11,1. Invlronm.nui W»»Wnf**ii, 6C
Report of the Health Risk Assessment
Core Research Plan Review
Subcommittee
Review of The Office of Research
and Development's Draft Core Research
Plan for Health Risk Assessment
AICKNCI ADVISOft Y ftOAlfi MHNMT Jyly'1>vo
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O. 8. ENVIRONMENTAL PROTECTION AGENCY
MOTIGI
This report has been written as a 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 pro-
ducts constitute a recommendation for use.
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ABSTRACT
This report presents the conclusions and recommendations of
the U.S. Environmental Protection Agency's Science Advisory Board
summarizing a review of the Office of Research and Development's
draft research plan for Core Health Risk Assessment* The Board's
concensus was that the proposal was well written, and identified
many worthwhile subjects for longer-term environmental health
research. At the same time, it failed to provide priority-setting
mechanisms, did not relate its agenda to on-going national research
programs, and seemed overly bound to a risk assessment paradigm.
Key Words; Environmental health research" risk assessment; long-
term research; core research.
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ORD HEALTH RISK ASSESSMENT CORE RESEARCH PIAN
REVIEW SUBCOMMITTEE ROSTER
Chairman
Dr. Morton Lippmann
Department of Environmental
Medicine
New York University Medical
Center
Membersand Consultants
Dr. Marshall Johnson
Department of Anatomy
Jefferson Medical college
Dr. Warner North
Principal, Decision Focus Inc.
Dr. Martha Radike
University of Cincinnati
Institute of Environmental
Health
Dr. John D. Spengler
Department of Environmental
Science
and Physiology
Harvard School of Public
Health
Dr. Jan A. J, Stolwijk
Department of Epidemiology and
Public Health
School of Medicine
Yale University
Dr. Bernard Weiss
University of Rochester
Medical School
Dr. Ronald Wyzga
Electric Power Research
Institute
Executive Secretary
Mr. Samuel Rondberg
US Environmental Protection
Agency
Science Advisory Board
499 South Capitol Street, S.W.
Room 508
Washington, D. C. 20460
Staff Secretary
Mary Winston
US Environmental Protection
Agency
Science Advisory Board
499 South Capitol Street, S.W,
Room 508
Washington, D. C. 20460
Director. Science Advisory
Board
Dr. Donald Barnes
US Environmental Protection
Agency
Science Advisory Board
401 M Street, S.W.
Washington, D. C. 20460
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TABLE OF CONTENTS
1.0 EXECUTIVE SUMMAOT . . , , 1
2.0 INTRODUCTION ,.»....„»,.„... 3
3.0 DETAILED FINDINGS 4
3.1 Conceptual Strategy ...... . . 4
3.2 Setting Research Priorities ............ 6
3.3 Appropriate Areas for Research ..... 7
4,0 CONCLUSIONS AND RECOMMENDATIONS ........... 11
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1.0 EXECUTIVE SUMMARY The Subcommittee net at Environmental
Protection Agency (EPA) Headquarters in Washington D.C. on April
4, 1990 to review the document "Core Research Program for Health
Risk Assessment" and heard briefings by Drs. Peter Preuss and Ken
Sexton, EPA Office of Research and Development (ORD) staff. The
core document represents part of a major initiative by EPA to
implement the 1988 Science Advisory Board (SAB) Future Risk report
recommendations for a substantial increase in resources (and a
concomitant increase in operational stability) for its long-term
research efforts. Two other parallel core research program drafts
are also being reviewed by the SAB, i.e., on ecological risk
assessment and risk reduction (primarily engineering technology and
pollution prevention).
The Subcommittee was specifically asked to address the
following questions:
a) Is the conceptual strategy clear?
b) Do we have the appropriate major areas for research?
c) Have we asked the right questions?
d) Within each of the major topics, do we have the proper
sub-elements? What's missing? What doesn't belong?
e) Is the rationale and need for each sub-element clear and
convincing?
f) Are the types of research proposed within the sub-elements
appropriate?
g) Does the discussion provide an adequate indication of
priorities for future research?
The briefing and document demonstrated a new and very welcome
change in ORD and the EPA's vision of its role. We endorse
strongly the plans to identify and support a core prograa with a
longer term research agenda, and the plan to have a broad oversight
committee guide the program. The core research program will help
ORD play a »uqh more important role in developing a better
fundamental scientific base for future regulatory and guideline
development, as well as a greater ability to anticipate emerging
problems and their scope and research needs.
