United States EPA Science Advisory EPA-SAB-EC-03-010
Environmental Board (1400A) June 2003
Protection Agency Washington DC www.epa.gov/sab
Review of the draft Human
Health Research Strategy for
Improving Risk Assessment:
A Report of the US EPA
Science Advisory Board
A REPORT BY THE HUMAN
HEALTH RESEARCH STRATEGY
REVIEW PANEL OF THE EPA
SCIENCE ADVISORY BOARD
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June 23, 2003
The Honorable Marianne Lament Horinko
Acting Administrator
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460
Subject: Review of the draft Human Health Research Strategy for
Improving Risk Assessment: A Report of the US EPA Science
Advisory Board
Dear Ms. Horinko:
The Human Health Research Strategy Review Panel of the U.S. EPA Science Advisory
Board's Executive Committee met on November 20 - 22, 2002 to review the Agency's, draft
Human Health Research Strategy document (May 2002) (HHRS document). The HHRS
document outlines the Office of Research and Development s (ORD) vision for core research in
human health risk assessment over a 5 to 10 year horizon.
The HHRS document presents four strategic directions and research priorities for ORD s
future core research program in human health. They include the following: 1) Research on
harmonizing risk assessment approaches; as defined by the HHRS document, this refers to the
development of a consistent set of principles and guidelines for drawing inferences from
scientific information. 2) Research on aggregate and cumulative risk, which includes data
collection and the development of methods to characterize the magnitude and nature of the
pollutants to which people are exposed, as well as the timing and sequence of those exposures.
3) Research on susceptible and highly exposed subpopulations to better characterize the
contributions of life stage, genetic factors, and preexisting disease. 4) Research to enable
evaluation of public health outcomes from risk management actions.
The Panel was asked to address the following charge questions: (1) Does the document
establish the appropriate direction and research areas (i.e., aggregate-cumulative risk,
harmonization, susceptible subpopulation, effectiveness of public health outcome) for a long-
term, core research program on human health risk assessment? (2) Will the research that is
described reduce uncertainty in the risk assessment process? (3) For the research areas selected,
does the strategy provide a clear framework for a multi disciplinary research program? (4) Does
the strategy pro vide a logical approach for framing research to evaluate the impact of risk
management decisions on human health? The Panel has provided their major comments and
recommendations in the context of the four areas of research.
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In our view, the HHRS document represents an important initial effort to outline a
strategic research direction for what is arguably the premiere research organization on this
subject in the world. The conceptual framework and general approaches outlined in the HHRS
document should help provide better direction and focus for the ORD's Multiyear Plan on
Human Health Research. Thus, the strategic research directions described in the document can
have a direct impact on the overall focus of the risk assessment research community, both within
and outside the Office of Research and Development.
In response to charge question 1 and 2, we support, in general terms, the four major
strategic research directions put forth in the HHRS document and aggress that the research that is
described will reduce uncertainty in the risk assessment process. As described in the HHRS
document, ORD intends to develop technologies/methods to study mode or mechanism of action
as part of the framework to develop an integrated research program to harmonize risk
assessment. We recommend that the HHRS document should clearly articulate the importance
of validation of these tools. Research in laboratory animals should be focused on improving
general understanding of mechanisms / modes of toxic action. Special attention should be given
to vigorously evaluating those methods and models for their utility and applicability to humans.
There should be coordination between animal and human research to ensure that animal models
adequately represent the human conditions. It is important that existing models and technologies
for characterizing exposure and dose continue to be validated for use in risk assessment. It is
similarly crucial that emerging technologies be formally validated if their full promise is to be
realized.
A major source of uncertainty in characterizing aggregate and cumulative risk,
identifying highly-exposed subpopulations and linking risk management decisions to public
health outcomes arises from a lack of knowledge about the sources of exposure and dose. We
would like to emphasize our belief that basic research is still necessary for characterizing source,
fate, transport, exposure and dose (potential and actual), particularly in a way that is relevant to
the strategic directions identified in the document.
In developing a research strategy for studying susceptible populations, we agree that
more effort must be directed toward defining, understanding, and identifying the most
susceptible populations. While children are of prime concern, other age groups, people with
preexisting diseases and those with genetic predispositions for heightened susceptibility must
also be considered. Additionally, while we appreciate the boundaries of the regulatory authority
placed on EPA, it does question whether the full public health implications of either effects or
exposure data can be understood without evaluating them in a broader environmental context.
The impact of lifestyle, neuropsychological factors (such as stress), socioeconomic status,
gender and nutrition (as well as other factors) on an individual s response to environmental
chemicals were not sufficiently discussed in the document.
In response to charge question 3, we also agree that the strategy acknowledges the
importance of and provides a reasonable framework for a multidisciplinary research program
in support of the selected research areas. The strategic directions, if they are fully and
successfully implemented, should yield new insights and generate a stronger interdisciplinary
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research environment in the Agency s long-term core research program. Moreover, given the
development of new cellular and molecular tools, increasingly more powerful computer-based
modeling and bioinformatic methodologies, and the continuing development of sophisticated
epidemiological and biostatistical techniques, the development of these strategies is timely.
In response to charge question 4, we highly recommend that a more thorough explanation
of public health outcomes as they relate to risk management actions be presented. This should
include providing increased details about the methods to be used and the outcomes to be studied.
We recognize the need for evaluating the impact from risk management decisions and strongly
encourage a multidisciplinary approach in achieving these goals. This will require effective
interactions and communication across disciplines within the Agency, as well as essential
partnering with other federal and state government entities, research centers and academia.
In closing, the Board recognizes and appreciates the efforts of the Agency's staff in
developing and presenting this research strategy. The panel looks forward to your response to
this report.
Sincerely,
Dr. William Glaze, Chair Dr. James E. Klaunig, Chair
EPA Science Advisory Board Human Health Research Strategy Review Panel
EPA Science Advisory Board
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NOTICE
This report has been written as part of the activities of the Science Advisory Board, a public
advisory group providing extramural scientific information and advice to the Administrator and
other officials of the Environmental Protection Agency. The Board is structured to provide
balanced, expert assessment of scientific matters related to problems facing the Agency. This
report has not been reviewed for approval by the Agency and, hence, the contents of this report
do not necessarily represent the views and policies of the Environmental Protection Agency, nor
of other agencies in the Executive Branch of the Federal government, nor does mention of trade
names or commercial products constitute a recommendation for use.
Distribution and Availability: This EPA Science Advisory Board report is provided to the EPA
Administrator, senior Agency management, appropriate program staff, interested members of the
public, and is posted on the SAB website (www.epa.gov/sab). Information on its availability is
also provided in the SAB monthly newsletter (Happenings at the Science Advisory Board).
Additional copies and further information are available from the SAB Staff [US EPA Science
Advisory Board (1400A), 1200 Pennsylvania Avenue, NW, Washington, DC 20460-0001; (202)
564-4533)].
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ABSTRACT
An ad hoc panel of the U.S. EPA Science Advisory Board s Executive Committee met to
provide advice on four charge questions relating to the strategic directions for the Office of
Research and Development s (ORD) core research program in human health risk assessment.
The research directions, outlined in the Human Health Research Strategy (HHRS) document,
were based on the evaluation of research needs from the Agency s regulatory and regional
programs and consideration of recommendations from external advisory groups. The priority
research areas identified in the HHRS document include (1) research on harmonizing risk
assessment approaches, (2) research on aggregate and cumulative risk (3) research on susceptible
and highly exposed subpopulations and (4) research to enable evaluation of pub lie health
outcomes.
The panel affirmed their support for the integrative, multidisciplinary approach that the
Human Health Research Strategy appears to embrace. The panel suggested that harmonization
will be best achieved by fully considering information on mechanisms / modes of action in risk
assessment. The panel recommended that strategic research planning should focus on advancing
such knowledge, while recognizing that harmonization does NOT mean that a single
methodology should be used for assessment of all toxicities and pollutants. The panel agreed
that focus on aggregate and cumulative exposure and risk is an appropriate and logical next step
in the evolution of human health risk assessment. The panel noted that the HHRS document
acknowledges the importance of reducing uncertainties in all aspects of the source-to-effects
continuum, however, it would benefit from further elaboration on and a more balanced
presentation of areas of research needs and, in particular, the allocation of resources necessary
for elucidating the events leading up to exposure. In attempting to identify susceptible
populations, the panel acknowledged the importance of understanding the role of predisposing
factors including genetic predisposition, gender, age (particularly children and the elderly), and
disease [and immune] status in determining how an organism will respond to chemical or
physical agents. In addition, they recommended that contributory risks should also be included,
such as, the impact of lifestyle, neuropsychological factors including stress, and living
conditions, such as socioeconomic factors, passive or active smoking, and nutrition. The panel
also noted that the discussion of pub lie health outcomes was less developed in the HHRS
document and therefore, it was difficult to evaluate the intended research strategy. The
conceptual details of the methodological approaches to be used in the evaluation of risk
management actions are needed. Furthermore, the panel also recommended that concepts of
population-based epidemiologic research such as attributable or preventable risk, competing
risks, sentinel health events, body burden, and other related concepts be addressed explicitly.
