United States
Environmental Protection
Agency
Office of Research and
Development
Washington, DC 20460
EPA/600/R-98/087
February 1998
www.epa.gov
Research Plan for
Endocrine Disruptors
Estradiol-17(3
-------
On the cover: Three dimensional ball and stick representation of estradiol-17p. The model and
surface were constructed with the Sybyl and MolCad molecular modeling packages, by Tripos
Associates, St. Louis, MO. The aromatic A ring is depicted to the left. The surface surrounding
the ball and stick figure represents the electron density volume of the estradiol-17(3 that might be
recognized by the estrogen receptor protein. Computer modeling approaches such as these are
used to explore physical-chemical properties that either promote or deter ligand-receptor binding
interactions and thus can aide in the construction of predictive structure-activity relationships
for environmental chemicals. Figure courtesy of Dr. Tom Wiese, University of North Carolina
Curriculum in Toxicology Research Fellow.
-------
ORD Research Plan for Endocrine Disrupters
OFFICE OF RESEARCH AND DEVELOPMENT
US ENVIRONMENTAL PROTECTION AGENCY
RESEARCH PLAN FOR ENDOCRINE DISRUPTORS
February, 1998
-------
ORD Research Plan for Endocrine Disrupters
FOREWORD
The 1996 Strategic Plan for the Office of Research and Development (ORD) sets
forth ORD's vision, mission, and long-term research goals. As part of this strategic
process, ORD used the risk paradigm to identify EPA's top research priorities for the next
several years. The ORD Strategic Plan is thus the foundation for the research strategies
and research plans that ORD has developed, or is in the process of developing, to identify
and describe individual high-priority research topics. A research plan is different from a
research strategy. While a research strategy provides the framework for making and
explaining decisions about program purpose and direction, as well as relative priorities and
research distributions, a research plan defines the research program that EPA is pursuing.
The research strategy, as an overarching view of research needs and priorities, forms the
basis for the research plan and provides a link between the ORD Strategic Plan and the
individual research plan. In turn, the research plan links the research strategy to individual
laboratory implementation plans (which serve as the blueprints for work at ORD's national
laboratories and centers) by defining the research topic at the project level. One of these
high-priority research topics is endocrine disrupting chemicals (EDCs).
The Research Plan for Endocrine Disrupters was developed through
recommendations from two EPA workshops (April 1995 in Raleigh, NC, covering human
and ecological needs from a broad-scale, risk-assessment-based approach; and June
1995 in Duluth, MN, focusing on ecological research needs) and their subsequent risk
assessment breakout groups, the scientific judgment of the ORD Research Planning
Committee, and internal and external peer reviews. ORD developed this research plan
because of the possibility of serious effects on human and wildlife populations and the
persistence of some EDCs in the environment.
The key scientific questions the EDC research plan sets out to address are:
*• What EDC-related effects are occurring in exposed human and wildlife
populations?
*• What are the chemical classes of interest and their potencies?
*• What are the dose-response characteristics in the low-dose region?
*• Do EPA's testing guidelines adequately evaluate potential endocrine-mediated
effects?
*• What extrapolation tools are needed?
What are the effects of exposure to multiple EDCs, and will a toxicity equivalency
factor (TEF) approach be applicable?
How and to what degree are human and wildlife populations exposed to EDCs?
What are the major sources and environmental fates of EDCs?
How can unreasonable risks be managed?
To answer these questions, the EDC research plan establishes the following
research priorities in the form of ten broad categories of research needs: basic research,
biomarkers, database development, exposure determination, exposure follow-up, mixtures,
-------
ORD Research Plan for Endocrine Disrupters
multi-disciplinary studies, risk assessment methods, hazard identification, and sentinel
species.
This research plan is an important accountability tool because it makes clear the
rationale for, and the intended products of, EPA's endocrine disrupter research. By
specifying in advance how EPA will manage its scientific data and information products,
EPA can communicate the results of its EDC research effectively to its clients,
stakeholders, and the public. This research plan is also an important budget tool, enabling
EPA to clearly track progress toward achieving its EDC research goals, as required by the
1993 Government Performance and Results Act.
Lawrence W. Reiter, Ph.D.
Acting Deputy Assistant Administrator
for Science, ORD
-------
ORD Research Plan for Endocrine Disrupters
PEER REVIEW
Peer review is an important component of research plan development. The peer
review history for this research plan follows:
Initial Internal Agency Review:
ORD Science Council:
Lead Reviewers:
Submitted for Comments
to the Endocrine Disrupter
Working Group of the
Committee on the
Environment and
Natural Resources (CENR)
External Peer Review:
Reviewers:
February, 1996
Final Clearance, December, 1996
Rick Linthurst, NERL
Jennette Wiltse, NCEA
April, 1997
July 8-9, 1997, Washington, DC.
William Cooper, Michigan State University
George Daston, Procter & Gamble Co.
Peter DeFur, Virginia Commonwealth University, Chair
Paul Foster, Chemical Industry Institute of Toxicology
Michael Fry, University of California, Davis
Louis Guillette, University of Florida
Holly Hattemer-Frey, SAF*Risk
Susie Humphreys, U.S. Food and Drug Administration
Timothy Kubiak, U.S. Fish and Wildlife Service
Stephen Safe, Texas A&M University
Susan Shober, National Center for Health Statistics
Richard Seegal, New York State Department of Health
Coordinated by: Eastern Research Group, Inc.
Bill Word, Risk Assessment Forum, Project Officer
Final Acceptance by ORD:
ORD Executive Lead:
March, 1998
Larry Reiter, NHEERL
IV
-------
ORD Research Plan for Endocrine Disrupters
AUTHORS
Gerald Ankley, NHEERL
Elaine Francis, OSP
Earl Gray, NHEERL
Robert Kavlock, NHEERL, Chair
Suzanne McMaster, NHEERL
David Reese, NCERQA
Greg Sayles, NRMRL
Anne Sergeant, NCEA
Daniel Vallero, NERL
-------
ORD Research Plan for Endocrine Disrupters
TABLE OF CONTENTS
I. INTRODUCTION 1
II. REGULATORY BACKGROUND 5
III. RESEARCH ISSUES 7
IV. RESEARCH APPROACH AND ACTIVITIES 10
Biological Effects Studies 12
Issue 1. Chemical Classes and Potencies 12
Issue 2. Testing Protocols 13
Issue 3. Dose Response Relationships 13
Issue 4. Endocrine Profiles in Wildlife 15
Issue 5. Extrapolation to Populations 16
Issue 6. Mixtures 18
Exposure Studies 19
Issue 1. Characterization Framework 19
Issue 2. Exposure Assessment Tools 20
Issue 3. Environmental Concentrations 22
Linkage Studies 24
Issue 1. Risk Assessment Integration 24
Issue 2. Exposure Characterization 25
Issue 3. Status and Trends 27
Issue 4. Risk Management Approaches 28
V. RESEARCH IMPLEMENTATION GUIDANCE 30
VI. REFERENCES 32
APPENDIX I. TIME LINES TO ADDRESS OVERARCHING QUESTIONS 33
APPENDIX II. SUMMARY DELIBERATIONS OF EPA WORKSHOPS 34
APPENDIX III. RESEARCH MATRIX FROM ORD STRATEGIC PLAN 36
APPENDIX IV. CROSS TABULATION OF ISSUES WITH RESEARCH QUESTIONS 39
APPENDIX V. FOCAL AREAS, PRIORITY AND TIME FRAME FOR ISSUES 42
APPENDIX VI. PRIORITY RANKING FACTORS 45
APPENDIX VII. GPRA ALIGNMENT 47
VI
-------
ORD Research Plan for Endocrine Disrupters
I. INTRODUCTION
It has been suggested that humans and domestic and wildlife species have suffered
adverse health consequences resulting from exposure to environmental chemicals that interact
with the endocrine system. However, considerable uncertainty exists regarding the relationship(s)
between adverse health outcomes and exposure to environmental contaminants. Collectively,
chemicals with the potential to interfere with the function of endocrine systems are called
endocrine disrupting chemicals (EDCs). EDCs have been defined as exogenous agents that
interfere with the production, release, transport, metabolism, binding, action, or elimination of the
natural hormones in the body responsible for the maintenance of homeostasis and the regulation
of developmental processes.
To date, these problems have been identified primarily in wildlife species with relatively
high exposures to specific compounds, including organochlorines such as DDT and its
metabolites, PCBs and dioxins, or in domestic animals foraging on plants with high levels of
phytoestrogens (Kavlock et al., 1996). Effects noted in wildlife that have a documented or
presumed relationship to altered endocrine function include imposex in molluscs exposed to the
alkyltins, vitellogenin induction in fish living near sewage outfalls (recently linked to concentrations
of ethynyl estradiol), changes in sex steroids in fish near kraft-mill outfalls, abnormal reproductive
development in alligators in Lake Apopka following a pesticide spill, nearly complete mortality of
Lake Ontario lake trout in the sac-fry stage (presumably resulting from exposure to dioxin-like
compounds), eggshell thinning in birds from exposure to DDT and its metabolites, and birth
defects in Lake Michigan cormorants exposed to PCBs and other Ah-receptor ligands. Also, a
variety of adverse effects on reproductive development have been observed in laboratory rodents
exposed to very low levels of dioxin.
