conclusions
ifi Risk Context
IV. Other Information
6.2. Checklist for Summary of Characterization of Hazard Identification
6.3. Checklist for Summary of Dose-Response Characterization
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6.4. Checklist for Summary of Characterization of Exposure
6.5. Checklist for Integrative Analysis
NOTE: The following checklists contain references to specific appendices. These references
indicate the location of examples that illustrate the issues addressed in the checklist.
6.1. CHECKLIST FOR RISK CHARACTERIZATION SUMMARY
6.1.1. Scope and Background
A. Whenever possible, summarize information in a table or checklist for easy comparison
across risk factors, exposure scenarios, etc., and provide appropriate supporting
narratives.
B. Describe the purpose and scope of the assessment (e.g., regulatory purpose, policy
analysis, health effects assessment). If known, indicate the type of decision(s) the
assessment was designed to support. Is this a reassessment?
1. Indicate which of the components (hazard identification, dose-response assessment,
or exposure assessment) this assessment contains.
2. Indicate the importance of the issue addressed by the assessment. (e.g., it has
national ramifications and could affect large numbers of people; it is site specific and
affects a small number of people).
C. Describe the level of effort put into the assessment. State the reasons that justify the level
of effort put into the assessment (e.g., high visibility/priority pollutant, limited resources,
limited scientific information, statutory mandate, Agency/Program policy).
D. Present an overview of the environmental occurrence and/or overall public health
concern. (See appendices K, L, and M.)
1. Indicate why this pollutant is of concern. Indicate what is known about the extent of
exposures and particularly sensitive subpopulation(s) that make this pollutant of
concern. Sunmiarize what is known about the potential health effects and size of the
population at risk.
2. If this is a screening assessment, there may not be a lot of supporting information
concerning exposures andlor health effects. Indicate that this is the case, and try to
summarize what, if anything, is generally known about possible exposures, sensitive
subpopulation(s), andlor potential health effects and size of the population at risk.
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6.1.2. Risk Conclusions
A. Whenever possible, summarize information in a table or checklist for easy comparison
across risk factors, exposure scenarios, etc., and provide appropriate supporting
narratives. (See appendices E, J, and K.)
B. When summarizing the risk conclusions, keep the following questions in mind: What do
other risk assessors, decision makers, and the public need to know about the primary
conclusions and assumptions and about the balance between confidence and uncertainty
in the assessment? What are the strengths and limitations of the assessment? (See
appendices K and L.)
C. Summarize the “overall picture of risk” based on the ha ’iird identification, dose-response
assessment, and exposure assessment. Evaluation of the “overall picture of risk” applies
only to assessments that contain all three risk assessment components. (See appendices
E,K,L,andM.)
1. What are the major conclusions and strengths of the overall assessment?
2. Consider and integrate all the lines of evidence to determine the plausibility of the
human health hazard, considering the human exposures of concern and the
confidence in the underlying data. It is the judgment in total that is important.
D. Summarize the major conclusions and strengths of the ha7ard identification, dose-
response assessment, and exposure assessment. Indicate the major limitations and
uncertainties in each of these three analyses. (See appendices E, K, L, and M.)
B. IdentiI y the issues raised by this assessment, and indicate if they are “major” or “minor.”
Risk managers often want to have all the issues identified and their importance noted so
they can then focus on only the important issues. (See appendices ( and L).
F. Identify research needed to fill important data gaps to reduce uncertainty in the
assessment results. (See appendix L.)
1. Note which areas would be the best to invest in over a reasonable time frame to
reduce uncertainty.
2. Indicate how new data will reduce these uncertainties.
3. Indicate whether consensus exists concerning what should be studied. If there is no
consensus, indicate what is in dispute.
G. Identify the key science policy options (e.g., choice of model, use of default values) in
each of the three main analyses. (See appendices E and J.)
1. Identify what alternative approaches, if any, were evaluated.
2. Summarize the reasons for the options selected.
3. Indicate how this choice affects the results of the assessment. NOTE: The final
result of the risk assessment is affected by all the science policy choices made along
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the way. Therefore, it is very important to discuss the effect of each choice and, to
the extent possible, the effect of all the choices combined.
H. Indicate the degree of consensus AND discuss the extentlstrength of disagreement over
the underlying science. Summarize the views both inside EPA and outside (e.g.,
industry, environmentalists). (See appendix L.)
If this is a reassessment, indicate how the results in the new assessment compare with the
results in the old assessment.
1. Indicate if the level of concern has changed between assessments. If so, indicate the
reasons.
2. Indicate if there is a “real” difference between the two assessments and if this
difference is something to be concerned about.
6.1.3. Risk Context
A. Whenever possible, summarize information in a table or checklist for easy comparison
across risk factors, exposure scenarios, etc., and provide appropriate supporting
narratives. (See figures 2 and 3 of appendix E and appendices H and K.)
B. Summarize how this risk compares with other risks. If possible, also make the
comparison in the context of the potential overall public health impact. Use professional
judgment and be careful to select examples of comparative risks that are reasonable and
meaningful with respect to the subject risk. Be aware that past assessments of chemicals
or other stressors may have been conducted using different risk assessment guidelines and
methodologies and may not be comparable with the subject risk without an appropriate
explanation. Also consider how the public might perceive the risk(s) selected for
comparison.
1. Where appropriate, indicate how this risk compares with other risks evaluated by
NCEA, other EPA Program Offices, or others outside EPA.
2. If appropriate, indicate how this risk compares with other similar risks that EPA has
made decisions about.
3. If appropriate, indicate how this risk compares with risks evaluated by international
organizations.
4. Describe the limitations of making these comparisons. Indicate how these
comparisons are affected by Program Office differences in underlying assumptions
and the acceptance or rejection of different studies for calculating risk estimates.
C. If this is not a complete risk assessment, still indicate how the results of the evaluation
compare with similar evaluations performed by EPA or other agencies and groups. For
example, if only the hazard identification and cancer dose response have been conducted,
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then indicate how the weight of evidence and cancer potency of the subject chemical
compare with that for other similar chemicals evaluated by NCEA.
D. Identify and summarize other relevant risk assessment information.
1. Indicate what other risk assessments or components of risk assessments have been
conducted on this pollutant by EPA, other Federal agencies, or other organizations
(both national and international). Identify significantly different conclusions that
merit discussion. Reference these other risk assessment documents, and indicate why
they are relevant to the subject risk.
E. Indicate how detailed this assessment is compared with other assessments prepared by
this Office (e.g., is this an in-depth or more of a preliminary assessment compared with
the kind of assessments this Office “usually” produces? How do the quality of the data,
the number of studies, and the sophistication of the assessment methods compare with
those of assessments usually produced by this Office?)
F. Indicate how the level of confidence in the science of this assessment compares with the
level of confidence of the data used to support other parts of the assessment, such as the
economic analysis or assessment of alternative technologies.
6.1.4. Other Information
A. Identify and summarize other relevant information that has not already been summarized
and that would be useful to the risk manager or the public in this situation.
6.2. ChECKLIST FOR SUMMARY OF CHARACTERIZATION OF HAZARD
IDENTIFICATION
In full assessments, the hazard identification should involve extensive evaluation and
assessment of all the health effects literature for the chemical(s) or agent(s) of interest. All major
health endpoints of potential concern should be evaluated. In screening assessments, the hazard
identification may be very limited in scope, data indicating potential h i7ard may be scarce,
and/or the analysis may be selective (e.g., only one endpoint may be assessed). The hazard
identification in screening assessments may involve identification and assessment of only the key
studies (both positive and negative studies) from the health effects literature, with the focus only
on the critical health endpoint and the scientific literature addressing that health endpoint.
A. Whenever possible, summarize information in a table or checklist for easy comparison
across health effects, risk factors, etc., and provide appropriate supporting narratives.
(See appendix G, figure G-l.)
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B. When characterizing the hazard identification, keep the following central question in
mind: What do we know about the capacity of this environmental agent for causing
adverse effects in laboratory animals and in humans? Also, what factor(s) accounts for
the greatest uncertainty in the hazard identification and why? (See appendices F, I, and
K.)
C. Indicate what issues have been raised by this part of the assessment, and note if they are
“major” or “minor.” Managers often want to have all the issues identified and their
importance noted so they can focus on only the important issues.
D. Summarize the conclusions regarding the potential hazards posed by the agent and
include, as appropriate, a discussion of the following:
1. ConfIdence in conclusions.
2. Alternative conclusions about the potential hazard that could be supported by the
data. Alternative conclusions are more likely to result from the use of different
underlying assumptions and/or the acceptance/rejection of different studies.
3. Strengths and weaknesses of the supporting database, including significant data gaps
and other database deficiencies.
4. How the conclusions might be affected by data on specific endpoints that are missing
or inadequate.
5. Highlights (e.g., rationale and plausibility) of major assumptions. Distinguish
assumptions based on science from those based on science policy.
6. Major uncertainties. Identify and, if possible, prioritize the uncertainties.
7. Issues in the hazard identification over which there is controversy or scientific dispute
either inside or outside the Agency.
8. If this is a reassessment, how do the results of the hazard identification in the new
assessment compare with the results in the old assessment? Has the level of concern
changed? If so, why? Is there a “real” difference between the hazard identifications
of the two assessments, and is this difference something to be concerned about?
(See appendices F, I, K, and L.)
6.3. CHECKLIST FOR SUMMARY OF DOSE-RESPONSE CHARACTERIZATION
In full assessments, the data must be sufficient to support a quantitative assessment of the
dose-response relationship for the effect(s) of concern. The data should support calculation of a
potency estimate or slope factor for cancer and an oral reference dose (RfD) or inhalation
reference concentration (RfC) for noncancer effects. In screening assessments, the dose-response
evaluation may be very limited in scope and more qualitative than quantitative. Because of an
incomplete database, it may be possible to report only some health effects observed at a limited
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number of exposure levels. Alternatively, the data in a screening assessment may support a
limited quantitative assessment that can identify an exposure level of concern or a target level
considered to pose an acceptable or minimal degree of nsk.
A. Whenever possible, summarize information in a table or checklist for easy comparison
across health effects, models, etc., and provide appropriate supporting narratives. (See
appendices E and G.)
B. When characterizing the dose-response assessment, keep the following central question in
mind: What do we know about the biological mechanism(s) and dose-response
relationships underlying any effects observed in laboratory or epidemiology studies
supporting the assessment? Also, what factor(s) accounts for the greatest uncertainty in
the dose-response assessment and why?
C. Summarize the conclusions of the dose-response assessment and include a discussion of
the following:
1. Confidence in the conclusions.
2. Dose-response model that was selected and alternative plausible models that also are
supported by the data. How would the results change if an alternative model was
used?
3. Strengths and weaknesses of the supporting database, including significant data gaps
and other database deficiencies.
4. Highlights (e.g., rationale and plausibility) of major assumptions. Distinguish
assumptions based on science from those based on science policy.
5. How the results would change if one or more of the major assumptions was changed.
6. Major uncertainties in the data and model used. Identify and prioritize the major
uncertainties.
7. If a new quantitative method was used, how does that affect the estimate of dose
response? (i.e., if the “new” method is a deviation from the “usual” NCEA or EPA
practice, it is useful to indicate what the results would be by using the “old” method.
This allows the manager to see how the results change based just on the use of a new
methodology.)
8. If this is a reassessment, how do the results of the dose-response evaluation in the new
assessment compare with the results in the old assessment? Has the level of concern
changed? If so, why? Is there a “real” difference between the dose-response curves
of the two assessments, and is this difference something to be concerned about?
9. Issues in any part of the dose-response assessment over which there is controversy or
scientific dispute either inside or outside the Agency.
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10. Research needed to fill the significant data gaps and reduce uncertainty in the
assessment.
(See appendix E.)
6.4. CHECKLIST FOR SUMMARY OF CHARACTERIZATION OF EXPOSURE
In full assessments, the exposure analysis will be quantitative and should involve
modeled and/or monitored data. The distribution of exposures to the chemical, agent, or mixture
should be fully characterized for the general population and/or subpopulation(s) of concern. In
screening assessments, the exposure analysis may be only qualitative or quantitative but limited
in scope, and there may be only a qualitative discussion and evaluationof factors affecting
exposure. If there are no exposure data, information may be presented on surrogates for
exposure, such as emission estimates and/or estimates of populations living in a given area or
within a given distance of a source. Alternatively, if the data can support a formal exposure
assessment, the screening assessment typically may rely on very simple models, with many of
the inputs to the model based on default assumptions and/or very limited data or modeled values.
A. Whenever possible, summarize information in a table or checklist for easy comparison
across exposure scenarios, models, etc., and provide appropriate supporting narratives.
(See appendices E, G, and J.)
B. When characterizing the exposure assessment, keep the following central question in
mind: What do we know about the paths, patterns, and magnitude of human exposure
and the number of persons likely to be exposed? Also, what factor(s) (e.g., concentration,
body uptake, duration/frequency of exposure) accounts for the greatest uncertainty in the
exposure estimate and why? (See appendices E, J, and K.)
C. Summarize the conclusions of the exposure assessment and discuss the following:
1. Main findings (e.g., population exposed, pathways of exposure, duration and
magnitude of exposure, variability of exposure in exposed populations, sources of
exposure). (See appendix K.)
2. Results obtained using different approaches (e.g., modeling, monitoring, probability
distributions). How do different approaches change the assessment results, and how
much confidence is there in each alternative method and its exposure estimate?
3. Weight of evidence supporting input parameters used to calculate exposure;
confidence in the results and conclusions obtained, including limitations and major
uncertainties of the exposure assessment and the range of the most reasonable values
selected for the assessment. Identify and prioritize the uncertainties. (See appendix
K.)
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4. Issues in any part of the exposure assessment over which there is controversy or
scientific dispute either inside or outside the Agency.
5. Highlights of major assumptions. Distinguish assumptions based on science from
those based on science policy.
6. If this is a reassessment, how do the results of the new exposure assessment compare
with the results of the old exposure assessment? Has the level of exposure or concern
changed? If so, why? Is there a “real” difference between the two exposure
assessments, and is this difference something to be concerned about?
7. Research needed to fill the significant data gaps and reduce uncertainty in the
assessment.
(See appendices E, J, and L.)
63. CHECKLIST FOR INTEGRATiVE ANALYSIS
The integrative analysis is part of the risk characterization and is the final step in a risk
assessment. The conclusions of the hazard identification, dose-response assessment, and
exposure assessment are pulled together in the integrative analysis. By combining the
information from these three components of the risk assessment, the integrative analysis provides
an evaluation of the nature, importance, and often the magnitude of human andlor environmental
risk, including attendant uncertainty, that is believed to result from exposure to a particular
environmental pollutant under particular circumstances. To the extent possible, the integrative
analysis answers the question, “What is the impact (in terms of occurrence of potential adverse
effects in, or increased risk to, a population) from exposure to the agent?” The integrative
analysis should provide a sense of both the degree of confidence in the risk assessment results
and where the supporting data lie between strong evidence in humans and weak evidence in
animals or other systems.
Screening assessments have a less extensive supporting database and lack the level of
detail in their resulting evaluations in comparison with full assessments. If the screening
assessment is missing one or more of the three assessment components (hazard identification,
dose-response assessment, or exposure assessment), then it is impossible to conduct an
integrative analysis. If the screening assessment has all three assessment components, then an
integrative analysis should be conducted. Issues listed below that cannot be addressed should be
identified and the reason given as to why they cannot be addressed (e.g., limitations of the
assessment and/or supporting database, limited resources).
A. Whenever possible, summarize information in a table or checklist for easy comparison
across exposure scenarios, models, effects, etc., and provide appropriate supporting
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narratives. (See appendix E.) See section 6.1 for the Risk Characterization Summary
checklist. This summary represents the synopsis of the integrative analysis.
B. Discuss the elements to be addressed in an integrative analysis (be sure to distinguish
between the methods used for quantifying risks of developing cancer vs. noncancer
effects, e.g., the hazard quotient method used for assessing noncancer risks and its
interpretation with respect to risk and uncertainty are different from the methods used to
assess cancer risks):
1. Underlying rationale for the risk estimate.
2. Highlights of the strengths and weaknesses of the evidence and assumptions in the
risk assessment. Identify major assumptions and distinguish assumptions based on
science from those based on science policy.
3. Effect that the major biological and model uncertainties have on the conclusions
reached in the hazard identification, dose-response assessment, and exposure
assessment and overall estimate of risk. To the extent possible, quantify the impact of
these effects on the overall estimate of risk.
4. Estimates of the distribution of exposures/risks in the general population.
5. Estimates of exposures/risks for population subgroups especially at risk from
exposure to the subject pollutant and/or especially sensitive to such exposures. (See
appendix K.)
6. Risk estimates developed using alternative assumptions and/or methods and the
scientific rationale supporting these alternative approaches.
7. Strengths and limitations of the data in support of hazard identification, dose-
response, and exposure assessments. (See appendix K.)
8. What is the exposure level that produced the observable effects in humans and/or
animals and that was used as the basis of the risk estimate? How does this level
compare with ambient exposure levels (i.e., how far is exposure being extrapolated
from the observable effects level to expected, or known, ambient levels?) (See
appendix K.)
9. Key assumptions used to estimate the risks, and the basis for the acceptance of these
assumptions in this situation. (See appendix K.)
10. Specific conditions and routes of exposure believed to cause or contribute to the risk.
(See appendix K.)
11. Degree of confidence in the existence and magnitude of the risk estimate, and
quantitative bounds on the risk estimate. If the data permit, develop a quantitative
risk distribution, with confidence bounds, and discuss the methods used to generate
the distribution.
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12. Key parameter(s) that drives the assessment and whether research is being conducted
that might reduce any important uncertainties associated with that parameter. If data
permit, try to quantify the uncertainty through sensitivity analyses.
13. Important scientific controversies, science policy choices, and scientifically plausible
alternatives that could significantly affect the conclusions of the assessment.
Alternative interpretations of the data may be considered on the basis of their
biological plausibility or some other legitimate underlying scientific basis.
14. Range of risk descriptors (central tendency, high end of individual risk, population
risk, risk to important subgroups) consistent with each of several plausible exposure
scenarios.
15. If this is a reassessment, how do the results in the new assessment compare with the
results in the old assessment? Has the level of concern changed? If so, why? Is
there a “real” difference between the overall risk predicted by the two assessments,
and is this difference something to be concerned about?
(See appendix K.)
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7. ABOUT THE APPENDICES
The appendices that follow provide three different kinds of information relevant to the
preparation of characterizations. Appendices A through D contain verbatim copies of the risk
characterization guidance contained in NCEA’s risk assessment guidelines for ecological effects
and exposures, reproductive toxicity, cancer risk, and exposure assessments, respectively.
Appendices E through M contain briefcase studies that illustrate some of the principles
of risk characterization and provide some useful examples of how to organize and present
information in a characterization. Appendices E through M are organized into the following
three sections: Background, Critique, and The Case Study. The critiques are limited to issues
relevant to the preparation of a risk characterization and do not involve an evaluation of the
technical accuracy of the information presented. By the time a risk characterization or
characterization of a risk assessment component is being prepared, it is reasonable to expect that
the technical information has been checked for accuracy and completeness. The critiques focus
solely on whether the case study meets the Administrator’s four values (clarity, transparency,
reasonableness, and consistency), contains the essential information identified in the checklists
presented in chapter 6 of this guidance, or illustrates any of the other concepts of risk
characterization identified in this guidance. Table 2 presents a summary of some key
information from appendices E through M. This table can be used to quickly see how each case
study relates to the components of a risk assessment (e.g., relationship to figure 1, chapter 2),
what parts of the chapter 6 checklists it illustrates, what other relevant risk characterization
points it illustrates, and which of the Administrator’s four values it exemplifies.
Appendices N and 0 provide sample lists of questions that were developed and used by
NCEA-W risk assessors during the preparation of the risk characterizations for dioxin and
trichioroethylene, respectively. Although these questions are chemical specific, they illustrate
part of a thought process that was conducted to identify key pieces of information that needed to
be addressed in those risk characterizations. Developing such questions early in the risk
assessmentlcharacterization process is a very useful exercise to help ensure that important
infonnation is addressed. These questions can be easily modified to make them relevant for
other assessments.
The following appendices contain excerpted material that is relevant to the issue of risk
characterization preparation. To minimize the size of this guidance document, we have omitted
reference lists, “text notes,” and copies of appendices cited in several of the following
appendices. Therefore, wherever an appendix refers the reader to specific references, “text
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notes,” or other sections of the appendix not included here, the reader should obtain the original
document from which the appendix has been excerpted to find this information.
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LIST OF APPENDICES
NOTE: The current guidance document does not endorse the technical position of any
statements made in appendices E through M. These examples are to be used strictly as
illustrations for different ways to present complex material in a manner that is clear and easily
understandable.
Appendix A. Characterization of Ecological Effects and Exposures A-i
Appendix B. Characterization of Reproductive Toxicity B-i
Appendix C. Characterization of Cancer Risk C-i
Appendix D. Characterization for Exposure Assessments D-l
Appendix E. Risk Characterization Framework for Asbestos E-1
Appendix F. Hazard Identification for Brominated Alkane (BA) F-i
Appendix G. Summary Figures Describing Risks Associated With Dioxin and
Dioxinlike Compounds in North America G-l
Appendix H. Example of Comparative Risks for Lung Cancer Associated
With Radon Exposure H-i
Appendix I. Hazard Identification Summary for “Substance 4” I-i
Appendix J. For Dioxinlike Compounds, Summary of Exposure Findings
and Uncertainties for North America J- 1
Appendix K. Characterization of Human Health and Wildlife Risks From
Anthropogenic Mercury Emissions in the United States K-i
Appendix L. Workers, EMFs and Cancer L-l
Appendix M. Nitrate and Nitrite in Drinking Water M-1
Appendix N. Questions Used to Develop NCEA’s Dioxin Risk Characterization N-I
Appendix 0. Questions Used to Develop NCEA’s Trichioroethylene
Risk Characterization 0-1
31
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Table 2. Guide for cross-referencing examples in the appendices with the Administrator’s four values and the
checklists in chapter 6
Case study
Relationship
to figure 1
Relationship to
Administrator’s
values
Relationship
to checklist
(see chapter 6)
Other points illustrated
Appendix E
(Asbestos)
Risk characterization summary
and summaries for hazard
identification, dose-response
assessment, exposure assessment
Clarity
Transparency
Consistency
Reasonableness
6.1
6.2
6.3
6.4
6.5
Figure 19 provides tabular framework for
organizing and displaying summary of key
risk assessment information, issues,
assumptions, and values. Figures 2 and 3
provide graphic means of displaying and
comparing cancer risk across chemicals and
studies.
Appendix F
(Brominated
alkane)
Summary of hazard identification
for cancer only
Clarity
Transparency
6.2
Clear, concise summary of evidence of
carcinogenicity for brominated alkanes.
Appendix 0
(Dioxin)
Risk characterization summary
and summaries of dose-response
and exposure assessments
Transparency
6.2
6.3
6.4
Illustrates margin of exposure (MOE) by
plotting human exposure levels and
threshold for noncancer health effect levels.
Appendix H
(Radon)
Risk characterization summary
and risk communication
Clarity
6.1
Illustrates how to put subject risk in context
of other well-known risks.
Appendix I
(“Substance 4”)
Summary of hazard identification
for cancer
Clarity
6.2
Illustrates how to summarize information
and highlight key facts of interest to
managers.
Appendix J
(Dioxin)
Exposure assessment
characterization
Clarity
Transparency
6.1
6.4
Framework for organizing, summarizing,
and displaying key risk assessment
information and showing link between key
findings, underlying scientific support, and
areas of uncertainty.