The Subcommittee also found that the document was very well
written and constituted a thorough and well conceived description
of important EPA and national research needs in environmental
health. The authors deserve commendation for developing a document
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which is very responsive to SAB recommendations and expands upon
them in a constructive and thoughtful way. We found little to
criticize vis-a-vis those topics covered in the document, but did
note that it failed to address somes other significant elements,
Among these are:
a) The document, as reflected in its title, is too narrowly
focussed on a paradigm for core research on risK
assessment, At the sane time, it generally ignores
research activities on risk assessment methods jjer se.
The core research program can and should address a broad
range of EPA needs, but should also deal with the
interaction between the health research program described
in this plan, and Agency needs for risk assessment
methods.
b) The document does not discuss how research priorities are
to be set. It outlines a broad range of worthy endeavors,
but describes an agenda that would consume far more re-
sources than those likely to be available in the next few
years, Thus, it is essential......jfchjaJE subsequent drafts
describe the mechanismsfor priority setting and staging
for the most critical needs.
c) The document does not adeguately address how the new EPA
initiatives will fit into the larger national effort in
environmental health research. It should Include a
description of the mechanismsby which ORD will monitor
progress in areas of common interest in the National
Institute of Environmental Health Sciences (NIEHS^. the
National Institute of Occupational Safety and Health
(HIOSH) . the Agency for Toxic Sub,stances_and Disease
Registry fATSDIU . the National Center for Health
Statistics fNCHS^ . and other relevant institutions, and
how its Qwn_inJLtiatives will supplement, complement, and
utilize the results of these......other programs.
Section 4*0, Conclusions and Recommendations, provides
additional comment on the issues noted above, and some suggestions
for improving future iterations of the draft plan.
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2-° iMtROPPCTiQK By the late 1980s, most observers of EPA's
Office of Research and Development (QRD) recognized that the
program's research '•portfolio" was unbalanced, being overweighed
with near-term activities directed at specific regulatory problems
and issues, to the detriment of longer-term, broader gauge efforts
designed to improve (or attain) fundamental understanding of
critical areas which underlie IPA'S scientific activities—e.g.,
source-exposure, exposure-dose, and dose-response relationships—
needed to improve health risk assessment. At ORD'S request, the
SAB reviewed the research program's overall directions and
strategies and issued the 1988 report "Future Risk"1. The report
encouraged QRD to place greater emphasis on planning and supporting
research on more basic environmental health issues, and to develop
and implement "basic core research programs in areas where it has
unique responsibilities and capabilities."
ORD's response was to create such an identified program, with
a long-term commitment of resources, intended to improve
understanding of fundamental environmental health, ecological, and
risk reduction issues. To help explicate and direct the effort,
draft core research plan documents were prepared for each of the
three areas noted, and the SAB was asked to review them.
The Health Core Research Plan Review Subcommittee carried out
their review on April 4, 1990, at EPA Headquarters in Washington
D.C. The charge to the Subcommittee provided the basic structure
for the meeting, and contained the following elements;
a) Is the conceptual strategy clear?
b) Do we have the appropriate major areas for research?
c) Have we asked the right questions?
d) Within each of the major topics, do we have the proper
sub-elements? What's missing? what doesn't belong?
e) is the rationale and need for each sub-element clear and
convincing?
f) Are the types of research proposed within the sub-elements
appropriate?
g) Does the discussion provide an adequate indication of
priorities for future research?
U.S. EPA, Science Advisory Board, Future Risk!
Strategies tor The 1990s. SAB-EC-88-040, Washington D.C.,
September, 1988.
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The following report represents the results of the
Subcommittee's analysis of the draft Core Research document, and
its discussions with senior ORD management staff during the
meeting.
3.0 DETAILED FINDINGS The Subcommittee«s findings are subsumed
into three major categories dealing with: the conceptual structure
of the core document; the appropriate content of a core research
program? and the setting of research priorities. Within these
categories, this report also addresses specific details on program
content and the planning and coordination, of a core program.
3*1 Conceptual Strategy Because so much of the Agency's current
efforts are guided by the conventional risk assessment framework,
the core program document adopted what is, in essence, an analogous
structure. Although such a model serves the explain to an audience
within the Agency the directions the core program seeks to pursue,
its scope may be too limited to serve EFA's future needs.
Alternative models should be explored* as well. The Relative Risk
Reduction Study2, for example, examined environmental health issues
from a much broader perspective, and included facets for which 1PA
currently has no legal or operational responsibility, such as
occupational exposures and their consequences.