In humans, the consequences of prenatal exposure to DES on the reproductive tract of
both females and males are well known and developmental neurological problems have been
identified in children exposed to PCBs and/or PCDFs. In addition, reports of declines in the quality
and quantity of sperm production in humans over the last four decades, and increases in certain
cancers (breast, prostate, testicular) that may have an endocrine-related basis have led to
speculation about environmental etiologies.
Despite these reported effects, we know little about their causes and the concentrations
of EDCs that would induce effects in various populations. Nevertheless, it is known that the
normal functions of all organ systems are regulated by endocrine factors. Small disturbances in
endocrine function, especially during certain stages of the life cycle such as development,
pregnancy and lactation, can lead to profound and lasting effects. Based upon recognition of the
potential scope of the problem, the possibility of serious effects on the health of populations, and
the persistence of some endocrine-disrupting agents in the environment, research on endocrine
disrupters was identified as one of the six high-priority topics in the ORD Strategic Plan (USEPA,
1996a). If future health effects and exposure studies conclude that humans and the ecosystem
are at significant risk due to exposure to EDCs, research on how best to lower or eliminate the risk
will be needed. The key questions that this research plan must answer are:
>> What effects are occurring in exposed human and wildlife populations?
>> What are the chemical classes of interest and their potencies?
>> What are the dose-response characteristics in the low-dose region?
>> Do our testing guidelines adequately evaluate potential endocrine-mediated
-------
ORD Research Plan for Endocrine Disrupters
effects?
>> What extrapolation tools are needed?
>~ What are the effects of exposure to multiple EDCs, and will a TEF approach be
applicable?
>~ How, and to what degree, are human and wildlife populations exposed to EDCs?
>> What are the major sources and environmental fates of EDCs?
>~ How can unreasonable risks be managed?
A time line for addressing these overarching questions is presented in Appendix I.
Given EPA's mandate to protect both public health and the environment, the Agency is in
a unique position to provide leadership in this area. Therefore, in response to the growing public
health concerns related to chemicals in the environment that have the potential to act as endocrine
disrupters, EPA's Office of Research and Development (ORD) held two workshops at which the
opinions of international experts were sought to help formulate a national research plan. The first
of these was held in April 1995 in Raleigh, NC, and covered both human and ecological needs
from a broad-scale, risk-assessment-based perspective (Kavlock et al., 1996). The second
workshop, held in Duluth, MN, in June 1995 built on the needs identified in the first workshop, but
with a focus on ecological research needs (Ankley et al., 1997). Details of the deliberations and
recommendations of these workshops are summarized in Section III (Research Issues) and
Appendix II. This research plan was developed from the recommendations provided by the
workshops, the scientific judgment of the ORD Research Planning Committee, reviews and input
from the chairpersons for the risk assessment breakout groups of the Raleigh workshop, internal
peer reviewers from across the Agency, the ORD Science Council, and an external peer review
panel convened by the Agency's Risk Assessment Forum.
The broad nature of the issue necessitates a coordinated effort on both the national and
international level. The National Science and Technology Council (NSTC), which advises the
President and his Cabinet on directions for federal research and development efforts, has
established a milestone for 1995-1998 to produce a national research strategy on endocrine
disrupting chemicals. This action led to formation of the Endocrine Disrupter Working Group
under the Committee on the Environment and Natural Resources (CENR) of the NSTC to guide
activities on a broader national scale (CENR, 1996). EPA chairs this coordination effort and has
been instrumental in establishing a communication network on endocrine disrupters that will
facilitate addressing the key research questions. The functions of the CENR workgroup are to:
! develop a federal research framework;
! inventory ongoing research activities in the federal government and elsewhere;
! provide a forum for information sharing among the various national organizations;
! outreach to non-federal organizations involved in endocrine disrupter issues; and
! hold periodic symposia as the research emerges.
The inventory of federal research on endocrine disruption has been used to evaluate the
current state of the federal effort, identify research gaps and establish priorities, and clarify
governmental roles and responsibilities. To date, nearly 400 projects have been identified as being
sponsored by the 14 participating agencies. The CENR framework and the inventory are available
on the Internet (http://www.epa.gov/endocrine), and a summary analysis has been published
(Reiter, et al., 1998). Due to the complex nature of the uncertainties posed by the endocrine
disrupter hypothesis, the overlapping concerns of federal agencies, and the resource constraints
-------
ORD Research Plan for Endocrine Disrupters
on the federal budget, close coordination and cooperation among federal agencies will be
essential to the resolution of the critical research questions. For example, a number of
participating agencies issued a joint Request for Proposals in FY98 to address the highest priority
data gaps. While the CENR will provide the umbrella for this coordination, individual agencies
are responsible for development of their own independent research plans. Therefore, an important
component of this present document must be to communicate with other federal organizations on
EPA's goals, priorities, and projected accomplishments.
EDCs were also identified as a high priority at the 1997 Environment Leaders' Summit of
the Eight. Included among the recommended action items were: 1) the development of an
international inventory of ongoing research activities; 2) the development of an international
scientific assessment; 3) the development of an international research strategy after completion
of the inventory and scientific assessment; and 4) support for an Organization of Economic and
Community Development (OECD) initiative to develop a battery of screening and testing
guidelines for EDCs that considers the special susceptibilities and exposures to children. In
conjunction with the CENR effort, a companion effort to inventory research has been conducted
in Europe (http://www.liwa.de/rneed), and efforts are currently underway under the auspices of
the World Health Organization's International Programme on Chemical Safety and OECD to
assemble an international inventory and assessment of the endocrine disrupter issue. In addition,
the National Research Council has also been commissioned by EPA's Office of Water and other
federal agencies to conduct a comprehensive, critical evaluation of the scientific literature and to
identify research needs. Results of this effort are expected to be available in the spring of 1998.
In the interim, ORD's Risk Assessment Forum has provided an overview of the current state of
knowledge of the science relative to environmental endocrine disruption in humans, laboratory
testing and wildlife species (USEPA, 1996b). This document contains an extensive assessment
of the principle adverse biological effects associated with exposure to endocrine-disrupting
chemicals.
In developing EPA's research plan, the committee noted that there are clearly important
areas for which other federal agencies have the research lead (e.g., the National Cancer Institute
and the Centers for Disease Control for studies on environmental causes of breast cancer, the
National Oceanic and Atmospheric Administration for immunological effects in marine mammals,
the National Science Foundation and the National Institute of Environmental Health Sciences for
the role of hormones in the normal differentiation of the brain and reproductive track).
Conversely, because of their scope and complexity, other problem areas need to be approached
by multiple organizations (e.g., development of short-term screening techniques, determination
of environmental contamination levels). In this plan, we first selected those areas where the EPA
should be playing at least a moderate role. Priorities were then assigned based upon an
assessment of the importance of the research to the EPA program offices, on the magnitude of
the uncertainties in the knowledge base, the sequence of research needed to obtain the final
answer, the possibility that the research would result in a significant product for hazard
identification, risk characterization or risk management and, finally, the technical feasibility of
conducting a successful project. It is expected that other EPA activities (e.g., the Dioxin
Reassessment and efforts to develop approaches for assessment of complex mixtures) will feed
into the information base.
This Research Plan for Endocrine Disrupters was developed to serve several purposes,
including:
1. To provide a roadmap to guide the Agency's efforts on endocrine disrupters,
3
-------
ORD Research Plan for Endocrine Disrupters
while at the same time remaining flexible enough to adjust to
recommendations evolving from the CENR and MAS efforts;
2. To establish distinctions between, and priorities for, the intramural and
extramural ORD research efforts;
3. To provide a research framework for the regulatory programs;
4. To inform Agency risk assessors and risk managers of the types of data being
generated for endocrine disrupting chemicals; and
4. To serve as the basis for coordination and communication of research activities
with other Federal agencies and other organizations affected by this issue.
Concepts for a multi-year research plan for the intramural and extramural programs
priorities are presented in Section V. It is anticipated that each Laboratory and Center within ORD
will develop an implementation plan for EDCs that allows the coordination and sequencing of the
research elements to occur. Recognizing the dynamic nature of the research front, we emphasize
that the priorities and sequencing that we propose be revisited in three to four years so the
strategy can be modified accordingly.
-------
ORD Research Plan for Endocrine Disrupters
II. REGULATORY BACKGROUND
The authorities and responsibilities of the Environmental Protection Agency are mandated
primarily by thirteen major environmental statutes (CRC Report to Congress, 1995). These
statutes direct EPA to perform a wide variety of activities with the goal of protecting human health
and the environment. These diverse activities include, but are not limited to: 1) identifying
hazardous or toxic substances; 2) setting specific allowable levels of exposure to chemicals that
are protective of human health and the environment; 3) controlling releases of chemicals into the
environment; 4) responding to spills or other releases of chemicals into the environment; 5)
developing a national inventory of chemical releases into the environment; 6) cleaning hazardous
waste sites to levels that assure protection of human health and the environment; 7) evaluating
new and existing chemicals for their ability to cause potential adverse human health and
environmental effects and requiring the gathering of data on environmental exposure levels and
potential human health and ecological effects when data are insufficient; and 8) reviewing and
analyzing information that pesticide manufacturers submit in support of registration or
reregistration to determine that a pesticide will not cause unreasonable adverse effects on the
environment or to humans. Chemicals that are known or suspected of being endocrine disrupters
are included in these mandated activities.