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Table 2. Guide for cross-referencing examples in the appendices with the Administrator’s four values and the
checklists in chapter 6 (continued)
Case study
Relationship
to figure 1
Relationship to
Administrator’s
values
Relationship
to checklist
(see chapter 6)
Other points illustrated
Appendix K
(Mercury)
Summaries for exposure
assessment, hazard identification,
and risk characterization
.
Clarity
Transparency
Reasonableness
.
6.1
6.2
6.4
Clear, simple descriptions of some areas of
uncertainty. Clear, concise description of
cancer risk estimate and effect of using
different values in key model parameters
and different exposure scenarios. Clear,
concise summary of human and animal
evidence of health effects from mercury
ingestion. Clear, simple summary of
potential public health concern from
mercury exposure and scientific basis for
this judgment.
Appendix L
(EMFs)
Summaries for risk
characterization and
characterization of hazard
identification, exposure
assessment
Clarity
Transparency
Reasonableness
6.1
6.2
6.4
Clear explanation of the meaning of
relative risk. Clear, concise discussion of
where research is needed. Clear, simple
descripttons of some areas of uncertainty.
Appendix M
(Nitrate/nitrite)
Risk characterization and hazard
identification characterization
summaries
Clarity
Transparency
6.1-11
6.2
Clear, concise summary of human and
animal evidence of health effects from
nitrite/nitrate ingestion. Clear, simple
summary of potential public health concern
from nitrite/nitrate exposure and scientific
basis for this judgment.
-------
APPENDIX A
CHARACTERIZATION OF ECOLOGICAL EFFECTS AND EXPOSURES
U.S. Environmental Protection Agency. (1996) Proposed guidelines for ecological risk assessment. Federal
Register 61(175’):47590-47602.
A-i
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5. RISK CHARACTERIZATION
Risk characterization (figure 5-1) is the final phase of ecological risk assessment. Its
goals are to use the results of the analysis phase to estimate risk to the assessment endpoints
identified in problem formulation (section 5.1), interpret the risk estimate (section 5.2), and
report the results (section 5.3).
Risk characterization is a major element of the risk assessment report. To be successful,
it should provide clear information to the risk manager to use in environmental decision making
(NRC, 1994; see section 6). If the risks are not sufficiently defined to support a management
decision, the risk manager may elect to proceed with another iteration of the risk assessment
process. Additional research or a monitoring program may improve the risk estimate or help to
evaluate the consequences of a risk management decision.
5.1. RISK ESTIMATION
Risk estimation determines the likelihood of adverse effects to assessment endpoints by
integrating exposure and effects data and evaluating any associated uncertainties. The process
uses exposure and stressor-response profiles which are developed according to the analysis plan
(section 3.5). Risks can be estimated by one or more of the following approaches: (1) estimates
expressed as qualitative categories, (2) estimates comparing single-point estimates of exposure
and effects, (3) estimates incorporating the entire stressor-response relationship, (4) estimates
incorporating variability in exposure and effects estimates, (5) estimates based on process models
that rely partially or entirely on theoretical approximations of exposure and effects, and (6)
estimates based on empirical approaches, including field observational data.
5.1.1. Risk Estimates Expressed as Qualitative Categories
In some cases, best professional judgment may be used to express risks qualitatively
using categories such as low, medium, and high or yes and no. This approach is most frequently
used when exposure and effects data are limited or not easily expressed in quantitative terms. A
U.S. Forest Service assessment used qualitative categories because of limitations on both the
exposure and effects data for the introduced species of concern as well as the resources available
for the assessment. (text note 5-1)
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/
— t
ANALYSIS
S
PROBLEM FORMULATION
S
ANALYSIS
S
RISK CHARACTERIZATION
S
Communicating Results to the Risk Manager
A
Risk Management
S
z.
n
0
0
0
0
00
°
0
0
0
0
0
0
Figure 5-1. Risk characterization.
/
/
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7
/
/
/
7
/
7
/
/
/
/
/
*
V
A
f -I_i
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5.1.2. Single-Point Estimates
When sufficient data are available to quantify exposure and effects estimates, the simplest
approach for comparing the estimates is to use a ratio of two numbers (figure 5-2a). Typically,
the ratio (or quotient) is expressed as an exposure concentration divided by an effects
concentration. Quotients are commonly used for chemical stressors, where reference or
benchmark toxicity values are widely available (text note 5-2).
The principal advantages of the quotient method are that it is simple and quick to use and
risk assessors and managers are familiar with its application. The quotient method provides an
efficient, inexpensive means of identifying high or low risk situations that can allow risk
management decisions to be made without the need for further information.
Quotients have also been used to integrate the risks of multiple chemical stressors. In this
approach, quotients for the individual constituents in a mixture are generated by dividing each
exposure level by a corresponding toxicity endpoint (e.g., an LC 50 ). Although the toxicity of a
chemical mixture may be greater (synergism) or less (antagonism) than predicted from the
toxicities of individual constituents of the mixture, a quotient addition approach assumes that
toxicities are additive or close to additive, which may be true when the modes of action of
chemicals in a mixture are similar (e.g., Könemann, 1981; Broderius et a!., 1995; Hermens et al.,
1984a,b; McCarty and Mackay, 1993; Sawyer and Safe, 1985).
For mixtures of chemicals having dissimilar modes of action, there is some evidence
from fish acute toxicity tests with industrial organic chemicals that strict additivity or less-than-
strict additivity is common, while antagonistic and synergistic responses are rare (Broderius,
1991). These experiences suggest that caution should be used when predicting that chemicals in
a mixture will act independently of one another. However, these relationships observed with
aquatic organisms may not be relevant for other endpoints, exposure scenarios, and species.
When the mode of action for constituent chemicals are unknown, the assumptions and rationale
concerning chemical interactions must be clearly stated.
The application of the quotient method is restricted by a number of limitations (see Smith
and Cairns, 1993; Suter, 1993a). While a quotient can be useful in answering whether risks are
high or low, it may not be helpful to a risk manager who needs to make a decision requiring a
quantification of risks. For example, it is seldom useful to say that a risk mitigation approach
will reduce a quotient value from 25 to 12, since this reduction cannot by itself be clearly
interpreted in terms of effects on an assessment endpoint.
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a: Comparison of point estimates
Exposure
estimate
(e.g., mean
concentration)
Stressor-response
estimate
(e.g., LC 10 )
b: Comparison of a point estimate of a stressor-response
relationship with uncertainty associated with an exposure
point estimate
Intensity of Stressor (e.g., concentration)
Figure 5-2. Risk estimation techniques. a. Comparison of exposure and stressor-response
point estimates. b. Comparison of a point estimate from the sfressor-response relationship
with uncertainty associated with an exposure point estimate.
V
(I )
C
U)
a
>‘
-a
0
I -.
0
e.g., uncertainty around
mean concentration
V
A-5
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Another potential difficulty with the quotient method is that the point estimate of effect
may not reflect the appropriate intensity of effect or exposure pattern for the assessment. For
example, an LC 50 derived from a 96-hour laboratory test using constant exposure levels may not
be appropriate for an assessment of effects on reproduction resulting from short-term, pulsed
exposures.
The quotient method cannot evaluate secondary effects. Interactions and effects beyond
what is predicted from the simple quotient may be critical to characterizing the full extent of
impacts from exposure to the stressors (e.g., bioaccumulation).
Finally, in most cases, the quotient method does not explicitly consider uncertainty (e.g.,
extrapolation from tested species to the species or community of concern). However, some
uncertainties can be incorporated into single-point estimates to provide a statement of likelihood
that the effects point estimate exceeds the exposure point estimate (figures 5-2b and 5-3). If
exposure variability is quantified, then the point estimate of effects can be compared with a
cumulative exposure distribution as described in text note 5-3. Further discussion of
comparisons between point estimates of effects and distributions of exposure may be found in
Suteretal., 1983.
In view of the advantages and limitations of the quotient method, it is important for risk
assessors to consider the points listed below when evaluating quotient method estimates.
• How does the effect concentration relate to the assessment endpoint?
• What extrapolations are involved?
• How does the point estimate of exposure relate to potential spatial and temporal
variability in exposure?
• Are data sufficient to provide confidence intervals on the endpoints?
5.1.3. Estimates Incorporating the Entire Stressor-Response Relationship
If the stressor-response profile described a curve relating the stressor level to the
magnitude of response, then risk estimation can examine risks associated with many different
levels of exposure (figure 5-4). These estimates are particularly useful when the risk assessment
outcome is not based on exceedance of a predetermined decision rule such as a toxicity
benchmark level.
There are both advantages and limitations to comparing a stressor-response curve with an
exposure distribution. The steepness of the effects curve shows the magnitude of change in
effects associated with incremental changes in exposure, and the capability to predict changes in
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/ \\ /
// \\ // \\
e.g., uncertainty around e.g., uncertainty around LC 10
mean concentration / \
> / /
I ‘
Intensity of Stressor (e.g., concentration)
e.g., probability that LC 10 > mean concentration
Figure 5-3. Risk estimation techniques: comparison of point estimates with associated
uncertainties.
A-7
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Intensity of Stressor (e.g., concentration)
Figure 5-4. Risk estimation techniques: sfressor-response curve versus a cumulative
distribution of exposures.
0.90
>‘
0
C
o
a,
I-
U-
, 0.50
>
a,
E
0
0.10
stressor
/. response
curve
cumulative
distribution of /
exposures
0.90
C
-C
C
0
0.
U)
a,
l x
C
0
a,
0.50 0-
0
0
U)
I —
U .-
0
C
0
0
a,
0.10
comparison of
90th percentile exposure
with EC 10
a
comparison of
50th percentile exposure
with EC
A-8
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the magnitude and likelihood of effects for different exposure scenarios can be used to compare
different risk management options. Also, uncertainty can be incorporated by calculating
uncertainty bounds on the stressor-response or exposure estimates. While comparing exposure
and stressor-response curves provides a predictive ability lacking in the quotient method, this
approach shares the quotient method’s limitations of not evaluating secondaiy effects, assuming
that the exposure pattern used to derive the stressor-response curve is comparable to the
environmental exposure pattern, and not explicitly considering uncertainties, such as
extrapolations from tested species to the species or community of concern.
5.1.4. Estimates Incorporating Variability in Exposure or Effects
If the exposure or stressor-response profiles describe the variability in exposure or effects,
then many different risk estimates can be calculated. Variability in exposure can be used to
describe risks to moderately or highly exposed members of a population being investigated,
while variability in effects can be used to describe risks to average or sensitive population
members. A major advantage of this approach is the capability to predict changes in the
magnitude and likelihood of effects for different exposure scenarios, thus providing a means for
comparing different risk management options. As noted above, comparing distributions also
allows one to identify and quantify risks to different segments of the population. Limitations
include the increased data requirements compared with previously described techniques and the
implicit assumption that the full range of variability in the exposure and effects data is
adequately represented. As with the quotient method, secondary effects are not readily evaluated
with this technique. Thus, it is desirable to corroborate risks estimated by distributional
comparisons with field studies or other lines of evidence. Text note 5-4 and figure 5-5 illustrate
the use of cumulative exposure and effects distributions for estimating risk.
5.1.5. Estimates Based on Process Models
Process models are mathematical expressions that represent our understanding of the
mechanistic operation of a system under evaluation. They can be useful tools both in the
analysis phase (see section 4.1.2.) and the risk characterization phase of ecological risk
assessment. For illustrative purposes, we distinguish between process models used for risk
estimation that integrate exposure and effects information (text note 5-5) and process models
used in the analysis phase that focus on either exposure or effects evaluations.
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99 99
90 90 .
0
.. .0
> 0.
70 70
.D Cl)
50 C l)
o
30 30
• 0.
C l)
0
0
I 10 10 -
I I
Comparison of 90th centile
concentration with 10th centile
oftheEC 5 s , •
10-2 10.1 100 101 102 310
Concentration in pgIL
Figure 5-5. Risk estimation techniques: comparison of exposure distribution of an
herbicide in surface waters with freshwater single-species toxicity data. See text note 5-4
for further discussion. Redrawn from SETAC, 1994a.
A- 10
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A major advantage of using process models for risk estimation is the ability to consider
“what if’ scenarios and to forecast beyond the limits of observed data that constrain risk
estimation techniques based on empirical data. The process model can also consider secondaiy
effects, unlike other risk estimation techniques such as the quotient method or comparisons of
exposure and effect distributions. In addition, some process models may be capable of
forecasting the combined effects of multiple stressors (e.g., Barnthouse et al., 1990).
Process model outputs may be point estimates or distributions. In either case, risk
assessors should interpret these outputs with care. Process model outputs may imply a higher
level of certainty than is appropriate and all too often are viewed without sufficient attention to
underlying assumptions. The lack of knowledge on basic life histories for many species and
incomplete knowledge on the structure and function of a particular ecosystem is often lost in the
model output. Since process models are only as good as the assumptions on which they are
based, they should be treated as hypothetical representations of reality until appropriately tested
with empirical data. Comparing model results to field data provides a check on whether our
understanding of the system was correct (Johnson, 1995) with respect to the risk hypotheses
presented in problem formulation.
5.1.6. Field Observational Studies
Field observational studies (surveys) can serve as risk estimation techniques because they
provide direct evidence linking exposure to stressors and effects. Field surveys measure
biological changes in uncontrolled situations through collection of exposure and effects data at
sites identified in problem formulation. A key issue with field surveys is establishing causal
relationships between stressors and effects (section 4.3.1.2).
A major advantage of field surveys is that they provide a reality check on other risk
estimates, since field surveys are usually more representative of both exposures and effects
(including secondary effects) found in natural systems than are estimates generated from
laboratory studies or theoretical models (text note 5-6). On the other hand, field data may not
constitute reality if they are flawed due to poor experimental design, biased in sampling or
analytical techniques, or fail to measure critical components of the system or random variations
(Johnson, 1995). A lack of observed effects in a field survey may occur because the
measurements are insufficiently sensitive to detect ecological effects, and, unless causal
relationships are carefully examined, effects that are observed may be caused by factors unrelated
A-Il
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to the stressor(s) of concern. Finally, field surveys taken at one point in time are usually not
predictive; they describe effects associated with only one scenario (i.e., the one that exists).
5.2. RISK DESCRIPTION
After risks have been estimated, risk assessors need to integrate and interpret the
available information into conclusions about risks to the assessment endpoints. In some cases,
risk assessors may have quantified the relationship between assessment endpoints and measures
of effect in the analysis stage (section 4.3.1.3). In other situations, qualitative links to assessment
endpoints are part of the risk description. For example, if the assessment endpoints are survival
of fish, aquatic invertebrates, and algae, risks may be estimated using a quotient method based on
LC 5 . Regardless of the risk estimation technique, the technical narrative supporting the
estimates is as important as the risk estimates themselves.
Risk descriptions include an evaluation of the lines of evidence supporting or refuting the
risk estimate(s) and an interpretation of the adverse effects on the assessment endpoint.
5.2.1. Lines of Evidence
Confidence in the conclusions of a risk assessment may be increased by using several
lines of evidence to interpret and compare risk estimates. These lines of evidence may be
derived from different sources or by different techniques relevant to adverse effects on the
assessment endpoints, such as quotient estimates, modeling results, field experiments, or field
observations. (Note that the term “weight of evidence” is sometimes used in legal discussions or
in other documents, e.g., Urban and Cook, 1986; Menzie et al., 1996. We use the phrase lines of
evidence to emphasize that both qualitative evaluation and quantitative weightings may be used.)
Some of the factors that the risk assessor should consider when evaluating separate lines
of evidence are:
• The relevance of evidence to the assessment endpoints
• The relevance of evidence to the conceptual. model
• The sufficiency and quality of data and experimental designs used in key studies
• The strength of cause/effect relationships
• The relative uncertainties of each line of evidence and their direction.
This process involves more than just listing the factors that support or refute the risk. The risk
assessor should carefully exanilne each factor and evaluate its contribution to the risk
assessment
A-12
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For example, consider the two lines of evidence described for the carbofuran example
(text notes 5-2 and 5-6): quotients and field studies. Both approaches are relevant to the
assessment endpoint (survival of birds that forage in agricultural areas where carbofuran is
applied), and both are relevant to the exposure scenarios described in the conceptual model
(figure 3-2). However, the quotients are limited in their ability to express incremental risks (e.g.,
how much greater risk is expressed by a quotient of “2” versus a quotient of “4”), while the field
studies had some design flaws (text note 5-6). Nevertheless, because of the great preponderance
of the data, the strong evidence of causal relationships from the field studies, and the consistency
between these two lines of evidence, confidence in a conclusion of high risk to the assessment
endpoint is supported.
Sometimes lines of evidence do not point toward the same conclusion. When they
disagree, it is important to distingthsh between true inconsistencies and those related to
differences in statistical powers of detection. For example, a model may predict adverse effects
that were not observed in a field survey. The risk assessor should ask whether the experimental
design of the field study had sufficient power to detect the predicted difference or whether the
endpoints measured were comparable with those used in the model. Conversely, the model may
have been unrealistic in its predictions. While it may be possible to use numerical weighting
techniques for evaluating various lines of evidence, in most cases qualitative evaluations based
on professional judgment are appropriate for sorting through conflicting lines of evidence. While
iteration of the risk assessment process and collection of additional data may help resolve
uncertainties, this option is not always available.
5.2.2. Determining Ecological Adversity
At this point in risk characterization, the changes expected in the assessment endpoints
have been estimated and described. The next step is to interpret whether these changes are
considered adverse. Adverse changes are those of concern ecologically or socially (section 1).
Determining adversity is not always an easy task and frequently depends on the best professional
judgment of the risk assessor.
Five criteria are proposed for evaluating adverse changes in assessment endpoints:
• Nature of effects
• Intensity of effects
• Spatial scale
• Temporal scale
• Potential for recovely.
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The extent to which the five criteria are evaluated depends on the scope and complexity
of the ecological risk assessment. However, understanding the underlying assumptions and
science policy judgments is important even in simple cases. For example, whe exceedance of a
previously established decision rule such as a benchmark stressor level is used as evidence of
adversity (e.g., see Urban and Cook, 1986, or Nabholz, 1991), the reasons why exceedences of
the benchmark are considered adverse should be clearly understood.
To distinguish ecological changes that are adverse from those ecological events that are
within the normal pattern of ecosystem variability or result in little or no significant alteration of
biota, it is important to consider the nature and intensity of effects. For example, for an
assessment endpoint involving survival, growth, and reproduction of a species, do predicted
effects involve survival and reproduction or only growth? If survival of offspring will be
affected, by what percentage will it diminish?
It is important for risk assessors to consider both the ecological and statistical contexts of
an effect when evaluating intensity. For example, a statistically significant 1% decrease in fish
growth (text note 5-7) may not be relevant to an assessment endpoint of fish population viability,
and a 10% decline in reproduction may be worse for a population of slowly reproducing trees
than for rapidly reproducing planktonic algae.
Natural ecosystem variation can make it veiy difficult to observe (detect) stressor-related
perturbations. For example, natural fluctuations in marine fish populations are often large, with
intra- and interannual variability in population levels covering several orders of magnitude.
Furthermore, cyclic events (e.g., bird migration, tides) are very important in natural systems.
Predicting the effects of anthropogenic stressors against this background of variation can be very
difficult Thus, a lack of statistically significant effects in a field study does not automatically
mean that adverse ecological effects are absent. Rather, risk assessors must consider factors such
as statistical power to detect differences, natural variability, and other lines of evidence in
reaching their conclusions.
Spatial and temporal scales need to be considered in assessing the adversity of the
effects. The spatial dimension encompasses both the extent and pattern of effect as well as the
context of the effect within the landscape. Factors to consider include the absolute area affected,
the extent of critical habitats affected compared with a larger area of interest, and the role or use
of the affected area within the landscape.
Adverse effects to assessment endpoints vary with the absolute area of the effect. A
larger affected area may be (1) subject to a greater number of other stressors, increasing the
complications from stressor interactions; (2) more likely to contain sensitive species or habitats;
A-l4
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or (3) more susceptible to landscape-level changes because many ecosystems may be altered by
the stressors.
Nevertheless, a smaller area of effect is not always associated with lower risk. The
function of an area within the landscape may be more important than the absolute area.
Destruction of small but unique areas, such as critical wetlands, may have important effects on
local wildlife populations. Also, in river systems, both riffle and pool areas provide important
micro habitats that maintain the structure and function of the total river ecosystem. Stressors
acting on some of these micro habitats may present a significant risk to the entire system.
Spatial factors are important for many species because of the linkages between ecological
landscapes and population dynamics. Linkages between one or more landscapes can provide
refuge for affected populations, and species may require adequate corridors between habitat
patches for successful migration.
The temporal scale for ecosystems can vaiy from seconds (photosynthesis, prokaryotic
reproduction) to centuries (global climate change). Changes within a forest ecosystem can occur
gradually over decades or centuries and may be affected by slowly changing external factors such
as climate. When interpreting ecological adversity, risk assessors should recognize that the time
scale of stressor-induced changes operateswithin the context of multiple natural time scales. In
addition, temporal responses for ecosystems may involve intrinsic time lags, so that responses
from a stressor may be delayed. Thus, it is important to distinguish the long-term impacts of a
stressor from the immediately visible effects. For example, visible changes resulting from
eutrophication of aquatic systems (turbidity, excessive macrophyte growth, population decline)
may not become evident for many years after initial increases in nutrient levels.
Considering the temporal scale of adverse effects leads logically to a consideration of
recovery. Recovery is the rate and extent of return of a population or community to a condition
that existed before the introduction of a stressor. (While this discussion deals with recovery as a
result of natural processes, risk mitigation options may include restoration activities to facilitate
or speed up the recovery process.) Because ecosystems are dynamic and even under natural
conditions are constantly changing in response to changes in the physical environment (weather,
natural catastrophes, etc.) or other factors, it is unrealistic to expect that a system will remain
static at some level or return to exactly the same state that it was before it was disturbed (Landis
et al., 1993). Thus, the attributes of a “recovered” system must be carefully defmed. Examples
might include productivity declines in an eutrophic system, reestablishment of a species at a
particular density, species recolonizationof a damaged habitat, or the restoration of health of
diseased organisms.
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Recovery can be evaluated in spite of the difficulty in predicting events in ecological
systems (e.g., Niemi et a!., 1990). For example, it is possible to distinguish changes that are
usually reversible (e.g., recovery of a stream from sewage effluent discharge), frequently
irreversible (e.g., establishment of introduced species), and always irreversible (e.g., species
extinction). It is important for risk assessors to consider whether significant structural or
functional changes have occurred in a system that might render changes irreversible. For
example, physical alterations such as deforestation in the coastal hills of Venezuela in recent
history and Britain in the Neolithic period changed soil structure and seed sources such that
forests cannot easily grow again (Fisher and Woodmansee, 1994).
Risk assessors should note natural disturbance patterns when evaluating the likelihood of
recovery from anthropogenic stressors. Ecosystems that have been subjected to repeated natural
disturbances may be more vulnerable to anthropogenic stressors (e.g., over fishing, logging of
old-growth forest). Alternatively, if an ecosystem has become adapted to a disturbance pattern, it
may be affected when the disturbance is removed (fire-maintained grasslands). The lack of
natural analogues make it difficult to predict recovery from novel anthropogenic stressors (e.g.,
synthetic chemicals).