The core program draft plan describes a broad program of
research, much of which corresponds to prevailing EPA activities.
Again, the specific aims are scientifically laudable. EPA,
however, is not equipped to pursue all of these laudable aims
simultaneously, nor should it do so. Few clues are yielded by the
document about the process, or, more importantly, the total
framework around which the elements of the program will be fixed.
Questions about agents, or classes of agents, cannot be assigned
to a secondary role because they help determine how a problem will
be structured, nor does the proposal provide guidance to the Agency
to call for more research on quantified structure activity research
(QSAR) , exposure markers, and mechanisms, another possible approach
to organizing the program.
2An on-going SAB project to assess the relative risks of
various environmental agents/toxicants to health, welfare, and the
ecosystem. The project is a review, re-assessment, and extension
of an earlier SPA staff effort (U.S. EPA, Unfinished Business.
Washington D.C., 1987).
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One crucial question that this program night help resolve, and
that is a key issue for the EPA, is the compatibility of risk
estimates based upon QSAR, biological (molecular) markers, in vitro
test systems, animal studies, and/or human data. In fact, the
entire core program could be conceived of as a plan for what could
be termed vertical integration of these different components.
Moving up and down this conceptual "ladder" would offer the
possibility of a more economical, immediate risk assessment
process. Some strategic vision, albeit not necessarily the or*?
above, is essential if the core program is to enlist interest and
support beyond EPA. This is of special importance if these
priorities and objectives are to be integrated with the objectives
and priorities of other agencies.
Another alternative conceptual model derives from posing the
issues from the point of view of society's broader health concerns*
That is, what are the major health questions facing our society?
To what extent are they linked to environmental variables both
directly and indirectly related to EPA concerns and
responsibilities? What kinds of information does EPA require to
provide such an assessment or to modify the risks? How does it
mesh with the needs and objectives of other agencies? Should such
an assessment be carried out by an inter-agency task force, and if
so, how frequently is such an effort required?
Lastly, this document should articulate why there is a need
for a core research program differing from the research activities
currently underway within the Agency, in part, it does state that
we need basic research on mechanisms and on relationships between
the elements of a risk assessment (sources, exposure, dose, etc.).
It is clear that such information will help the Agency make
informed risk assessment and risk management decisions. The
document presents a logical structure for linking not only the
elements of risk assessment, but also the interactions among media.
What is missing, in the broad conceptual view, is an explicit sense
of the objective of this research enterprise. The goal is not just
better predictive models or tabulation of the impact of
environmental exposures on the health of the nation's population.
Ultimately the goal of the core research program should be to
provide understanding, methodologies and information to improve the
status of the nation's health through more effective and efficient
management of all aspects of the environment. This calls for a
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more comprehensive vision and explication as to how the research
areas will be targeted and how the results will be utilized.
3.2 Setting Research Priorities The core research program
document provides, as noted above, a comprehensive list of
potentially needed health research. The research possibilities
mentioned are so vast, however, that even optimistic projections
of EPA resources would support only a fraction of the research
described. There is a great need to incorporate some mechanism for
setting priorities into the draft document. Without such a system
the selection of research elements is unclear and the program is
at best ambiguous.
The definition and choice of priority-setting mechanisms is
the responsibility of the EPft staff? however, these mechanisms
should probably incorporate some of the following features:
a) The magnitude of the environmental health problem
addressed should influence the research priority; the formulation
of such estimates would benefit from broad-based participation from
the scientific community and public interest groups in a stable and
on-going relationship.
b) The ability of the research to reduce uncertainty about
environmental health risks should be a significant factor in the
priority assessment.
c) Managerial input is clearly needed to define a cohesive
research program, but input is also needed from researchers who can
identify specific research opportunities which could contribute
greater than usual benefits. To accomplish this, we suggest that
a group composed of appropriate agency staff officials be
designated to communicate with appropriate governmental agencies
involved in basic research related to the environment and health.
Many of the basic research issues put forth in the draft document
are being addressed in other research programs, e.g., NIOSH, NIEHS,
NCI, ATSDR, etc. The charge of this "Research Communication
Committee" would be to react individually with scientific personnel
in other agencies, share EP&'s plans and results and explore each
agency's basic research plans and findings related to the U.S.
IPA's goals and objectives. These basic research data are to be
communicated to those implementing the core research program and
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to scientific personnel in the EPA actively engaged in related
investigations.