Recently, two environmental laws were enacted that specifically require the testing of
pesticides and other chemicals found in or on food or in drinking water sources to determine their
?estrogenic or other endocrine effects in humans." The Food Quality Protection Act of 1996
(FQPA) and the Safe Drinking Water Act Amendments of 1996 (SDWA) require EPA to develop,
within two years of enactment, a screening program using validated test systems to determine
whether substances may have an estrogenic or other endocrine effects in humans. The
screening program must undergo a public comment period and peer review and be implemented
within three years. The laws require that the manufacturers, registrants, or importers conduct the
testing of the pesticides and other substances according to the program EPA develops. At joint
workshops, cosponsored by EPA, the Chemical Manufacturers Association, and the World
Wildlife Fund, a number of assays potentially suitable for assessing EDCs (particularly exerting
(anti-) estrogenic/androgenic effects) were identified and critiqued (Gray et al., 1997; Ankley et
al. 1998).
Based upon input from those workshops and others, the Endocrine Disrupter Screening
and Testing Advisory Committee (EDSTAC), an advisory committee to EPA on implementation
of the FQPA and SDWA, is assembling a battery of assays for screening and testing potential
EDCs. These assays will be used to address the mandates of the FQPA and SDWA. In addition
to in vitro gene transcription assays, proposed Tier 1 Screening Tests include mammalian assays,
such as the uterotrophic test for estrogen and a Hershberger type assay for androgen action, in
conjunction with a short-term fish reproduction test and an amphibian metamorphosis assay for
thyroid-mediated processes. From a research planning perspective, the forthcoming EDSTAC
recommendations will be critical because several of the proposed non-mammalian screening and
testing assays will require some level of research to bring them to the point where they could be
considered standard methods.
In summary, to meet the needs of all of its mandates, the Agency needs the tools to be
able to:
1. Identify EDCs;
2. Evaluate their potential effects on human health and the environment;
-------
ORD Research Plan for Endocrine Disrupters
3. Discern when additional data are needed;
4. Develop the appropriate protocols should additional data be required;
5. Set allowable levels of exposure or releases to the environment that are protective of
human health and the environment;
6. Develop technological controls to prevent/reduce releases, in the first place; and
7. Remediate the risks associated with in-place EDCs.
While there is a wealth of data available on some endocrine disrupters, much more
research is needed in order for the Agency to carry out its mandates. For this reason, EPA is
embarking on a major research effort on endocrine disrupters. The objective of the EDCs
research program is to improve our knowledge and understanding of endocrine disrupters in the
environment so that we can improve our methods of assessment. This, in turn, will assist the
Agency in identifying the chemicals that pose an unreasonable risk, developing ways to prevent
or reduce their release into the environment, and developing means to remediate in-place EDCs
that pose an unreasonable risk.
-------
ORD Research Plan for Endocrine Disrupters
III. RESEARCH ISSUES
Answering the questions posed for the research program in endocrine disruption listed in
the Introduction will entail a coordinated effort by the scientific community, for the scope is
exceedingly broad and beyond the capabilities of any one research organization. One function
of the CENR Working Group on Endocrine Disrupters is to assist in partitioning research functions
among the participating agencies so that limited resources are used most effectively. Developing
methods for performing hazard and risk characterization of chemicals, quantitating exposure levels
and determining environmental fate of chemicals, and developing extrapolation tools, have been
traditional strengths of the EPA research program. It is these areas that we propose as our
primary contributions to the overall federal effort on EDCs.
Through the research needs workshops in 1995, ORD has provided national leadership
in the endocrine disrupter issue by fostering communications across government, private industry,
and the public. Several general comments about future research on endocrine disrupting
chemicals emanated from the discussions at the workshops. These include:
1. The great advantage in bringing together a multi-disciplinary group of scientists
representing human health and ecological concerns to help identify common
issues.
2. Because exogenous endocrine disrupting chemicals must interact at some level with the
natural receptor ligands within the body, and because the concentrations of the
natural ligands are maintained within life-cycle dependent narrow limits suggest
that the timing of exposure is a very significant factor in any assessment.
3. Many EDCs are persistent in the environment and bioaccumulate, and exposures are
widespread throughout the entire globe.
4. The mechanistic basis of the interaction with biological systems presages the induction
of subtle effects at low doses that must be interpreted as to their adversity.
In general, it was felt that linking specific exposures to specific effects in the environment
often would be difficult due to the complexities of exposure, the latency of the effects, and the at
times subtle nature of the outcomes. Such considerations will have significant effect on the
research activities necessary. Ten broad categories of research needs were identified: basic
research, biomarkers, database development, exposure determination, exposure follow-up,
mixtures, multi-disciplinary studies, risk assessment methods, hazard identification, and sentinel
species. Processes that should receive particular attention include are reproduction,
development, and immunocompetence.
There is a pressing need to identify the extent of the chemical universe of concern. This
clearly cannot consist of testing all chemicals in long-term chronic assays with multiple species.
Tools that should be quite useful include short-term in vitro and in vivo assays as well as
structure-activity relationship models, which in virtually all cases require further development and
validation with multi-species chronic toxicity tests. As noted in Section II, Congress mandated
EPA to develop a chemical program for environmental estrogens and other endocrine disrupters
by August 1998. The results of screening exercises using these types of tools could be linked to
key exposure data, such as production volume, persistence, etc. to help identify chemicals of
greatest concern and to provide focus for a monitoring program. These types of screening tools
would play
-------
ORD Research Plan for Endocrine Disrupters
significant roles in both prospective and retrospective assessments of the human health and
ecological risks of EDCs. A key consideration in developing these types of methods and models
is the ability to link results obtained in suborganismal systems to organismal-level effects.
To better assess the ecological risks of EDCs, work needs to be done to define linkages
between potential measures of effect (usually made at the level of the individual) and assessment
endpoints (which typically are at population and community levels). Similarly, linkages between
these measures at different levels of biological organization need to be defined better. For
example, induction of vitellogenin in male fish appears to be a very specific response to exposure
to estrogen mimics. However, it is unclear what this means in terms of reproduction. The basic
challenge in this research area is to identify those measures that both indicate exposure to EDCs
and predict their effects in populations. Furthermore, we must develop a better definition of
"normal" with respect to endocrine-regulated processes in commonly tested or monitored species
relative to effects manifested at the population level (the degree to which circulating levels of sex
steroids need to be altered before reproductive success is threatened). Steps need to be taken
to adapt existing assays used for ecological risk by incorporating exposure during key
developmental windows, and to ensure assessment of relevant endpoints for EDCs.
A major issue for endocrine disruption that must be addressed is the need to define what
constitutes an "adverse" health effect, especially considering the multiple levels of biological
observation (e.g., molecular to community level) at which effects can be observed. According to
EPA's interim position (USEPA, 1996b), the Agency does not consider endocrine disruption to be
an adverse endpoint per se, but rather to be a mode of action potentially relating to other
outcomes, routinely used in reaching regulatory decisions, such as carcinogenic, reproductive or
developmental effects. The document goes on to state that
"In general, due to the precise yet adaptable control mechanisms and the
intertwined nature of hormonal balance, modest amounts of chemical exposure
seldom compromise normal physiological functions. Fluctuations of hormone
concentration and receptor activities, by design, absorb some of environmental and
physiological challenges to maintain homeostasis in adults. Only when the
equilibrium control mechanisms are overwhelmed do deleterious effects occur. An
important question is whether homeostatic mechanisms are operative in the
embryo and fetus."
Therefore, an important component of the research program must be to understand when the
homeostasis border is crossed, and how this changes as a function of life stage and/or
reproductive strategy. In terms of ecological risk assessment, adverse effects are most often
defined in the context of decreased populations and, less frequently, by changes in community
structure. Metrics considered at the individual level that infer likely trends in population dynamics
are most commonly related to survival, growth, and reproduction. Thus, chemical exposures that
negatively affect these endpoints are considered adverse. Unfortunately, endpoints such as
survival, growth, and reproduction are fairly generic, in that they typically do not reflect specific
MOAs (modes of action) in terms of impact on any particular endocrine system. Endpoints that
do reflect MOA of concern generally occur at the suborganismal level, and often may not be
translated directly into adverse effects at the level of the individual. Yet, changes in the status of
systems at the molecular and cellular levels can be highly effective indicators, not only of MOA,
but of possible adverse effects at higher levels of organization that may not be manifested
immediately. Because of this, the need to understand the effects of EDCs at multiple levels of
biological organization is critical, particularly in terms of defining adverse effects as a function of
a specific MOA.
8
-------
ORD Research Plan for Endocrine Disrupters
Organisms seldom, if ever, actually encounter individual endocrine disrupting chemicals
in the environment, especially because of the potential for some chemicals to be persistent and
to bioaccumulate. In the development of specific research activities contained in the next section,
specific attention is given to the need to address the impacts of real-world situations in terms of
simultaneous (or sequential) environmental exposures to multiple EDCs. While this is noted in only
a single issue, it should be emphasized that the concern for mixtures transcends virtually every
other activity in this research plan.