The relative rate of recovery can also be estimated. For example, fish populations in a
stream are likely to recover much faster from exposure to a degradable chemical than from
habitat alterations resulting from stream channelization. Risk assessors can use knowledge of
factors such as the temporal scales of organisms’ life histories, the availability of adequate stock
for recruitment, and the interspecific and trophic dynamics of the populations in evaluating the
relative rates of recovery. A fisheries stock or forest might recover in several decades, a benthic
infaunal community in years, and a planktomc community in weeks to months.
Appendix E illustrates how the criteria for ecological adversity (nature and intensity of
effects, spatial and temporal scales, and recovery) might be used in evaluating two cleanup
options for a marine oil spill. This example also shows that recovery of a system depends not
only on how quickly a stressor is removed but also on how any cleanup efforts affect the
recovery.
5.3. REPORTING RISKS
When risk characterization is complete, the risk assessors should be able to estimate
ecological risks, indicate the overall degree of confidence in the risk estimates, cite lines of
evidence supporting the risk estimates, and interpret the adversity of ecological effects. Usually
this information is included in a risk assessment report (sometimes referred to as a risk
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characterization report because of the integrative nature of risk characterization). This section
describes elements that risk assessors should consider when preparing a risk assessment report.
Like the risk assessment itself, a risk assessment report may be brief or extensive
depending on the nature of and the resources available for the assessment. While it is important
to address the elements described below, risk assessors must judge the appropriate level of detail
required. The report need not be overly complex or lengthy, depending on the nature of the risk
assessment and the information required to support a risk management decision. In fact, it is
important that information be presented clearly and concisely.
While the breadth of ecological risk assessment precludes providing a detailed outline of
reporting elements, the risk assessor should consider the elements listed in text note 5-8 when
preparing a risk assessment report.
To facilitate mutual understanding, it is critical that the risk assessment results are
properly presented. Agency policy requires that risk characterizations be prepared “in a manner
that is clear, transparent, reasonable, and consistent with other risk characterizations of similar
scope prepared across programs in the Agency” (U.S. EPA, 1995c). Ways to achieve such
characteristics are described in text note 5-9.
After the risk assessment report is prepared, the results are discussed with risk managers.
Section 6 provides information on communication between risk assessors and risk managers,
describes the use of the risk assessment in a risk management context, and briefly discusses
communication of risk assessment results from risk managers to the public.
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6. RELATING ECOLOGICAL INFORMATION TO
RISK MANAGEMENT DECISIONS
After characterizing risks and preparing a risk assessment report (section 5), risk
assessors discuss the results with risk managers (figure 5-1). Risk managers use risk assessment
results along with other factors (e.g., economic or legal concerns) in making environmental
decisions. The results also provide a basis for communicating risks to the public.
Mutual understanding between risk assessors and risk managers can be facilitated if the
questions listed in text note 6-1 are addressed. Risk managers need to know what the major risks
(or potential risks) are with respect to assessment endpoints and have an idea of whether the
conclusions are supported by a large body of data or if there are significant data gaps. When
there is insufficient information to characterize risk at an appropriate level of detail due to a lack
of resources, a lack of a consensus on how to interpret information, or other reasons, the issues,
obstacles, and correctable deficiencies should be clearly articulated for the risk manager’s
consideration.
In making a decision regarding ecological risks, risk managers use risk assessment results
along with other information that may include social, economic, political, or legal issues. For
example, the risk assessment may be used as part of a risk/benefit analysis, which may require
translating resources (identified through the assessment endpoints) into monetary values. One
difficulty with this approach is that traditional economic considerations may not adequately
address things that are not considered commodities, intergenerational resource values or issues of
long-term or irreversible effects (U.S. EPA, 1995b). Risk managers may also consider risk
mitigation options or alternative strategies for reducing risks. For example, risk mitigation
techniques such as buffer strips or lower field application rates can be used to reduce the
exposure (and risk) of a new pesticide. Further, risk managers may consider relative as well as
absolute risk, for example, by comparing the risk of a new pesticide to other pesticides currently
in use. Finally, risk managers consider public opinion and political demands in their decisions.
Taken together, these other factors may render very high risks acceptable or very low risks
unacceptable.
Risk characterization provides the basis for communicating ecological risks to the public.
This task is usually the responsibility of risk m n gers. Although the final risk assessment
document (including its risk characterization sections) can be made available to the public, the
risk communication process is best served by tailoring information to a particular audience. It is
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important to clearly describe the ecological resources at risk, their value, and the monetary and
other costs of protecting (and failing to protect) the resources (U.S. EPA, 1995b).
Managers should clearly describe the sources and causes of risks, the potential adversity
of the risks (e.g., nature and intensity, spatial and temporal scale, and recovery potential). The
degree of confidence in the risk assessment, the rationale for the risk management decision, and
the options for reducing risk are also important (U.S. EPA, 1995b). Other risk communication
considerations are provided in text note 6-2.
Along with the discussions of risk and communications with the public, it is important for
risk managers to consider whether additional follow-on activities are required. Depending on the
importance of the assessment, confidence level in the assessment results, and available resources,
it may be advisable to conduct another iteration of the risk assessment (starting with problem
formulation or analysis) in order to facilitate a final management decision. Another option is to
proceed with the decision and develop a monitoring plan to evaluate the results of the decision
(see section 1). For example, if the decision was to mitigate risks through exposure reduction,
monitoring could help determine whether the desired reduction in exposure (and effects) was
achieved.
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APPENDIX B
CHARACTERIZATION OF REPRODUCTIVE TOXICITY
U.S. Environmental Protection Agency. (1996) Reproductive toxicity risk assessment
guidelines, part II, notice. Federal Register 61(212):56308-56313.
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VI. RISK CHARACTERIZATION
VLA. Overview
A risk characterization is an essential part of any Agency report on risk whether the report
is a preliminary one prepared to support allocation of resources toward further study, a site-
specific assessment, or a comprehensive one prepared to support ràgulatory decisions. A risk
characterization should be prepared in a manner that is clear, reasonable, and consistent with
other risk characterizations of similar scope prepared across programs in the Agency. It should
identify and discuss all the major issues associated with determining the nature and extent of the
risk and provide commentary on any constraints limiting more complete exposition. The key
aspects of risk characterization are: (1) bridging risk assessment and risk management, (2)
discussing confidence and uncertainties, and (3) presenting several types of risk information. In
this final step of a risk assessment, the risk characterization involves integration of toxicity
information from the hazard characterization and quantitative dose-response analysis with the
human exposure estimates and provides an evaluation of the overall quality of the assessment,
describes risk in terms of the nature and extent of harm, and communicates results of the risk
assessment to a risk manager. A risk manager can then use the risk assessment, along with other
risk management elements, to make public health decisions. The information should also assist
others outside the Agency in understanding the scientific basis for regulatory decisions.
Risk characterization is intended to summarize key aspects of the following components
of the risk assessment:
• The nature, reliability, and consistency of the data used.
•‘ The reasons for selection of the key study(ies) and the critical effect(s) and their
relevance to human outcomes.
• The qualitative and quantitative descriptors of the results of the risk assessment.
• The limitations of the available data, the assumptions used to bridge knowledge gaps
in working with those data, and implications of using alternative assumptions.
• The strengths and weaknesses of the risk assessment and the level of scientific
confidence in the assessment.
• The areas of uncertainty, additional data/research needs to improve confidence in the
risk assessment, and the potential impacts of the new research.
The risk characterization should be limited to the most significant and relevant data,
conclusions, and uncertainties. When special circumstances exist that preclude full assessment,
those circumstances should be explained and the related limitations identified.
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The following sections describe these aspects of the risk characterization in more detail,
but do not attempt to provide a full discussion of risk characterization. Rather, these Guidelines
point out issues that are important to risk characterization for reproductive toxicity.
Comprehensive general guidance for risk characterization is provided by Habicht (1992) and
Browner (1995).
VI.B. Integration of Hazard Characterization, Quantitative Dose-Response, and Exposure
Assessments
In developing each component of the risk assessment, risk assessors must make
judgments concerning human relevance of the toxicity data, including the appropriateness of the.
various test animal models for which data are available, and the route, timing, and duration of
exposure relative to the expected human exposure. These judgments should be summarized at
each stage of the risk assessment process. When data are not available to make such judgments,
as is often the case, the background information and assumptions discussed in the Overview
(Section I) provide default positions. The default positions used and the rationale behind the use
of each default position should be clearly stated. In integrating the parts of the assessment, risk
assessors must determine if some of these judgments have implications for other portions of the
assessment, and whether the various components of the assessment are compatible.
The description of the relevant data should convey the major strengths and weaknesses of
the assessment that arise from availability and quality of data and the current limits of
understanding of the mechanisms of toxicity. Confidence in the results of a risk assessment is a
function of confidence in the results of these analyses. Each section (hazard characterization,
quantitative dose-response analysis, and exposure assessment) should have its own summary,
and these summaries should be integrated into the overall risk characterization. Interpretation of
data should be explained, and risk managers should be given a clear picture of consensus or lack
of consensus that exists about significant aspects of the assessment. When more than one
interpretation is supported by the data, the alternative plausible approaches should be presented
along with the strengths, weaknesses, and impacts of those options. If one interpretation or
option has been selected over another, the rationale should be given; if not, then both should be
presented as plausible alternatives.
The risk characterization should not only examine the judgments, but also should explain
the constraints of available data and the state of knowledge about the phenomena studied in
making them, including:
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• The qualitative conclusions about the likelihood that the chemical may pose a specific
ha72rd to human health, the nature of the observed effects, under what conditions
(route, dose levels, time, and duration) of exposure these effects occur, and whether
the health-related data are sufficient and relevant to use in a risk assessment.
• A discussion of the dose-response patterns for the critical effect(s) and their
relationships to the occurrence of other toxicity data, such as the shapes and slopes of
the dose-response curves for the various other endpoints; the rationale behind the
determination of the NOAEL, LOAEL, and/or benchmark dose; and the assumptions
underlying the estimation of the RfD, Rft, or other exposure estimate.
• Descriptions of the estimates of the range of human exposure (e.g., central tendency,
high end), the route, duration, and pattern of the exposure, relevant pharmacokinetics,
and the size and characteristics of the various populations that might be exposed.
• The risk characterization of an agent being assessed for reproductive toxicity should
be based on data from the most appropriate species or, if such information is not
available, on the most sensitive species tested. It also should be based on the most
sensitive indicator of an adverse reproductive effect, whether in the male, the female
(nonpregnant or pregnant), or the developing organism, and should be considered in
relation to other forms of toxicity. The relevance of this indicator to human
reproductive outcomes should be described. The rationale for those decisions should
be presented.
If data to be used in a risk characterization are from a route of exposure other than the
expected human exposure, then pharmacokinetic data should be used, if available, to extrapolate
across routes of exposure. If such data are not available, the Agency makes certain assumptions
concerning the amount of absorption likely or the applicability of the data from one route to
another (U.S. EPA, 1985a, 1986b). Discussion of some of these issues may be found in the
Proceedings of the Workshop on Acceptability and Interpretation of Dermal Developmental
Toxicity Studies (Kinimel, C.A. and Francis, 1990) and Principles of Route-to-Route
Extrapolation for Risk Assessment (Gerrity et al., 1990). The risk characterization should
identify the methods used to extrapolate across exposure routes and discuss the strengths and
limitations of the approach.
The level of confidence in the hazard characterization and quantitative dose-response
evaluation should be stated to the extent possible, including placement of the agent into the
appropriate category regarding the sufficiency of the health-related data (see Section III.G.). A
comprehensive risk assessment ideally includes information on a variety of endpoints that
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provide insight into the full spectrum of potential reproductive responses. A profile that
integrates both human and test species data and incorporates both sensitive endpoints (e.g.,
properly performed and fully evaluated histopathology) and functional correlates (e.g., fertility)
allows more confidence in a risk assessment for a given agent.
Descriptions of the nature of potential human exposures are important for prediction of
specific outcomes and the likelihood of persistence or reversibility of the effect in different
exposure situations with different subpopulations (U.S. EPA, 1992; Clegg, 1995).
In the risk assessiiient process, risk is estimated as a function of exposure, with the risk of
adverse effects increasing as exposure increases. Information on the levels of exposure
experienced by different members of the population is key to understanding the range of risks
that may occur. Where possible, several descriptors of exposure such as the nature and range of
populations and their various exposure conditions, central tendencies, and high-end exposure
estimates should be presented. Differences among individuals in absorption rates, metabolism,
or other factors mean that individuals or subpopulations with the same level and pattern of
exposure may have differing susceptibility. For example, the consequences of exposure can
differ markedly between developing individuals, young adults and aged adults, including
whether the effects are permanent or transient. Other considerations relative to human exposures
might include pregnancy or lactation, potential for exposures to other agents, concurrent disease,
nutritional status, lifestyle, ethnic background and genetic polymorphism, and the possible
consequences. Knowledge of the molecular events leading to induction of adverse effects may
be of use in determining the range of susceptibility in sensitive populations.
An outline to serve as a guide and formatting aid for developing reproductive risk
characterizations for chemical-specific risk assessments can be found in Table 7. A common
format will assist risk managers in evaluating and using reproductive risk characterization. The
outline has twop . The first part tracks the reproductive risk assessment to bring forward its
major conclusions. The second part pulls the information together to characterize the
reproductive risk.
VLC. Descriptors of Reproductive Risk
Descriptors of reproductive risk convey information and answer questions about risk,
with each descriptor providing different information and insights. There are a number of ways to
describe risk. Details on how to use these descriptors can be obtained from the guidance on risk
characterization (Browner, 1995) from which some of the information below has been extracted.
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In most cases, the state of the science is not yet adequate to define distributions of factors
such as population susceptibility. The guidance principles below discuss a variety of risk
descriptors that primarily reflect differences in estimated exposure. If a full description of the
range of susceptibility in the population cannot be presented, an effort should be made to identify
subgroups that, for various reasons, may be particularly susceptible.
VLC.l. Distribution of Individual Exposures
Risk managers are interested generally in answers to questions such as: (1) Who are the
people at the highest risk and why? (2) What is the average risk or distribution of risks for
individuals in the population of interest? and (3) What are they doing, where do they live, etc.,
that might be putting them at this higher risk?
Exposure and reproductive risk descriptors for individuals are intended to provide
answers to these questions. To describe the range of risks, both high-end and central tendency
descriptors are used to convey the distribution in risk levels experienced by different individuals
in the population. For the Agency’s purposes, high-end risk descriptors are plausible estimates
of the individual risk for those persons at the upper end of the risk distribution. Given limitations
in current understanding of variability in individuals’ sensitivity to agents that cause reproductive
toxicity, high-end descriptors will usually address high-end exposure or dose. Conceptually,
high-end exposure means exposure above approximately the 90th percentile of the population
distribution,, but not higher than the individual in the population who has the highest exposure.
Central tendency descriptors generally reflect central estimates of exposure or dose. The
descriptor addressing central tendency may be based on either the arithmetic mean exposure
(average estimate) or the median exposure (median estimate), either of which should be clearly
labeled. The selection of which descriptor(s) to present in the risk characterization will depend
on the available data and the goals of the assessment.
VI.C.2. Population Exposure
Population risk refers to assessment of the extent of harm for the population as a whole.
In theory, it can be calculated by summing the individual risks for all individuals within the
subject population. That task requires more information than is usually available. Questions
addressed by descriptors of population risk for reproductive effects would include: What portion
of the population is within a specified range of some reference level, e.g., exceeds the RID (a
dose), the RfC (a concentration), or other health concern level?
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For reproductive effects, risk assessment techniques have not been developed generally to
the point of knowing how to add risk probabilities, although Hattis and Silver (1994) have
proposed approaches for certain case-specific situations. Therefore, the following descriptor is
usually appropriate: An estimate of the percentage of the population, or the number of persons,
above a specified level of risk or within a specified range of some reference level (e.g., exceeds
the Rf]), RfC, LOAEL, or other specific level of interest). The RID or RfC is assumed to be a
level below which no significant risk occurs. Therefore, information from the exposure
assessment on the populations below the MD or RfC (“not likely to be at risk”) and above the
RfD or RfC (“may be at risk”) may be useful information for risk managers. Estimating the
number of persons potentially removed from the “may be at risk” category after a contemplated
action is taken may be particularly useful to a risk manager considering possible actions to
ameliorate risk for a population. This descriptor must be obtained through measuring or
simulating the population distribution.
VLC.3. Margin of Exposure
In the risk characterization, dose-response information and the human exposure estimates
may be combined either by comparing the RID or RfC and the human exposure estimate or by
calculating the margin of exposure (MOE). The MOE is the ratio of the NOAEL or benchmark
dose from the most appropriate or sensitive species to the estimated human exposure level from
all potential sources (U.S. EPA, 1985a). If a NOAEL is not available, a LOAEL may be used in
the calculation of the MOE, but consideration for the acceptability would be different than when
a NOAEL is used. Considerations for the acceptability of the MOE are similar to those for the
selection of uncertainty factors applied to the NOAEL, LOAEL, or the benchmark dose for the
derivation of an RID. The MOE is presented along with the characterization of the database,
including the strengths and weaknesses of the toxicity and exposure data, the number of species
affected, and the information on dose-response, route, timing, and duration. The MD or RfC
comparison with the human exposure estimate and the calculation of the MOE are conceptually
similar, but may be used in different regulatory situations.
The choice of approach is dependent on several factors, including the statute involved,
the situation being addressed, the database used, and the needs of the decision maker. The RID,
RfC, or MOE are considered along with other risk assessment and risk management issues in
making risk management decisions, but the scientific issues that should be taken into account in
establishing them have been addressed here.
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VI.C.4. Distribution of Exposure and Risk for Different Subgroups
A risk manager might also ask questions about the distribution of the risk burden among
various segments of the subject population such as the following: How do exposure and
reproductive risk impact various subgroups? and What is the population risk of a particular
subgroup? Questions about the distribution of exposure and reproductive risk among such
population segments require additional risk descriptors.
Highly exposed
The purpose of this measure is to describe the upper end of the exposure distribution,
allowing risk managers to evaluate whether certain individuals are at disproportionately high or
unacceptably high risk. The objective is to look at the upper end of the exposure distribution to
derive a realistic estimate of relatively highly exposed individual(s). The “high end” of the risk
distribution has been defined (Habicht, 1992; Browner, 1995) as above the 90th percentile of the
actual (either measured or estimated) distribution. Whenever possible, it is important to express
the number or proportion of individuals who comprise the selected highly exposed group and, if
data are available, discuss the potential for exposure at still higher levels.
Highly exposed subgroups can be identified and, where possible, characterized, and the
magnitude of risk quantified. This descriptor is useful when there is (or is expected to be) a
subgroup experiencing significantly different exposures or doses from those of the larger
population. These subpopulations may be identified by age, sex, lifestyle, economic factors, or
other demographic variables. For example, toddlers who play in contaminated soil and
consumers of large amounts of fish represent subpopulations that may have greater exposures to
certain agents.
If population data are absent, it will often be possible to describe a scenario representing
high-end exposures using upper percentile or judgment-based values for exposure variables. In
these instances, caution should be taken not to overestimate the high-end values if a “reasonable”
exposure estimate is to be achieved.
Highly susceptible
Highly susceptible subgroups also can be identified and, if possible, characterized, and
the magnitude of risk quantified. This descriptor is useful when the sensitivity or susceptibility
to the effect for specific subgroups is (or is expected to be) significantly different from that of the
larger population. Therefore, the purpose of this measure is to quantify exposure of identified
sensitive or susceptible populations to the agent of concern. Sensitive or susceptible individuals
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are those within the exposed population at increased risk of expressing the adverse effect.
Examples might be pregnant or lactating women, women with reduced oocyte numbers, men
with “borderline” sperm counts, or infants. To calculate risk for these subgroups, it will be
necessary sometimes to use a different dose-response relationship; e.g., upon exposure to a
chemical, pregnant or lactating women, elderly people, children of varying ages, and people with
certain illnesses may each be more sensitive than the population as a whole.
In general, not enough is understood about the mechanisms of toxicity to identify
sensitive subgroups for most agents, although factors such as age, nutrition, personal habits (e.g.,
smoking, consumption of alcohol, and abuse of drugs), existing disease (e.g., diabetes or sexually
transmitted diseases), or genetic polymorphisms may predispose some individuals to be more
sensitive to the reproductive effects of various agents.
It is important to consider, however, that the Agency’s current methods for developing
reference doses and reference concentrations (RfDs and RfCs) are designed to protect sensitive
populations. If data on sensitive human populations are available (and there is confidence in the
quality of the data), then the RID is based on the dose level at which no adverse effects are
observed in the sensitive population. If no such data are available (for example, if the RfD is
developed using data from humans of average or unknown sensitivity), then an additional 3- to
10-fold factor may be used to account for variability between the average human response and
the response of more sensitive individuals (see Section IV).
Generally, selection of the population segments to consider for high susceptibility is a
matter of either a priori interest in the subgroup (e.g., environmental justice considerations), in
which case the risk assessor and risk manager can jointly agree on which subgroups to highlight,
or a matter of discovery of a sensitive or highly exposed subgroup during the assessment process.
In either case, once identified, the subgroup can be treated as a population in itself and
characterized in the same way as the larger population using the descriptors for population and
individual risk.
VI.C.5. Situation-Specific Information
Presenting situation-specific scenarios for important exposure situations and
subpopulations in the form of “what if?” questions may be particularly useful to give perspective
to risk managers on possible future events. The question being asked in these cases is, for any
given exposure level, what would be the resulting number or proportion of individuals who may
be exposed to levels above that value?
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“What if...?” questions, such as those that follow, can be used to examine candidate risk
management options:
• What are the reproductive risks if a pesticide applicator applies this pesticide without
using protective equipment?
• What are the reproductive risks if this site becomes residential in the future?
• What are the reproductive risks if we set the standard at 100 ppb?
Answering such “what if?” questions involves a calculation of risk based on specific
combinations of factors postulated within the assessment. The answers to these “what if?”
questions do not, by themselves, give information about how likely the combination of values
might be in the actual population or about how many (if any) persons might be subjected to the
potential future reproductive risk. However, information on the likelihood of the postulated
scenario would be desirable to include in the assessment.
When addressing projected changes for a population (either expected future
developments or consideration of different regulatoiy options), it usually is appropriate to
calculate and consider all the reproductive risk descriptors discussed above. When central
tendency or high-end estimates are developed for a scenario, these descriptors should reflect
reasonable expectations about future activities. For example, in site-specific risk assessments,
future scenarios should be evaluated when they are supported by realistic forecasts of future land
use, and the reproductive risk descriptors should be developed within that context.
VLC.6. Evaluation of the Uncertainty in the Risk Descriptors
Reproductive risk descriptors are intended to address variability Of risk within the
population and the overall adverse impact on the population. In particular, differences between
high-end and central tendency estimates reflect variability in the population but not the scientific
uncertainty inherent in the risk estimates. As discussed above there will be uncertainty in all
estimates of reproductive risk. These uncertainties can include measurement uncertainties,
modeling uncertainties, and assumptions to fill data gaps. Risk assessors should address the
impact of each of these factors on the confidence in the estimated reproductive risk values.
Both qualitative and quantitative evaluations of uncertainty provide useful information to
users of the assessment. The techniques of quantitative uncertainty analysis are evolving rapidly
and both the SAB (Loehr and Matanoski, 1993) and the NRC (1994) have urged the Agency to
incorporate these techniques into its risk analyses. However, it should be noted that a
probabilistic assessment that uses only the assessor’s best estimates for distributions of
population variables addresses variability, but not uncertainty. Uncertainties in the estimated
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risk distribution need to be evaluated separately. An approach has been proposed for estimating
distribution of uncertainty in noncancer risk assessments (Baird et al., 1996).