Keywords: Harmonization, Human Health, Risk Assessment, Aggregate Risk, Susceptible
Populations, Public Health, Research Strategy
n
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U.S. Environmental Protection Agency
Science Advisory Board
Human Health Research Strategy Review Panel*
CHAIR
Dr. James E. Klaunig, Professor and Director of Toxicology, Department of Pharmacology and
Toxicology, School of Medicine, Indiana University, Indianapolis, IN
Also Member: Environmental Health Committee
OTHER SAB MEMBERS
Dr. George Lambert, Associate Professor and Center Director, The Center for Childhood
Neurotoxicology and Exposure Assessment Environmental and Occupational Health Sciences
Institute, Robert Wood Johnson Medical School/ University of Medicine and Dentistry of New
Jersey, Piscataway, NJ
Member: Environmental Health Committee
Dr. Joseph Landolph, Associate Professor of Molecular Microbiology & Immunology,
Pathology, and Molecular Pharmacology & Toxicology, Cancer Research Laboratory, Keck
School of Medicine, University of Southern California, Los Angeles, CA
Member: Drinking Water Committee
Dr. Randy Maddalena, Scientist, Environmental Energy Technologies Division, Indoor
Environment Department, Lawrence Berkeley National Laboratory, Berkeley, CA
Member: Integrated Human Exposure Committee
Dr. Maria Morandi, Assistant Professor of Environmental Science & Occupational Health,
School of Public Health, University of Texas - Houston Health Science Center, Houston, TX
Member: Research Strategies Advisory Committee
CONSULTANTS
Dr. Paul Blanc, Professor, Division of Occupational and Environmental Medicine, University of
California San Francisco, San Francisco, CA
Dr. James E. Gibson, Research Professor of Pharmacology and Toxicology, Department of
Pharmacology and Toxicology, The School of Medicine at, East Carolina University, Greenville,
NC
Dr. Michael Jayjock, Research Fellow, Toxicology Department, Rohm and Haas Co., Spring
House, PA
Dr. Steven C. Lewis, Distinguished Scientific Associate, Toxicology and Environmental
Sciences, Exxon Mobil Biomedical Sciences, Inc., Annandale, NJ
Dr. Beate Ritz, Associate Professor, School of Public Health, UCLA, Los Angeles, CA
in
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Dr. Herbert Rosenkranz, Professor of Biomedical Sciences, Florida Atlantic University, Boca
Raton, FL
Dr. Bernard Weiss, Professor, Department of Environmental Medicine, University of Rochester
Medical Center, Rochester, NY
FEDERAL EXPERTS
Dr. Robert Spengler, Associate Administrator for Science, Agency for Toxic Substances and
Disease Registry, Atlanta, GA
SCIENCE ADVISORY BOARD STAFF
Dr. Suhair Shallal, Designated Federal Officer, US EPA Science Advisory Board (1400A),
1200 Pennsylvania Avenue, Washington, DC
Ms. Zisa Lubarov-Walton, Management Assistant, US EPA Science Advisory Board (1400A),
1200 Pennsylvania Avenue, NW, Washington, DC
* Members of this SAB Panel consist of (a) SAB Members: Experts appointed by the Administrator to serve on one
of the SAB Standing Committees (b) SAB Consultants: Experts appointed by the SAB Staff Director to a
one-yearterm to serve on ad hoc Panels formed to address a particular issue, (c) Liaisons: Members of
other Federal Advisory Committees who are not Members or Consultants of the Board, (d) Federal Experts:
"Federal Experts" are federal employees who have technical knowledge and expertise relevant to the
subject matter under review or study by a particular panel.
IV
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TABLE OF CONTENTS
I. EXECUTIVE SUMMARY 1
II. INTRODUCTION 5
III. ASSESSMENT OF HARMONIZATION STRATEGY 7
IV. AGGREGATE AND CUMULATIVE RISK 11
V. SUSCEPTIBLE POPULATIONS 16
VI. EVALUATION OF PUBLIC HEALTH OUTCOMES FROM RISK MANAGEMENT
ACTIONS 22
VII. CONCLUSION 26
APPENDIX A - ABBREVIATIONS AND ACRONYMS A-l
APPENDIX B - GLOSSARY B-l
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I. EXECUTIVE SUMMARY
On November 20-22, 2002, the Human Health Research Strategy Review Panel ( The
Panel; ) met to provide advice on four charge questions relating to the strategic directions for the
USEPA Office of Research and Development s (ORD) core research program in human health
risk assessment over the next five to ten years. The research directions were based on the
evaluation of research needs from the Agency s regulatory and regional programs and
consideration of recommendations from external advisory groups. The research strategy
discusses the major environmental problems, the principal scientific issues, and the priority
research areas that need to be addressed in order to resolve the problems. The priority research
areas identified in the Human Health Research Strategy (HHRS) document include (1) research
on harmonizing risk assessment approaches, (2) research on aggregate and cumulative risk (3)
research on susceptible and highly exposed subpopulations and (4) research to enable evaluation
of public health outcomes.
The panel has therefore provided comments and recommendations in the context of these
four areas of research focus to address the following charge questions: (1) Does the document
establish the appropriate direction and research areas (i.e., aggregate-cumulative risk,
harmonization, susceptible subpopulation, effectiveness of public health outcome) for a long-
term, core research program on human health risk assessment? (2) Will the research that is
described reduce uncertainty in the risk assessment process? (3) For the research areas selected,
does the strategy provide a clear framework for a multi disciplinary research program? (4) Does
the strategy provide a logical approach for framing research to evaluate the impact of risk
management decisions on human health?
The Agency has clearly invested a substantial amount of expertise, time, and energy into
developing the Human Health Research Strategy document. The panel agrees that the overall
goals outlined in the human health strategy are commendable and represent a significant step
towards overcoming the limitations of current risk assessment methods. However, the panel has
identified specific issues that require further consideration. The panel s major comments and
recommendations are as follows:
Research on the Harmonizing Risk Assessment Approaches
The HHRS document specifically includes "harmonization" of approaches to risk
assessment for cancer and other adverse health outcomes (i.e., "non-cancer" effects). The panel
interprets this focus as evidence of the Agency s over-arching commitment to applying the most
complete scientific understanding in support of health protection. In that regard, the panel
believes that "harmonization" will be best achieved by fully considering information on
mechanisms / modes of action in risk assessment. Strategic research planning should focus on
advancing such knowledge, while recognizing that harmonization does NOT mean that a
single methodology should be used for assessment of all toxicities and pollutants."
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The section on harmonization" is focused on developing principles and guidelines for
drawing inferences from scientific information and stresses that all methods'3 (biological and
statistical) should be consistently applied to toxicity, dosimetry, mode of action, and exposure
data in constructing risk assessments. Consequently, the research undertaken will concern
exposure, dose, effect, and risk assessment methodology. The panel applauds the idea of
developing mechanism-based techniques rather than be limited to an approach rigidly
dichotomized between cancer and non-cancer endpoints when scientifically inappropriate. In
addition, Agency research should address the need to integrate information from animal studies
with the results of studies in humans (experimental or epidemiological). Such an approach is
likely to yield new insights through cross-fertilization of ideas within an interdisciplinary
environment. Moreover, given the development of new powerful computer-based modeling and
bioinformatic methodologies, this is an opportune time to develop such a strategy.
Research On Aggregate And Cumulative Risk
The panel agrees that focus on aggregate and cumulative exposure and risk is an
appropriate and logical next step in the evolution of human health risk assessment. The HHRS
document recognizes the importance of reducing uncertainties in all aspects of the source-to-
effects continuum. Nonetheless, it would benefit from further elaboration on and a more
balanced presentation of areas of research needs and, in particular, the allocation of resources
necessary for elucidating the events leading up to exposure. Knowledge and understanding of
these events is crucial for developing effective risk management and public health protection
decisions. Our ability to characterize these events will be crucial in not only the assessment of
aggregate and cumulative risk but also in identifying highly exposed subpopulations and relating
risk management decisions to health outcomes. The HHRS should incorporate a more thorough
description of current exposure-related research within the ORD, the future direction of these
efforts, and their integration with the other research areas described in the document. Continued
improvements in communication and interactions across disciplines within and between
scientists in the NERL and NHEERL research programs, as well between ORD researchers,
academia, and public health agencies should be emphasized in order to achieve the goals of the
strategy.
Research On Susceptible And Highly Exposed Populations
Susceptibility embodies the fundamental question in risk assessment, that is, Who is
[when] at risk? It embodies the role of predisposing factors including genetic predisposition,
gender, age (particularly children and the elderly), and disease [and immune] status in
a Harmonization in this context refers to the development of a consistent set of principles and guidelines
for drawing inferences from scientific information. It does not mean that a single methodology should be
used for assessment of all toxicities and pollutants. Page 2-2, lines 24 - 27.
b Refers to those mentioned in the Hum an Hea Ith Resea rch Strategy (Internal R eview D raft), Office of Research and
Development, United States Environmental Protection Agency, May 2002.
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determining how an organism will respond to chemical or physical agents. It must also include
contributory risks, such as the impact of lifestyle, neuropsychological factors including stress,
and living conditions, such as socioeconomic factors, passive or active smoking, and nutrition.
These factors will have significant impact on the effects of environmental chemicals on human
health. These interactions require further study and need to be included in a comprehensive
strategy.
Due to the deliberate brevity of the HHRS document, much of the research detail is not
provided and leads to some degree of uncertainty about the research plan. The document
presents an emphasis on the development and application of animal models for assessing the
interaction between susceptibility and disease states and stage of development. Animal models
may be best employed to understand mechanisms of toxicity. Extrapolations of risk estimates
from animal data to risk assessments in humans, although frequently necessary, are difficult to
conduct. There should be coordination between animal research and human research, but the
reliability and applicability of some animal models as representative of the human condition
must be carefully determined. Too much emphasis is currently placed on screening rather than
on the deeper analyses that are suited for extrapolation to human risks. It is important to realize
that for certain human diseases relevant animal models may not be currently available. The
impact of stages of life, disease states, and genes on the consequences of exposure and all
aspects of pharmacokinetics/pharmacodynamics (PKPD) should be addressed in full by the
Agency. The program should direct more effort toward defining, understanding, and identifying
specifically the biologically susceptible and/or highly exposed individuals in the human
population in a host of disorders that can be altered or induced by the environment. These
disorders include neuropsychological dysfunction, asthma, cancer (polymorphisms in DNA
repair enzymes), and endocrine and developmental dysfunctions.