Available measures of effects, measures of exposure, and measures of organisms and
ecosystem characteristics for ecological risk assessment need to be adapted to classes of
organisms that have received little attention in terms of traditional toxicity test
methods/approaches, such as amphibians, non-teleostfish, passerine birds, etc. Two objectives
are addressed here: 1) better development of a comparative endocrinology/toxicology database,
and 2) better definition of baseline conditions for general processes and specific endocrine
function. Withoutthese, the usefulness of comparative endocrinology for assessing the ecological
risk of EDCs is significantly decreased. To characterize the relative risks of EDCs from an
ecological perspective, it is necessary that the data collected have a high degree of consistency.
This becomes critical in terms of coordinating existing monitoring programs so that biological
endpoints should include effects that indicate the impact of EDCs on individuals and populations,
and chemical characterization should include those xenobiotics suspected to exert toxicity through
endocrine disruption. Moreover, measurements made across different monitoring efforts should
overlap. This type of coordination is not necessarily a research issue, but is very important from
the standpoint of a coherent approach to risk assessment and management decisions concerning
EDCs.
If future health effects and exposure studies conclude that humans and the ecosystem are
at significant risk due to exposure to EDCs, research on how best to lower or eliminate the risk will
be needed. This research should be directed at managing the risks associated with high exposure
pathways. First, a survey should be conducted to characterize the important types of locations
or industrial processes where EDCs are released into the environment. For example, the majority
of the mass of EDCs may enter the environment via pesticide use in agriculture, or via wastewater
effluents from certain types of chemical industries. Second, unreasonable risk must be reduced
through various risk-management tools, many of which must be developed or fine tuned for EDCs.
For example, much of the risk may be associated with high concentrations of EDCs at hazardous
waste sites, such as in soils at Superfund sites, or in contaminated sediments. Risk-management
research associated with this scenario should concentrate on effective means of destroying or
containing EDCs at these sites. Alternatively, much of the risk associated with EDCs may be
linked to exposure associated with chemical plants where the use of or production of EDCs result
in exposure to workers or the neighboring ecosystem. In this case, risk-management research
should focus on engineered controls to minimize exposure to workers and pollution-prevention
strategies to reduce the use or production of EDCs.
-------
ORD Research Plan for Endocrine Disrupters
IV. RESEARCH APPROACH AND ACTIVITIES
Within this Chapter, specific research projects for biological effects and exposure research
have been organized following the matrix developed for endocrine disruption in the ORD Strategic
Plan (Appendix III). To provide a firmer basis for risk characterization, a third category, "Linkage
of Exposure and Biological Effects," was formulated to emphasize the critical need to integrate
these main components of the research program. In many cases, the biological effects research
cuts across human and ecological research problems, and a coordinated, interdisciplinary
approach is required. For example, EFF.1.1 (QSAR [Quantitative Structure-Activity Relationships]
Models of EDC Modes of Action) is targeted at providing tools of equal utility for predicting health
and ecological effects, as well as the targeting of exposure assessment efforts. Neither the
issues nor subissues are presented in priority order.
For each "issue" or activity, a brief description, priority (high, medium or low, plus a priority
score assigned by the planning committee (see below), and focus of the research (health,
ecological, exposure, or some combination) is provided. To place the activities into a hypothesis-
oriented context, each issue was evaluated according to which of the nine overarching questions
stated in the Introduction it addressed. This crosswalk (Appendix IV) clearly demonstrates the
areas of greatest uncertainty in our understanding of endocrine disruption. Two questions are the
predominant driving forces (What effects are occurring in exposed human and wildlife
populations? and How and to what degree are humans and wildlife populations exposed to
EDCs?). The need to identify chemical classes of concern, develop extrapolation tools,
understand the effects of multiple exposures and understand the sources of exposure are most
evident as secondary questions addressed by the issues. They illustrate the extent to which these
questions transcend many of the proposed activities. A time line in which individual issues should
be addressed is presented in Appendix Va-c, while the derivation of the overall priority and priority
score is contained in Appendix VI. The priority score was based on the evaluation of each issue
against five major ranking criteria (Programmatic Relevance, Magnitude of Biological Concern,
Potential Impact of Outputs; Sequencing of the Research, and Feasibility of Technical Success)
as judged on a scale of 1 (most important) to 3 (less important) by members of the planning
committee. The priority score is a non-weighted sum of all ranks on all factors, and is adjusted
such that the issue with the lowest score (highest overall priority) received a value of 1.
Throughout the reviews of this research plan, a number of lower priority items were
eliminated, leaving a high proportion of issues ranked "high." Although these issues are all within
the mission of ORD, the resources to successfully address all of them are unlikely to be available.
Hence, the individual Laboratories and Centers will be need to be selective when developing the
actual implementation plans. The most critical uncertainties lie in determining whether humans
and wildlife populations are being impacted by levels of endocrine disrupters in the ambient
environment and in determining the sources of those exposures. Appendix VII arrays the EDC
projects according to the risk assessment paradigm and is consistent with presentation under the
Government Performance and Results Act (GPRA). GPRA requires each federal agency to
submit, by September 30, 1997, to the Office of Management and Budget and Congress a five-
year strategic plan. The plan was required to include:
• a comprehensive mission statement.
• general goals and objectives, including outcome-related goals and objectives.
• a description of how the goals and objectives are to be achieved.
• a description of the program evaluations used in establishing or revising general
10
-------
ORD Research Plan for Endocrine Disrupters
goals and objectives.
Each agency is also required to submit a performance plan covering each program activity
set forth in the Agency's budget, which must be consistent with the strategic plan. ORD's research
on endocrine disrupters falls under EPA's "Goal 8: Sound Science, Improved Understanding of
Environmental Risk, and Greater Innovation to Address Environmental Problems. Objective 3:
Emerging Risk Issues. Subobjective 3.2: Endocrine Disrupters."
11
-------
ORD Research Plan for Endocrine Disrupters
BIOLOGICAL EFFECTS STUDIES:
Research on the pathogenesis of EDC-induced adverse health effects includes studies
to identify EDCs, describe dose response relationships, and evaluate the impact of EDCs on
developmental, reproductive, immune, neurobehavioral, and endocrine system functions in young
and mature organisms. Studies that examine the latent effects of EDCs following exposure during
a critical life stage should be of particular focus. Approaches for obtaining this information include
studies of humans, laboratory animals, and wildlife (including invertebrate, fish, amphibian, reptile,
avian, and mammalian species) exposed to suspected EDCs. The broad objectives of the
research plan to evaluate the ecological risk of EDCs are twofold: 1) determine their risk relative
to other stressors on populations and communities, both from a prospective and retrospective
standpoint; and 2) develop or modify methods for testing and evaluating chemicals and
environmental samples to ensure that those exerting toxicity through specific endocrine axes will
be characterized. Both objectives require a reduction in uncertainty in prediction of risk across
levels of biological organization, including better linkage of measurement and assessment
endpoints. They also require an increased understanding of processes and species at risk,
including an understanding of modes of action. General research needs and specific research
approaches necessary to meet these needs are listed below. It should be noted that the specific
research approaches usually address more than one of the general issues identified below, much
of the necessary research can (or should be) interrelated.
EFFECTS ISSUE 1. DETERMINE THE CLASSES OF CHEMICALS THAT ACT AS EDCS AND
THEIR POTENCIES.
EFF.1.1 DEVELOPMENT OF IN VITRO AND IN VIVO SCREEN ING METHODS AN D QSAR
MODELS OF EDC MODES OF ACTION, FOR EXAMPLE, RECEPTOR BINDING,
GENE ACTIVATION AND ENZYME INHIBITION ENCOMPASSING
VERTEBRATE AND INVERTEBRATES.
Short-term in vitro and in vivo methods need to be developed to screen for EDCs
with specific modes of action (MOAs), including alterations in hormone levels and
induction of specific ligand inducible genes (e.g., vitellogenin). The results of these
assays should be calibrated against effects on integrated processes (development,
reproduction) at the level of the individual. Quantitative structure-activity
relationship (QSARs) models need to be developed for EDCs for key events such
as receptor-binding of xenobiotics, transcriptional activation, and posttranscriptional
events to serve as screening tools for evaluating the chemical universe.
Endocrine-mediated processes related to reproduction and development should be
highlighted. In addition to being useful tools for prospective risk analyses, QSAR
models can provide critical insights in retrospective evaluations of risk. For
toxicants that are metabolically activated, QSAR models would allow one to identify
the potentially active metabolite for in vitro testing.
High Priority (Adjusted Score from Appendix Vl=1), Human Health and Ecological
Focus
12
-------
ORD Research Plan for Endocrine Disrupters
EFFECTS ISSUE 2. EVALUA TE CURRENT TESTING AND MONITORING PROCEDURES FOR
ADEQUACY OF ASSESSMENT OF EDC EFFECTS.
EFF.2.1 DEVELOPMENT, STANDARDIZATION, AND UTILITYOF IN VITRO AND IN VIVO
TEST METHODS TO IDENTIFY ENDOCRINE DISRUPTING ACTIVITY.
Present tests to assess toxicity provide little information on the MOA of a chemical
or the potential to produce latent effects after developmental exposure. For human
health effects, the proposed improvements to the EPA multi-generational test will
provide improved EDC detection for hazard identification and dose-response, but
these tests are expensive and take years to complete. However, multi-generational
tests are seldom used for ecological risk assessment. Hence, short-term tests are
also needed to detect EDC activity. Efforts should focus on those MOAs known
to be exhibited by relevant environmental chemicals, including estrogenicity, anti-
androgenicity, Ah-receptor binding, and anti-thyroidal activity. In addition to initial
ligand receptor binding, endpoints should include EDC-induced changes in normal
endocrine-mediated transcriptional activation. Due to EPA's Congressional
mandate and the direct regulatory implications of this area, research planning
should be done in coordination with EPA regulatory program offices.