Table 7. Guide for Developing Chemical-Specific Risk Characterizations for
Reproductive Effects
PART ONE
Summarizing Major Conclusions in Risk Characterization
Hazard Characterization
A. What is (are) the key toxicological study (or studies) that provides the basis for health concerns for
reproductive effects?
• How good is the key study?
• Are the data from laboratory or field studies? In a single or multiple species?
• What adverse reproductive endpoints were observed, and what is the basis for the critical
effect?
• Describe other studies that support this finding.
• Discuss any valid studies which conflict with this fmding.
B. Besides the reproductive effect observed in the key study, are there other health endpoints of concern?
What are the significant data gaps?
C. Discuss available epidemiological or clinical data. For epidemiological studies:
• What types of data were used (e.g., human ecologic, case-control or cohort studies, or
case reports or series)?
• Describe the degree to which exposures were described.
• Describe the degree to which confounding factors were considered.
• Describe the degree to which other causal factors were excluded.
D. How much is known about how (through what biological mechanism) the chemical produces adverse
reproductive effects?
• Discuss relevant studies of mechanisms of action or metabolism.
• Does this information aid in the interpretation of the toxicity data?
• What are the implications for potential adverse reproductive effects?
fi. Comment on any nonpositive data in animals or people, and whether these data were considered in the
hazard characterization.
F. If adverse health effects have been observed in wildlife species, characterize such effects by discussing
the relevant issues as in A through E above.
G. Summarize the hazard characterization and discuss the significance of each of the following:
• Confidence in conclusions.
• Alternative conclusions that are also supported by the data.
• Significant data gaps.
• Highlights of major assumptions.
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II. Characterization of Dose-Response
A. What data were used to develop the dose-response curve? Would the result have been significantly
different if based on a different data set?
• If laboratory animal data were used:
Which species were used?
Most sensitive, average of all species, or other?
Were any studies excluded? Why?
• If epidemiological data were used:
Which studies were used?
Only positive studies, all studies, or some other combination?
Were any studies excluded? Why?
Was a mets-analysis performed to combine the epidemiological studies? What approach
was used?
Were studies excluded? Why?
B. Was a model used to develop the dose-response curve and, if so, which one? What rationale supports
this choice? Is chemical-specific information available to support this approach?
• How was the RfD/RIC (or the acceptable range) calculated?
• What assumptions and uncertainty factors were used?
• What is the confidence in the estimates?
C. Discuss the mute, level, and duration of exposure observed, as compared to expected human
exposures.
• Are the available data from the same route of exposure as the expected human
exposures? If not, are pharmacokinetic data available to extrapolate across route of
exposure?
• How far does one need to extrapolate from the observed data to environmental
exposures? One to two orders of magnitude? Multiple orders of magnitude? What is the
impact of such an extrapolation?
D. If adverse health effects have been observed in wildlife species, characterize dose-response
informalion using the process outlined in A through C above.
III. Characterization of Exposure
A. What are the most significant sources of environmental exposure?
Are there data on sources of exposure from different media?
What is the relative contribution of different sources of exposure?
What are the most significant environmental pathways for exposure?
B. Describe the populations that were assessed, including the general population, highly exposed groups,
and highly susceptible groups.
C. Describe the basis for the exposure assessment, including any monitoring, modeling, or other analyses
of exposure distributions such as Monte Carlo or krieging.
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D. What are the key descriptors of exposure?
Describe the (range of) exposures to: “average” individuals, “high-end” individuals, general
population, high exposure group(s), children, susceptible populations, males, females (nonpregnant,
pregnant, lactating).
How was the central tendency estimate developed?
What factors and/or methods were used in developing this estimate?
How was the high-end estimate developed?
Is there information on highly exposed subgroups?
Who are they?
What are their levels of exposure?
How are they accounted for in the assessment?
E. Is there reason to be concerned about cumulative or multiple exposures because of biological, ethnic,
racial, or socioeconomic reasons?
F. If adverse reproductive effects have been observed in wildlife species, characterize wildlife exposure
by discussing the relevant issues as in A through E above.
G. Summarize exposure conclusions and discuss the following:
• Results of different approaches, i.e., modeling, monitoring, probability distributions;
• Limitations of each, and the range of most reasonable values;
• Confidence in the results obtained, and the limitations to the results.
PART TWO
Risk Conclusions and Comparisons
N. Risk Conclusions
A. What is the overall picture of risk, based on the hazard, quantitative dose-response, and exposure
characterizations?
B. What are the major conclusions and strengths of the assessment in each of the three main analyses (i.e.,
hazard characterization, quantitative dose-response, and exposure assessment)?
C. What are the major limitations and uncertainties in the three main analyses?
D. What are the science policy options in each of the three major analyses?
What are the alternative approaches evaluated?
What are the reasons for the choices made?
V. Risk Context
A. What are the qualitative characteristics of the reproductive hazard (e.g., voluntary vs. involuntary,
technological vs. natural, etc.)? Comment on fmdings, if any, from studies of risk perception that
relate to this hazard or similar hazards.
B. What are the alternatives to this reproductive hazard? How do the risks compare?
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C. How does this reproductive risk compare to other risks?
How does this risk compare to other risks in this regulatory program, or other similar risks that the
EPA has made decisions about?
Where appropriate, can this risk be compared with past Agency decisions, decisions by other federal or
state agencies, or common risks with which people may be familiar?
Describe the limitations of making these comparisons.
D. Comment on significant community concerns which influence public perception of risk.
VI. Existing Risk Information
Comment on other reproductive risk assessments that have been done on this chemical by EPA, other
federal agencies, or other organizations. Are there significantly different conclusions that merit
discussion?
VII. Other Information
Is there other information that would be useful to the risk manager or the public in this situation that has
not been described above?
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APPENDIX C
CHARACTERIZATION OF CANCER RISK
U.S. Environmental Protection Agency. (1996) Proposed guidelines for carcinogen risk assessment.
Federal Register 61(79):17999-I 8001.
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5. RISK CRARACTERIZATION
5.1. PURPOSE
The risk characterization process includes an integrative analysis followed by a
presentation in a Risk Characterization Summary, of the major results of the risk assessment.
The Risk Characterization Summary is a nontechnical discussion that minimizes the use of
technical terms. It is an appraisal of the science that supports the risk manager in making public
health decisions, as do other decision making analyses of economic, social, or technology issues.
It also serves the needs of other interested readers. The summary is an information resource for
preparation of risk communication information, but being somewhat technical, is not itself the
usual vehicle for communication with every audience.
The integrative analysis brings together the assessments and characterizations of hazard,
dose response, and exposure to make risk estimates for the exposure scenarios of interest. This
analysis is generally much more extensive than the Risk Characterization Summary. It may be
peer-reviewed or subject to public comment along with the summary in preparation for an
Agency decision. The integrative analysis may be titled differently by different EPA programs
(e.g., “Staff Paper” for criteria air pollutants), but it typically will identify exposure scenarios of
interest in a decision making and present risk analyses associated with them. Some of the
analyses may concern scenarios in several media, others may examine, for example, only
drinking water risks. It also may be the document that contains quantitative analyses of
uncertainty.
The values supported by a risk characterization throughout the process are transparency
in environmental decision making, clarity in communication, consistency in core assumptions
and science policies from case to case, and reasonableness. While it is appropriate to err on the
side of protection of health and the environment in the face of scientific uncertainty, common
sense and reasonable application of assumptions and policies are essential to avoid unrealistic
estimates of risk (U.S. EPA, 1995). Both integrative analyses and the Risk Characterization
Summary present an integrated and balanced picture of the analysis of the hazard, dose response,
and exposure. The risk analyst should provide summaries of the evidence and results and
describe the quality of available data and the degree of confidence to be placed in the risk
estimates. Important features include the constraints of available data and the state of
knowledge, significant scientific issues, and significant science and science policy choices that
were made when alternative inteipretations of data existed (U.S. EPA, 1995). Choices made
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about using default assumptions or data in the assessment are explicitly discussed in the course
of analysis, and if a choice is a significant issue, it is highlighted in the summary.
5.2. APPLICATION
Risk characterization is a necessary part of generating any Agency report on risk, whether
the report is preliminary to support allocation of resources toward further study or
comprehensive to support regulatory decisions. In the former case, the detail and sophistication
of the characterization are appropriately small in scale; in the latter case, appropriately extensive.
Even if a document covers only parts of a risk assessment (hazard and dose response analyses for
instance), the results of these are characterized.
Risk assessment is an iterative process that grows in depth and scope in stages from
screening for priority-making, to preliminary estimation, to fuller examination in support of
complex regulatory decision making. Default assumptions are used at every stage because no
database is ever complete, but they are predominant at screening stages and are used less as more
data are gathered and incorporated at later stages. Various provisions in EPA-administered
statutes require decisions based on findings that represent all stages of iteration. There are close
to 30 provisions within the major statutes that require decisions based on risk, hazard, or
exposure assessment. For example, Agency review of premanufacture notices under section 5 of
the Toxic Substances Control Act relies on screening analyses, while requirements for industry
testing under section 4 of that Act rely on preliminary analyses of risk or simply of exposure. At
the other extreme, air quality criteria under the Clean Air Act rest on a rich data collection
required by statute to undergo reassessment every few years. There are provisions that require
ranking of hazards of numerous pollutants--by its nature a screening level of analysis--and other
provisions that require a full assessment of risk. Given this range in the scope and depth of
analyses, not all risk characterizations can or should be equal in coverage or depth. The risk
assessor must carefully decide which issues in a particular assessment are important to present,
choosing those that are noteworthy in their impact on results. For example, health effect
assessments typically rely on animal data since human data are rarely available. The objective of
characterization of the use of animal data is not to recount generic issues about interpreting and
using animal data. Agency guidance documents cover these. Instead, the objective is to call out
any significant issues that arose within the particular assessment being characterized and inform
the reader about significant uncertainties that affect conclusions.
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5.3. PRESENTATION OF RISK CHARACTERIZATION SUMMARY
The presentation is a nontechnical discussion of important conclusions, issues, and
uncertainties that uses the hazard, dose-response, exposure, and integrative analyses for technical
support. The primary technical supports within the risk assessment are the hazard
characterization, dose response characterization, and exposure characterization described in this
guideline. The risk characterization is derived from these. The presentation should fulfill the
aims outlined in the purpose section above.
5.4. CONTENT OF RISK CHARACtERIZATION SUMMARY
Specific guidance on ha7ard, dose response, and exposure characterization appears in
previous sections. Overall, the risk characterization routinely includes the following, capturing
the important items covered in hazard, dose response, and exposure characterization.
• primary conclusions about hazard, dose response, and exposure, including equally
plausible alternatives,
• nature of key supporting information and analytic methods,
• risk estimates and their attendant uncertainties, including key uses of default
assumptions when data are missing or uncertain,
• statement of the extent of extrapolation of risk estimates from observed data to
exposure levels of interest (i.e., margin of exposure) and its implications for certainty
or uncertainty in quantifying risk.
• significant strengths and limitations of the data and analyses, including any major
peer reviewers’ issues,
• appropriate comparison with similar EPA risk analyses or common risks with which
people may be familiar, and
• comparison with assessment of the same problem by another organization.
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APPENDIX D
CHARACTERIZATION FOR EXPOSURE ASSESSMENTS
U.S. Environmental Protection Agency. (1992) Guidelines for exposure assessment.
Federal Register 57(104):22929-22930.
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7. PRESENTING THE RESULTS OF THE EXPOSURE ASSESSMENT
One of the most important aspects of the exposure assessment is presenting the results. It
is here that the assessment ultimately succeeds or fails in meeting the objectives laid out in the
planning as discussed in Section 3. This section discusses communication of the results, format
considerations, and suggested tips for reviewing exposure assessments either as a final check or
as a review of work done by others.
7.1. Communicating the Results of the Assessment
Communicating the results of an exposure assessment is more than a simple summary of
conclusions and quantitative estimates for the various pathways and routes of exposure, The
most important part of an exposure assessment is the overall narrative exposure characterization,
without which the assessment is merely a collection of data, calculations, and estimates. This
exposure characterization should consist of discussion, analysis, and conclusions that synthesize
the results from the earlier portions of the document, present a balanced representation of the
available data and its relevancy to the health effects of concern, and identify key assumptions and
major areas of uncertainty. Section 7.1.1 discusses the exposure characterization, and Section
7.1.2 discusses how this is used in the risk characterization step of a risk assessment.
7.1.1. Exposure Characterization
The exposure characterization is the summary explanation of the exposure assessment. In
this final step, the exposure characterization:
provides a statement of purpose, scope, level of detail, and approach used in the
assessment, including key assumptions;
• presents the estimates of exposure and dose by pathway and route for individuals,
population segments, and populations in a manner appropriate for the intended risk
characterization;
• provides an evaluation of the overall quality of the assessment and the degree of
confidence the authors have in the estimates of exposure and dose and the conclusions
drawn;
• interprets the data and results; and
• communicates results of the exposure assessment to the risk assessor, who can then
use the exposure characterization, along with characterizations of the other risk
assessment elements, to develop a risk characterization.
As part of the statement of purpose, the exposure characterization explains why the
assessment was done and what questions were asked. It also reaches a conclusion as to whether
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the questions posed were in fact answered, and with what degree of confidence. It should also
note whether the exposure assessment brought to light additional or perhaps more appropriate
questions, if these were answered, and if so, with what degree of confidence.
The statement of scope discusses the geographical or demographic boundaries of the
assessment. The specific populations and population segments that were the subjects of the
assessment are clearly identified, and the reasons for their selection and any exclusions are
discussed. Especially sensitive groups or groups that may experience unusual exposure patterns
are highlighted.
The characterization also discusses whether the scope and level of detail of the
assessment were ideal for answering the questions of the assessment and whether limitations in
scope and level of detail were made because of technical, practical, or financial reasons, and the
implications of these limitations on the quality of the conclusions.
The methods used to quantify exposure and dose are clearly stated in the exposure
characterization. If models are used, the basis for their selection and validation status is
described. If measurement data are used, the quality of the data is discussed. The strengths and
weaknesses of the particular methods used to quantify exposure and dose are described, along
with comparison and contrast to alternate methods, if appropriate.
In presenting the exposure and dose estimates, the important sources, pathways, and
routes of exposure are identified and quantified, and reasons for excluding any from the
assessment are discussed.
A variety of risk descriptors, and where possible, the full population distribution is
presented. Risk managers should be given some sense of how exposure is distributed over the
population and how variability in population activities influences this distribution. Ideally, the
exposure characterization links the purpose of the assessment with specific risk descriptors,
which in turn are presented in such a way as to facilitate construction of a risk characterization.
A discussion of the quality of the exposure and dose estimates is critical to the credibility
of the assessment. This may be based in part on a quantitative uncertainty analysis, but the
exposure characterization must explain the results of any such analysis in terms of the degree of
confidence to be placed in the estimates and conclusions drawn.
Finally, a description of additional research and data needed to improve the exposure
assessment is often helpful to risk managers in making decisions about improving the quality of
the assessment. For this reason, the exposure characterization should identify key data gaps that
can help focus further efforts to reduce uncertainty.
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Additional guidance on communicating the results of an exposure assessment can be
found in the proceedings of a recent workshop on risk communication (American Industrial
Health Council, 1989).
7.1.2. Risk Characterization
Most exposure assessments will be done as part of a risk assessment, and the exposure
characterization must be useful to the risk assessor in constructing a risk characterization. Risk
characterization is the integration of information from hazard identification, dose-response
assessment, and exposure assessment into a coherent picture. A risk characterization is a
necessary part of any Agency report on risk whether the report is a preliminary one prepared to
support allocation of resources toward further study or a comprehensive one prepared to support
regulatory decisions.
Risk characterization is the culmination of the risk assessment process. In this final step,
the risk characterization:
• integrates the individual characterizations from the hazard identification, dose-
response, and exposure assessments;
• provides an evaluation of the overall quality of the assessment and the degree of
confidence the authors have in the estimates of risk and conclusions drawn;
• describes risks to individuals and populations in terms of extent and severity of
probable harm; and
• communicates results of the risk assessment to the risk manager.
It provides a scientific interpretation of the assessment The risk manager can then use the risk
assessment, along with other risk management elements, to make public health decisions. The
following sections describe these four aspects of the risk characterization in more detail.
7.1.2.1. Integration of Hazard Identification, Dose-Response, and Exposure Assessments.
In developing the hazard identification, dose-response, and exposure portions of the risk
assessment, the assessor makes many judgments concerning the relevance and appropriateness of
data and methodology. These judgments are summarized in the individual characterizations for
h rd identification, dose-response, and exposure. In integrating the parts of the assessment, the
risk assessor determines if some of these judgments have implications for other parts of the
assessment, and whether the parts of the assessment are compatible. For example, if the hazard
identification assessment determines that a chemical is a developmental toxicant but not a
carcinogen, the dose-response and exposure information is presented accordingly; this differs
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greatly from the way the presentation is made if the chemical is a carcinogen but not a
developmental toxicant.
The risk characterization not only examines these judgments, but also explains the
constramts of available data and the state of knowledge about the phenomena studied in making
them, including:
the qualitative, weight-of-evidence conclusions about the likelihood that the chemical
may pose a specific hazard (or hazards) to human health, the nature and severity of
the observed effects, and by what route(s) these effects are seen to occur. These
judgments affect both the dose-response and exposure assessments;
• for noncancer effects, a discussion of the dose-response behavior of the critical
effect(s), data such as the shapes and slopes of the dose-response curves for the
various other toxic endpoints, and how this information was used to determine the
appropriate dose-response assessment technique; and
• the estimates of the magnitude of the exposure, the route, duration and pattern of the
exposure, relevant pharmacokinetics, and the number and characteristics of the
population exposed. This information must be compatible with both the hazard
identification and dose-response assessments.
The presentation of the integrated results of the assessment draws from and highlights
key points of the individual characterizations of hazard, dose-response, and exposure analysis
performed separately under these Guidelines. The summary integrates these component
characterizations into an overall risk characterization.
7.1.2.2. Quality of the Assessment and Degree of Confidence
The risk characterization summarizes the data brought together in the analysis and the
reasoning upon which the assessment is based. The description also conveys the major strengths
and weaknesses of the assessment that arise from data availability and the current limits of
understanding of toxicity mechanisms.
Confidence in the results of a risk assessment is consequently a function of confidence in
the results of analysis of each element: hazard, dose-response, and exposure. Each of these three
elements has its own characterization associated with it. For example, the exposure assessment
component includes an exposure characterization. Within each characterization, the important
uncertainties of the analysis and interpretation of data are explained so that the risk manager is
given a clear picture of any consensus or lack thereof about significant aspects of the assessment.
For example, whenever more than one view of dose-response assessment is supported by the data
and by the policies of these Guidelines, and choosing between them is difficult, the views are
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presented together. If one has been selected over another, the rationale is given; if not, then both
are presented as plausible alternatives.
If a quantitative uncertainty analysis is appropriate, it is summarized in the risk
characterization; in any case a qualitative discussion of important uncertainties is appropriate. If
other organizations, such as other Federal agencies, have published risk assessments, or prior
EPA assessments have been done on the substance or an analogous substance and have relevant
similarities or differences, these too are described.
7.1.2.3. Descriptors of Risk
There are a number of different ways to describe risk in quantitative or qualitative terms.
Section 2.3 explains how risk descriptors are used. It is important to explain what aspect of the
risk is being described, and how the exposure data and estimates are used to develop the
particular descriptor.
7.1.2.4. Communicating Results of a Risk Assessment to the Risk Manager
Once the risk characterization is completed, the focus turns to communicating results to
the risk manager. The risk manager uses the results of the risk characterization, technologic
factors, and socioeconomic considerations in reaching a regulatory decision. Because of the way
these risk management factors may impact different cases, consistent, but not necessarily
identical, risk management decisions must be made on a case-by-case basis. Consequently, it is
entirely possible and appropriate that a chemical with a specific risk characterization may be
regulated differently under different statutes. These Guidelines are not intended to give guidance
on the nonscientific aspects of risk management decisions.
7.2. Format for Exposure Assessment Reports
The Agency does not require a set format for exposure assessment reports, but individual
program offices within the Agency may have specific format requirements. Section 3 illustrates
that exposure assessments are performed for a variety of purposes, scopes, and levels of detail,
and use a variety of approaches. While it is impracticable for the Agency to specif an outline
format for all types of assessments being performed within the Agency, program offices are
encouraged to use consistent formats for similar types of assessments within their own purview.
All exposure assessments must, at a minimum, contain a narrative exposure
characterization section that contains the types of information discussed in Section 7.1. For the
purpose of consistency, this section should be titled exposure characterization. Placement of this
section within the assessment is optional, but it is strongly suggested that it be prominently
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featured in the assessment. It is not, however, an executive summary and should not be used
interchangeably with one.
7.3. Reviewing Exposure Assessments
This section provides some suggestions on how to effectively review an exposure
assessment and highlights some of the common pitfalls. The emphasis in these Guidelines has
been on how to properly conduct exposure assessments; this section can serve as a final checklist
in reviewing the completed assessment. An exposure assessor also may be called upon to
critically review and evaluate exposure assessments conducted by others; these suggestions
should be helpful in this regard.
Reviewers of exposure assessments are usually asked to identify inconsistences with the
underlying science and with Agency-developed guidelines, factors, and methodologies, and to
determine the effect these inconsistences might have on the results and conclusions of the
exposure assessment. Often the reviewer can only describe whether these inconsistencies or
deficiencies might underestimate or overestimate exposure.
Some of the questions a reviewer should ask to identify the more common pitfalls that
tend to underestimate exposure are:
Has the pathways analysis been broad enough to avoid overlooking a sign flcant
pathway? For example, in evaluating exposure to soil contaminated with PCBs, the exposure
assessment should not be limited only to evaluating the dermal contact pathway. Other
pathways, such as inhalation of dust and vapors or the ingestion of contaminated gamefish from
an adjacent stream receiving surface runoff containing contaminated soil, should also be
evaluated as they could contribute higher levels of exposure from the same source.
Have all the contaminants of concern in a mixture been evaluated? Since risks resulting
from exposures to complex mixtures of chemicals with the same mode of toxic action are
generally treated as additive (by summing the risks) in a risk assessment, failure to evaluate one
or more of the constituents would neglect its contribution to the total exposure and risk. This is
especially critical for relatively toxic or potent chemicals that tend to drive risk estimates even
when present in relatively low quantities.
Have exposure levels or concentration measurements been compared with appropriate
background levels? Contaminant concentrations or exposure levels should not be compared with
other contaminated media or exposed populations. When comparing with background levels, the
exposure assessor must determine whether these concentrations or exposure levels are also
affected by contamination from anthropogenic activities.
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Were the detection limits sensitive enough to make interpretations about exposures at
levels corresponding to health concerns? Were the data interpreted correctly? Because values
reported as not detected (ND) mean only that the chemical of interest was not found at the
particular detection limit used in the laboratory analysis, ND does not rule out the possibility that
the chemical may be present in significant concentrations. Depending on the purpose and the
degree of conservatism warranted in the exposure assessment, results reported as ND should be
handled as discussed in Section 5.
Has the possibility of additive pathways been considered for the population being
studied? If the purpose of the exposure assessment is to evaluate the total exposure and risk of a
population, then exposures from individual pathways within the same route may be summed in
cases which concurrent exposures can realistically be expected to occur.