Research To Enable Evaluation Of Public Health Outcomes From Risk Management Actions
In considering public health outcomes, the panel recommends that the Agency provide a
clear delineation of which public health problems are to be addressed. Furthermore, the
conceptual details of the methodological approaches to be used in the evaluation of risk
management actions are needed. In the HHRS document, epidemiologic research is used as a
generic term without consideration of specific study designs and purposes such as cohort or case
control approaches, molecular epidemiology, time series studies, and exposure assessment
methods such as biomonitoring or population exposure models. The panel also recommends that
concepts of population-based epidemiologic research such as attributable or preventable risk,
competing risks, sentinel health events, body burden, and other related concepts be addressed
explicitly. Because this chapter is incomplete, it is difficult to evaluate the intended research
strategy. Although it is clear that partnering with other agencies and secondary data analysis
will be pivotal in any strategy to be developed, this must be preceded by clarifying the public
health outcomes of interest.
In closing, the panel would again like to reaffirm their support for the integrative,
multidisciplinary approach that the Human Health Research Strategy appears to embrace. In
implementing the strategy, additional attention should be focused on the suggestions put forth in
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this review document. Issues such as the rigorous evaluation of methods and models for their
utility and applicability are essential to achieving the goal of improving risk assessment.
Defining, understanding, and identifying the most susceptible populations, in addition to
increased detail concerning the public health outcomes to be studied and the methods to be used
will assist in focusing the effort and resources needed to meet the expectations outlined in the
HHRS document. The panel also encourages the Agency to work in conjunction with state and
other federal agencies, as well as academia and research centers as it implements this strategy.
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II. INTRODUCTION
The mission of the U.S. Environmental Protection Agency (EPA) is to protect public
health and safeguard the natural environment (i.e., air, water, and land). Risk assessment is an
integral part of this mission in that it identifies and characterizes environmentally related health
problems. The EPA s Office of Research and Development (ORD) conducts research that
contributes to the scientific foundation for risk assessment and risk management decisions in
EPA s regulatory pro grams. Since 1996, ORD has used arisk-based strategic planning process
in consultation with EPA s Program and Regional Offices and the external scientific community
to set research priorities. From this process, research to improve human health risk assessment
was identified as one of six priority research areas in the 1997 Update to ORD s Strategic Plan
(U.S. EPA, 1997a) and ORD Strategic Plan (U.S. EPA, 2001b). As such, fundamental human
health research is also part of the ORD Sound Science Program under Goal 8, which is one of
EPA s ten strategic environmental goals in accordance with the requirements of the Government
Performance and Results Act (GPRA).
The Human Health Research Strategy (HHRS) document presents a conceptual
framework for future human health research by EPA s ORD. This research strategy outlines
ORD s core research effort to provide broader, more fundamental information that will improve
understanding of problem-driven health risk issues encountered by the EPA s Program and
Regional Offices. The scope of this research document is strategic in that it discusses broad
themes and general approaches. Implementation of an integrated research program on human
health is described in greater detail in ORD s Multiyear Plan on Human Health Research.
The Multiyear Plan identifies specific performance goals and the measures needed to
achieve those goals over a 5 to 10 year period. Each Laboratory and Center in ORD is also
developing an approach linking research at the project level to the goals and measures in the
Multiyear Plan and the general themes outlined in the HHRS document. Based on the needs of
the EPA s Program and Regional offices, recommendations made by external advisory groups,
and goals established by EPA in response to the Government Performance and Result Act
(GPRA) under Sound Science (Goal 8), ORD has identified two strategic research directions that
will be pursued over the next 5 to 10 years.
The first, Research to Improve the Scientific Foundation of Human Health Risk
Assessment, aims to reduce critical uncertainties in the state of the science of human health risk
assessment through research targeted at three specific areas harmonizing cancer and
non-cancer assessments, assessing aggregate and cumulative risk and determining risk to
susceptible human subpopulations. The second strategic direction, Research to Enable
Evaluation of Pub lie Health Outcomes from Environmental Risk Management Decisions, is
more application-oriented in that it aims to use both existing and new human health risk
assessment methods and techniques to evaluate the public health impact of regulatory decisions.
Research in these two strategic areas is expected to improve the scientific foundation for EPA s
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risk assessments and lead to principles that can be used to evaluate the effectiveness of risk
management actions aimed at improving environmental public health.
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III. ASSESSMENT OF HARMONIZATION STRATEGY
The section on harmonization within the HHRS document is focused on developing
principles and guidelines for drawing inferences from scientific information and stresses that
methods should be consistently applied to toxicity, dosimetry, mode of action, and exposure data
in constructing risk assessments. Consequently, the research undertaken will concern exposure,
dose, effect, and risk assessment methodology.
The HHRS document specifically includes "harmonization" of approaches to risk
assessment for cancer and other adverse health outcomes (i.e., "non-cancer" effects). The panel
interprets this focus as evidence of the Agency s over-arching commitment to applying the most
complete scientific understanding in support of health protection. In that regand, the panel
believes that "harmonization" will be best achieved by fully considering information on
mechanisms / modes of action in risk assessment. Strategic research planning should focus on
advancing such knowledge, while recognizing that "harmonization does NOT [emphasis added]
mean that a single methodology should be used for assessment of all toxicities and pollutants."
The panel applauds the idea to develop mechanism-based methodologies and to do away
with different approaches in conducting risk assessments on cancer and non-cancer endpoints
when scientifically appropriate. Such a new approach is certain to yield new insights as well as
to generate an exciting research environment that will promote an interdisciplinary cooperation
leading to the cross-fertilization of ideas. Moreover, given the development of new powerful
computer-based modeling and bioinformatic methodologies this is an opportune time to develop
such a strategy.
The HHRS document emphasizes that the research will involve effects of
environmentally relevant doses or concentrations of those pollutants selected for study. The
panel advises that the strategy state that both high and low doses be studied in order to elucidate
the likely shape of the dose-response curve and to determine whether different modes or
mechanisms of action may be operating at low and high doses. Too often, there is unwarranted
reliance on extrapolating from high dose effects and corresponding mechanisms into the low
dose region where there is an entirely different mode or mechanism in operation. For example,
on p.2-2 of the document, there is a discussion of non-genetic processes for cancer and non-
cancer effects, such as cell death leading to tissue regeneration and tumor formation. However, it
needs to be recognized that this process is driven by the high doses common in laboratory animal
studies and some occupational settings, not from ambient exposure situations. Attempts to
incorporate mechanism / mode of action data into risk assessment need to consider repair as well
as background rates of cell death/division which may, in some cases, dwarf those induced by
low-level exposures. There is an excellent opportunity herewith to assure that any risk
assessment is using the appropriate endpoint effect and the mode/mechanism of action that is
appropriate at specified exposures.
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The statement (in the form of a promise) in lines 24-28 on page 2-5 of the HHRS
document states that, ORD s effects research will lead to BBDR models that take into account
the sequence of early biological events leading to adversity (i.e., mechanisms or modes of
action) for multiple endpoints, the shape of the dose-response curves at low doses, and the
influence of interspecies differences. This may be overly optimistic, because achieving these
goals will be dependent on developments in laboratory research and epidemiology.
The research objectives outlined on page E-3 of the HHRS reveal some deficiencies in
the proposed strategy. The promise of advancements in risk modeling is not accompanied by a
critical commitment to developing the underlying biological data necessary for such
advancements. The third objective is, arguably, the best example. Amodel to "...compar[e] risk
across all health endpoints using mechanistic information..." is the promise; unfortunately,
insufficient emphasis is given to developing the necessary mechanistic information. Mechanistic
knowledge must provide the basis for developing such models.
A brief passage, beginning at the bottom of page 1-11 (continuing on page 1-12) deserves
note. The statement says, "Research on harmonizing risk assessment addresses the need to
develop a consistent approach for the use of mechanistic information in all health risk
assessments." This sentence is a blur of two almost-totally-independent ideas. Whether
harmonization is needed (i.e., a single approach, regardless of the toxicological end-point) is
open to debate. But, in any case, it is a question that is totally separate from whether the use of
mechanistic data is the best choice / basis for that harmonization. The panel suggests that the
two questions should be addressed separately - and successively- in the strategic plan. For all
practical purposes, "yes" answers to both questions have been taken as "articles of faith," entirely
without challenge or study.
Although one aspect of the HHRS document is research efforts to reduce uncertainty, the
proposed use of emerging technologies such as genomics, proteomics and in silico methods
(including, computational toxicology and bioinformatics) could actually increase the uncertainty
of risk assessments and lead to faulty risk management paradigms. What is badly needed is
standardization and validation of these technologies run side by side using conventional toxicity,
exposure, and dose and effect methodology. Genomics, proteomics and in silico methods
cannot, in and of themselves, serve as diagnostic tools to discern toxicological pathways leading
to adverse effects unless they have been rigorously validated. This will require a substantial
investment in equipment as well as expertise in molecular biology, genomics, bioinformatics,
computer modeling. While from a research perspective these are exciting possibilities, it might
be wise to wait until current research [including the NIEHS toxicogenomics] can be evaluated
to determine whether this is a fruitful avenue to develop within EPA to fulfill this part of the
Strategy. In the event that the subsequent decision is to proceed, decisions will have to be made
regarding whether in vitro or in vivo specimens will be studied etc.
The HHRS document suggests [p. 2-6] that the current endocrine disrupters effort will
provide a proof-of-concept . While that endeavor is extensive and will be able to rely on
appreciable data, still the question needs to be asked: is this a good model for all health effects?
The health effects of endocrine disrupters can be expected to be receptor-mediated. Most health
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effects of concern can occur by mechanisms that do not necessarily involve receptors. In any
case, absent extensive knowledge of the mechanism / mode of action, the study of endocrine
disruption does not lend itself to "proof of concept."
The HHRS document is also proposing to generate a proof-of-concept using endocrine
disrupting chemicals because ORD had experience in determining environmental exposure
levels to these chemicals and in developing in vivo and in vitro tests. For these multiple agents
which ones should be chosen for study, those that affect male fertility, female fertility, cancer,
thyroid disorders, immune disorders, child development, precocious puberty, autism, or wildlife?