High priority (Adjusted Score from Appendix Vl=13), Human and Ecological Focus
EFFECTS ISSUE 3. DETERMINE THE SHAPES OF THE DOSE-RESPONSE CURVES FOR
EDCs AT RELEVANT EXPOSURES AND THE TISSUE LEVELS ASSOCIATED WITH
ADVERSE EFFECTS.
EFF.3.1 MODE-OF-ACTION STUDIES FOR DEVELOPMENTAL AND REPRODUCTIVE,
CENTRAL NERVOUS SYSTEM, AND NEUROENDOCRINE TOXICITY IN
LABORATORY ANIMALS FOLLOWING DEVELOPMENTAL EXPOSURES.
A more complete understanding of specific chemical MOA is required for
between-chemical and between-species extrapolation. Since many EDCs elicit
toxicity through receptor-based interactions, these chemicals particularly should be
amenable to MOA research. Other endocrine disrupting agents may act through
membrane receptors, enzyme alterations, and other non-nuclear receptor-based
pathways. Research in this area should be coupled with QSAR analyses and
comparative endocrinology and toxicology. The emphasis of this research should
be on mechanisms that operate in the low end of the dose-response curve and the
development of quantitative descriptions of rate limiting steps for later incorporation
into formal BBDR (Biologically Based Dose-Response) Models.
High Priority (Adjusted Score from Appendix Vl=23); Human and Ecological Focus
13
-------
ORD Research Plan for Endocrine Disrupters
EFF.3.2 DEVELOPMENTAL AND ACUTE EFFECTS OF EDCs ON IMMUNE FUNCTION
OF LABORATORY ANIMALS.
Numerous reports of immune alterations have been reported in EDC-exposed
wildlife populations and children. Studies of EDCs in animal models are needed
to verify these effects under controlled conditions.
High/Medium Priority (Adjusted Score from Appendix Vl=27); Human and
Ecological Focus
EFF.3.3 STUDIES USING ANIMAL MODELS OF SUSPECTED EDC-INDUCED HUMAN
DISEASES SUCH AS REDUCTIONS IN SPERM COUNTS, AND INCREASED
INCIDENCES OF INFERTILITY, TESTICULAR CANCER, HYPOSPADIAS,
ENDOMETRIOSIS, BREAST CANCER AND PROSTATE CANCER.
For several of the aforementioned conditions, adequate animal models have not
been developed and validated. Validated animal models can greatly enhance the
process of identifying the potential of EDCs to produce diseases in the human
population. Specifically, research is needed on models of testicular cancer,
endometriosis, breast cancer, and benign prostatic hyperplasia and prostate
cancer. Once these animal models are developed, they can be used to test
hypotheses that low, environmentally relevant doses of EDCs can induce similar
conditions in humans.
High priority (Adjusted Score from Appendix Vl=10); Human Focus
EFF.3.4 PHARMACOKINETIC STUDIES OF HIGHLY RELEVANT EDCs WITH
PARTICULAR FOCUS ON CRITICAL PERIODS OF DEVELOPMENT OF
REPRODUCTIVE, NEUROENDOCRINE AND IMMUNE SYSTEMS.
The lack of validated pharmacokinetic (PK) models to predict transplacental and
breast milk deposition of EDCs in fetal and neonatal target organs limits our ability
to determine when adverse concentrations would result as a consequence of
chronic and acute maternal exposures. We anticipate that PK models for
developmental EDC exposure can be readily developed and would provide
extremely useful predictive information for characterizing dose-response
relationships on the basis of delivered dose to the target tissue.
High Priority (Adjusted Score from Appendix Vl=24); Human Focus
EFF.3.5 DEVELOPMENT OF BIOLOGICALLY BASED DOSE-RESPONSE MODELS FOR
HIGHLY RELEVANT EDCs WITH PARTICULAR FOCUS ON CRITICAL PERIODS
OF DEVELOPMENT OF REPRODUCTIVE AND IMMUNE SYSTEMS AND THE
CENTRAL NERVOUS SYSTEM.
Understanding the various steps in the pathogenesis of adverse effects is key to
14
-------
ORD Research Plan for Endocrine Disrupters
reducing the uncertainties in extrapolation of animal test data to humans. BBDR studies should
be linked to the development of PK models described in EFF.3.4. Incorporating modes of action
in quantitative risk models is essential to understanding the risks of low dose exposures, which
should be the primary area of emphasis for this research area. Although these models are of high
relevance and great potential impact, they, are also extremely complex to construct and represent
relatively high risk research projects.
High/Medium Priority (Adjusted Score from Appendix Vl=34); Human Focus
EFF.3.6 STUDIES ON THE MODES OF ACTION OF EDCs ON CELLULAR, MOLECULAR,
NEUROENDOCRINE CENTRAL NERVOUS SYSTEM FUNCTION IN PUBERTAL
AND ADULT LABORATORY RODENTS.
Steroid and thyroid hormones are important in the regulation of puberty in
developing animals and in modulating central nervous system function in adults.
Therefore, these processes potentially are sensitive to alteration by EDCs, and
research is needed to characterize the extent of the impact relative to other
endpoints of known responsiveness.
Medium priority (Adjusted Score from Appendix Vl=37); Human Focus
EFFECTS ISSUE 4. DESCRIBE THE NORMAL ENDOCRINE PROFILES IN WILDLIFE
SPECIES.
Little is known about normal variability in different wildlife species relative to most
endocrine systems or endocrine-mediated endpoints, such as temporal variations in basic
hormonal profiles and developmental and fecundity rates. A recent example of how this can be
a problem arose in a study in which apparent differences in plasma sex steroids in fish collected
from several field locations were reported, but it was unclear whether these differences were due
to site-specific (e.g., contaminant) factors or normal temporal variations in the test species (e.g.,
correlated with reproductive cycles). Data of this type can be collected in routine (field) monitoring
experiments, or in more focused comparative physiology and toxicology studies. Because
endocrine processes are highly conserved across species, particularly across vertebrates,
comparative studies are important to help extrapolate outcomes based on MOA determinations.
For example, it would be important to establish whether a chemical that causes estrogenic effects
in one species also causes them in other species. In fact, this is a major (but unproven)
supposition in the design of screening assays for EDCs by EDSTAC. Thus, it is important that the
technical underpinnings of the assumption of commonality in response be assessed fully across
species. Although basic endocrinology research is funded to some extent by other federal
agencies, this type of research generally has not been systematic enough to serve as a basis for
the type extrapolations needed by EPA to deal with EDCs. This does highlight, however, the need
for continued coordination among federal agencies with respect to EDC-related research.
EFF.4.1 DEFINITION OF "BASELINE" ENDOCRINE STATUS IN WILDLIFE
POPULATIONS AND THEIR LABORATORY SURROGATES.
15
-------
ORD Research Plan for Endocrine Disrupters
At present, we are uncertain about the normal values of many EDC-influenced
factors in fish and wildlife populations. These include elements such as
intracellular receptor numbers, circulating hormone concentrations, developmental
rates, reproductive capacity, population sex rations, and age structures. This type
of information is critical not only for extrapolation in prospective risk assessments,
but for effective monitoring in retrospective analyses.
High Priority (Adjusted Score from Appendix Vl=26), Ecological Focus
EFF.4.2 STUDIES IN COMPARATIVE ENDOCRINOLOGY AND TOXICOLOGY.
Basic endocrine system structure and function can be remarkably well-conserved
across phyla. However, many key and potentially sensitive species have not been
evaluated with respect to endocrine function, particularly from a toxicology
perspective. Thus, baseline research on specific endocrine systems related to
reproduction, development, and immunocompetence across several representative
classes of animals could reduce uncertainty associated with among species
extrapolations. These types of studies should specifically include those organisms
which historically have received little attention in terms of environmental toxicology,
and/or are experiencing declines in populations. Part of this task would be to use
laboratory studies to confirm EDC-related hypotheses generated from field studies.
The key for using comparative endocrinology and toxicology data to extrapolate
among species will be the concurrent development of biologically based dose-
response and PB-TK models; this modeling perspective is needed in recognition
of the fact that it is impossible to test every permutation of chemical and species.
Medium Priority (Adjusted Score from Appendix Vl=33), Ecological Focus
EFF.4.3 STUDIES ON THE ROLE OF HORMONES IN SEXUAL DIFFERENTIATION OF
NONMAMMALIAN SPECIES AND THE EFFECTS OF EDCs ON THIS PROCESS
IN INVERTEBRATE, AVIAN, REPTILIAN, AMPHIBIAN, AND FISH SPECIES.
Numerous alterations of reproduction have been attributed to EDC exposure during
development of wildlife species. It is often impossible to determine the biological
plausibility of these speculations because the hormonal regulations of sexual
differentiation are not completely, or are poorly understood in nonmammalian
vertebrates.
Medium Priority (Adjusted Score from Appendix Vl=36); Ecological Focus
EFFECTS ISSUE 5. EXTRAPOLATE EFFECTS AT THE INDIVIDUAL LEVEL TO
POPULATIONS FOR FISH WILDLIFE SPECIES.