Some questions a reviewer should ask to avoid the more prevalent errors that generally
tend to overestimate exposure are:
Have unrealistically conservative exposure parameters been used in the scenarios? The
exposure assessor must conduct a reality check to ensure that the exposure cases used in the
scenario(s) (except bounding estimates) could actually occur.
Have potential exposures been presented as existing exposures? In many situations,
especially when the scenario evaluation approach is used, the objective of the assessment is to
estimate potential exposures. (That is, f a person were to be exposed to these chemicals under
these conditions, then the resultant exposure would be this much.) In determining the need and
urgency for regulatory action, risk managers often weigh actual exposures more heavily than
higher levels of potential exposures. Therefore, the exposure assessment should clearly note
whether the results represent actual or potential exposures.
Have exposures derivedfrom “not detected” levels been presented as actual exposures?
For some exposure assessments it may be appropriate to assume that a chemical reported as not
detected is present at either the detection limit or one-half the detection limit. The exposure
estimates derived from these nondetects, however, should be clearly labeled as hypothetical since
they are based on the conservative assumption that chemicals are present at or below the
detection limit, when, in fact, they may not be present at all. Exposures, doses, or risks estimated
from data using substituting values of detection limits for “not detected” samples must be
reported as “less than” the resulting exposure, dose, or risk estimate.
Questions a reviewer should ask to identify common errors that may underestimate or
overestimate exposure are:
Are the results presented with an appropriate number ofsign ficant figures? The number
of significant figures should reflect the uncertainty of the numeric estimate. If the likely range of
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the results spans several orders of magnitude, then using more than one significant figure implies
more confidence in the results than is warranted.
Have the calculations been checked for computational errors? Obviously, calculations
should be checked for arithmetic errors and mistakes in converting units. This is overlooked
more often than one might expect.
Are the factors for intake rates, etc. used appropriately? Exposure factors should be
checked to ensure that they correspond to the site or situation being evaluated.
Have the uncertainties been adequately addressed? Exposure assessment is an inexact
science, and the confidence in the results may vary tremendously. It is essential the exposure
assessment include an uncertainty assessment that places these uncertainties in perspective.
If Monte Carlo simulations were used, were correlations among input distributions
known and properly accounted for? Is the maximum value simulated by this method in fact a
bounding estimate? Was Monte Carlo simulation necessary? (A Monte Carlo simulation
randomly selects the values from the input parameters to simulate an individual. If data already
exist to show the relationship between variables for the actual individuals, it makes little sense to
use Monte Carlo simulation, since one already has the answer to the question of how the
variables are related for each individual. A simulation is unnecessary.)
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APPENDIX E
RISK CHARACTERIZATION FRAMEWORK FOR ASBESTOS
U.S. Environmental Protection Agency. (1991) Indoor air—assessment. A review of indoor air quality risk
characterization studies. Prepared by the Office of Research and Development, Washington, DC.
EPA/60018-901044, March.
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BACKGROUND
Figure 19 (see pp. E-6 through E-9) is a risk characterization framework developed by
EPA (1991) to provide a systematic approach for analyzing and presenting the results from risk
characterization studies for various indoor air pollutants. This framework was used as the basis
for review and comparison of risk estimates and risk assessment methodologies associated with
indoor air pollutants. The information in the framework was filled out for each individual study
used to support the risk estimates and the risk characterization. Relevant information for each
component (see columns A through K, figure 19) and the critical assumptions concerning risk
estimates and exposure estimates were abstracted from each document and recorded on attached
forms. Although this framework was used as a means to guide the literature review of the
supporting documents and subsequent analyses, it could provide a useful format for organi’ing
and summarizing the critical information from a risk characterization.
EPA (1991) also provided two suggested summary figures (see figures 2 [ p. E-1O] and 3
[ p. E-1 1]) for displaying risk information obtained from several different studies on various
indoor air pollutants. We have modified these two summary figures by deleting information on
environmental tobacco smoke. The two approaches presented in these figures give different
results and are “best analyzed in combination with regard to weight-of-evidence evaluations.”
This source did not indicate how to incorporate weight-of-evidence considerations. These
summary figures provide useful insights into the relative significance of indoor air pollutants
such as radon, asbestos, and volatile organic compounds. The ranges shown in figure 2 are for
different point estimates of risk and do not represent a statistical confidence interval or range of
uncertainty. The information presented in this figure comes from column I of the Risk
Characterization Framework (see figure 19). Figure 3 presents the range of estimates of
population risk of cancer, as number of cancer cases that are projected for a defined population
and for a specified exposure scenario during 1 year. The information presented in this figure
comes from column K of the Risk Characterization Framework (see figure 19). Displaying
comparative risk information in the manner illustrated in figures 2 and 3 may be useful to address
the issue of risk context in a risk characterization summary. This type of display provides a
simple way to show the reader how the magnitude of the subject risk compares to the magnitude
of risks from exposure to other pollutants. It is important to accompany such figures with
appropriate explanatory text and to select comparative risks that are relevant to the subject risk.
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CRITIQUE
The format of the table in figure 19 has value for summarizing and presenting risk
characterization information. As an adjunct to more detailed text that describes the ingredients
of the risk analysis and the risk characterization, this type of table could be used to present
complex information in a manner that is understandable to managers.
This table was critiqued according to the Administrator’s requirements of clarity,
transparency, reasonableness, and consistency. The strengths and weaknesses in each of these
areas are pointed out using table 2 (see chapter 7) and the checklists in chapter 6 of this risk
characterization guidance document as a guide. Overall, this case study aptly summarizes the
key features of asbestos risk in both occupational and nonoccupational settings. However, it
does so at the expense of adequate descriptions and discussions about the public health concerns
and health effects associated with asbestos exposure. Consequently, some readers may not be
able to understand all of the assumptions and approaches used in this risk analysis. The net
result is that, in the absence of appropriate accompanying text, the Administrator’s key
requirements are not met in this case study.
Risk Characterization Summary: Clarity and Transparency
The risk characterization framework (figure 19) is very useful. Each component of the
risk assessment is listed. Under each component, a concise summary of the ingredients and
approaches used in the analysis is displayed, including quantitative risk estimates. Comments
and assumptions considered in the analysis are contained in the table. Nonetheless, the
summaries and the comments presuppose an understanding of the risk assessment process. The
rationale for selection of the linear nonthreshold dose-response model is not discussed. The
reason for use of the relative risk model for lung cancer and the absolute risk model for
mesothelioma is not mentioned. The response factor discussion does not clearly distinguish
between occupational and nonoccupational exposures. The approach used to estimate an
individual’s risk is stated clearly, but the approach used to estimate the risk for populations is
incomplete. More information on the characteristics of the population subgroups considered to
be at risk and the source used to estimate their numbers would be helpful for the reader. A brief
description of the adverse health effects due to exposure (i.e., lung cancer and mesothelioma) is
needed. There is no summary of health effects studies that have been conducted on asbestos.
The reliance of both occupational exposure data and occupational epidemiology data to develop
risk estimates for nonoccupational exposures is not explained and cannot be discerned from the
text.
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Figures 2 and 3 illustrate useful ways to present comparative risk information on the
carcinogenicity of asbestos and several other common inhaled toxicants. These figures allow the
reader to easily compare the magnitude of the cancer risk from asbestos to the magnitude of the
cancer risk from the other chemicals. As indicated in U.S. EPA, 1991, these two figures
accompany figure 19, which explains the key assumptions for calculating the asbestos risk. To
support the Administrator’s value of clarity, it is necessary to have text accompany figures 2 and
3 to explain how these graphs were constructed and how to interpret them. It also would be
useful to take two of the chemicals, as an example, and explain how to interpret the graphs to
compare the cancer risks.
Hazard Identification Summary: Clarity, Transparency, and Reasonableness
The classification of asbestos products into nine categories is very useful. Common
terms are used, but examples are not given to facilitate understanding. The relationship of
building products to consumer products is not explained. The pathway of exposure is not stated
clearly. Consequently, some readers may not understand the depth and breadth of the sources
being considered in this analysis. The text fails to explain that asbestos is virtually ubiquitous in
the environment and that the key ingredient of public health concern is prolonged exposure to
asbestos in building products and consumer products.
Dose-Response Assessment Summary: Clarity and Transparency
The description of dosimetry factors and dose is very good. The rationale for selection of
the linear nonthreshold dose-response model is not discussed. The reason for use of the relative
risk model for lung cancer and the absolute risk model for mesothelioma is not mentioned. The
response factor discussion does not clearly distinguish between occupational and
nonoccupational exposures. A brief description of the adverse health effects due to exposure
(lung cancer and mesothelioma) is needed. There is no summary of health effects studies that
have been conducted on asbestos. The reliance on both occupational exposure data and
occupational epidemiology data to develop risk estimates for nonoccupational exposures is not
explained and cannot be discerned from the text. The rationale for reliance on the 1983 study by
Selikoffet a!. is not discussed.
Exposure Assessment Summary: Clarity and Transparency
Lifetime exposure estimates for each product category are clearly stated. The
significance of relating these estimates to the 1983 study is not explained. There is no mention
of uncertainties concerning asbestos exposure. Age and gender differences are not clearly noted.
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The significance of the confounding effect of smoking is not mentioned. It is difficult to follow
the approach used to construct the exposure levels and durations because not all of the
infonnation used in these analyses is summarized in the table. This may cause some confusion
for some readers.
TEE CASE STUDY
See figure 19 (pp. E-6 through E-9), figure 2 (p. E-1O), and figure 3 (p. E-l 1).
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Figure 19. Asbestos: Mauskopf (1987)
Page 1 of 4
x1
RISK CHARACTERIZATION FRAMEWORK
(Data from Reference In Footnote 1)
Predictive Source Pollutant Exposure 1 Dosinady Response Lifetime 1 Exposed Risk to Exposed
Risk Equation Factors Conceisiration DuratIon/SettIng Exposure Factors Dose Factor Indlvdunl Risk Population Population
(A) (B) (C) X (0) - (H) X (F) - (G) X (H) - (I) X (.1) (K)
L - L.. -
Elements of Building Asbestos Long duration Weighted 40 hr,/wk Yearly lifetime Carcinogenic Incidence Children/home Total excess
risk equation materials lifetime 50 wks/yr avenge potency cases
Indoors, home average from Adults
Household Indoors, work all sources Breathing rate Worker
products Outdoors 1 m’ihr mt/fiber Homemaker
9 Categories 5 occupational Occupationni: I fiber/mi Occupational: Lung cancer ug , n c 0.9 million Lung cnnces
I) Friction and 4 non 1.4 E+7 llbcti 2.0 E+9 fibers 7.0 E - .3 Cml Occupational: Occupational occupationally Occupational
products occupational per year per year 5.4 E-2 cxposurc: exposed exposure:
2) A/C pipe exposure Nonoccupational: 3.8 E-4 339 cases
3) Coatings and categories Nonoccupational: or Nonoccupational: 2.8 E-2 Nonoccupatlonal 150 million Nonoccupationai
sealants 1.9 E+5 fibers 9.5 ES Cml exposure nonoccupa- exposure:
4) Paper Durations ranged per year I fiber/yr Mesothetioma 2.7 E-6 tionally 406 cases
products between I and 5.0 E-l0 fibers Occupational: exposed
5) V/A floor tile 30 years perml 3.1 E-2 Mcm lhc linmu
6) Caskels/ Nonoccupatiunsi: Occupational Occupational
packing 4.2 E-2 exposure exposure:
7) Textiles 2,2 E-4 197 cases
8) A/C Sheets Nonoccupational Nonoccupational
9) Plastics exposure exposure:
4. OE.6 599 cases
Qualitative 4- ----- - - --Uazsrd ldentiflcst lon - -- ------ - - --- -- - - —-—- --- -- ----4
Information
Quantitative I - - -— Exposure Assessment --- - - -4 4-— --——Dose-Response— 4 ----- — Risk Characterization —--—-------------4
Information Exposure estimates, when possible, were developed based on data collected for each stage in the used a relative risk model to predict Column (K) shows the author’s estimates of the total
product lifc .cyclc for nine product types, These data were collected from several studies and were lung cancer. Uscd an absolute risk number of excess cases of lung canccr and mesothelioma
assumed to correspond to 1983 levels. Future exposures were based on relative changes in Ihture model for mesothelioma. that will occur over a 100 year period. The number of
production levels. Occupational data assumed appiy for cases arc not equal for each year of this period.
nonoccupational exposures due to
linear dose-response relationship.
Qualltatlveor I —--- ———-—--—---—-—---—-—---- -- RJskAsseument—— — ______
Quantitative The author applies a life-table model approach taking into consideration time and duration of exposure, latency period, survival, other causes of death, and demographic characteristics.
Analysis
Footnotes: I: Reference: Mauskopf, LA., (19117), “Projections of Cancer Risks Attributable to Future Exposure to Asbestos,” Ri ,rkAnaly.ris. 7:4:477.486.
2: Additional comments: The numbers presented in columns (B), (F), (0), and (H) have been calculated from the author’s results to fit into this linear characterization fluimework, and are not those directly
reported in the article.
-------
Column
Data )
Comments
A
Risk equations used by
Mauskopf (see further
explanation in following
text)
Linear, no threshold dose-response relationships proposed by Nicholson (1983) were used to convert
information on asbestos exposure into excess lung cancer and mesothelioma incidence rates.
For lung cancer, Nicholson postulated a relative risk model that includes a 10-year latency period
between onset of exposure and increased risk:
= I L K fd 4 . 10) where:
= annual excess risk of lung cancer
1 = age-specific lung cancer incidence rate without exposure to asbestos
K 1 = the dose-response factor (from Selikoffet al., 1979)
f= level of exposure, fibers per milliliter (column G above)
d(t 10 ) = duration of exposure from onset until 10 years before the current age (t)
For mesothelioma, Nicholson postulated an absolute risk model:
Km1T(t I0) 3 (t l0 d) 3 ], t>10+d
= K 1 J(t-lO) 3 , l0+d>t>I0
=0 1o>t
where:
= annual excess risk of mesothelioma
K 1 = dose-response factor (from Selikoffet al., 1979)
f= level of exposure, fibers/milliliter (column G above)
= time since first exposure
d total duration of exposure (column D above)
B
Sources of exposure
Risk was calculated for each of nine categories of asbestos products manufactured between 1985 and
2000 on a product-by-product basis. Projections of the annual growth rates for these nine products
were made and with the exception of friction materials all growth rates were predicted to be negative.
C
Pollutant concentration
The author used data on exposure levels, which are based on available data. While the author cites
several studies on which the exposure assessment was based, no specific pollutant concentration values
were presented in the article.
Figure 19. Asbestos: Mauskopf (1987)
Page 2 of 4
t;tl
-------
Column
Data
Comments
D
Exposure duration/setting
The total number of person-years of exposure for each of the nine product categories was estimated
using exposure data for 1983, the production indices, and the mean duration of exposure for each year
of production, Five occupational and four nonoccupational exposure categories are included where
relevant for each of the nine product categories. Mean levels of exposure were assumed to remain
constant at the 1983 levels during the years 1985-2000 except for the consumer use category where
they were assumed to vary with production levels. For each product, the population at risk was
subdivided into exposure categories according to when in the product life-cycle exposure takes place
and whether they were exposed occupationally, in the ambient air, or in the use of the product. Each
exposure category was also subdivided into 10-year age groups. Durations within exposure categories
ranged from Ito 30 years. Exposures prior to 1985 and after the lifetime of products produced within
1985-2000 were not included in this analysis.
E
Exposure
Exposure levels expressed as fibers per year were presented for each exposure category for each of the
nine product categories that occur during: primary manufacture, secondary manufacture (for
occupational only), installation, use, and repair/disposal. The exposure levels reported are assumed to
correspond to 1983 levels. The exposure levels reported range from 30 to 1,560 million fibers per year
from occupational exposures, and 3 x l0 to 2.79 million fibers per year for nonoccupational
exposures. Average lifetime exposures expressed in million fibers per year were calculated as
weighted averages over all product and exposure categories. Exposure levels, durations, and
populations were estimated based on 1983 levels presented in table I and the methodology outlined in
RTI (1985). This exposure level is a weighted average across exposure categories and time. The
authors’ analysis does not show exposure as constant across either variable. Therefore, these weighted
averages cannot be used to back-calculate either duration or pollutant concentration.
F
Dosimetry factors
The unit of measure for dose in the risk model is fibers/milliliter of air inhaled. The risk models used
were developed from occupational studies with typical exposures of 40 hours/week, 50 weeks/year and
a breathing rate of I m 3 /hour. Since data from the occupational exposure studies indicate that excess
mortality from lung cancer and mesothelioma is proportional to both the level and duration of exposure
to asbestos fibers, it is reasonable to use these dosimetry factors to normalize exposure to indoor air. I
fiber/mL x 40 hr/wk x 50 wk/yr x m 3 /hr x 106 mL/m 3 2 x iø fibers/yr.
0
Dose
This value represents the yearly lifetime average dose normalized to an occupational exposure setting.
The total exposure in fibers per year is divided by the dosimetry factor of 2 x IO mL/yr to obtain the
normalized concentration, as if that exposure occurred during a typical work year of 40 hours per
week, 50 weeks per year and a breathing rate of I m 3 per hour.
Figure 19. Asbestos: Mauskopf (1987)
Page 3 of 4
[ 71
oc
-------
Column
Data
Comments
H
Response factor
These response factors represent the average lifetime risks from asbestos exposures of an
occupationally normalized exposure of I f/mL. These response factors were back-calculated by
dividing lifetime individual risk (column I) by dose estimates (column G). For both lung cancer and
mesothelioma, the occupational and nonoccupational values were within the same order of magnitude.
Differences exist between the occupational and nonoccupational values. For lung cancer, the risk
factors are sensitive to exposure duration and concentration with nonoccupational exposures tending to
be of longer duration and lower concentration, supporting a lower risk factor than the occupational
setting. Mesothelioma is highly sensitive to age at exposure. The higher risk factor for the
nonoccupational exposures is supported by the fact that exposures would likely occur earlier in life on
the average than for occupational exposures.
I
Lifetime individual risk
Lifetime probability of lung cancer or mesothelioma from exposure to asbestos products manufactured
between 1985 and 2000. Lifetime individual risks presented were those back-calculated from excess
cases and exposed population. The author reported lifetime individual risks in table VI. There is an
unexplained discrepancy between the values shown here and those reported by the author for
occupational exposures. Values of 3.1 i0 4 for lung cancer and 2.1 x for mesothelioma were
reported by the author. Values for nonoccupational were in agreement.
J
Exposed population
Lung cancer rates are assumed to be age dependent and also to vary according to smoking habits, sex,
race, and exposure duration and intensity, while mesothelioma incidence rates are assumed to be
independent of age, sex, race, and smoking habits, but dependent on exposure duration and intensity
and age at onset of exposure. 150 million for nonoccupational exposures represents the total exposed
population. Individuals within this group may have been exposed to multiple sources.
K
Risk to exposed population
The total number of cases of lung cancer and mesothelioma, 1,541, are predicted to be distributed over
the next 100 years. The author presents projections of excess cancer and mesothelioma for each
decade from 1995 to 2095 attributable to asbestos products manufactured between 1985 and 2000 for
each exposure type.
Figure 19. Asbestos: Mauskopf (1987)
Page 4 of 4
-------
Figure 2. Comparison of Individual Lifetime Cancer Risk Due to Indoor Air Pollutants
0
—
• £
—
.5
10.1
10.2
I o
I o-
I 0’
I o
10”
I 98th percentIle A I Metropolitan A 195% UCL A Tancrede
Mean * I Non-Metropolitani IMLE at al. (1987)
see
Median I I I
I I I I Figure 17
— EPA (1987)
.1 L
see Figure 4
.
I
I I I
BEIRIVi
(1988)
I
— S’Figure5 I I I
I
NCRP (1984) I
I
see FIgure 6 I I
I Ici: L .
I ‘- tt c w I I
I I
— I .. . ‘ll6 ’ i
JôIA 3 l
‘
I ii
I
I I I I (1981)
i At’ see
Figure 16
I I I I
I Lung Cancer A
Mesothelloma I
I
I
I
I
I
I
Occupational
L_..__....
I
I
I
i
:
I
I Nonoccupational
r
I •
I
— I
I I I
i
I I I
I
A
I
I
I I I
I
I
1
I
Tancrede et al.
(1987)
Los Angeles, CA
see Floure 13
I I
I Wallace McCann et al. McCann
(1985) I (1986) et al. (1986)
I see Figure 14 see Figure 15 I see Figure 18
.
I
Mauskopf
(1987)
I see Figure 19
Radon I
I
Volatile Organics
I
I
Formaldehyde
I
I
Asbestos
(Adapted from EPA, 1991)
-------
20,000 High Estimate
•0
cn
LI.
15,000
(1987) see
_ Figure 4
C 10000
oc
c i)
(U
E 5,000 - Low Estimate Wallace (1985)
i . See Figure 14
C)
,-Total
f—Metropolitan Mauskopf (1987)
0 _____________ I I ;Nonmetropoii•tan • 19
Radon Volatile Asbestos
Organics
Figure 3. Comparison of Annual Cancer Cases Due to Indoor Air Pollutants
(Adapted from EPA, 1991)
-------
APPENDIX F
HAZARD IDENTIFICATION FOR BROMINATED ALKANE (BA)
U.S. Environmental Protection Agency. (1996) “Narrative 5, brominated alkane (Ba).” In Proposed guidelines
for carcinogen risk assessment. Federal Register 61(79): 18002-18003.
F-i
-------
BACKGROUND
NCEA’s 1996 Proposed Guidelines for Carcinogen Risk Assessment contains a series of
case studies that illustrate many of the principles of cancer risk assessment. The case study on
brominated alkane (BA) was selected to illustrate one approach for summarizing the evidence
from a detailed hazard identification assessment. This example is intended to provide ideas for
summarizing epidemiology and toxicity studies. It shows how one can organize the results of the
analysis according to the weight of evidence and present the conclusions with comments
concerning uncertainty, where appropriate.
CRiTIQUE
The summarization of cancer hazard identification for BA is a concise description of the
author’s conclusion that it is highly likely to be carcinogenic in humans. The strength of this
example is its clarity and transparency. The headings organize the discussion in a complete and
effective manner. The briefing summary is presented in a hierarchical maimer that organizes the
analysis to support the conclusions persuasively. Only the conclusions of the individual
laboratory animal toxicity studies and the epidemiology studies are assessed, summarized, and
compared. Unnecessary details about the design and findings from each study are avoided in the
presentation of the evidence. The brief description of the structure activity relationship of BA
and the affinity of its metabolites for DNA is presented in a manner to support the conclusions
described for the epidemiology studies and the laboratory animal studies. Technical jargon is
avoided throughout the discussion yet essential details are summarized effectively.
The major weaknesses of this case study are the failure to describe the purpose of this
assessment and the public health concerns about BA and the significance of the uncertainty noted
for negative studies. The source of BA in the environment and the routes of exposure are
presumed. The public health concern is not mentioned. Not all readers will understand the
assignment of BA to the “likely” carcinogen group. While negative studies are noted clearly,
their significance to the weight of evidence could be explained in more detail.
F-2
-------
THE CASE STUDY
NARRATIVE #5
Brommated Alkane (BA)
CAS# XXX
CANCER HAZARD SUMMARY
Brominated alkane (BA) is likely to be a human carcinogen by all routes of exposure.