3.3 Appropriate Areas tog Research we are all keenly aware of
the shifts in our society; for example, the marked changes in age
distribution. Is such a factor likely to alter our relative
emphasis on different aspects of environmental health, such as how
we evaluate exposures, mechanisms, and effects? This is one
example of the kinds of questions that should guide a program
designed to propel the Agency's future research agenda.
The proposed agenda, described in the core program document,
is clearly written and conforms to what we expect of a solid
scientific enterprise—within the areas it addresses. Perhaps the
problem is its very solidity. A more extended perspective, even
one marked by speculation would have afforded both EPA and its
presumed audience a much better grasp of the possibilities.
I*ooJting at specific program content, it is obvious the
implementation of the proposed core plan would consume far more
resources than those likely to be available in the next few years*
Thus, choices must be made in the allocation of available funds.
One basic decision in this regard, is whether to spread the
resources among a broad variety of research options and in-house
competence building or, alternatively, to focus the program on a
smaller set of options in order to have a more visible yield in a
few high priority areas. In the latter case, exploratory efforts
could be devoted to some areas that would be candidates for future
high priority research efforts.
The Review Committee favors the latter option, and believes
that productive efforts in the initial target areas will build
support for the further development and maintenance of a productive
core program in health research. In selecting research areas for
focused research, consideration should be given to those targets
ofopportunity whererelatively modest levels of support could
yield very substantial yields of research results on population
exposuresf dosimetrv. and exposure-response relationships. Among
the activities deserving of consideration in this regard are:
a) Systematic acquisition, quality-assurance, organization,
and utilization of data sets on environmental concentrations,
biomarkers, health outcomes and their interrelationships. This
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activity can demonstrate the extent and magnitude of health effects
associated with environmental exposures in some cases, and generate
hypotheses for further research in others. Specific opportunities
for research in this area are well described in Section 5 of the
February Draft supplied to the Subcommittee.
b) The development of methods and means to extrapolate
results from animal and in vitro studies to humans. A considerable
portion of the scientific discussion of human health effects is
based on laboratory studies of animals and of animal tissues in
vitro. Given the difficulties of conducting human clinical and
epidemiological research, animal and in vitro research will
continue to provide the most significant health information in many
areas. If In vitro data are ever to be utilized in quantitative
risk assessment, there is a strong need to develop methods to
extrapolate results from these studies to the human condition. A
particularly fruitful approach could be to collect data from animal
and in vitro studies for chemicals where good human data are
available» Toxicants that exert their effects via similar
mechanisms may be quantified by in vitro studies. One potentially
useful approach is to set up a mechanism for acquiring the large
data bases on biomarkers and exposure levels among industrial
workers. Many large companies have historic as well as current
data that can become an exceptionally rich and useful data base for
studies of biomarker validation and exposure-response. With the
proper safeguards and means of protection of confidentiality and
data source, it is possible that the !PA could acquire data from
many cooperative companies.
An understanding of how human risks for various measures of
dose are expressed in animals could also greatly enhance future
efforts to predict human risk from animal studies. Within this
broader context, the core document should more explicitly address
reproductive toxicity. We learned from the thalidomide experience
in 1960 that there are agents which are considered "safe" on the
basis of adult toxicity, but which have a unique capability to
interfere with the developmental process at doses below those which
adversely affect maternal health. If the EPA is to deal with this
issue, a research effort must be designed to identify families of
agents that have this property; to develop a concept of the
quantification of selectivity? and to determine whether or not one
can detect patterns of toxicants which fall, or do not fall, within
this group*
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c) A systematic acquisition and exploitation of lexicological
data bases relating organ toxicity and toxicological dose in
animals and humans (as discussed in the draft core document on
pages 4-6 and following), is a logical and cost-effective target
of opportunity. Such data are valuable for risk assessment based
on interspecies extrapolation.
In prioritizing research needs, the Subcommittee has
identified several key areas beyond those denoted as "targets of
opportunity." These key areas include:
a) Research on Integrated Exposure Assessment, We recognize
the need for multimedia models, as discussed in Section 2.3,4. of
the core document. We encourage ORD to examine total human
exposure assessment needs, with efforts aimed at improved
environmental measurement techniques and biomarlcers, and their
validation.
b) A strategic Approach to Dosimetry. Section 3.1.1.
provides a framework for a systematic examination of the
state-of-the-art in dosimetry. The results of this examination can
be used to guide future research for developing PB-PK models in
particular, and dosimetry research in general.