There is a need to identify and validate measurement endpoints that are indicative of the
effects of EDCs at individual and sub-organismal levels and at the level of populations and
16
-------
ORD Research Plan for Endocrine Disrupters
communities. Linkages among proposed measurement endpoints are uncertain. For example,
at the level of the individual, the impact of induction of vitellogenin in male fish exposed to
estrogenic chemicals on reproductive success is not known. Similarly, impacts on
endocrine-mediated processes at the level of the individual can be difficult to translate into
population-level effects. This linkage also is key to defining relationships between measurement
and assessment endpoints in ecological risk assessments. In this plan, we identify general criteria
to consider in terms of species selection (e.g., those that have received little attention in the past,
but might be experiencing population-level declines). However, these recommendations should
be taken in the context of specific research issues. Not all wildlife species can or will be
considered in terms of ecological research with EDCs; this is logistically impossible. Therefore,
species will be selected to enable extrapolation of potential EDC effects across animal species
and classes.
EFF.5.1 BIOASSAYS FOR EVALUATING INTEGRATED EFFECTS.
Many of the standard toxicity tests currently in use for regulatory activities such as
product registration and monitoring environmental samples are inadequate for
detecting some of the key reproductive, developmental, and immunological effects
of EDCs. Problems include use of species that are insensitive to specific EDCs,
lack of exposure during critical windows of sensitivity, and failure to consider latent
or EDC-specific effects. These tests should be modified where possible and new
assays developed as needed. When selecting species or endpoints for assessing
effects of EDCs, care should be taken to ensure that the information gathered is
useful for predicting population-level effects. This effort should be coordinated with
activities covered under EFF.5.2 and LNK.2.2 so that as measurement endpoints
are developed to the level of the individual, they are then evaluated at the
population/community levels.
High Priority (Adjusted Score from Appendix Vl=26); Ecological Focus
EFF.5.2 EVALUATION OF EFFECTS AT POPULATION AND COMMUNITY
LEVELS.
It is necessary to translate measurement endpoints collected at lower levels of
biological organization into impacts at population and, if possible, community
levels. Moreover, there may be measurement endpoints sensitive to the effects of
EDCs both at population (e.g., sex ratios) and community (e.g., guild structure)
levels. In either case, further research is needed to quantify EDC impacts at these
higher levels of organization. Experimental systems that can prove particularly
useful include microcosms and mesocosms. Although EPA no longer utilizes
mesocosm data as part of the pesticide registration process, mesocosms are
useful in the context of specific tests of experimental hypotheses. The use of
mesocosms to test EDC effects on populations in a true environmental setting
offers a powerful and cost-effective alternative to full-scale field studies. (Note that
as EFF.5.1 proceeds, this would become a high priority).
High/Medium Priority (Adjusted Score from Appendix Vl=22); Ecological and
Exposure Focus
17
-------
ORD Research Plan for Endocrine Disrupters
EFF.5.3 DETERMINATION OF SENTINEL SPECIES
Appropriate sentinel species for monitoring need to be identified. Selection of
sentinel or keystone species is highly context-specific, so research planning should
not be based upon selection of any particular class/species of animals, but on
"problem" chemicals and sites or toxicological endpoints and issues. From that,
appropriate animal models for research can be identified. Considerations for their
selection should include: 1) representation of different life history strategies; 2)
species vagility with respect to exposure distribution; 3) representation of multiple
taxonomic and trophic levels; 4) manipulability of species in laboratory tests; 5)
availability of baseline information; and 6) the degree of distribution (i.e.,
widespread or local) of a species. Surrogate (non-endangered, noncommercial)
species for study need to be identified for which effects can be related to
endangered or commercially important species.
High priority (Adjusted Score from Appendix Vl=26); Ecological Focus
EFFECTS ISSUE 6. CHARACTERIZE THE EFFECTS OF EXPOSURE TO MULTIPLE EDCs.
EFF.6.1 SYSTEMATIC STUDIES OF THE INTERACTIONS OF LOW,
RELEVANT DOSAGE LEVELS OF MIXTURES OF RELEVANT
EDCs.
In most cases, humans and other organisms are exposed to relatively low doses
of mixtures of chemicals with EDC activity. It is unclear how such mixtures will
behave. While some scientists have reported that effects will typically be additive
in nature, others have reported that estrogens and anti-estrogens will cancel one
another out, while some other studies indicate that EDCs act synergistically. While
this is the only issue devoted exclusively to the study of mixtures, the issue of
multiple exposures impacts on many of the other issues identified in this plan
(Appendix IV).
High Priority (Adjusted Score from Appendix Vl=16); Human and Ecological Focus
18
-------
ORD Research Plan for Endocrine Disrupters
EXPOSURE ASSESSMENT STUDIES:
The pathways between source and exposure to EDCs are complex. Many of the
suspected EDC's studied are organic compounds or organic forms of a few heavy metals that
persist, bioaccumulate, and biomagnify in the food chain. Knowledge of the nature of these
factors is basic to predicting future exposures and the efficacy of exposure prevention strategies.
Forexample, slightvariations in chemical form and physicochemical characteristics (e.g., planarity,
isomerization, and polarity), may manifest themselves in various ways that affect exposure (e.g.,
differences in transport and routes of exposure, increased or decreased bioavailability, changes
in exposure pathways, potential for atmospheric and hydrological transformation, and fate).
Another major challenge is the need to understand complex exposure patterns, rather than
simple net annual exposure. As discussed under Biological Effects Studies, there are certain to
be windows of vulnerability to exposure because of temporal and seasonal patterns of endocrine
functions. For example, exposure to one EDC during an animal's mating season may have
significant effects, whereas for another EDC, exposure during gestation may be more crucial.
Therefore, ORD will conduct exposure research of endocrine disrupting substances within the
Agency's risk assessment framework, and will explore methods and models to measure and
predict exposure to these substances.
ORD's exposure research will emphasize three areas. The first involves better physico-
chemical characterization of a few known or highly suspect EDCs to obtain a better near-term
understanding of the potential effects of chemicals of current concern. The second area is
developing pathway models (e.g., compartmental transport, fate, or transformation) for chemicals
that are likely to be endocrine disrupters. In both of these areas, existing information in the public
literature or in EPA data files will be evaluated to establish current capabilities and identify data
gaps and uncertainties. The third area is to reduce uncertainties in the flux of EDCs in and out
of sediments, a major exposure source for many bioaccumulative compounds.
EXPOSURE ISSUE 1: DEVELOP A FRAMEWORK TO CHARACTERIZE, DIAGNOSE, AND
PREDICT ECOLOGICAL AND HUMAN EXPOSURE TO EDCs.
EXP.1.1 IDENTIFICATION AND EVALUATION OF CLASSES OF SUSPECTED EDCs TO
WHICH HUMANS AND ECOSYSTEMS ARE LIKELY TO BE EXPOSED IN THE
ENVIRONMENT.
The physico-chemical attributes of substances associated with endocrine
disruption, which occur with suspect EDCs in the environment, or that have
transport, transformation, and fate characteristics similar to EDCs need to be
systematically characterized. Once distinguishing chemical characteristics have
been identified for suspected EDCs, generic categories of attributes may be
defined and used to screen new or previously unsuspected substances for EDC
potential. Definition of generic categories would also facilitate the development of
EDC scenarios and uncertainty distributions for subsequent exposure modeling
research. Attribute categories will be updated as additional information becomes
available under Exposure Issue 3 and Effects Issue 1.
19
-------
ORD Research Plan for Endocrine Disrupters
High Priority (Adjusted Score from Appendix Vl=9); Exposure Focus
EXP.1.2 DEVELOP, SELECT, AND APPLY COMPARTMENTAL MODELS TO ENHANCE
UNDERSTANDING OF HOW EDCs BEHAVE IN ENVIRONMENTAL MEDIA AND
TO PREDICT EDC EXPOSURES.
The environmental media through which EDCs are transported can be treated as
compartments in mathematical models. Research is needed to identify the major
compartments through which EDCs move, change, accumulate, and reside. The
models will then account for the persistence, bioaccumulation, bioconcentration,
and biomagnification of chemicals within each environmental medium according
to the physicochemical properties identified in EXP.1.1. Models that diagnose or
predict the movement of EDCs from source to receptor will be applied, adapted, or
developed to simulate EDC movement and change in the environment.
Geographic scale will play a crucial role in model selection. There may be a need
for predictive capability on the micro scale (e.g., occupational, residential), field
scale (e.g., production plant emissions), regional scale (e.g., farm applications
impacting watersheds) and global scale (e.g., long-range transport with exposure
at remote sites). For human exposure, the initial focus should be on the micro-
scale, whereas for ecosystems, regional models are needed.
High Priority (Adjusted Score from Appendix Vl=28); Exposure Focus
EXPOSURE ISSUE 2: PROVIDE ADEQUATE (SENSITIVE, RELIABLE, AND INEXPENSIVE)
TOOLS TO ESTIMATE EXPOSURE TO EDCs.