The weight of evidence for human carcinogenicity is at the high end of agents in the “likely”
group. Findings are based on very extensive and significant experimental fmdings that include
(a) tumors at multiple sites in both sexes of two rodent species via three routes of administration
relevant to human exposure, (b) close structural analogues that produce a spectrum of tumors like
BA, (c) significant evidence for the production of reactive BA metabolites that readily bind to
DNA and produce gene mutations in many systems including cultured mammalian and human
cells, and (d) two null and one positive epidemiologic studies; in the positive study, there may
have been exposure to BA. These findings support a decision that BA might produce cancer in
exposed humans. In comparison to other agents considered likely human carcinogens, the
overall weight of evidence for BA puts it near the top of the grouping. Given the agent’s
mutagenicity, which can influence the carcinogenic process, a linear dose-response extrapolation
is recommended.
Uncertainties include the lack of adequate information on the mutagenicity of BA in
mammals or humans in vivo, although such effects would be expected.
SUPPORTING INFORMATION
Human Data
The information on the carcinogenicity of BA from human studies is inadequate. Two
studies of production workers have not shown significant increases in cancer from exposure to
BA and other chemicals. An increase in lymphatic cancer was reported in a mortality study of
grain elevator workers who may have been exposed to BA (and other chemicals).
Animal Data
BA produced tumors in four chronic rodents studies. Tumor increases were noted in
males and females of rats and mice following oral dermal and inhalation exposure (rat--oral and
two inhalation, mouse--oral and dermal). It produces tumors both at the site of application (e.g.,
skin with dermal exposure) and at sites distal to the portal of entry into the body (e.g., mammary
F-3
-------
APPENDIX G
SUMMARY FIGURES DESCRIBING RISKS ASSOCIATED WITH DIOXIN AND
DIOXINLIKE COMPOUNDS IN NORTH AMERICA
G-1
-------
BACKGROUND
NCEA has developed figure G-1 for the purpose of explaining the risks associated with
exposure to dioxin. Although parts of this figure have been used in various EPA dioxin
briefings, including a May 1995 dioxin briefing package for EPA’s Science Advisory Board, this
figure does not yet appear in any published report or paper. It is being considered for inclusion
in the risk characterization of the Dioxin Risk Assessment.
CRmQIJE
The strengths of this figure are that it graphically illustrates margin of exposure (MOE)
by plotting background exposure level and threshold for noncancer effects; shows how a variety
of health effects are used to derive threshold level for noncancer effects; plots cancer and
noncancer effects on the same scale (for any dose the reader can determine both the cancer risk
and whether the threshold for noncancer effects is exceeded); shows dose and corresponding
body burden on same scale, allowing the reader to use whichever metric is desired; and includes
key reference values (i.e., World Health Organization’s Tolerable Daily Intake).
This type of figure also could be very useful in NCEA risk characterizations because it
provides a concise visual representation of the MOE and where its boundaries lie in relation to
various effects seen in humans and test animals. The MOE represents the “bottom line”
conclusion of the integrative analysis portion of the risk characterization.
The weaknesses of this figure are that it does not present variability/uncertainty in
background exposures or threshold for noncancer effects and currently does not extend cancer
risk line all the way to the end of the dose scale (this will be fixed before figure is finalized).
TIlE CASE STUDY
Figure G-1 shows the relationships among exposure (dose) to an environmental pollutant
(dioxin), the risk of cancer, and the levels at which noncancer effects may be seen. The
noncancer effects currently are labeled as A, B, and C since final decisions have not been made
about which effects and corresponding threshold levels should be included. In this case, human
dose is expressed as picograms of dioxin/kg body weight/day (pg/kg/day), and the corresponding
body burden (computed using a simple steady-state pharmacokinetic model) is shown as an
alternative dose metric. The upper bound on the risk of cancer is expressed as the increased
individual lifetime risk, based on the EPA dioxin slope factor and represented by the diagonal
line. This figure shows that the background exposure levels (e.g., — 1 pg/kg/day) are associated
with upper-bound individual probabilities of cancer risk close to 1 x 10 (e.g., increased
probability of cancer may be as high as one in 10,000, based on a lifetime exposure to dioxin and
G-2
-------
related compounds at background levels; “true” risks are likely to be less and may even be zero
for some individuals). Also, an upper-bound incremental risk level of one in a million (lxl(r 6 )
is associated with a dose of 0.01 pg/kg/day. At dose levels around an order of magnitude above
the background dose, some type of adverse noncancer effect may be expected in an exposed
population. As dose increases, adverse noncancer effects also are expected to increase both in
severity and number of different effects.
G-3
-------
1x10 3
I
a 1x10 5
. -J
1x10
Effect A (Animals)
i ••usu•u
10 100 1,000 10,000
i i Iuiu Nonadverse Biological Effects
a) H
U)
0’ ;
><
UJ
Effect B (Humans)
2
0)
1 4— iii...i
Adverse Effects
ww
0> ___
04.I
ow ___
z
FIGURE G-1. DIOXIN EFFECTS IN RELATION TO EXPOSURE LEVELS (DRAFT)
V MarginL
of
Exposure
Effect C (Humans)
Observed Onset of
/
EPA 1x1O Risk
WHO TDI
c )
(nglkg TEQ)
.1
I
WHO NOAEL
10
.01
100
.1
I
I
-------
APPENDIX H
EXAMPLE OF COMPARATIVE RISKS FOR LUNG CANCER ASSOCIATED WITH
RADON EXPOSURE
U.S. Environmental Protection Agency. (1992) A citizen’s guide to radon (second edition): the guide to
protecting yourself and your family from radon. U.S. Department of Health and Human Services,
Washington, DC, 402-1(92-001.
H-i
-------
BACKGROUND
“A Citizen’s Guide to Radon” was developed for widespread public distribution to alert
citizens to the risks of radon exposure and how to ameliorate those risks. Although this
document was not a risk characterization, the tables are a useful way to illustrate risk in context,
and as such, this type of presentation could be a useful part of a risk characterization summary.
Pages H-3 and H-4, taken from the “Citizen’s Guide,” indicate, in a simple manner, the risk of
lung cancer at different radon exposure levels. The table also puts the risk of lung cancer from
radon exposure in the context of some other risks (e.g., drowning, dying in a car crash) that are
familiar to the average citizen. This table demonstrates how risk can be put “in context” by
comparing the subject risk to another risk that is familiar to the reader. Care must be taken to
select comparison risks that are appropriate and “make sense” relative to the subject risk.
CRITIQUE
The value of this case study lies in the construction of the tables and the easily
understandable manner in which they present information on the lung cancer risk from radon
exposure in the context of other familiar risks. The information may have been made more
useful to the reader if it also presented information on the risk of contracting lung cancer from
smoking alone. Further, the information accompanying the table should distinguish between
voluntary and involuntary risks and should discuss this issue with reference to how the public
perceives risk.
Depending on the audience for this information, it may be more useful to present ranges
of risk rather than point estimates. Presenting ranges may be more appropriate for audiences
with a more technical background or for risk managers.
While the message is simple and clear, the tables should provide some footnotes to help
explain how to interpret the information and to define terms, such as pCiIL.
Tift CASE STUDY
See pp. H-3 and H-4.
H-2
-------
THE RISK OF LIVING WITH RADON
Ra .lon gas decays into radioactive particles that can get trapped in your
lungs when you breathe. As they break down further, these particles
release small bursts of energy. This can damage lung tissue and lead to
lung cancer over the course of your lifetime. Not everyone exposed to
elevated levels of radon will develop lung cancer. And the amount of time
between exposure and the onset of the disease may be many years.
Like other environmental pollutants, there is some uncertainty about
the magnitude of radon health risks. However, we know more about
radon risks than risks from most other cancer-causing substances. This
is because estimates of radon risks are based on studies of cancer in
humans (underground miners). Additional studies on more typical
populations are under way.
Smoking combined with radon is an especially serious health risk.
Stop smoking and lower your radon level to reduce your lung cancer
risk.
Children have been reported to have greater risk than adults of
certain types of cancer from radiation, but there are
currently no conclusive data on whether children
are at greater risk than adults from radon.
Your chances of getting lung cancer from
radon depend mostly on:
• How much radon is in your home
• The amount of time you spend in your home
• Whether you are a smoker or have ever
smoked
Scientists are
more certain
about radon
risks than risks
from most other
cancer-causing
substances
H-3
-------
RADON RISK IF YOU SMOKE
Radon
Level
If 1,000 people who smoked were
exposed to this level over a lifetime..,
The risk of cancer from
radon exposure
compares to...
WHAT TO DO:
Stop smoking and...
2OpCl/L
About 135 people could getlung
cancer
- 100 times the nskof
drowning
Fix yourhome
10 pCl/L
About 71 people could get’luug cancer
- 100 times the risk of
dyinginahomefire
Fix your home
8 pCIJL
About 57 people could get lung cancer
Fix your home
4 pCIJL
2 pCl!L
About 29 people could get lung cancer
About 15 people could get lung cancer
— 100 times the risk of
dying In an airplane crash
-2 times the risk of dying
in a car crash
Fix your home
Consider fixing
between 2 and 4
pCl/L
1.3
pC IIL
0.4
pClfL
About 9 people could get lung cancer
About 3 people could get lung cancer
(Average indoor radon
level)
(Average outdoor radon
level)
(Reducing radon
levels below 2 pCIIL
is difficult)
It’s never
too late to
reduce your
risk of lung
cancer.
Don’t wait to
test and fix
4ote: If you are a former smoker, your risk may be lower.
a radon
problem. RADON RISK IF YOU NEVER SMOKED
you are a
smoker,
stop
smoking.
Radon
Level
If 1,000 people who never smoked
were exposed to this level over a
lifetime..,
The risk of cancer from
radon exposure
compares to...
WHAT TO DO:
20 pCl/L
About 5 people could get lung cancer
The risk of being killed
Fix your home
in a violent crime
10 pCl/L
About 4 people could get lung cancer
Fix your home
8 pCVL
About 3 people could get lung cancer
-10 times the risk of
dying in an airplane crash
Fix your home
Fix your home
4 pCl/L
About 2 people could get lung cancer
The risk of drowning
2 pClJL
About I person could get lung cancer
The risk of dying in a
home fire
Consider fixing
between 2 and 4
pOlL
1.3
Less than person could get lung cancer
(Average indoor radon
pC IfL
level)
(Reducing radon
levels below
0.4
Less than I person could get lung
(Average outdoor radon
2 pCI/L is difficult)
pC l/L
cancer
level)
Note: If you are a former smoker, your risk may be higher.
H-4
-------
APPENDIX I
HAZARD IDENTIFICATION SUMMARY FOR “SUBSTANCE 4”
U.S. Environmental Protection Agency. (1996) Proposed guidelines for carcinogen risk assessment. Prepared
by the Office of Research and Development, Washington, DC. EPAJ600TP-921003C.
I—i
-------
BACKGROU?W
EPA’s Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996) contains
several examples of weight-of-evidence (WOE) evaluation regarding a chemical’s potential for
inducing cancer. These examples are based on available information about real substances and
are selected to illustrate the principles of WOE evaluation and the application of the WOE
classification scheme. These case studies show the interplay of differing lines of evidence in
reaching a conclusion. This appendix presents the WOE evaluation for a chlorinated alkene
solvent called “substance 4.”
CRITIQUE
The major strength of this example is the clarity of the evaluation and the conclusion.
The analysis is organized concisely according to headings that present the WOE argument.
Nontechnical language is used to summarize the WOE which supports the conclusion of the
analysis effectively. The language of the evaluation and conclusion is a particularly noteworthy
example of clarity. The summaries of the human and laboratory animal studies and the
metabolic studies are concise and devoid of unnecessary technical details about study design and
analysis of results. Critical information on the nature of effects seen in laboratory studies and in
humans is described. Important supporting data, as well as limitations of the information, are
presented. Uncertainties associated with exposure and the suitability of animal models for
human effects are described. Further, the possibility of different interpretations of the combined
information is acknowledged.
The weakness of this case study is that the purpose of the analysis is not stated, nor is the
significance of substance 4 to the dry cleaning industry indicated. In addition, many technical
terms are used but not defined or explained. The use of the terms “cohort” and “case-control” to
describe epidemiologic studies and “hepatocellular adenoma” and “carcinoma” to describe the
health effects are examples of where highly technical terms are used but not defined. These
terms may not be understood by many readers. Consequently, some readers may not fully
understand this characterization. While it is desirable to eliminate all technical terms to facilitate
a general understanding, it is not always possible to do so. In such cases, it is useful to define
terms in the text or include a glossary if there is a large number of very technical terms.
It would be useful to describe the public health concern about the presence of this
chemical in the environment, how it is emitted into the environment, and the routes of exposure
that may occur. The description of the metabolism of this chemical, while useful, may be too
technical for many readers. The review of the data and mode of action could be improved and
made more clear and transparent by providing the reason for the analysis and using simpler
1-2
-------
terms, or giving a brief explanation of the terms, where possible. This type of improvement
would create a tone in the review sections that matches the clarity and transparency of the
evaluation and conclusion sections.
THE CASE STUDY
Example 4: “Likely Human Carcinogen “—All Routes/Linear and Nonlinear Extrapolation
Human Data
Substance 4 is a chlorinated alkene solvent. Several cohort studies of dry cleaning and
laundry workers exposed to substance 4 and other solvents reported sign f1cant excesses of
mortality due to cancers of the lung, cervix, esophagus, kidney, bladder, lymphatic and
hematopoietic system, colon, or skin. No sign fi cant cancer risks were observed in a subcohort
of one of these investigations of dry cleaning workers exposed mainly to substance 4. Possible
confounding factors such as smoking, alcohol consumption, or low socioeconomic status were
not considered in the analyses of these studies.
A large case-control study of bladder cancer did not show any clear association with dry
cleaning. Several case-control studies of liver cancer ident fied an increased risk of liver cancer
with occupational exposure to organic solvents. The spec fIc solvents to which workers were
exposed and exposure levels were not ident fled
Animal Data
The potential carcinogenicity of substance 4 has been investigated in two long-term
studies in rats and mice of both sexes by oral administration and inhalation.
Sign jficanr increases in hepatocellular carcinomas were induced in mice of both sexes
treated with substance 4 by oral gavage. No increases in tumor incidence were observed in
treated rats. Limitations in both experiments included control groups smaller than treated
groups, numerous dose adjustments during the study, and early mortality due to treatment-
related nephropathy.
In the inhalation study, there were sign ficantly increased incidences of hepatocellular
adenoma and carcinoma in exposed mice of both sexes. In rats of both sexes, there were
marginally significant increased incidences of mononuclear cell leukemia (MCL) when
compared with concurrent controls. The incidences of MCL in control animals, however, were
higher than historical controls from the conducting laboratory. The tumor finding was also
judged to be biologically sign ifi cant because the time to onset of tumor was decreased and the
disease was more severe in treated than in control animals. Low incidences of renal tubular cell
-------
adenomas or adenocarcinomas were also observed in exposed male rats. The tumor incidences
were not statistically sign fl cant but there was a sign ficant trend.
Other Key Data
Substance 4 has been shown to be readily and rapidly absorbed by inhalation and
ingestion in humans and laboratory animals. Absorption by dermal exposure is slow and
limited Once absorbed, substance 4 is primarily distributed to and accumulated in adipose
tissue and the brain, kidney, and liver. A large percentage of substance 4 is eliminated
unchanged in exhaled air, with urinary excretion of metabolires comprising a much smaller
percentage. The absorption and distribution profiles of substance 4 are similar across species
including humans.
Two major metabolites (trichioroacetic acid ( rCA), and trichloroethanol), which are
formed by a P-450-dependent mixed-function oxidase enzyme system, have been identified in all
studied species, including humans. There is suggestive evidence for the formation of an epoxide
intermediate based on the detection of two other metabolires (oxalic acid and trichioroacetyl
amide). In addition to oxidative metabolism, substance 4 also undergoes conjugation with
glutathione. Further metabolism by renal beta-lyases could lead to two minor active metabolites
(trichiorovinyl thiol and dichiorothiokenre).
Toxicokinetic studies have shown that the enzymes responsible for the metabolism of
substance 4 can be saturated at high exposures. The glutarhione pathway was found to be a
minor pathway at low doses, but more prevalent following saturation of the cytochrome P-450
pathway. Comparative in vitro studies indicate that mice have the greater capacity to metabolize
to TCA than rats and humans. Inhalation studies also indicate saturation of oxidative
metabolism of substance 4, which occurs at higher dose levels in mice than in rats and humans.
Based on these findings, it has been postulated that the species d fferences in the carcinogenicity
of substance 4 between rats and mice may be related to the djfferences in the metabolism to TCA
and glutarhione conjugates.
Substance 4 is a member of the class of chlorinated organics that often cause liver and
kidney toxicity and carcinogenesis in rodents. Like many chlorinated organics, substance 4 itself
does not appear to be mutagenic. Substance 4 was generally negative in in vitro bacterial
systems and in vivo mammalian systems. However, a minor metabolite formed in the kidney by
the glutathione conjugation pathway has been found to be a strong mutagen.
The mechanisms of induced carcinogenic effects of substance 4 in rats and mice are not
completely understood It has been postulated that mouse liver carcinogenesis is related to liver
peroxisomalprol feration and toxicity of the metabolite TCA. Information on whether or not
1-4
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TCA induces peroxisomal proliferation in humans is not definitive. The induced renal tumors in
male rats may be related either to kidney toxicity or the activity of a muragenic metabolite. The
mechanisms of increases in MCL in rats are not known.
Evaluation
Available epidemiologic studies, taken together, provide suggestive evidence of a
possible causal association between exposure to substance 4 and cancer incidence in the laundry
and dry cleaning industries. This is based on consistent findings of elevated cancer risks in
several studies of different populations of dry cleaning and laundry workers. However, each
individual study is compromised by a number of study deficiencies including small numbers of
cancers, confounding exposure to other solvents, and poor exposure characterization. Others
may interpret these findings collectively as inconclusive.
There is considerable evidence that substance 4 is carcinogenic to laboratory animals. It
induces tumors in mice of both sexes by oral and inhalation exposure and in rats of both sexes
via inhalation. However, due to incomplete understanding of the mode of mechanism of action,
the predictivity of animal responses to humans is uncertain.
Animal data of structurally related compounds showing common target organs of toxicity
and carcinogenic effects (but lack of mutagenic effects) provide additional support for the
carcinogenicity of substance 4. Comparative toxicokinetic and metabolism information indicates
that the mouse may be more susceptible to liver carcinogenesis than rats and humans. This may
indicate d fferences of the degree and extent of carcinogenic responses, but does not detract from
the qualitative weight of evidence of human carcinogeni city. The toxicokinetic information also
indicates that oral and inhalation are the major routes of human exposure.
Conclusion
Substance 4 is likely to be carcinogenic to humans by all routes of exposure. The weight
of evidence of human carcinogenicity is based on: (a) demonstrated evidence of carcinogenicity
in two rodent species of both sexes via two relevant routes of human exposure; (b)the
substance ‘s similarity in structure to other chlorinated organics that are known to cause liver
and kidney toxicity and carcinogenesis in rodents; (c) suggestive evidence of a possible
association between exposure to the substance in the laundry and dry cleaning industries and
increased cancer incidence; and (d) human and animal data indicating that the substance is
absorbed by all routes of exposure.
In comparison with other agents designated as likely carcinogens, the overall weight of
evidence places it in the lower end of the grouping. This is because there is a lack of good
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evidence that observed excess cancer risk in exposed workers is due solely to substance 4.
Moreover, there is considerable scientific uncertainty about the human sigi4flcance of certain
rodent tumors associated with substance 4 and related compounds. In this case, the human
relevance of the animal evidence of carcinogenicity relies on the default assumption.
Overall, there is not enough evidence to give high confidence in a conclusion about any
single mode of action; it appears that more than one is plausible in different rodent tissues.
Nevertheless, the lack of mutagenicity of substance 4 and its genera! growth-promoting effect on
high background tumors as well as its toxicity toward mouse liver and rat kidney tissue support
the view that the predominant mode is growth-promoting rather than mutagenic. A mutagenic
contribution to carcinogenicity due to a metabolite cannot be ruled out. The dose response
assessment shoul4 therefore, adopt both default approaches, nonlinear and linear
extrapolations. The latter approach is very conservative since it likely overestimates risk at low
doses in this case, and is primarily useful for screening analyses.
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APPENDIX J
FOR DIOXJNLIKE COMPOUT4DS, SUMMARY OF EXPOSURE FINDINGS AND
UNCERTAINTIES FOR NORTH AMERICA
U.S. Environmental Protection Agency. (1996) Draft risk characterization for estimating exposure to
dioxinlike compounds. Prepared by the Office of Research and Development, Washington, DC.
EPAJ600/6-881005.
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BACKGROUND
Appendix J provides a table and accompanying text used to summarize and display some
of the results of NCEA’s Dioxin Risk Assessment. This chart originally was developed for the
risk characterization but was moved to the executive summary of the risk assessment because it
was too detailed and, when combined with other tables, too long. This type of table still
represents a useful way to summarize and present large amounts of information and may be
appropriate for some risk characterizations.
This particular tabular format provides an example of a clear, concise, easily
understandable way to identify the key findings and link them to both the associated scientific
support and the area of uncertainty. Accompanying the table, additional text provides a more
detailed discussion of the supporting data and underlying uncertainties and how these affect the
assessment results. This additional text is provided for each “Finding” listed in the table.
Appendix J provides an example of the kinds of information that can be included in thi
additional text for finding 1 of the table.
CRITIQUE
The strengths of this example are that it concisely and clearly summarizes major findings
and associated support and uncertainties. The literature citations add transparency (i.e., guides
reader back to literature).
A weakness of this example is that it may be too detailed for risk characterization. The
literature citations may not be relevant to many readers of the risk characterization, and this
weakens the readability of the document. It is unclear if the range of estimated tissue levels
(finding 8) reflects uncertainty in the assessment or variability within the population. It may be
helpful to clarify in the text accompanying this table that the uncertainty column is not intended
to address the issue of variability.
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THE CASE STUDY
Table J-1. For dioxinlike compounds, summary of exposure findings and uncertainties for
North America (all concentrations on lipid basis)
Finding
Support
Uncertainty
1. General
population
tissue levels for
CDD/CDFs
average about
20-40 ppt TEQ
* 1987 NHATS (adipose tissue); 28 ppt TEQ, n=865
(US)
* Patterson et al., 1994 (adipose tissue); 26 ppt TEQ, n=4
(US)
* Schecter, 1991 (adipose tissue); 24 ppt TEQ, n15
(US); 36 ppt TEQ, n=46 (Canada)
* Schecter et aL, 1994 (blood); 41 ppt TEQ, n= 100 (uS)
* Cole et al., 1995 (blood); 21 to 41 ppt TEQ, n=132
(Canada)
* Schecter et aL, 1989a (human milk); 17 ppt TEQ, n=42
(US)
* Mean TEQ based on all studies combined: 28 ppt
* Standard deviation for all studies combined: 7 ppt
Representativeness of general
population
2. Tissue levels
of PCBs average
10-30 ppt TEQ,
about two-thirds
of CDD/CDF
TEQs
* Patterson et al., 1994 (adipose tissue); 14 ppt TEQ,
n=:28 (US)
* Schecter et al., 1989c (adipose tissue); 12 ppt TEQ, n=3
(US)
* Williams and LeBel, 1991 (adipose tissue); 28 ppt
TEQ, n ’=62 (Canada)
* Patterson et al., 1994 (blood); 14 ppt TEQ, n=240 (US)
* Schecter et al., 1993 (blood); 10 ppt TEQ, n=5 (US)
* Cole et al., 1995 (blood); 8 ppt TEQ, n=132 (Canada)
* Dewailly et aL, 1994 (blood); 11 ppt TEQ, n=I0-57
(Canada)
* Sheet al., 1995 (human milk); 16 ppt TEQ, n=12 (US)
* Hong et al., 1992 (human milk); 13 ppt TEQ, n=5 (US)
* Dewailly et al., 1994 (human milk); 13 ppt TEQ, n=96
(Canada)
* Total TEQ based on all studies combined: 21 ppt
* Representativeness of general
population
* Small sample size
* Support for PCB TEFs
* Analytical difficulty with PCBs
3. PCBs raise
average tissue
levels to 30-70
ppt TEQ.