Is this relevant to real world exposures? The panel suggests selecting 2 or 3 adverse endpoints
of concern that will allow for a stepwise process to reduce uncertainty and for developing a
paradigm for future risk assessments that perhaps could become more reliant on panomics (aka,
genomics, proteomics, and transcriptomics) and in silico techniques (including, computational
toxicology and bioinformatics). The panel advises that the Agency revisit the agents,
circumstances of exposure and adverse health effects (as denoted in Appendix A of the HHRS
document) to consider whether there are more promising case studies for "proof of concept"
efforts than is afforded by the study of putative endocrine disrupters.
The HHRS document states on line 30, page 2-7, to line 2, page 2-8, that "An important
focus of ORD's risk assessment research on harmonization will be the development of
approaches to characterize variability and uncertainty in reference toxicity values and to provide
a probabilistic framework for estimating risks associated with exposures above the reference
toxicity values." That sentence is neither a statement of research goals...nor is it useful guidance.
Indeed, it's a pre-emptive judgment that current risk assessment methods (probabilistic) should
replace current safety assessment methods (deterministic) in all cases.
Again, an unnecessary and restricting condition is placed on the research plan in lines 7-
10, page 2-8, namely, that a specific tool (categorical regression) will be the tactical focus for
applying the research results. With that said, the same sentence correctly, and clearly, states the
desirable strategic goal of developing risk / safety assessment tools that can, in turn, inform
assessments of costs and economic benefits. A much stronger emphasis should be made on
research to advance the goals of improving the basis for assessments of costs, substitution risks,
and benefits. To the extent that economic components are raised in the HHRS document, there
should be commensurate economic research strategies proposed the can be evaluated by
scientific peer review.
Although, much time and effort have gone into preparing the plan, before the promise of
this plan can be realized, at least two improvements are necessary. First, the plan must be
revised to provide truly strategic guidance, complemented byjustification(s) for the strategic
direction. Second, a clear and concise set of metrics must be agreed upon. Those metrics must
be employed to assess the performance of the research program, to enhance that performance, or
to redirect resources, if necessary.
In order to provide a clear framework for a multi disciplinary research program, the
strategy should fully recognize the important contributions from the public health community,
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through population-based research. To the extent that ORD research on risk assessment methods
will focus on how to incorporate mode-of-action information for health endpoints, the panel
believes an appropriate framework has been outlined. The Agency does realize that as it moves
forward with this research strategy, pressure will be brought in the form of an onslaught of data
generated by the new panomics technologies and that these approaches will far outpace the
research and guidance on interpretation and application in risk assessment . Nevertheless
overall, the proposed EPA strategy is greatly preferred to the impulsive or inappropriate
interpretation of poor quality data from badly designed studies. The EPA ORD approach is
sound and logical.
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IV. AGGREGATE AND CUMULATIVE RISK
This component of the Strategy presents a good foundation for improving the scientific
merits of risk assessment, but one that would benefit from adding a significantly greater level of
direction especially related to prioritization of the broad range of research efforts.. The scientific
elements of human health risk assessment are nicely illustrated in Figure 1-3 of the HHRS
document (summarized below).
The source-to-effect continuum in Figure 1-3 clearly shows the relationship between the
output (modeled or measured) from each step along the way, and the input to the next step or
process. By analogy, errors or uncertainties related to early events on the continuum could only
propagate and grow throughout the entire process. As a result, these uncertainties will not only
impact prospective analysis such as aggregate/cumulative risk and efforts to identify highly
exposed subpopulation, but also retrospective analyses needed to relate biomarker data to
exposure, or to evaluate the health outcomes related to risk management decisions. The
document would benefit from a more thorough discussion of the uncertainties in the source to
exposure linkages, particularly in the Executive Summary, the Introduction and in the relevant
sections under Scientific Uncertainties (i.e., Section 2.2.1 and 3.2).
While the panel agrees that exposure assessment represents fully half of the risk
assessment paradigm, as a scientific discipline, exposure assessment is dramatically
underdeveloped and very much behind the scientific progress of toxicology. Indeed, the
scientific and technological foundations of toxicology are well established, and cutting-edge
technical advances and programs in the realm of physiologically based pharmacokinetics and
toxicogenetics are well along. Unfortunately, the same cannot be said of exposure assessment
where our knowledge and understanding of the most fundamental determinants of exposure are
missing. For example, there is a dearth of knowledge on 1) indoor source strengths and building
material emission profiles, 2) indoor absorptive sinks and chemistry; 3) outdoor to indoor
penetration factors; 4) near-field exposure; 5) dermal transfer factors; 6) the effect of HVAC
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systems on indoor source emission rates, transport, fate and concentrations, 7) activity patterns,
and 8) model evaluation. Thus, these gaps and opportunities should represent a vital piece of
research planning.
Since the outputs from sources become the inputs to transport, errors or lack of
knowledge within the realm of sources or other early events on the continuum can only
propagate and grow throughout the entire risk assessment process. Further, knowledge and
understanding of the elements and processes that reside on the Outside part of the diagram are
crucial for the design and formulation of risk management decisions that effectively reduce the
effects on the Inside part of the continuum. Although the HHRS document does establish the
appropriate direction and research areas for a long-term, core research program on human health
risk assessment, as written, it does not reflect a balance in the need for research on uncertainties
in the pre-exposure links of the risk paradigm as compared to the post-exposure components.
Specific research objectives described in the HHRS document indicate a general
movement towards more mechanistically based cellular-level research and in-silico modeling
approaches to better characterize the dose-response relationship. Chemical source,
environmental fate, transport and exposure models that are needed to support
aggregate/cumulative analyses are often based on empirical and/or theoretical relationships that,
in the opinion of this panel, have not been fully developed or adequately evaluated for accuracy.
These pre-exposure elements of the source-to-risk continuum are identified in the current plan
but they are not prominently recognized and outlined as critical early tasks for intensive or
ongoing research. Identification, prioritization and quantitative characterization of near-field
and far-field emission sources, adsorptive sinks, and air/surface chemistry and multimedia
interactions would have a major positive impact on our ability to reduce uncertainty in the
analysis of human exposure and subsequent risk. This basic research should be included in the
current strategic plan because it is a large generic task that is not being done anywhere else in the
world in a broad-based or comprehensive program.
Another element in figure 1-3 of the HHRS document that does not receive adequate
attention in the document includes relating environmental concentrations to exposure
concentrations and characterizing contact and intake/uptake mechanisms that describe the
movement of chemical compounds onto and into the body. Further, neither existing fate and
exposure models nor data provide the temporal and spatial resolution necessary to support
significant advances in research related to aggregate/cumulative exposures or research
identifying highly exposed subpopulations. Increasing the resolution and the reliability of
models and the relevance of data that represent the pre-exposure links will be particularly
important to the successful of the proposed strategy.
The panel acknowledges that many of these pre-exposure research areas are covered in
specific problem driven research (2-11, line 21; 7-3, line 21. problem driven research However,
the document needs to provide information about these specific program areas and how that
research will integrate with the exposure-to-effect research highlighted in the strategy.
Continued hypothesis-driven research to develop and evaluate these pre-exposure modeling and
measurement techniques should be highlighted as an early and relatively high priority research
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area. Indeed, the entire HHRS Strategic plan should be examined to provide an appropriate
balance of allocated resources such that the uncertainties associated with these early
determinants of risk are reduced at the same rate as those related with the later biological events
that culminate in adverse health effects. The panel recommends that the HHRS be revised to
reflect on-going research, and current work plans on source-to-human exposure characterization
and modeling. Hyperlinks to these relevant, specific exposure measurement, characterization,
and modeling research programs should be added to the next iteration of HHRS.
The HHRS document emphasizes the importance of the combined and iterative use of
measurements and models. Figures 1-5 and 1-6 show a process by which premises lead to
measurements, measurements lead to models, models lead to better premises, and better
premises lead to additional experiments and better-informed measurements In contrast r, the
HHRS document also states that the ultimate objective is to develop an integrated modeling
framework (page 2-12, line 14) or a framework to link models all the way from source to
human health effects (page 3-10, line 3). This implies that the Agency expects to complete the
iterative process of experimentation and discovery and arrive at a final, comprehensive modeling
framework. It is not entirely clear that such a framework would have the desired effect of
providing more confidence in exposure-dose-response relationships (page 3-10 line 4).
Confidence in a model comes not from how many links or processes are included but rather from
how well the modeling framework as a whole has been validated. It is important to remember
that there are theoretical, philosophical and practical issues that make validation of these
complex modeling frameworks extremely difficult, if not impossible.
Although the ORD recognizes the importance of model evaluation, the HHRS document
is unclear as to the general approach that will be taken to insure the accuracy of models or
modeling frameworks before they are used in human health risk assessment or in the
reconstruction of exposure from biomarker data or in the evaluation of public health outcomes.
The dilemma is that collecting relevant data for evaluating the accuracy of a model is expensive
and time consuming. Even if model predictions match measurements for a given scenario, this
only provides a snapshot comparison and does not assure that the model will perform adequately
in a prospective or retrospective analysis or for a different scenario. The panel recommends that
the HHRS document discuss how the Agency will evaluate the models and methods that are part
of the strategy and insure their applicability and credibility.
The discussion of the exposure research related to identifying highly exposed
subpopulations begins with the statement that the overall objective should be the development of
a model (2-20, line 12) while in reality, the overall objective is to identify highly exposed
subpopulations of children and important sources and pathways of exposure. Granted the steps
required to develop a model are similar to those required to identify the highly exposed
subpopulation. Nevertheless, the panel recommends that the overall focus be clarified in the
document and placed on the outcome (i.e., identification of highly exposed individuals) rather
than development of the model.