The Science Advisory Board's 1995 report to EPA, Beyond the Horizon: Using Foresight
to Protect the Environmental Future said, "EPA should attempt to identify, monitor, and analyze
the most potentially serious of these unconventional stressors, and then assess their adverse
effects on human health and ecological systems." A major shortcoming of analytical
environmental chemistry is its inability to monitor for non-volatile, non-extractable, or thermally
labile (unconventional) organic pollutants, which often may be the most prevalent compounds in
many environmental samples. A true assessment of ecological and human risk can be obtained
only with the ability to characterize and monitor this unknown fraction. Very few methods address
the extraction, characterization, and identification of EDCs in tissue, either plant or animal, and
this may very well end up being the limitation of most of the existing methodologies. An initial
subelement under this Issue will be to gain a better understanding of our ability to collect, prepare,
and analyze environmental and biological samples for a few EDCs selected based upon toxicity
and bioavailability to select organisms, and presence and persistence in the environment.
EXP.2.1 IMPROVED UNDERSTANDING OF TRANSPORT, TRANSFORMATION, AND
FATE OF EDCs IN ENVIRONMENTAL MEDIA
Many of the suspect EDCs identified to-date are low-solubility, neutral organic
20
-------
ORD Research Plan for Endocrine Disrupters
compounds that are highly sorbed to organic carbon phases of sediments,
suspended particles in the water column, airborne particulate matter, and soil. While
currently available predictive tools (based on hydrophobic solution theory) are
reliable for estimating movement and change of some EDCs between the sediment
and water column, comparable tools for estimating kinetics of sorption and
desorption processes are lacking. Research is needed to develop models to predict
these processes for ionizable EDCs undervaluing pH and ionic strength conditions.
In addition to sorption kinetics, the biological relevance of EDCs should be
understood better. This includes the interactions of microbial, chemical, and
physical processes. The interplay of theses processes should be an overarching
theme for any study of fate in the environment. Transformation processes of
significant relevance to EDCs include the action of chemical and biological
reductants in anaerobic and low dissolved oxygen environments, such as an
assessment of the role of sulfur-based nucleophiles in reducing the sulfur in the
herbicide atrazine, and the passage of EDCs among abiotic and biotic systems,
such as sediment flora and gut, gill, and other benthic fish tissues.
High Priority (Adjusted Score from Appendix Vl=28); Exposure and Ecological Focus
EXP.2.2 DEVELOP MEASUREMENT METHODS FOR EDCs IN ANIMAL AND PLANT
TISSUE AND ENVIRONMENTAL COMPARTMENTS
To understand the risks of EDCs, improved field methods are necessary to
characterize their fate and transport. Methodologies must be developed and used
to optimize monitoring and analytical throughput in all environmental media, with
high sensitivity. For example, piscine populations exposed to sewage discharge
plumes have shown intersexuality. However, causality has not been established.
To improve the weight of evidence, research is needed to improve sample
extraction methods, extract preconcentration, chromatographic separation, and
analyte detection.
High Priority (Adjusted Score from Appendix Vl=10); Exposure and Ecological Focus
EXP.2.3 DEVELOP EXPOSURE SCREENING TOOLS AND BIOMARKERS FOR EDCs.
EDC concentrations in human and wildlife tissues and other biological media must
be compared to concentrations in the abiotic environment. Promising research has
begun in the development of probes for gene expression resulting from EDC binding
to hormone receptors in fish and wildlife. Exposures of organisms to EDCs can be
detected with good sensitivity by probing for changes in gene expression brought
on by hormone receptor binding. Biomarkers of exposure are needed to screen
ecosystems for exposures, improve exposure estimates in future epidemiological
studies, and assist in developing and verifying human and ecosystem exposure
models. These techniques should aid in identifying and characterizing sources and
intensity of exposures. This screening and biomarker research will entail
collaboration with the pharmacokinetic research described in the Effects Section.,
and the results will be incorporated into the biotic components of exposure models
21
-------
ORD Research Plan for Endocrine Disrupters
developed under EXP.1.2.
High Priority (Adjusted Score from Appendix Vl=21); Exposure and Ecological Focus
EXPOSURE ISSUE 3: DETERMINE THE TOTAL ECOSYSTEM AND HUMAN EXPOSURES TO
EDCs OF CONCERN.
The research on exposure described previously will increase our understanding of the
potential risks from EDCs substantially. It will also identify and prioritize targeted uncertainties
requiring further study. For example, the compartmental modeling studies under Exposure Issue
1 may indicate that, for chemicals having certain physico-chemical properties, air-to-watertransport
is the predominant factor in enhancing exposures. If so, more intense research would be needed
on atmospheric phase equilibria and deposition of these compounds. Exposure to other
compounds may be more influenced by microbes in sediments, suggesting another area for more
intense research, but not for others. On a broader scale, effects research may identify a high
potency EDC that also potentially has a widespread exposure. This may necessitate an exposure
or epidemiological study of this EDC. Gathering reliable data from the field is necessary for direct
assessment of EDC exposure, for development and verification of predictive and diagnostic
exposure models, and for priority setting for additional study of vulnerable or contaminated sites.
EXP.3.1 STUDY MATERNAL/INTERGENERATIONAL TRANSFER OF EDCs.
For endocrine disrupter MOAs, certain stages of development in humans and
wildlife present windows of exposure, where the organism is particularly vulnerable
to hormonal disruption. Depending upon their reproductive strategy, developing
organisms may be exposed directly to EDCs, or may receive exposure via the egg
yolk, or may be exposed via transplacental and lactational transfer. In most cases,
there is a dearth of information regarding the magnitudes of exposure that
developing invertebrates, amphibia, fish, reptiles, birds, and mammals face
concerning EDCs. The uptake, storage and magnification of EDCs in the parental
organisms and the amount of EDCs transferred to the embryonic and neonatal
animals should be studied. Selection of animal models should be based upon
reproductive or physiological characteristics, such as placental mammals, life cycle,
developmental stage at hatching, and sex determination mechanisms. The results
will be incorporated into the exposure model that include biotic compartments of
exposure models developed under the Exposure Issue.
Medium Priority (Adjusted Score from Appendix Vl=35); Exposure, Human Health
and Ecological Focus
EXP.3.2 STUDY BIOACCUMULATION OF EDCs IN FOOD WEBS.
There is a need for field studies to measure available human and wildlife tissue and
other biological media for EDCs to compare concentrations in the abiotic
environment to concentrations in the food chain. The use of the top carnivores and
22
-------
ORD Research Plan for Endocrine Disrupters
higher level species does not obviate the need for the study of
bioavailability, and concentrations of EDCs in lower trophic levels.
However, it provides a framework for the study of the entire ecosystem, and
baseline data regarding the build up on EDCs. These considerations will be
incorporated into the pilot studies described in the next section. This task
can provide data on EDC levels in wildlife tissues that can serve as an
ecological counterpart to the human data collected in EXP.3.3.
Medium Priority (Adjusted Score from Appendix Vl=34); Exposure and Ecological
Focus
EXP.3.3 POPULATION-BASED DISTRIBUTIONS OF EDC EXPOSURES
There is a need to determine the distribution of exposures to endocrine disrupting
chemicals in the environment to evaluate the proportion of the general population
that may be at risk to adverse health effects. Consideration should be given to
ensuring that existing programs such as NHANES (National Health and Nutrition
Survey) include monitoring of the important classes of EDCs such as phthalates,
phenols, phytoestrogens, organochlorines, and other pesticides and herbicides.
The availability of such information would tell us whether the general population is
exposed and whether exposure characteristics differ among subpopulations.
High Priority (Adjusted Score from Appendix Vl=22), Exposure and Human Focus
23
-------
ORD Research Plan for Endocrine Disrupters
LINKING BIOLOGICAL EFFECTS, EXPOSURE AND RISK MANAGEMENT RESEARCH:
One of the potential strengths of the research program within ORD is to bridge the gaps
between effects, exposure, and risk management-based research through interaction of the various
centers and laboratories. Since the extent of the need for risk management research is unknown
at this time, the majority of this section discusses a linked effects and exposure research program.
We have attempted to formulate an integrative effects and exposure program by designing
project areas in which both types of research must work together to accomplish the objectives. We
also introduce risk reduction issues in a general sense. The importance of these projects are not
in accordance with their position at the conclusion of the Research Issues Section because the
groundwork on specific issues relevant to effects and exposure research had to precede this
section for full comprehension of the scope of required coordinated effort. The efforts to address
the effects and exposure issues presented in this research plan must be implemented
comprehensively. The research results must be linked to ensure that the biological responses in
human and wildlife populations can be compared to environmental concentrations and pathway
estimates from exposure models and field investigations. In some instances, the scope of the
research necessitates extramural expertise to augment our research capabilities or assume primary
research responsibilities (through the grants program).
Data bases that contain information about EDCs need to be identified and reviewed, and
methods are needed to improve coordination, reliability, and access by the scientific community.
EXP.1.1 and LNK.1.1 will first prioritize potential problem areas based upon exposure (elevated
concentrations of EDCs) or effects (organisms exhibiting responses possibly related to endocrine
disruption). Reliable and standardized data bases are vital in testing effects and exposure
hypotheses and in validating the compartmental, exposure, and effects models. Compartmental
models and laboratory studies must be linked to field research through mechanism-based dose-
response models. Exposure levels observed in the field will be used as a basis for identifying
realistic dose ranges in laboratory experiments.