* Derived from above conclusions
* Same as above
J-3
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J-1. For dioirnlike compounds, summary of exposure findings and uncertainties for
North America (all concentrations on lipid basis) (continued)
4. Intake of
CDD/CDF in
genera!
population
averages about
100 pg TEQ/day
PK modeling
*Djetb J U.S. studies
* Diet-based European studies
* Steady-state and half-life assumptions
in PK model
* Food levels based on few samples
* Effects of food preparation and cooking
5. PCBs raise
general
population
exposure to 170
pg TEQ/day
* Extrapolation based on human tissue data
* Diet-based U.S. studies
* Diet-based U.K. study (MAFF, 1996)
* Steady-state and half-life assumptions
in PK model
* Food levels based on few samples
* Effects of food preparation and cooking
* Support for PCB TEFs
6. Tissue levels
of dioxin-like
compounds
generally
increase with
age
* Low levels CDD/Fs in fetuses and infants (Schecter et
a!., 1995; Beck eta!., 1994)
* Age dependency shown in adipose CDD/F data from
1987 NHATS (U.S. EPA, 1991)
* Age dependency shown for PCBs in blood data from
Germany (Papke eta!., 1996)
* No data from individuals over 80 years
old
7. General
population
CDD/F tissues
levels are higher
in the United
States (and other
industrialized
countries) than
in less
industrialized
countries.
* Schecter, 1994
* No data for less industrialized countries
outside Asia
8. Range of
tissue levels and
general
population
exposures could
extend over 3
times higher
than means
* Patterson eta!., 1994
*S jsfjeal modeling
* 1987 NHATS
* Representativeness of general
population
* Small sample size
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Finding #1. The average CDD/CDF tissue level for the general adult US. population is
probably within the range of 20 to 40ppt rEQ on a lipid basis. The midpoint of this range, 30
ppt, is a reasonable estimate of the average. (Cross-Reference: Volume II, Chapter 6)
As discussed below all available human tissue studies have uncertainties that prevent a
precise, statistically-based estimate of the national mean level of CDD/F. The means of the
individual studies range from 20 to 40 ppt TEQ. This relatively narrow range produced from a
wide variety of studies using different approaches, suggests that the true, national, adult mean is
within this range. Averaging all data across all studies listed below yielded a mean of29 ppt
TEQ. Further support for these conclusions regarding CDD/CDF human tissue levels are based
on the following:
• Three US. adipose studies and one Canadian study. The 1987 NHATS analysis of 48
adipose tissue samples composired from 865 samples resulted in a mean TEQ of28
ppt. Patterson et a!. (1994) reported a mean TEQ of26ppt (n=4). Schecter (1991)
reported a mean of 24 ppt TEQ (n 15). Schecter (1991) reported a mean TEQ of36
pptfor Canada (n=46).
• Two North American blood studies. Schecter et a!. (1994) reported a mean TEQ of
41 ppt (n100, composited into one sample) and Cole et al. (1995) reported TEQs
rangingfrom 20.8 ppt to 41.2 ppt (n=132, composited into 14 samples).
• One North American human milk study. Schecter et al. (1989a) reported a mean
TEQ ofl6.5ppt on a lipid basis (n=42).
• Data from other industrialized countries. Body-burden levels among industrialized
nations are reasonably similar. Schecter (1991) reported TEQ levels in adipose
tissue of69ppt (n=4)for Germany and 38ppt (n=6)for Japan. Beck et al. (1994)
reported a TEQ level of 56 ppt for adipose tissue in Germany (n=20), and Gonzalez
et al. (n.d.) reported a mean TEQ of 41.8 ppt for adipose tissue in Spain (n1 7).
Schecter et al. (1992b) reported the following TEQ levels in blood: Germany - 42ppt
(n=102), and Japan - 31 ppt (pool—5O-100). The following TEQ levels in human
milk were reported. Germany - 27ppt (n185), Japan - 26ppt (2 pools of 3 samples
each) (Schecter et a!., 1989a, 1989b), Belgium - 34ppt (n =9) (Van Cleuvenbergen et
al., 1994), the United Kingdom - 33ppt (n80) (Startin eta!., 1989, Duarte-
Davidson et al., 1992), Germany - 3Oppt (n112) (Beck et al., 1994), The
Netherlands - 31 ppt (n200) (Tuinstra et a!., 1994) and 28ppt (n=35) (Pluim et al.,
1994b), and New Zealand - 1 7ppt (n=37) (Bates et a!., 1994).
J-5
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Except for NHATS, the number ofpeople in these studies is relatively small and participants
were not selected to be representative of the general adult population. Biases may have also
been present in NHATS. Thus, it is uncertain whether these data are representative of the
general population.
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APPENDIX K
CHARACTERIZATION OF HUMAN HEALTH AND WILDLIFE RISKS FROM
ANTHROPOGENIC MERCURY EMISSIONS IN THE UNITED STATES
U.S. Environmental Protection Agency. (1996) Mercury study report to Congress, vol. VI, executive
summary. Science Advisory Board review draft, Washington, DC. EPAI4S2IR-961001a.
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BACKGROUND
EPA’s Characterization of Human Health and Wildlife Risks from Anthropogenic
Mercury Emissions in the United States (U.S. EPA, 1996) is a report to the U.S. Congress. It is a
good example of a complete risk characterization and the component analyses that support it. Of
particular import is the analysis of both human health and ecological issues in this document.
CRITIQUE
This case study is a good example of a complete risk characterization. Its major strengths
are the clear, concise discussion of the evidence and the organization of the evidence to form an
overall conclusion. It illustrates how a large amount of information and different approaches
required in the exposure assessment and the risk analysis can be summarized efficiently and
effectively. The conclusion illustrates good ways to organize conclusions and describe data
limitations and uncertainties in the component analyses.
Its major weakness is that all of the ingredients of the risk characterization are not
contained in one location in this report.
Overall, this case study aptly summarizes the key features of public health and
environmental concern about mercury. Technical language is used appropriately without undue
use of jargon or acronyms. Tenms are defined adequately, and the conclusions of the risk
analysis are described in the context of data limitations and uncertainties. Conclusions are set
apart and clearly stated in understandable language.
The term “risk characterization” is used as the heading for Volume VI of this report. As
such, there is no “summary” entitled risk characterization as defined by the Administrator’s 1995
policy memorandum and this NCEA risk characterization guidance document. This makes it
difficult for the reader to find the location of the risk characterization. The Executive Summary,
Volume I, contains a brief and incomplete risk characterization. However, the Executive
Summary of Volume VI contains the essential ingredients of a risk characterization.
Risk Characterization and Dose-Response Summaries: Clarity and Transparency
The description of dose is technical but clear and concise. Neither the rationale for
selection of particular models nor the approach used for calculations is contained in the
summary. The models are defined and the results are summarized. The reader is referred to the
particular volume where the modeling analyses were done for more information. The discussion
concerning biological responses to mercury is clear and concise in the summary, clearly noting
exposure pathways and the results of acute and chronic exposure to both humans and animals.
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Risk Characterization and Hazard Identification Summaries: Clarity, Transparency, and
Reasonableness
The hazard identification describes the different species of mercury, their sources, and
transport mechanisms in a clear and concise manner. The concern about the potential and extent
of adverse health effects is well described with indications of both data limitations and
uncertainty.
Risk Characterization and Exposure Assessment Summaries: Clarity and Transparency
Exposure estimates for humans and target animal species derived from models are
described in a clear and concise manner. Limitations and uncertainties concerning exposure are
noted with the consequences to rendering conclusions about mercury exposure.
Exposure Assessment Summary: Clarity, Transparency, and Reasonableness
The discussion about exposure to mercury is complete with emphasis on the sources and
pathways of concern. Concern about the consequences of exposure to population segments of
concern and to animal species is described succinctly.
THE CASE STUDY
EXECUTIVE SUMMARY
Section 112(n) (1) (B) of the Clean Air Act (CAA), as amended in 1990, requires the US.
Environmental Protection Agency (U S. EPA) to submit a study on atmospheric mercury
emissions to Congress. The sources of emissions that must be studied include electric utility
steam generating units, municipal waste combustion units and other sources, including area
sources. Congress directed that the Study evaluate many aspects of mercury emissions,
including the rate and mass of emissions, health and environmental effects, technologies to
control such emissions and the costs of such controls.
Volume Vlpresents the risk characterization for mercury emitted to the environment from
anthropogenic sources. Risk characterization is the last step of the risk assessment process as
originally described by the NationalAcademy of Sciences (NAS, 1983) and adopted by US. EPA
(US. EPA, 1994, 1992). This step evaluates assessments of human health and ecological effects,
identifies human subpopulations or ecological species exposed to mercury, assesses exposures
from mult4ile environmental media and describes the uncertainty and variability in these
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assessments. In addition to the NAS (1983) source, guidance from the recent report Science and
Judgment in Risk Assessment (NAS/NRC 1994) andfrom the Policy for Risk Characterization at
the US. Environmental Protection Agency (issued in March, 1995, by the Administrator of US.
EPA) were also followed The latter document reaffirmed the principles and guidance found in
the Agency’s 1992 Policy Guidance on Risk Characterization for Risk Managers and Risk
Assessors.
Volume Vt of this Report summarizes and integrates the exposure and effects information
for mercury presented in Volumes III, IV and V into an overall risk characterization for humans
and wild! fe. First, technical characterizations of the human and wildlife health effects of
mercury are described, with accompanying discussion of uncertainty in the quantitative risk
estimates. In Chapter 4 a technical characterization of the exposure of selected human and
wildl fe populations to mercury ispresentea again accompanied by a discussion of uncertainty.
Also in Chapter 4 are estimates of the size of the wildl fe and human populations that are
exposed to methyl mercury. Literature reports on mercury tissue levels in piscivorous wildlife
species and the size of selected wildl [ e populations are also presented. An overall
characterization of the risk is presented in Chapter 5, raking two approaches. In the first, RiD
values and lowest adverse effect levels (LOAELs) for wild! ife and humans are used to estimate
fish tissue concentrations of mercury that are below the risk level for selected piscivorous
wild! fe species and hypothetical human populations. Chapter 5 concludes with a comparison of
recommendations from various groups with an interest in mercury.
During episodes of methyl mercury poisoning, both human subpopularions and wildl fe
species have been affected by mercury po isoning. Clinical poisoning of humans from methyl
mercwy occurred in epidemics in Iraq (Ba/dr eta!., 1973, Amin-Zald eta!., 1979) and Japan
(Harada, 1968, 1977, 1995), and smaller outbreaks have occurred in additional populations. In
the middle decades of this centwy, consumption of grain treated with mercury fungicides
produced severe andfrequent poisoning among wildl fe species (Borg et aL, 1979).
Consequently, in the risk characterization both human subpopulations and wildl fe species were
considered
As a chemical element mercury cannot be created or destroyed The same amount has
existed on the planet since the earth was formed Mercury, however, can cycle in the
environment as a result of both natural and anrhropogenic activities. Both measured data and
the results from global modeling have led to the understanding that anthropogenic mercury
emissions equal or exceed those from natural sources (such as volcanic activity, volatilization
from the oceans, etc.). Human and natural activity has the overall effect of making more
mercury biologically available. Emissions of mercury from human activity are thought to.
K -4
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contribute from between 50 to 75 of the current total annual input of mercury to the atmosphere.
There are data and modeling results that indicate that the amount of mercumy mobilized and
released into the biosphere has increased since the beginning of the industrial age.
The Inventory ofAnthropogenic Mercury Emissions in the United States (Volume II
of this Report) comprehensively examined mercury sources to the extent supported by available
data. The inventory included many manufacturing processes, a variety of combustion sources
(including sewage sludge burning and crematories) and miscellaneous sources (such as
laboratory use, electrical lamp breakage and dental amalgam preparation). The exposure
assessment in Volume III of this Report focussed on those source categories having sign /Icant
emissions in the aggregate, sources with the potential for individual facilities to have a localized
impact on the environment and sources for which there were sufficient data to support an
intelligent use of exposure models. The sources were electric utility boilers, municipal waste
incineration, medical waste incineration, chior-alkali plants, primary lead smelters and copper
smelters.
In this Mercury Study Report to Congress, three species of mercury were considered:
elemental (Hg 0 ), inorganic mercury or mercuric mercury (Hg+ 2 ) and methyl mercury. Data in
both humans and experimental animals show that all three forms of mercury evaluated in this
Report (elemental, inorganic and methyl mercury) can produce adverse health effects. Except
for people whose occupation brings them in contact with elemental mercury, humans will be
exposed primarily to methyl mercury; that exposure will be largely through consumption offish.
Methyl mercury can produce a variety of adverse effects, depending on the dose and time
of exposure. To present a comprehensive estimation of methyl mercury effects in humans, many
d fferent health endpoints were evaluated by US. EPA using established Risk Assessment
Guidelines. Methyl mercury has been shown to cause tumors in mice at doses that produce
severe non-cancer toxicity. The data are limited but lead to the conclusion that low dose
exposures to methyl mercury are not likely to cause cancer in humans. Based on data on effects
related to mutation formation (changes in DNA), there is concern that methyl mercury could
increase frequencies of mutations in human eggs and sperm. These data were not sufficient,
however, to permit estimating the amount of methyl mercury that would cause a measurable
mutagenic effect in a human population. Data in both humans and animals are sufficient to
judge methyl mercury to be a human developmental toxicant; that is, a material that would
produce effects during the period of human development (from conception to sexual maturity).
The developmental deficits noted have been associated with nervous system damage, or
neurotoxicity. Neurotoxicity is also the effect of concern when adults are exposed to methyl
mercury, but developmental delays are the critical effect.
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Data were sufficient for calculation of quantitative estimates for general systemic toxicity
for elemental mercury (reference concentration, or RfC, of 3. Oxi 0 mg/rn 3 ), inorganic mercury
(RiD of 3xl(F mg/kg-day) and methyl mercury (RID of 1x10 4 mg/kg-day). These estimates seem
to be very close in magnitude. The endpoints for the methyl mercury and elemental mercury
estimates are similar: neurologic deficits. It should be noted, however, that the endpoint for
methyl mercury was the observation of developmental delays in children exposed in utero and
the endpoint for elemental mercury was measurement of sensitive indicators of neurologic
damage in adults. There may be route-spec y’Ic effects on dose response that have not been
investigated The endpoint for inorganic mercury was measurement of changes leading to
immune-mediated kidney damage in rats. There is evidence of kidney damage in mercury-
exposed humans. The inorganic mercury RID has a relatively large uncertainty factor (1000 due
to lack of a NOAEL, lack of a life-time study and extrapolation from animal data to humans);
thus, the RID may not be strictly comparable to the methyl mercury RID in terms of magnitude.
A previous RID for methyl mercury of 3x1 (74 mg/kg-day had been calculated by U S. EPA
based on observation ofparesthesia in adults who had consumed contaminated seed grain in
Iraq in the early 1970s. Both a quantitative uncertainty analysis and a consideration of
reporting errors in adult paresthesia have led to the conclusion that this is not the most reliable
endpoint for use in a quantitative estimate of risk Concern had been raised as to whether the
RID based on effects in adults was protective of developmental effects. A new RID based on
application of a benchmark approach to developmental neurotoxicity in children exposed in
utero is within a numerical factor of three of the older estimate based on observation in adults.
A quantitative uncertainly analysis of this RID indicates that it is likely to be protective for all
developmental endpoints.
The exposure assessment made use of computer-based models for long range transport of
mercury (RELMAP) and impact of mercury emissions near the point of emissions (COMPDEP
and IEM2). Data on measured mercury levels in various environmental media were not
sufficient for a nationwide survey of mercwy but were used for comparison with the modeled
estimates. For RELMAP results, measured data corroborate modeled estimates and geographic
trends. Exposure assessments were conducted for nine different hypothetical human receptors in
several settings (near a lake, urban, etc.). The assessment of exposure pathways consequent to
emissions of mercury from anthropogenic sources indicates that the major exposure to both
humans and wildljfe is to methyl mercury in fish.
The broad ecosystem effects of mercury are not completely understood No applicable
studies of the effects of mercury on intact ecosystems were found Consequently,
characterization of risk for non-human species did not attempt to quantify effects of mercury on
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ecosystems, communities, or species diversity. The characterization focused on (1) quantities of
mercury that adversely affect the health of sensitive subpopulations of wildl?fe species; and (2)
the co-location of these populations with areas of elevated mercury exposure secondary to
ambient, anthropogenic emissions of methyl mercury. To this end wildlife criteria (WC) were
calculated for three piscivorous (i.e., fish-eating) birds and two mammals. The WC is a mercury
level in water that is expected to be without harm for the species. The WC considers the
bioaccumulation of mercury in the large and small fish eaten by the mammals or birds. WC
calculation used bioaccumulation factors (BAF) to estimate mercury tissue level for trophic level
3 and trophic level 4 fish, given a concentration of mercury in the water column. The BAFs were
derived by application of two (BAF 3 ) or three (BAF 4 ) methodologies and field data on fish and
water mercury concentrations; derivation of the BAFs and the quantitative uncertainty analysis
are described in Volume V The effects data for mammals were from a short-term study of
neurotoxicity in mink The data for piscivorous birds were from a three-generation study in
mallard ducks. The WC are these: mink, 415 pg mercury/L water; otter, 278 pg/L; kingfisher,
193 j g/L; osprey, 483 pg/L; bald eagle 538 pg/L.
There is uncertainty and variability associated with each WC. These include lack of
long-term studies for mammals, lack of a no adverse effect level (NOAEL) for birds, and
extrapolation from one species to another. It is not known if the species selected for WC
development are the most sensitive or appropriate species, nor ifprotecting individual animals
or species will guarantee protection of their ecosystem from effects of mercury. There are
uncertainties and expected variability in the BAF; it was the subject of a quantitative uncertainty
analysis.
Sizes ofpopulations potentially at risk for methyl mercury exposure were estimatedfor
both humans and wildlife species. These were compared to measured levels of mercury
contamination. Women of child-bearing age are one group of concern, because methyl mercury
is a developmental toxicant. Even short-term exposures to methyl mercury could adversely affect
development because of the sensitivity of the developmental process. Moreover methyl mercury
persists in tissues; dietary intakes just prior to pregnancy may be of concern in addition to
methyl mercury intakes during pregnancy. Another cause for concern is that using estimates on
the number ofpregnant women in the age group 15 through 44 years, 9.5% of women are
pregnant in any given year; thus the size of the impacted population is not negligible. The
number of women of child-bearing age was determined in the 1990 US. Census. This census
estimated that the total female population ages 15 through 44 years was 58,222,000 in the 48
contiguous states.
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Data on fish consumption for a general population of women in the United States were
developed from the United States Department ofAgriculture ‘s Continuing Surveys of Individual
Food Consumption for the period 1989-1991 (CSFH 89/91). Cross-sectional data on food
consumption collected over a three year period were used to estimate longer-term dietary
patterns. CSFII 89/91 reported that 30.5% of women ages 15 through 44 years consume fish at
least once in a 3-day period This does not mean that the other 69.1% of women avoidfish
consistently; rather that fish did not appear as a dietary item during the three days during which
the food diaries were kept. There are 17,371,000 women who are fish consumers. If the 95th
percentile is determined to be “high end” and as 9.5% of the female population from ages 15
through 44 years are pregnant in a gn’en year, the number ofpregnant, “high end”fish
consumers in the contiguous United States numbers about 84,300. Fish consumption, measured
mercury in fish and the human RJD and LOAEL are compared graphically in Chapter 4.
Comparisons are made for the general US. population, women of child-bearing age and
children 15 years and younger.
Additional data on fish consumption from a longitudinal food survey were also analyzed.
The National Purchase Diary, Inc. surveyed families in 1973 and 1974 and found that 94% of
persons reported consuming fish at least once during a month long period The top one percent
of consumers ingesredfish and shellfish at levels over 100 grams per day. Using these data on
fish consumption the number of maternal-fetal pairs at risk in any given year was estimated to be
in excess of5O, 000 women and developing infants.
A quantitative assessment of risk of methyl mercury exposure from contaminated fish has
been performedfor three hypothetical humans receptors andfive wildlife species. Estimated
LOAELs and RJDs were combined with modeledfish mercury levels and amounts offish
consumed; the result was a level ofmercwy in fish that f consumed on a daily basis would result
in exposure to the RID or LOAEL. These numbers are presented for interspecies comparison; if
health endpoints are considered equivalent, then the kingfisher is the most impacted by mercury
contamination inftslt There are a number of uncertainties in this analysis, including the lack of
comparability in terms of sensitivity (or, conversely, adversity) of the endpoints used in the
effects assessments.
Conclusions
The following conclusions are presented in approximate order of degree of certainty in
the conclusion, based on the quality of the underlying database. The conclusions
pro gress from those with greater certainty to those with lesser certainty .
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• There is a plausible link between methyl mercuiy concentrations in freshwater fish
and anthropogenic mercury emissions. The degree to which this linkage occurs
cannot be estimated quantitatively at this time.
• Among humans and wildlife that consume fish, methyl mercury is the predominant
chemical species contributing to mercury exposure.
• Methyl mercury is known to cause neurotoxic effects in humans via the food chain.
• The human RiD for methyl mercury is calculated to be 1 x 1 0 mg/kg body
weight/day. While there is uncertainty in this value, there are data and quantitative
analyses of health endpoints that corroborate and support a reference dose within a
range of an order of magnitude. A quantitative uncertainty analysis indicates that
the human RiD based on observation of developmental neurotoxicity in children
exposed to methyl mercury in utero is likely to be protective of human health.
• The RID is a confident estimate (within a factor of 10) of a level of exposure without
adverse effects on those human health endpoints measured in the Iraqi population
exposed to methyl mercury from grain. These included a variety of developmental
neurotoxic signs and symptoms. The human RID is for ingested methyl mercury; no
distinction was made regarding the food or other media serving as the ingestion
vehicle.
• US. EPA calculates that members of the US. population ingest methyl mercury
through the consumption offish at quantities of about 10 times the human reference
dose. This amount of methyl mercury is equivalent to the benchmark dose used in the
calculation of the reference dose; the benchmark dose was taken to be an amount
equivalent to the NOAEL. The NOAEL was an ingested amount of]. lug per kg body
weight per day. Consumption of mercury equivalent to the NOAEL is predicted to be
without harm for the majority of a population. Individual risks cannot be determined
from the available data.
• Prediction of risk cannot be made for ingestion of methyl mercury above the
benchmark dose given the currently available data in humans.
• Concentrations of mercury in the tissues of wildlife species have been reported at
levels associated with adverse health effects in laboratory studies in the same
species.
• Dietary survey databased on short-term, cross-sectional sampling periods indicate
that approximately 30 percent of the general US. population consumes fish at least
once during a three-day period. Among this group offish consumers, roughly 50
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percent are predicted to consume methyl mercury at the RfD. Consuming methyl
mercury at levels equal to the RiD is equated to be without harm.