Although the panel agrees that a focus on aggregate exposures and cumulative risk is a major
step forward in how the Agency establishes criteria for the protection of public health, the
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Agency should be cautious in the assumption of the one paradigm fits all approach to risk
assessment. This approach may not be warranted, especially if resources are limited. For
example, while it is true that intakes tend to result from multipathway/multiroute processes, it is
not unusual from a one-pathway/one route combination to explain the preponderance of the
exposure and the dose. In such cases, it may not be cost effective, or even desirable, to
exhaustively investigate aggregate exposure and aggregate risk. It may be useful to identify early
on which exposure and pollutants fall in this category so resources are allocated more
effectively. It is also important to recognize that uncertainties will never be completely
eliminated. Even though the ORD recognizes the need for selection criteria to identify the most
appropriate model (2-3, line 13) in the context of harmonizing risk assessment, similar criteria
for model selection should also be part of the other model intensive areas of research in the
strategy. This is particularly important as the number and complexity of models, continues to
increase. The panel recommends that research to help identify the appropriate level of model
complexity for a given exposure/risk scenario should be a component of the research on
aggregate and cumulative risk.
Using pharmacokinetic models of the exposure-to-dose continuum in reverse for relating
measured biomarker data to exposure is ambitious but clearly offers potential for reducing
uncertainty in the risk assessment process. It should be noted however, that the statement:
"Combined with proper modeling techniques and some knowledge of possible exposure patterns
and measurement, biomarker data can be used to estimate dose and exposure" is still a
hypothesis. It remains unclear how or to what degree the variability and uncertainty related to
physiological parameters in the population and/or to the specific exposure scenario will
influence the ability to perform back calculations in the absence of additional measurements.
However, even if these model lack the ability to characterize prior exposures based in biomarker
data, well formulated models that have been evaluated for accuracy (validated) and advanced
statistical methods should help to identify critical data needs and lead to measurement strategies
that will improve our ability to perform these inverse calculations.
A possibility that needs to be recognized and incorporated into the research on aggregate
and cumulative risk is an awareness of potentially positive or adaptive biological responses
associated with low-level exposures. It is anticipated that a U-shaped dose-response curve at
low (environmentally relevant) concentrations of single and multiple compounds could be quite
common (Calabrese EJ, Baldwin LA, Holland CD: Hormesis a highly generalizable and
reproducible phenomenon with important implications for risk assessment, Risk Anal. 1999: 19:
261-81). This information could be exceedingly valuable in identifying practical thresholds of
human response in defined populations which in-turn could speak to the potential impact of any
risk management activity aimed at lowering human exposure. The panel suggests that non-
monotonic dose-response proximate to actual exposure levels is a potential outcome (hypothesis)
that should be incorporated into this research.
A commendable feature of the proposed approach (and one of the underlying principles
of the HHRS) is that the integrated strategy provides for the intimate collaboration among
ORD s Laboratories and Centers, so that research findings and study results can be incorporated
across research programs through feedback. This collaboration has existed in the past but in a
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less than transparent and consistent manner. In particular, the barriers to communication between
the exposure and human health research programs at ORD need to be further eliminated for the
HHRS to be successful. The HHRS document should explicitly address how findings from
exposure research will be incorporated as one of the fundamental inputs to health research. The
integration of this process with EPA s extramural research through NCER s STAR program is
also a positive aspect of the strategy, although the mechanism for establishing a link is not yet
specified in the HHRS document. . Our explicit recommendation is that communications and
interactions between the various groups be proactively nurtured and supported within the plan.
Although the research areas described in the strategy are ambitious and will certainly
require a longer commitment than a 5-10 year time frame, there is opportunity for early
interaction between modelers and experimentalists that can lead to rapid advances in the
exposure and risk sciences. Specifically, improved communication among modelers,
experimentalists (data collection) and public health experts across ORD and the external
scientific community can open up a number of new opportunities for evaluating existing data
and models and for identifying critical data and modeling needs.
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V. SUSCEPTIBLE POPULATIONS
The reviewers commend the EPA for emphasizing biologically susceptible and highly
exposed populations as a high priority area in need of additional knowledge and research.
Overall, the HHRS document is an excellent draft, and the panel strongly agrees with the overall
goals of the section on Susceptible Populations. The panel acknowledges the multidisciplinary
requirements of such research. The panel commends the Agency on its efforts to further develop
the necessary scientific linkages between different parts of the Agency, between the Agency and
other governmental agencies and university research centers, and the support of
multidisciplinary research centers in and outside the academic community as described in the
HHRS document.
Understanding the upper tails of the exposure distributions and identifying the key
factors that contribute to variability in human exposure will draw on many of the existing and
new methods/tools developed to assess aggregate and cumulative exposures. The panel s
comments related to identifying highly exposed individuals are included in the previous section.
The remainder of this section focuses on the question of susceptible populations.
Susceptible Populations in EPA s Human Health Research Strategy
The HHRS document describes research approaches to the question of susceptible
populations in broad terms. Its focus is directed towards early development, but the potential
impact of chemical exposures during advanced age is also acknowledged, as is the possibility of
long latency, delayed effects. The reviewers would agree the primary research focus should be
the interaction between the developing human (conception through adolescents) and the
environmental but also emphasize the need to conduct research on differently aged individuals,
the elderly (page 21, Effects Research ). The contributions of genetic predispositions and
concurrent disease are also recognized. In strict biological terms, the scope of the research effort
is reasonable; although the more detailed plans to follow is where the most intense examinations
will be directed. Due to the deliberate brevity of the HHRS document, much of the research
detail is not provided and leads to some degree of uncertainty about the research plan.
One major constituent of susceptibility closely tied to public health outcomes seems to be
lacking in the research plan, however. The panel appreciates the legislative and regulatory
boundaries placed on EPA, but questions whether the full public health implications of either
effects or exposure data can be understood without evaluating them in a broader environmental
context. Certain groups, often those that experience the highest levels of exposure, are
vulnerable in many other ways as well. Such disadvantaged populations experience inequalities
in health and social status that parallel what the planning document terms pre-existing disease.
Such inequities comprise a collection of risks that logically fall within the arena of cumulative
risks and that substantially alter an individual s response to environmental chemicals and the
interaction between health status (such as disease states) and the environment. Some of these
factors are listed on page 2-17, but primarily within the framework of exposure, although the
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executive summary mentions stressors other than pollutants. Empirically, moreover, studies
based on the developmental neurotoxicity of lead and PCBs demonstrate differences in
susceptibility associated with the social environment, a phenomenon that has been termed effect
modification. Experimental models can be devised to explore analogous variables in animal
studies, and the ORD laboratories should be capable of undertaking such research. For example,
in rats, the effects of enriched environments (large social groups, play objects) can be
compared to those in rats raised in deprived environments (single housing, no play objects.)
The panel recommends that ORD also utilize animals whose DNA repair genes or tumor
suppressor genes are altered or deleted and/or whose proto-oncogenes are mutated or transposed
and placed under the control of strong promoters in order to model the cancer risk of similarly
susceptible human groups.
The impact of factors such as neuropsychological states (stress or neurobehavioral
dysfunction), threatening environments, exposure to environmental tobacco smoke,
socioeconomic status, drug and alcohol abuse, and maternal and child nutrition on environmental
health were not explicitly noted in the HHRS document These factors interact with
environmental chemicals and should be a leading focus of future research. The influence of
these factors on genetics, age, and disease-specific susceptibility to the adverse effects of
environmental chemicals must also be studied.
No direct mention is made of studies on how early exposure to contaminants may alter
the development of organ systems and functions. The panel recognizes ORD s efforts in this
area, but it is important for the HHRS document to indicate how such interactions may modulate
the response to exposures later in life. For example, how do early exposures affect the
development of the immune system, which, in turn could determine the outcome of cancer and
non-cancer endpoints?
The research plan tends to emphasize the development and application of animal models
(e.g., page2-19, line 5, and onpage 2-21, line26). Animal models may be necessary to
understand mechanisms of toxicity, but the extrapolation of risk estimates from animal data to
risk assessment in humans, although frequently necessary in the absence of human data, is
fraught with hazards and caries an inherent degree of lack of specificity and accuracy. In
developmental toxicology, extrapolation from animal studies to predict the effects of chemicals
on the developing human, although often yielding crucial insights, has also at times proven to be
a misleading predictor of toxicity, sometimes underestimating, sometimes overestimating threats
to human health. It is also important to realize that, for many human outcomes or diseases (e.g.,
arsenic and skin cancer), relevant animal models have yet to be developed. Animal research and
human research need to be closely coordinated, and the validity of the animal models as
representative of the human condition must be carefully determined and cautiously applied.
Many animal studies, for example, including those conducted by EPA, have relied on single
high-level exposures. These issues with animal models underscore the need for expanded human
research, employing both controlled exposure and field studies. In summary, the panel supports
the Agency s plans to develop and apply new animal models and also encourages Agency plans
to conduct studies of certain kinds in humans, such as the acquisition of physiologically based
pharmacokinetic and pharmacodynamic (PKPD) data, that are within current ethical guidelines.
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The impact of stages of life, disease states, and genes on exposure and all aspects of
PKPD should be addressed in full by the Agency. Each subsection (genetic, stage of life, and
disease state) should be implemented within a full PKPD framework. The capacity of stage of
life cycle to influence all the aspects of PKPD is well documented, although major gaps in
knowledge still exist. The same in-depth discussion and approach is relevant for genetic issues
and disease state-related effects. Against a background of impaired health, risk evaluations need
to weigh how exposure to environmental chemicals toxins might further modify PKPD. The
discussion on page 2-18, lines 25-28, should therefore be expanded to include all the PKPD
parameters.
For example, the PKPD approach would practically or theoretically examine the effects
of disease state. Certain disease states could alter both exposure and PKPD. One example may
be children with autism or developmental delay who mouth their hands and toys to a greater
degree than the average child. The adult with anemia may also have increased pica. The child
experiencing an asthmatic attack may breathe more frequently and thereby be exposed to more
air pollutants. Further, the adult or child with dermatitis may absorb chemicals transcutaneously
more than the individual with intact skin. Certain illnesses that alter physiologic states
prevailing during pregnancy can alter hepatic and renal clearance and also metabolic profile. In
addition, host defense may be altered in humans who have cancer with a depressed host defense
mechanism or who are receiving chemotherapy to treat cancer. The inclusion of the concept of
how disease states alter PKPD parameters and consequently alter risk could be included in the
section on page 20. The same approach can be taken with genetics, since genotype can alter
exposure (genetic predisposition to autism), transport proteins, clearance, metabolic profiles, and
end organ sensitivity.