c) Research on biomarkers. The Environmental Health
Committee of the SAB has recently examined the ORD biomarkers
research strategy. The following is an appropriate excerpt from
their report that refers to both near term and longer range
efforts: "EPA's recommendations would be guite reasonable if
examined in isolation, and if there were substantially greater
resources to implement them. However, even if all the projected
resources were available for the development of new, more sensitive
biomarkers, it would only permit modest incremental contributions
to those already being developed in the Health Effects Research
Laboratory of EPA (HERL) , NIOSH, ATSDR, NIEHS, and the NIEHS
Superfund program project grants at academic centers." Thus, the
mechanism for communication with other agencies recommended in
Section 3.2 (c) is especially appropriate to the biomarkers
program.
d) Development of models for chronic disease etiology. One
extremely important research area not addressed in the document is
the development of chronic deficits in performance and function
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following a repetitive series of acute exposures. conventional
animal models have been ineffective for important endpoints such
as: l) developmental deficits deafly associated with low levels
of environmental lead exposure; 2) increased rates of bronchitic
symptoms in children living in areas of high ambient aerosol
acidity? and 3} reduced rates of lung function growth in children
exposed to environmental tobacco smoke. Means of addressing these
kinds of slowly developing chronic disease effects from low-level
and intermittent environmental exposures should be a major focus
of EPA's long-range research planning.
e) Research on risk assessment, i-e*, the synthesis and
interpretation of health science to provide a basis for risk
management decision making by the Agency. Recent reports by the
SAB on the revised guidelines for risk assessment of
reproductive/developmental toxicants3 and on asbestos4 are two cases
in which valuable areas for further research are identified-
Subcommittee suggests that in future development of the
core program, additional external input would be of benefit, in
terms of improved coverage and depth of coverage. Such input would
ensure that various research areas, even though well represented
in the core plan, are up to date and not simply a repackaging of
the research interests of the Agency scientists* Just because a
research area is of long time interest to Agency scientists does
not mean that it merits th« emphasis perhaps evident in the
document .
It is suggested that a workshop or similar means be used tQ
oyejrcome thes_e__types of potential ___ problems. gicrnificant input
from leaders,, in diverse areas * who are _ not Agency
employees or contractors,* In general, development of an
Agency/ Academic ongoing interaction would be markedly useful to the
Agency scientists.
of Proposed Revisions to the Guidelines for Health
Assessment of Su-*tt?eet Developmental toxicants, SPA^SAB-EHC-90-013,
April, 1990.
4Letter Report to Administrator William K. Rellly, EJ?A-SAB-
Letter-90-002.
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4.0 qQHCEOSIQNS AMP agCOMMENDATlQUfl The Subcommittee found the
draft plan to toe well written, and to provide a thorough and well
conceived description of important EPA and national research needs
in environmental health* The authors deserve commendation for
developing a document which is responsive to earlier SAB
recommendations and which builds upon them in a constructive and
thoughtful way. Little was found to criticize in the content of
the document. On the other hand, the document does laclc some
significant elements. Among these are:
a) The document, as reflected in its title, is too narrowly
focussed on a risJc assessment paradigm for core research?
at the same time, it generally ignores research on risk
assessment methodologies, per se. The core research
program can and should address the broader range of EPA
needs, but should also address the interaction between the
health research program in this plan, and Agency needs for
risk assessment methods.
b) The document is inadequate as a tool or guide for setting
research priorities. It describes a broad range of worthy
endeavors, but in doing so creates an agenda that would
require far more resources than those anticipated to be
available in the next few years. Thus, it is essential
that subsequent iterations jiescribe mechanisms for
priority setting and time phasing for the most critical
needs.
c) The document does not adequately address how the new EPA
initiatives will fit into the larger national effort in
environmental health research. It should include a
description of the mechanisms by which ORD wi1\_monitor
progress and plans in areas ofcommon interest in NIEHS.
NIOSH. ATSDR. NCHS, etc, and how jts own initiatives will
supplement, complement;f and utilize the results of these
othef programs.
d) The Agency should give serious consideration to the
suggestions for specific research areas provided in
section 3.3 above—"targets of opportunity." integrated
exposure assessment, strategic dosiaetrv approaches.
biomarkers research, risk assessment methodology, and
models for chronic disease etiology,
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r
e) provision should be made for increased external input^tg
EPA res_g_ar_ch._ planning bv the many other science
institutions in the jf_edeyaL_gQgerrment and the private
sector. Some mechanisms for accomplishing this are
suggested above, but the possibilities for setting up
fruitful interactions is by no neans limited to those
noted.
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