• Based on longer-term data that recordedfish consumption for one-month periods,
approximately 94% of the population consumedfish at least once during that period.
• Using both the longitudinal and cross-sectional survey data, it is estimated that 1 to
2 percent of women of child-bearing age consistently consume fish and shellfish at
intakes of 100 grams per day or greater. Whether or not methyl mercury intakes are
elevated above the NOAEL depends on the concentration of methyl mercury in the
fish and shellfish consumed.
• US. EPA estimates that approximately one-third offish and shellfish consumed are
from freshwarer/estuarine habitats that may be affected by local sources of mercury.
• Case reports in the literature document that sick and/or dying animals and birds with
seriously elevated tissue mercury concentrations have been found in the wild. These
wildlife have mercury concentrations elevated to a level documented in laboratory
studies to produce adverse effects in these species. For a spec /Ic case report
concurrent exposure to other sources of ill health cannot be excluded.
• Modeled estimates of mercury concentration in fish around hypothetical mercury
emissions sources predict exposures at the wildlife WC. The wildlife WC, like the
human RfD, is predicted to be a safe dose over a lifetime. It should be notea
however, that the wildlife effects used as the basis for the WC are gross clinical
manifestations or death. Expression of subtle adverse effects at these doses cannot
be excluded
• Data are not sufficient for calculation of separate reference doses for children, in
utero exposure and the aged.
• Comparisons of dose-response and exposure estimates through the consumption of
fish indicate that certain species ofpiscivorous wildljfe are more exposed on a per
kilogram body weight basis than are humans. The implications for wildlife health
are uncertain.
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APPENDIX L
WORKERS, EMFs, AND CANCER
Harvard Center for Risk Analysis. (1995) Workers, EMFs, and cancer. Issues of Risk in Perspective,
Volume 3, Number 2.
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BACKGROUND
Excerpts have been taken from the Harvard Center for Risk Analysis (1995) to illustrate
how complex risk assessment information can be summarized and expressed in relatively simple,
understandable terms.
The first excerpt summarizes the evidence of leukemia in humans from exposure to
electromagnetic fields (EMFs). This excerpt also indicates the importance and public interest of
this issue, based on the amount of money being spent on research and the fact that many stories
have appeared in the media. This type of summary could be appropriate as part of a hazard
identification summary and/or risk characterization summary. The second excerpt provides a
concise way of explaining why it is important to study occupational exposures to EMFs to
determine if this could be a risk factor for children. Again, this type of summary could be
appropriate as part of a hazard identification summary and/or risk characterization summary.
The third excerpt provides a clear, simple explanation of two terms (i.e., relative risk and 95%
confidence interval) used routinely in statistical analyses and risk assessments. Excerpt 4
provides a simple, easily understood summary of how close on the horizon better information
lies in order to reduce the uncertainty in the risk evaluation. Excerpt 5 provides a clear, simple
description of some critical areas of uncertainty in the measurement of EMFs. This type of
synopsis could be appropriate for an exposure assessment characterization and summary.
CRITIQUE
The excerpts presented in this appendix are written in a clear, reasonable, and transparent
manner. Although many terms have been simplified and explained, there are still several terms,
such as “tumor promotion hypotheses” and “effects on cell signaling,” that need to be defined.
Additionally, the explanation of the 95% confidence interval needs to be broadened to include a
discussion of how confident the authors are in the data and the findings. The checklists
presented in chapter 6 of this guidance document recommend constructing a table, whenever
possible, to assist in the communication of what is known and what is uncertain in the risk
characterization and risk assessment document. Such a table, if added to the Harvard (1995)
assessment, would improve communication of information and would add value to the
characterizations. Based on the excerpts presented, a table, such as the following, might be
useful:
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Known
Uncertain
Numerous stories in the print and electronic media have
highlighted electric and magnetic fields (EMFs) as a possible
cause of human cancer.
There are significant differences of opinion on this issue
(EMFs as a cause of cancer) among responsible scientists.
In the epidemiologic literature on EMFs and cancer, many
types of cancers are studied, but leukemias are the most
frequently reported disease.
The available human data on EMPs and leukemia are too
inconsistent to establish a cause-and-effect relationship, but
there is enough evidence of association to raise concern.
There is some evidence that nonionizing radiation (including
very low intensity EMFs) can affect cells, but studies using
whole animals have indicated few adverse effects of long-
term exposure to EMFs.
If EMFs in the workplace do cause modest increases in the
risks of leukemia, brain cancer, andlor breast cancer, it is
unlikely that epidemiology alone will be able to establish
such effects.
Not only is there imprecision in the technology currently
used to assess EMFs in the field, there is also disagreement
over what constitutes exposure and what elements the
exposure monitors should be measuring.
THE CASE STUDY
Excerpt 1
Over the last year, numerous stories in the print and electronic media have highlighted
electric and magnetic fields (EMFs) as a possible cause of human cancer. Readers may
recall reports about three spec fIc types of cancer: leukemia, brain cancer and breast
cancer. These news stories followed publication of large-scale, epidemiologic studies of
workers exposed to EMFs on the job. While there are sign ficanr differences of opinion
on this issue [ the overall weight of evidence about EMFs and human cancer], among
responsible scientists,.., there are also important points of agreement about what is
known and not known, and about what can be learned through future research.
Interest in the relationship between EMF and cancer was triggered in 1979 when an
association was reported between utility wire configurations outside homes and the
occurrence of childhood leukemia. This report, supported by some later reports,
generated considerable scientific debate and public concern. Since then, numerous
laboratory and human studies have been launched to study the possible health effects of
low level EMFs, many of which are still in progress today. It has been estimated that the
public and private sectors in the US. are now spending $25 to $30 million per year on
research into EMFs and human health.
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Overall, the available human data on EMF’s and leukemia are too inconsistent to
establish a cause-and-effect relationship, but there is enough evidence of association to
raise concern. There is relatively little biological data to support the hypothesis that
EMFs, by themselves, can cause leukemia. Some research investigators believe that the
measured levels of EMF energy absorbed by the human body in household and
occupational settings are far below what would be required to disrupt chemical bonds in
the DNA, as would be required to cause leukemia or other cancers. Large-scale animal
tests of EMFs are underway, as well as testing of tumor promotion hypotheses and effects
on cell signaling, but there is no strong basis for believing that experimentalists will be
able to resolve this issue in the near future.
Excerpt 2
If EMFs in homes are “potent” enough to cause leukemia in children (a hypothesis still
under intense study), then it is prudent to examine whether more highly exposed workers
are experiencing adverse health effects from EMFs on the job. Employees in the utility
and manufacturing sectors of the economy are logical groups to study because they are
exposed to various patterns, frequencies, and magnitudes of EMFs. Almost all of the
chemicals known to cause cancer in people were identj/Ied through studies of exposures
to workers.
If EMFs are not shown to cause cancer in adult workers, it is still possible that EMFs
could cause childhood cancers. Not only is it possible that children are particularly
susceptible to carcinogenic stimuli, but childhood and adult leukemia may be subtly
different diseases with potentially different causes. New epidemiologic studies of
children and adults exposed to EMFs at home are in progress and should be published in
the years ahead.
Excerpt 3
In the epidemiologic literature on EMFs and cancer, many types of cancers are studied,
but leukemias are the most frequently reported disease. About half of the 30 or so
published studies examining EMF and leukemia (including the first positive report of
leukemia in the workplace in 1982) have found a higher rate of various forms of leukemia
among men in occupations with presumed exposure to EMF. Many of these excesses are
statistically sign flcant by conventional measures, particularly when subgroups of
exposed workers are examined for spec f Ic types of leukemia. The associations appear to
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be stronger for acute leukemia..., but some studies also report associations with chronic
leukemia. The associations are more consistent for certain occupational categories, such
as lineman, electrical engineers, and electricians. The magnitudes of the excess risks
(technically called relative risks or RRs’) are typically modest, ranging from near 1.0 to
2.0. A RR 1.5 implies that exposed workers experience 50% more cases of disease than
other workers (or than members of the general adult population). The RR represents the
best estimate of excess risk based on the study data, with the statistical uncertainty in the
result expressed as the 95% confidence interval or Ci (The 95% CI estimates a range of
values in which we are 95% certain that the ‘true ‘RR value lies, assuming that the data
and models are unbiased)
Excerpt 4
If EMF5 in the workplace do cause modest increases (i.e., RRs of 1.5 to 2.0) in the risks
of leukemia, brain cancer, and/or breast cancer, it is unlikely that epidemiology alone
will be able to establish such effects. Even large and well-designed observational studies
of workers are unlikely to detect with consistency modestly elevated relative risks due to
the inevitable sources of measurement error in epidemiology. There are some notable
instances where epidemiologic discovery of carcinogens has preceded experimental
confirmation and delineation of biological mechanisms (e.g., smoking and lung cancer,
benzene and leukemia), but the relative risks for these agents were typically well above
2.0.
Thus, while the need persists for continued improvements for epidemiology, it seems
likely that a critical element in furthering scient flc progress in this field is more
biological understanding of the effects of EMF5 and the operating mechanisms of action.
The current biological database is incomplete and scientists disagree about whether such
progress is likely.
Some scientists argue that low level ambient exposures to EMFs are unlikely to cause
cancer because the energies imparted by such exposures are far below both those that
cause damage by heating body tissue and those that damage DNA. Other scientists argue
that disruption of normal cell growth and d fferentiation, recognized features of
carcinogenesis, may be influenced by low level EMFs. There is some evidence that non-
ionizing radiation (including very low intensity EMFs in the 50-60 Hz range) can affect
cells, but studies using whole animals have indicated few adverse effects of long-term
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exposure to EMFs. There has been little reproducible evidence of chromosomal damage
caused by exposure to EMFs. If EMFs do play a role in cancer formation, it may be as
promoters, or co-promoters after the process is initiated by exposure to chemical
substances. At the cellular level, numerous studies have demonstrated various biological
responses following exposure to EMFs, but it remains unclear how they may contribute
to the carcinogenic process. The results of these studies have also been inconsistent, and
many have yet to be replicated
Excerpt 5
One key issue complicating the investigation of exposure to EMFs is the question of how
to measure them. Not only is there imprecision in the technology currently used to assess
EMFs in the fiela there is also disagreement over what constitutes exposure and what
elements the exposure monitors should be measuring. EMF is a very broad category,
and scientists contend that any effects seen in epidemiologic or laboratory studies may
depend on what elements of electric and/or magnetic fields (e.g., wave-length or
frequency, intensity ofthefiel4 degree ofpolarization, whether the field is continuous,
intermittent, or transient) are being measured, and what exposure parameters (such as
time-weighted average, peak field levels, or l fetime exposure) are being investigated
Each element may play a role in the potential impact of EMFs, yet there is little
consensus on what parameters we should be capturing. In other words, scientists agree
that how EMFs are measured may matter a lot, but they do not yet know which exposure
measures, f any, are physiologically meaningfid.
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APPENDIX M
NITRATE AND NITRITE IN DRINKiNG WATER
National Research Council. (1995) Nitrate and nitrite in drinking water. Subcommittee on Nitrite and Nitrate
in Drinking Water, Committee on Toxicology. Washington, DC: National Academy Press,
pp. 1-6, 45-49.
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BACKGROUND
The Safe Drinking Water Act directs EPA to establish national drinking water standards
for chemical and biological contaminants in public water supplies. These standards, called
maximum-contaminant-level goals (MCLGs) and maximum-contaminant levels (MCLs), are to
be set at concentrations at which no adverse effects on human health occur or are expected to
occur from lifetime consumption, allowing a margin of safety. These standards are to be
reviewed periodically to ensure continued protection of public health. The National Research
Council’s Subcommittee on Nitrite and Nitrate in Drinking Water recently reviewed these
standards. The case study portion contains excerpts taken from this review. Excerpt 1
summarizes the human and animal evidence on the health effects from ingesting nitrate/nitrite
and discusses the subpopulation (i.e., infants) at highest risk. This type of summary could be
appropriate as part of the h z ird identification and risk characterization summaries. Excerpt 2
summarizes the potential public health concerns from exposure to nitrate/nitrite and notes the
scientific basis for this judgment. This type of summary could be appropriate as part of a risk
characterization summary.
CRITIQUE
The excerpts presented in this appendix seem somewhat clear, reasonable, and
transparent The information presented does a good job of summarizing the risks without going
into a lot of technical detail that the risk manager may not need. There are, however, instances
where more detailed information might be useful. For example, the narrative states that
“Methemoglobinemia in adults is rare,” but it provides no clues under what circumstances
methemoglobinemia can manifest itseff in adults. There is also a fair amount of chemistry
discussed in the document This discussion would likely be unclear to nonchemists. Examples
here include “Methemoglobinemia occurs when nitrite oxidizes the Fe 2 in hemoglobin to Fe 3 ”
and “nitrate and nitrite are not carcinogenic unless they are administered concurrently with
nitrosatable amines.” How does nitrate get converted to nitrite? The text should provide more
explanation and definition of these terms.
THE CASE STUDY
Excerpt 1
Methemoglobinemia is the primary adverse health effect associated with human exposure
to nitrate or nitrite. To cause methemoglobinemia [ a potentially serious effect in blood
cells], nitrate must be converted to nitrite. Methemoglobinemia occurs when nitrite
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oxidizes the Fe 2 in hemoglobin to Fe 3 , a form that does not allow oxygen transport [ in
the blood]. Methemoglobinemia in adults is rare; most methemoglobinemia victims are
infants who have been fed formula mixed with nitrate-containing well water or food with
a high nitrate content or who have diarrhea.
Results of epidemiologic studies are inadequate to support an association between high
nitrate or nitrite exposure from drinking water in the United States and increased cancer
rates in humans. In laboratory animals, nitrate and nitrite are not carcinogenic unless
they are administered concurrently with nitrosatable amines. Studies in humans are also
inadequate to support an association between nitrate or nitrite exposure and
reproductive or development effects. Results of studies in laboratory animals suggest
that reproductive and developmental toxicity might occur, primarily at high doses, which
also can produce maternal methemoglobinemia. . . . Developmental effects of nitrite that
have been reported in rodents appear to result from exposure after birth and not in utero.
Further research on the possible reproductive or developmental effects of nitrate or
nitrite would be helpful.
At high doses, inorganic nitrite, but not nitrate, can produce hypotension [ low blood
pressure] in humans as a result of its action as a smooth muscle relaxer.
There are very few published reports of methemoglobinemia occurring in infants whose
drinking water contains nitrate at less than 50 mg/L, and none of the reported cases
occurred in the United States.
Excerpt 2
there are no convincing data to suggest that nitrate or nitrite is associated with any
adverse effect other than methemoglobinemia,...a no-observed-adverse-effect-level
(NOA EL) for nitrate of 10mg of nitrate nitrogen per liter (1.6 mg/kg-day) [ was ident fled]
on the basis of epidemiologic studies.... That value is equivalent to nitrate at 44mg/L. To
obtain a reference dose (RID) from the NOAEL, an uncertainty factor of 1 was used
because the NOAEL was derived from studies in humans of the most sensitive
subpopulation [ infants]. For nitrite, . . . assume that the conversion rate of nitrate to
nitrite by gastrointestinal tract bacteria in infants is about 10%, from which an R of
1mg of nitrite nitrogen per liter (0.1 6mg/kg-day) was calculated That value is
equivalent to nitrite at 3.3 mg/L.... The MCLGs for nitrate and nitrite are based on those
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RjDs. Assuming a water consumption of 0.64 lid by a 4-kg infant, the MCLGs for nitrate
nitrogen and nitrite nitrogen are 10 mg/L and 1 mg/L, respectively
[ It was] concluded that exposure to nitrate concentrations found in drinking water in
the United States is unlikely to contribute to human cancer risk Attempting to limit
nitrate or nitrite exposure on the basis of carcinogenicity would implicate the diet, and
vegetables in particular, as the primary source of risk for most of the US. population.
But diets rich in vegetables have consistently been shown to reduce cancer risk Any
theoretical cancer risk should be weighed against the benefits of eating vegetables.
Available data are inadequate to support an association between nitrate and nitrite
exposure from drinking water and any noncancer effects except for methemoglobinemia
in infants, which might occur as a result of exposure to nitrate-contaminated water or to
vegetables with high concentrations of nitrate or as a result of increased endogenous
nitrate synthesis in cases of infection. Limiting infant exposure to nitrate would be a
sensible public health measure. It could be accomplished by minimizing exposure to both
foods and water that are high in nitrate and by protecting infants from infection.
Infection is the major contributor to methemoglobinemia from nitrate exposure; the
incremental contribution of drinking water is negligible. There are few published reports
of methemoglobinemia occurring at concentrations of drinking water nitrate less than
SOmg/L, and these [ reports] are of uncertain quality. In addition , no cases of
methemoglobinemia occurring at exposure concentrations less than 5Omg/L have been
reported in the United States. The absence of reported cases might in part be due to the
lack of requirements for reporting cases of methemoglobinemia.
.EPA ‘s current .. .MCLGs of nitrate at 44mg/L (nitrate nitrogen at 1 Omg/L) and nitrite at
3.3 mgIL (nitrite nitrogen at 1 mg!L) are adequate to protect human health... These
MCLGs are adequate to protect human health from the potential consequences of
exposure to nitrate and nitrite in public water supplies because they are based on human
data derived from the most sensitive subpopulation [ infants] and because no cases of
methemoglobinemia have been reported in the United States at dosages below the
MCLGs.
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APPENDIX N
QUESTIONS USED TO DEVELOP NCEA’S DIOXIN RISK CHARACTERIZATION
N-i
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During the development of NCEA’ s reassessment of the exposure and health effects
components of the dioxin risk assessment, team members developed a series of key questions
they believed were important to address in the risk characterization. As noted in NRC’s 1996
updated risk assessment guidance (NRC, 1996), this is an important step to perform early in the
risk assessment process. Although these questions are specific for dioxin, most could easily be
modified to make them applicable for characterizing other risks. NCEA-W risk assessors may
want to consider addressing the following questions.
1. What are the current major sources of dioxin and related compounds?
2. Have the relative sources of dioxin compounds in the environment changed over time?
3. Are there other suspected but uncharacterized sources of dioxin?
4. What is the known mass balance between current sources and deposition? What can be
inferred about recycling of dioxinlike compounds within the environment?
5. Once released, where do dioxinlike compounds go?
6. Do they move around readily in the environment?
7. What are the major pathways to human exposure?
8. What foods contain minute amounts of dioxin and related compounds? Is the pattern different
for PCCDs/PCDFs and dioxinlike PCBs? What can be expected in air? Water? Other
media?
9. What do we know about average exposure levels in the United States today? High-end
(>90%) exposures? Reasonable worst case? Theoretical upper bound? Can a general
population exposure distribution be generated with reasonable certainty?
10. What major assumptions are made regarding sources, fate, and transport in order to estimate
current human exposures?
11. Once humansbanimals are exposed, what happens to the dioxinlike compounds? Are they
metabolized? Eliminated?
12. What is the pattern of persistent compounds in human tissues? How does this compare to
patterns in laboratory animals? Can comparative body burdens be estimated?
13. What are the primary biochemicallcellular changes observed/expected in humans exposed to
TCDD? To a mix of PCDDsIPCDFsIPCBs? Are these similar to what has been observed
in animals?
14. In animals, bow do these early events in the sequelae of exposure/response relate to later
events? Frank toxicity?
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15. What is known about the effects of TCDD exposure on humans? Are other effects expected
but currently undetectable? Why?
16. At what level of exposure/body burden of TCDD do these known effects occur?
17. How does consideration of other dioxinlike compounds change this picture? Are different
effects expected? What is known about additional potential hazards from animal studies?
18. How would you characterize potential health hazards of TCDD? And dioxin and related
compounds? How important is the concept of toxicity equivalence in estimating the effects
of this group of compounds?
19. What is the “observed range” of exposure for animal effects of TCDD? Other
PCDD/PCDFs? Dioxin-like PCBs? Observed range based on body burden?
20. How does this observed range compare with average population exposures to TCDD? To
TEQ for PCDDs and PCDFs? To total TEQ, including dioxinlike PCBs?
21. How do “benchmark doses” for TCDD compare with the above? What can be inferred using
the TEFs? What are the major areas of uncertainty in this approach? Can this uncertainty be
quantified?
22. Why is there an issue with looking at risks from incremental exposures from specific
sources? Can impacts on body burdens be calculated?
23. What is the concept of “additivity to background,” and why is it important?
24. Why does environmental lead provide a good analogy with dioxin and dioxin-related
compounds? Are there other similar analogies to be drawn?
REFERENCE
National Research Council. (1996) Understanding risk, informing decisions in a democratic
society. Washington, DC: National Academy Press.
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APPENDIX 0
QUESTIONS USED TO DEVELOP NCEA’S TRICHLOROETHYLENE
RISK CHARACTERIZATION
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Early in the development of the integrated analysis and risk characterization of NCEA’s
trichioroethylene (TCE) risk assessment, the team developed a series of issues to consider being
addressed. Although these questions are specific for ICE, most could easily be modified to
make them applicable for characterizing other risks. When NCEA-W risk assessors are in the
early planning stages of an assessment, they may want to consider the following types of
questions to address in their characterizations.
A. Carcinogenic Hazard of TCE and Its Metabolites
Issue 1. Why do we need to consider metabolites as important agents for TCE’s
carcinogenic hazard?
Issue 2. Can susceptible populations be identified based on differential metabolism rates
or development of the P450 and GSH enzyme systems?
Issue 3. What does the epidemiologic evidence, as an integrated whole, indicate about
TCE exposure and cancer?
Issue 4. What is the significance of the genetic toxicity data for indicating a carcinogenic
hazard from TCE?
Issue 5. What is the evidence that TCE and its metabolites are carcinogenic in rodents?
Issue 6. How does TCE induce liver tumors in mice? Include results of bioassays of
metabolites.
Issue 7. How does TCE induce kidney tumors in rats?
B. Characterization of the Hazard Evaluation—Critical Issues in the Quantitative Analysis
Issue 1. How does the pharmacokinetics (PK) scale from mice and rats to humans?
What are the strengths and limitations of the current PK models?
Issue 2. What dose metrics should be considered for evaluating risk for lung, liver, and
kidney tumors?
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Issue 3. What endpoints can be adopted as the response measure for lung, liver, and
kidney cancer?
issue 4. How can information on the mode of action guide the selection of dose-response
approaches?
issue 5. How does PK uncertainty influence the analysis?
Issue 6. What factors need to be considered in a margin of exposure approach?
C. Critical Issues in the Assessment of TCE’s Noncancer Effects
Issue 1. What are the important noncancer toxicities of TCE, and at what exposure levels
are they observed? Include neurological and immunological effects and developmental
toxicity, including cardiac anomalies.
Issue 2. What endpoints can be used to develop a reference dose (RID) and a reference
concentration (RfC)?
Issue 3. How can PK information be used in developing the lowest-observed-adverse-
effects level or benchmark concentration in the RfD and RfC analyses?
Issue 4. What needs to be considered in selecting uncertainty factors?
D. Characterization of Noncancer Assessment—Critical Issues in the Exposure Assessment
Issue 1. What are the major sources of TCE and its metabolites?
Issue 2. Why do we need to consider exposure to sources of agents with similar
metabolites as TCE?
Issue 3. What do we know about the size and characteristics of the populations exposed
to TCE and its metabolites?
Issue 4. Which populations have high-end exposures to TCE and its metabolites?
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E. Characterization of Exposure Assessment
Issue 1. Considering the cun ently available data for TCE and its metabolites, how can
we best characterize the human risks associated with exposure to TCE?
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