End organ vulnerability is most often thought of when discussing disease states. The
discussion here (page 2-18, line 4) examines how end organ effects may differ during various
stages of development. For clarity, the HHRS document should state that specific adverse
effects, ranging from functional impairment to anatomical birth defects, depend upon a restricted
window of susceptibility during development. Also the agency should determine how
preexisting end organ dysfunction may alter the sensitivity, type, or severity of a chemical
induced adverse effect on end organ function, such as the effect of air pollutants on lung function
in individual with asthma or neurotoxicant on neurobehavioral function of children with
neurobehavioral dysfunction or psychiatric dysfunction.
The HHRS document should provide more specificity in defining, understanding, and
identifying sensitive individuals in the human population subject to disease that can be altered or
induced by environmental exposures. These diseases include neurobehavioral function, asthma,
and cancer. For example, for cancer, will the most susceptible populations be fetuses with
germline mutations, such as Li Fraumeni Syndrome (germline p53 mutations), or
polymorphisms at various DNA repair loci, including but not limited to, Xeroderma
Pigmentosum (XP), or Ataxia Telangetasia (AT), or who have polymorphisms in drug
metabolizing enzymes (glutathione transferase, cytochrome P450 enzymes, etc.)? These
sensitive individuals additionally, may come from economically disadvantaged, nutritionally
disadvantaged, and perhaps also environmentally disadvantaged backgrounds. Or, will these
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sensitive individuals constitute young children who have Li Fraumeni Syndrome, or the rare XP
or AT mutations, or those who are infected with the more frequent Human Immunodeficiency
Virus (HIV), have contracted Acquired Immunodeficiency Syndrome (1C), and are also
economically disadvantaged? Recognition should be given to how the effect of polymorphisms
in enzymes such as glutathione transferase and other enzymes would interact with these germline
mutations in defining the most sensitive receptors. Defining and identifying these highly
susceptible subpopulations ("sensitive receptors") for many disease states, including cancer, is
very important. This consideration should be incorporated into the HHRS document. Additional
specific details should be given in the section entitled, "Research on Susceptible and Highly-
Exposed Subpopulations (Page 2-17).
No definition of susceptibility to cancer would be complete without taking into account
the fact that cancer incidence increases as the fourth or fifth power of age. Translating this
finding into data based on the emerging science of molecular epidemiology provides an
opportunity to determine whether specific chemical carcinogens that are environmental
pollutants do indeed contribute to cancer induction in humans at specific organ sites. That is,
molecular biomarkers of cancer development can be used to trace a population response even if
the exposure occurred during childhood.
All of these considerations emphasize why the plan should define susceptible populations
in more detail, including identifying the biological reasons for the increased susceptibility, for
example, including those with genetic, disease-related, and age-specific predispositions, and
those uniquely exposed to environmental/occupational carcinogens. More explicit definitions
will assist in the pursuit of mechanistic research based on susceptibility. The HHRS document
should also describe how animals whose DNA repair or tumor suppressor genes are mutated or
deleted or whose proto-oncogenes are mutated or altered would be utilized to model the cancer
risk of similarly susceptible human groups.
In its discussions of aggregate and cumulative risk, the HHRS document refers to the
Food Quality Protection Act (FQPA) as a useful example because it specifies a common mode of
action as a criterion for calculating cumulative risk. Although the HHRS document recognizes
the possibility of different modes of action (page 2-15), cumulative risk can also depend on
common endpoints. For example, studies of the developmental neurotoxicity due to exposure to
PCBs, lead, and methyl mercury have all employed IQ measures as criteria, but it is far from
evident that the same mechanisms are responsible for the parallel outcomes. Certain
populations, too, are known to experience elevated exposures to combinations of these agents,
suggesting that commonalities among endpoints should play a role in cumulative risk models
equivalent to commonalities among mechanisms. Put another way, elevated exposure to one (or
class of) toxic agent may render that population more susceptible to the adverse effects of
another (or class of) toxic agent The HHRS document refers to such a possibility (p. 2-15) only
glancingly. Quantifying commonalities in this situation is a challenging problem that deserves
more exposition.
A problem complicating risk assessment and adding to uncertainties is the question of
dose-response relationships. In most of its discussions of dose-response modeling and
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formulation, the HHRS document seems to accept the conventional assumption of mono tonic
dose-response functions. Especially since endocrine disruption gained prominence as an
environmental health question, this assumption seems increasingly questionable, even for agents
such as lead. Non-monotonic dose-response functions for both carcinogens and non-carcinogens
have been the subject of recent conferences and federal government review panels. The panel
believes that HHRS planning should more directly pursue this question because of its
implications for linking exposure and effects and because of the role the Strategy accords
exposure-response modeling.
Although uncertainties lurk in every aspect of risk assessment, a major source of
uncertainty arises from the huge diversity of environmental exposures. This maybe the most
challenging question confronting attempts to link exposures to public health. New risk
assessment prototypes may have to be developed to provide a coherent strategy for formulating
the appropriate research. The HHRS document should clarify what EPA research (ORD) has
achieved so far in reducing uncertainty in risk assessment. The reasons for proceeding along a
specified research path are not clearly explained and need to be supported in a historical context.
The definition of susceptibility in the HHRS document leads to a discussion of how to
take account of biological variability in populations. One source of variability is mostly
overlooked, however. The current HHRS document does not explicitly recognize the importance
of studying both sexes to determine susceptibility. Does ORD have stated policies about this
issue? Even recent publications from the NHEERL show reliance on only one sex in
experimental studies in the areas of inhalation toxicology and neurotoxicology. Given the vast
differences in disease prevalence and risk factors seen in human populations, and, now, the
importance attached to endocrine disrupters, the panel believes that unequivocal recognition of
such differences should be incorporated into HHRS planning.
The multidisciplinary requirements in study design dictate the need for multidisciplinary
cooperative efforts, both within the EPA and between the EPA, other governmental agencies,
and environmental centers in universities. The EPA could also consider partnering with the
National Cancer Institute (NCI), CDC, ATSDR and theNIEHS, to incorporate them into this
multidisciplinary research framework. They could also partner with the Environmental
Protection Agencies of the various States, such as the Office of Environmental Health Hazard
Assessment of the California EPA, and with investigators at research institutes and universities,
and encourage them to participate in this overall strategy of multidisciplinary research. This
would maximize the strength of this overall research effort led and coordinated by the EPA. The
EPA should lead this effort, conduct much of the research, and also co-ordinate the efforts of
extramural scientists and regulators, where common interests exist in regulation of specific
toxins and carcinogens. This cooperation would maximize efficiency ofutilization of resources,
strengthen the overall research effort, and eliminate redundant efforts.
The HHRS document selects out cancer and neurodegenerative disease as two categories
of diseases that are of particular interest in children. Reproductive, neurodevelopmental, and
endocrine disorders should not be accorded less emphasis. The questions invoking the greatest
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concern could be explicated more clearly in the kind of matrix noted above. Perhaps the
statement on page 2-24, line 17, should be explained in greater detail.
The HHRS document states that there is a plan to conduct much of their research on
childhood asthma through the National Children s Study. This pivotal and critical statement
should be explained in much more detail. The reasons to focus on asthma should be explained,
and the reasons to de-emphasize other disease states should be discussed, particularly disease
states that could have greater longitudinal impact on the nation. The National Children s Study
should greatly enhance our grasp of those factors influencing susceptibility. It will not be
definitive, however, because susceptibility is a complex function of many variables that will
require much additional research to elucidate.
The overall intent of the Strategy is to reduce risk to the public from exposure to
carcinogens and toxicants. Therefore, the impact of diet and lifestyle in cancer risk should also
be considered, since these factors can significantly modify cancer risk, and in some cases are the
predominating factors. In the case of prostate cancer, for example, caloric intake and dietary fat
apparently contribute significantly to risk, thereby defining another type of susceptible
subpopulation. In addition, effort should be made to identify the most potent carcinogens that
the public is likely to be most heavily exposed to. Then, the EPA should conduct risk
assessment on these highly carcinogenic chemicals to which the public is heavily exposed first,
to mitigate levels of these chemical agents. Commencing this effort with a model genotoxic
carcinogen, such as aflatoxin Bl, where there is a plethora of data on aflatoxin Bl-DNA
covalent adducts in animals and in humans and synergism between hepatitis B virus infection
and aflatoxin Bl exposure in liver cancer induction, and with a model non-genotoxic carcinogen,
such as TCDD, whose effects are mediated through binding of TCDD to the AHH receptor and
resultant influences on gene expression, is recommended. Modern risk assessment procedures
should be first modeled on these two compounds, or similar compounds, to determine how
difficult and expensive it will be, and how much effort it will require to develop and employ
advanced risk assessment procedures. For example, new conceptual models using mathematical
functions to describe uncertainty distributions for risk of exposure to each set of chemical
toxicants or carcinogens will need to be developed. Distributions of risk, including risk for
sensitive receptors, should be incorporated in the risk assessment calculations where feasible. It
is also necessary, as the HHRS document recognizes, to develop appropriate risk assessment
procedures for important mixtures of highly carcinogenic chemicals to which humans are
exposed, and to determine whether the resultant risks are additive, antagonistic, or synergistic to
populations exposed to these mixtures.
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VI. EVALUATION OF PUBLIC HEALTH OUTCOMES FROM RISK
MANAGEMENT ACTIONS
To date, the Agency has mainly focused on products (e.g., publications in the scientific
literature or implementation of certain controls) or very broad measurements (e.g. number of
children living in non-attainment areas) as indicators of the impact of its programs on
environmental health. These measurements are not appropriate indicators of effectiveness in
attaining the ultimate mandate of EPA, i.e., to protect public health and the environment.
Therefore, the strategy s intent to measure outcomes is a move in the right direction. However,
this is an extraordinarily difficult task, and one to which EPA needs to devote considerable
thought and effort before moving ahead with the formulation of a research plan in this area.
The panel agrees that the phrase Public Health Outcomes as used in the HHRS
document needs to be explained in more detail. The public health perspective is largely absent: it
is axiomatic of pub lie health that detailed mechanisms need not be completely elucidated prior to
preventive action being taken. Furthermore, what the public health outcomes are or how they
will be selected is not clear from the material presented. While the HHRS document mentions
(public health) outcome oriented goals and measures of success, it is unclear throughout most
of the HHRS document whether these outcomes are mostly health-related or also include the
outcome of pollution prevention measures or remediation end points as public health outcomes.
In addition, the HHRS document does not make clear whether the research strategy is intended
to address disease alone as a measure of health status, or whether it includes broader concepts
such as wellness or quality of life.
Concerning measures of success, the panel found the opening paragraph of the Section
(page 3-1) misplaced (environmental compliance costs seemed to be the tail waging the dog of
public health protection). Moreover, since there is no discussion in the HHRS document of
health costs analysis (disability, health care utilization, cost of lost life) it seemed very odd to
begin the entire discussion in terms of cost and leave it at that. This section of the HHRS
document should be deleted (section 3, page 1, lines 4 to beginning of line 10).
There were no specific concepts of "epidemiologic studies presented. Moreover the
Agency should be encouraged to incorporate a public health component in its population
exposure studies (i.e., population exposure studies are not simply a subset of a general
epidemiologic approach.) Thus, the section is addressing two of four suggested approaches in a
rather non-descript fashion. The panel recommends that greater detail be provided to clarify
what type of epidemiologic study is meant (such as cohort, case-control, time-series, molecular
epidemiologic studies). Additionally, the HHRS document implies in some of the examples
chosen that measuring toxin levels in human samples (biomonitoring such as blood lead
monitoring) might serve as a cornerstone of public health outcome assessment. The panel
believes that this is a very reasonable approach to explore Any analysis of such population-
based data, testing for time trends or correlates of either exposure (with the biological
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monitoring as the dependent variable) or, if possible, disease outcomes (biological or health
outcome monitoring as the independent predictor) would be an epidemiologic undertaking.
The panel agreed that it is an oversight that an explicit discussion of the concept of
"biologic monitoring" is missing from this HHRS document. A better explanation of how
priorities would be set for which indicators to collect data via biological monitoring is needed,
even by broad classes. A suggested starting point could be a review of the Toxic Release
Inventory (TRI) data for the 30 largest volume substances together with a listing of matching
and reasonably sensitive biologic markers (such as for metals, organo-chlorines, cholinesterase
inhibitors, PAHs). This is especially relevant in light of the CDC pilot data from NHANES III.
The inclusion of an example in this regard would help to clarify what the approach (and breadth)
of the Strategy is. For example, the EPA has modified its arsenic standard in drinking water.
Perhaps a figure in the text or an appendix could show the relationship between arsenic ingestion
and health outcomes and the impact of differing standards. The risk management decisions to
lower the level would/should result in fewer arsenic health outcomes (skin cancers and bladder
cancers, for example). How might research be conducted to demonstrate this impact from a rule
change? The example could be expanded to provide some of the necessary approaches for
research, surveillance, and additional analysis.
A reduction in exposure is an outcome that can be measured with current methodologies
given sufficient resources. Withmodels that are available today (or combinations of models), it
may be possible to apportion the fraction of the decrease in exposure due to regulatory
intervention, and the portion of the reductions in exposure that occurred consequent to changes
in technology or other determinants, which might have occurred without regulatory intervention.
Such case studies could be developed with currently available methodologies for lead, for
example, for which there is a wealth of information for establishing the chain of events
describing the continuum from emissions to health effects. There are significant historical data
demonstrating the parallel between the decrease in airborne lead concentrations and blood levels
that can be associated with the removal of Pb from gasoline (although this particular regulation
was not directed at protecting the public from the health effects of lead, but was adopted as part
of the ozone control strategy when catalytic converters were mandated). An improvement in
health or decrease in disease resulting from regulatory enforcement, however, would be much
more difficult to establish because of the many uncertainties in risk assessment and the
multiplicity of technological and societal factors that affect health and disease status and trends
in the population. It is possible, for example, for the Agency to promote a rule that actually
decreases the risk for developing a particular disease but, simultaneously, societal and economic
factors increase the probability of developing the disease through other mechanisms with a much
larger net effect. Frequently, those societal and other factors are not recognized early in the
process. Thus the Agency could deem a particular regulatory effort ineffectual and reverse its
course, when in reality the rule or regulation had the effect it was intended in terms of public
health protection. Thus, in the case of Pb, a health outcome measure would have to demonstrate,
for example, improvements in IQ paralleling decreases in blood lead. IQ, however, is affected
by many other societal factors and, in spite of the wealth of data and studies on Pb health effects
that are available, it would be much more difficult to apportion the regulatory and non-regulatory
determinants of improvements in IQ than of reductions in blood Pb. The Agency needs to engage
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more fully in an exercise of defining the characteristics of health outcome measures amenable
to the purpose of tracking the effectiveness of the Agency s regulations.
Furthermore, in terms of epidemiologic approaches, the emphasis on data set linkages
would be far more relevant were it connected to a discussion of prototypical epidemiologic
approaches and their applicability and feasibility in the context of the stated goals. For example,
if the EPA considered a "sentinel health event"0 approach, how would the events be chosen for
which surveillance tracking might be established? The TRI database cross-tabulated with target
organ effects might be a reasonable starting point. A tabular presentation of disease outcomes
with a reasonable environmental population attributable risk would also be highly informative.
This would not have to be all-inclusive but rather a starting point for the public feedback alluded
to in the Appendix. Examples might include: Parkinsonism (manganese, carbon disulfide);
aplastic anemia (benzene); bladder cancer (arsenic); skin cancer (LTV); heat stroke deaths
(meteorological conditions); and non-malignant respiratory mortality (particulate pollution). By
definition, some of these disease outcomes would be studied through mortality records; others
could be studied through a variety of other secondary data sources. The panel also suggested that
while the HHRS document mentions some endpoints, a full range of outcomes should be
considered, including biomarkers of exposure (vs. environmental measures), biomarkers of early
effect (e.g., liver, kidney function changes), child development, toxic endpoints, disease
endpoints, behavior changes, and social-community changes. It seems fairly clear that unlike the
biologic monitoring component, these studies would not be based on an EPA lead in primary
data collection. Thus a primary/secondary data dichotomy might be useful to define.
Within the secondary data analysis realm, it is likely that certain epidemiologic
techniques will be more important than others, but this discussion is also lacking in the draft
document. There is not even a reference to time-series analyses, for example. Also it is not clear
that compiling existing databases will be helpful since most of these databases were constructed
to comply with regulatory standards or serve other needs than to supply adequate data (at the
individual level) for meaningful epidemiologic studies that could lend themselves to drawing
causal inferences. It would be much more helpful to evaluate each of these databases with
respect to usefulness for epidemiologic exposure or outcome assessment at the individual or
ecologic level. For example, if these data can only be used at an ecologic level, one will have to
address problems, in epidemiologic terms, concerning the ecologic fallacy . The issue of
tracking manifestations of disease in non-humans as a marker of human health outcomes should
also be considered; this would provide a linkage between epizootics and human epidemiologic
studies (e.g. West-Nile virus).
Furthermore, if the ultimate goal is to establish linkages between sources, environmental
concentrations, exposure, effects, and effectiveness of management actions, and - assuming that
effects refer to health effects - this most likely means that individual level human data has to be
collected. It is not clear how this can be accomplished in an adequate manner without designing
0 Sentinel health events methodology refers to the identification of target conditions for surveillance in research
based on the likelihood that individual cases may be attributable to the specific risk factors of interest.
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specific and appropriate epidemiologic studies for each question under consideration. It was
noted that all examples for effectiveness evaluations for diverse risk management actions cited
are examples from non-environmental areas (vaccination etc) in which it is possible to collect
individual level exposure and outcome data. These examples are inappropriate as models for
assessing the effectiveness of reducing environmental pollutants at the population level
especially if widespread low-level contamination in large populations is a concern and for which
there most likely will be no easy means of linking exposures to individual health outcomes.
Questions such as whether an action prevented, reduced, eliminated, or modified a disease
outcome may not only be difficult, but impossible to answer for most chronic and complex
diseases with multiple risk factors and etiologies. The research goals should be calibrated with
these major limitations in mind.
Finally, a discussion of the challenges associated with risk reduction evaluation of
complex diseases is missing from the draft document. Fundamental to this is recognition that the
fact that most diseases have multiple risk factors and pathways or so-called competing risks. A
comparison of estimates derived from risk assessment models to actual health outcome rates
predicted by the model may depend on the prevalence and importance of other causal or
modifying or competing factors for a complex disease. Therefore, the reduction of just one
(environmental) risk factor may or may not lead to a reduction of the prevalence/incidence of a
health outcome that depends upon a multitude of factors. These factors may be increasing or
decreasing concomitantly (e.g. a reduction in air pollution and an increase in asthma rates in the
former East-Germany does not lend itself to the conclusion that air pollution causes or
exacerbates asthma). Taking the example of lead exposure reduction and cognitive impairment,
not only would it be methodologically difficult to show longitudinally that a reduction of blood
lead levels in children leads to improved cognition, this direct linkage may not be necessary.
Biological monitoring data demonstrating a decreased lead burden would be scientifically
sufficient to support a positive health impact in light of established dose-response relationships
and consistent with accepted principles of public health that emphasize prudent intervention in
the absence of incomplete certainty. Furthermore, a systematic (generic) framework for all
before/after comparisons is problem-ridden since each complex disease will have its own unique
challenges and most likely will require a custom tailored epidemiologic approach. In order to
establish any trends in disease over time, it may be necessary -to not only to measure the disease
in question (such as asthma) consistently but we may also have to wait generations or decades to
see these trends - periods too long for any policy making purposes.
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VII. CONCLUSION
The Human Health Research Strategy (May 2002 -Draft- HHRS) outlines the ORD's
vision for core research in human health risk assessment over a 5 to 10 year horizon. The HHRS
document represents a remarkable effort to outline a strategic research direction for what is
arguably the premiere research organization on this subject in the world. The HHRS document
is comprehensive and well written. The HHRS is well thought-out relative to the various
elements that need to be considered, with an emphasis on long-term core research to reduce
uncertainty in human health risk assessment using a multidisciplinary research approach the
intramural research capabilities of the individual ORD Laboratories and Centers, and extramural
research sponsored by ORD. The conceptual framework and general directions outlined in the
HHRS provide direction and focus for the ORD's Multiyear Plan on Human Health Research.
The Multiyear Plan, in turn, influences the development of individual program work plans on the
project level at ORD Laboratories and Centers. These individual project level work plans will
likely influence research outside of the Agency through a range of funding mechanisms. Thus,
the strategic research directions described in this document can, and likely will have a direct
impact on the overall focus of the community of risk assessment research, both within and
outside the ORD. The authors are to be congratulated for the hard work and hard-won insights
evidenced throughout this HHRS document. Indeed, it provides an invaluable service to the
broader scientific community just in the deliberation and presentation of the various definitions.
Upon even modest reflection, it is clear that the identification, construction, and implementation
of a plan that will guide the ORD s core human health research program over the next decade
will be an exceedingly difficult but important task. Most important is that the very recognition
of this need is quite significant and worthy of commendation from the risk assessment
community.
A substantive concern is the breadth of the proposed strategy in the context of a 5 to 10
year plan, and given the state of the science of the various disciplines that will address the areas
of uncertainty described in HHRS document (summarized in pages E-3 to E-4). The overall plan
is highly ambitious, even if collaboration and partnering with other agencies is a guiding
principle, and considering that the research objectives are directed at the fundamental principles
and factors that underlined the effects and the exposures leading to those effects. There is a
broad range of scientific uncertainties that may not be addressable in the proposed time frame.
For example, the nature of pollutant mixes is so complex that we are more likely to have a longer
list of research questions than any firm answers within the proposed time frame. Judicious
selection of case studies is a reasonable approach.
The two prong research strategy directed at 1) addressing and reducing significant
uncertainties in human health risk assessment, and 2) developing and introducing measures that
track the public health effectiveness of regulatory mandates of the Agency are clearly delineated
in the HHRS document. The first strategic direction is consistent with the ORD s and Agency s
strategic goals, and it is clearly responsive to many comments and suggestions from the SAB
and external scientific review panels of the Agency s programs. The second prong of the strategy
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moves beyond the typical product measures of effectiveness to the ultimate question of the
impact of the Agency s action on public health.
ORD s plan to focus on developing a multidisciplinary, integrated program that will
build linkages between exposure, dose, effect and risk assessment methods to provide the
scientific basis for harmonizing risk assessment approaches, predicting aggregate and cumulative
risk, and protecting susceptible subpopulations is highlighted in great detail. In addition, the
effort that ORD will apply to develop an integrated research program utilizing its intramural
scientific capacity in conjunction with extramural grants, cooperative agreements, and
interagency agreements is clearly described. The importance of the efforts that have been and
will continue to be made to identify and foster collaboration with other Federal and State
agencies, as well as academic and private organizations having research programs that
complement ORD s research efforts is well articulated. The panel encourages these efforts and
believes that they are essential for the ultimate success of the overall strategy.
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APPENDIX A - ABBREVIATIONS AND ACRONYMS
A TSDR Agency for Toxic Substance and Disease Registry
BBDR Biologically Based Dose Response Modeling
CDC Centers for Disease Control and Prevention
D BPs Disinfection By-Products
EPA U.S. Environmental Protection Agency
FDA U.S. Food and Drug Administration
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FQPA Food Quality Protection Act
GAO U.S. General Accounting Office
GPRA Government Perfomlance and Results Act
NAS National Academy of Science
NCEA National Center for Environmental Assessment (EP NORD)
NCER National Center for Environmental Research (EP NORD)
NERL National Exposure Research Laboratory (EP NORD)
NHANES National Health and Nutrition Examination Survey
NHEERL National Health and Environmental Effects Research Laboratory (EP NORD) NHEP
National Human Exposure Program
NHEXAS National Human Exposure Assessment Survey
NIOSH National Institute for Occupational Safety and Health
NRC National Research Council (NAS)
NRMRL National Risk Management Research Laboratory (EP NORD)
ORD Office of Research and Development (EPA)
P AH Polycyclic Aromatic Hydrocarbon
PBPK Physiologically Based Pharmacokinetic Modeling
PCB Polychlorinated Biphenyl
PM Particulate Matter
RfC Reference Concentration
Rill Reference Dose
SAB EPA's Science Advisory Board
SAR Structure-Activity Relationship
SHEDS Stochastic Human Exposure and Dose Simulation Model
STAR EP NORD Science to Achieve Results Extramural Grants Program
TEF Toxic Equivalent Factor
UF Uncertainty Factor
VOC Volatile Organic Compound
WHO World Health Organization
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APPENDIX B - GLOSSARY
Aggregate Exposure: The combined exposure of an individual or defined population to a
specific agent or stressor via relevant routes, pathways, and sources (working definition
developed by EP A Science Policy Council).
Aggregate Risk The risk resulting from aggregate exposure to a single agent or stressor
(working definition developed by EPA Science Policy Council).
Biological Markers or Biomarkers: Indicator signaling events in biological systems or
samples. There are three classes ofbiomarkers: exposure, effect, and susceptibility. A marker of
exposure is an exogenous substance or its metabolite(s) or the product of an interaction between
a xenobiotic agent and some target molecule or cell that is measured in a compartment within an
organism. A marker of effect is a measurable biochemical, physiological, or other alteration
within an organism that, depending on magnitude, can be recognized as an established or
potential health impairment or disease. A marker of susceptibility is an indicator of an inherent
or acquired limitation of an organism' s ability to respond to the challenge of exposure to a
specific xenobiotic.
Biologically-Based Dose Response (BBDR) Model: A model that describes biological
processes at the cellular and molecular level linking the target organ dose to the adverse effect.
Childhood: Nominally, the period from birth through the onset of puberty. However, the Human
Health Research Strategy addresses adverse effects on the developing organism that may result
from exposure to environmental agents, starting with preconception exposures to parents and
continuing through gestation and postnatallyup to the time of maturation of all organ systems.
Cumulative Risk: The combined risks from aggregate exposures to multiple agents or stressors
(working definition developed by EPA Science Policy Council).
Dose: The amount of a substance available for interactions with metabolic processes or
biologically significant receptors after crossing the outer boundary of an organism. The potential
dose is the amount ingested, inhaled, or applied to the skin. The applied dose is the amount of a
substance presented to an absorption barrier and available for absorption (although not
necessarily having crossed the outer boundary of the organism). The absorbed dose is the
amount crossing a specific absorption barrier (e.g., the exchange boundaries of the skin, lung,
and digestive tract) through uptake processes. Internal dose is a more general term denoting the
amount absorbed without respect to specific absorption barriers or exchange boundaries. The
amount of the pollutant available for interaction by any particular organ or cell is termed the
biologically effective dose for that organ or cell.
Effectiveness: The improvement in health outcome that a prevention strategy can produce in
typical community-based settings.
Efficacy: The improvement in health outcome that a prevention strategy can produce in expert
hands under ideal circumstances
Exposure: Contact of a pollutant, physical, or biological agent with the outer boundary of an
organism; exposure is quantified as the concentration of the agent in the medium over time.
Margin of Exposure: The ratio of the critical NOAEL to the expected human exposure level.
Mechanism of Action: The complete sequence of biological events that must occur to produce a
toxic effect.
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Mode of Action (MOA): A less-detailed description of the mechanism of action in which some,
but not all, of the sequence of biological events leading to a toxic effect is known.
Nonthreshold Effect: An effect for which it is assumed that there is no dose, no matter how
low, for which the probability of an individual's responding is zero.
No-Observed-Adverse-Effect Level (NOAEL): The highest exposure level at which there are
no statistically or biologically significant increases in the frequency or severity of adverse effects
between the exposed population and its appropriate control.
Outcome Measure: The final health consequence ( e.g., cases prevented, quality-adjusted life
years) of an intervention.
Pharmacodynamics: The determination and quantification of the sequence of events at the
cellular and molecular levels leading to a toxic response to an environmental agent (also called
toxicodynamics ).
Pharmacokinetics: The determination and quantification of the time course of absorption,
distribution, biotransformation, and excretion of pollutants (also called toxicokinetics ).
Physiologically-Based Pharmacokinetic (PBPK) Model: A model that estimates the dose to a
target tissue or organ by taking into account the rate of absorption into the body, distribution
between target organs and tissues, metabolism, and excretion.
Program Office: An EP A organizational unit that administers a major EP A program (i.e., Air
and Radiation; Water; Prevention, Pesticides, and Toxic Substances; and Solid Waste and
Emergency Response).
Reference Concentration: An estimate (with uncertainty spanning perhaps an order of
magnitude) of a continuous inhalation exposure to the human population (including sensitive
subpopulations) that is likely to be without an appreciable risk of deleterious noncancer effects
during a lifetime.
Reference Dose: An estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily exposure to the human population (including sensitive subpopulations) that is likely to be
without an appreciable risk of deleterious noncancer effects during a lifetime.
Susceptibility: Increased likelihood of an adverse effect related to intrinsic (i.e., life stage,
genetic predisposition) or extrinsic deteffilinants (i.e., preexisting disease) unique to the
organism.
Threshold Effect: An effect for which there is some dose below which the probability of an
individual's responding is zero.
Uncertainty Factor (UF): One of several factors used in calculating an exposure level that will
not cause toxicity from experimental data. For example, UF's are used to account for the
variation in susceptibility among humans, the uncertainty in extrapolating from experimental
animal data to humans, and the uncertainty in extrapolating data from studies in which agents are
given for less than a lifetime.
Vulnerability: Synonymous with susceptibility
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