As the EDC research program matures, it is likely that risk management research will need
to be added to the linked research activities. Already there is sufficient evidence to conclude that
some EDCs present unacceptable risk in limited situations. Ongoing and future health effects and
exposure studies may conclude there is larger scale, unacceptable risk of exposure of EDCs to
humans and ecosystems. Significant research on how best reduce the risk to acceptable levels
will be needed. This research should be directed at managing unacceptable risks associated with
high exposure pathways. General risk management approaches that would need specific
development for EDCs include: (1) removal of high-mass sources of EDCs in the environment
through site remediation; (2) pollution prevention to minimize the use, release, or production of
EDCs; and (3) engineered controls to reduce exposures to humans and the ecosystem to
acceptable levels when source removal and pollution prevention approaches are not suitable.
LINKAGE ISSUE 1. INTEGRATE HUMAN AND ECOLOGICAL EFFECTS RESEARCH WITH
EXPOSURE RESEARCH WITHIN THE RISK ASSESSMENT PARADIGM.
LNK.1.1 ESTABLISH FRAMEWORKS FOR COMPREHENSIVE EDC INVESTIGATIONS
AND ASSESSMENTS
24
-------
ORD Research Plan for Endocrine Disrupters
The primary goal of this effort is to identify, characterize, prioritize, and assess the
potential exposures and effects to selected suspect EDCs through a joint effort of
NHEERL, NERL, NRMRL, and NCEA. On the assessment side, a framework will
be developed to integrate experimental and observational data for both human
health and ecological effects in order to conduct holistic risk assessment for EDC
MOAs. This effort will consider how best to incorporate MOAs, multiple chemical
exposure, critical life stages, criteria for adversity, dose-response relationships, and
inter-species comparisons. Such tools will be needed as the knowledge base on
endocrine disrupters increases over the next few years. From a review of the
current state of knowledge and data bases for several suspect endocrine disrupters
(i.e., physicochemical data, fate-and-transport information, anticipated human and
ecological effects, and exposure), an initial risk characterization of a few chemicals
within a specific class will be developed collaboratively. A framework that
characterizes potential exposure pathways and effects will be used to generate
probability matrices that: (1) identify potential routes of exposure and health
outcomes; and (2) array suspected endocrine disrupters against potential exposure
pathways and health outcomes. Such efforts should facilitate the evaluation of
causality of reported adverse health effects. This data base will also provide the
basis for clearly identifying major gaps in both exposure and effects relative to
endocrine disrupters, establish a strong linkage between the needs to identify and
characterize source distributions, provide the basis for prioritizing research efforts
proposed for assessing exposures and effects identified in integrated field
assessment (LNK.2.2), and provide a framework for integrated both exposure and
effects results to develop appropriate risk assessment and risk management
strategies.
High Priority (Adjusted Score from Appendix Vl=24); Exposure, Ecological and
Human Focus
LINKAGE ISSUE2. DETERMINE CLASSES AND CONCENTRATIONS OF EDCs ASSOCIATED
WITH OBSERVATIONS OF ENDOCRINE DISRUPTION.
LNK.2.1 EVALUATION OF EXISTING DATA AND CURRENT PROGRAMS.
Efforts are needed to: (1) develop a data base of chemicals (and their effective
concentrations) known to cause, or strongly suspected of causing, reproductive and
developmental effects via an EDC related mechanism; (2) identify loading estimates
for determining exposure to potential EDCs; (3) identify appropriate reference sites;
and (4) factor loading estimates, geographic distribution, and life history traits in
potential sensitivities of specific populations. These efforts will assist in hypothesis
generation and identification of information gaps needed for implementation of the
integrated studies described in other linkage projects. There is a good deal of
archived biological and environmental chemistry data that could be used to identify
hot spots/problem areas and species at risk. Examples of existing monitoring
programs in the U.S. that may be useful include EPA's Environmental Monitoring
and Assessment Program (EMAP), the National Status and Trends Program (BEST)
25
-------
ORD Research Plan for Endocrine Disrupters
of the NBS, and the National Water Quality Assessment Program (NAWQA)
administered by the U.S. Geological Survey. We need to improve our use and
dissemination of existing exposure and effects data, as well as the use of specimen
banking. Suitable historical control/reference data for assessment of effects must
be identified, data must be collected with a high degree of consistency, and effects
of EDCs must be explored in individual organisms as well as populations.
High Priority (Adjusted Score from Appendix Vl=29); Ecological and Exposure Focus
LNK.2.2 INTEGRATED EFFORTS ON WILDLIFE AT EDC-CONTAMINATED SITES.
Coordinated effects and exposure measurements are needed for areas suspected
to be contaminated with high concentrations of EDCs. Here, biomarker researchers
can test screening tools, in situ results can be compared to in vivo and in vitro
findings, and biologically plausible hypotheses (exposure and/or effects) can be
evaluated. Several specific sites will be selected based upon strong weight of
evidence that populations have been affected by exposure to EDCs. This evidence
can consist of ecological epidemiology, positive response or exposure screens,
historical data (from LNK.1.1) suggesting that EDCs are present in environmental
media, or where fate models suggest a hot spot. An ecosystem approach should
be adopted and multiple phylogenetic groups and trophic levels should be studied
at a given site. The site will be used to test and validate predictive, integrated
models that utilize structure-activity relationships (SAR), toxico kinetics,
bioenergetics, environmental chemistry, and population ecology, provide a means
for testing effects and exposure screening tools, and will provide multimedia sample
material foranalytical methods development (EXP.2.2). To provide all the necessary
expertise, this would have to be a carefully coordinated intramural and extramural
effort, with clear need for cooperative agreements rather than grants.
High Priority (Adjusted Score from Appendix Vl=14); Ecological and Exposure
Focus
LNK.2.3 EXAMINE HUMAN POPULATIONS FOLLOWING DEVELOPMENTAL EXPOSURE
TO EDCs FOR ALTERATIONS IN CENTRAL NERVOUS SYSTEM,
REPRODUCTIVE OR IMMUNOLOGICAL FUNCTION.
A number of human populations have been exposed to EDCs at high to moderate
dosage levels of EDCs (e.g., PCBs, PCDFs, DES) during development. These
populations should be thoroughly studied for latent adverse effects to determine if
observations from rodent studies (e.g., low sperm counts, infertility in male and
female offspring, shortened reproductive life span, ovarian atrophy, increases in
prostatitis, etc.) with these chemicals are manifest in humans after in utero
exposure. Thus, the DES sons should be reexamined for declines in sperm
numbers and semen quality and increases in benign prostatic hyperplasia and
prostate cancer, and the DES daughters should be followed for increased incidence
of reproductive abnormalities and cancers as they age. Similarly, populations
exposed to high levels
of p,p'-DDE in areas of the world where it is still in use should be examined for
26
-------
ORD Research Plan for Endocrine Disrupters
increased incidences of cryptorchidism, testicular cancer, and urogenital
malformations, as these are induced by in utero exposure to antiandrogens
in rodents, primates, and humans. Such studies should make every effort
to link effects with exposure or exposure-related parameters. Consideration
should also be given to additional studies on potent, high-volume EDCs
other than those discussed above.
High Priority (Adjusted Score from Appendix Vl=19), Human and Exposure Focus
LNK2.4 EPIDEMIOLOGICAL STUDIES OF HUMAN POPULATIONS EXPOSED AS
ADULTS.
Cohort-based approaches searching for adverse health outcomes in EDC-exposed
populations and case-control approaches on specific health effects (such as
reductions in sperm counts or increased incidences of infertility, hypospadias,
endometriosis, or cancers of the breast and reproductive tract) are needed to
ascertain the range of possible risks resulting from EDC exposures. For example,
a number of human populations (albeit mostly male), have been exposed
occupationally to EDCs (e.g., DDT, ODD, DDE, TCDD, DBCP, PCBs) at moderate
to high dosage levels as adults. These populations should be studied for latent
adverse effects. Although adults are not typically the most sensitive human
subpopulation for the effects of EDCs, these data can be compared to high dose
data obtained in adult male rodent studies to determine if humans and rodents
respond in a similar manner. Although obtaining accurate and relevant exposure
information is likely to be difficult, case-control studies of suspected EDC induced
diseases will be useful in the overall evaluation of the hypothesis that such effects
are related to specific exposures.
High/Medium Priority (Adjusted Score from Appendix Vl=25), Human and Exposure
Focus
LNK.2.5 STUDIES OF WILDLIFE POPULATIONS TO ESTABLISH
RELATIONSHIPS BETWEEN EDCs AND IMMUNE FUNCTION.
Numerous reports of immune alterations have been reported in EDC-exposed
wildlife populations. These observations need to be replicated in additional
populations. Results should be compared to outputs of EFF.3.2.
Medium to Low Priority (Adjusted Score from Appendix Vl=41); Ecological and
Exposure Focus
LINKAGE ISSUE 3. ESTABLISH STATUS AND TRENDS OF HUMAN AND WILDLIFE
ENDOCRINE DISRUPTION AND EDC EXPOSURE
To establish the scope of potential EDC-mediated effects, there is a need to collect exposure and
27
-------
ORD Research Plan for Endocrine Disrupters
effects data systematically from different ecosystems. It is clear that existing or proposed
resources would not allow development of major new monitoring program for EDCs. However,
coordination with existing programs with respect to the type of data collected as well as evaluation
of existing data could prove extremely valuable. Determination of exposure levels responsible for
population level effects is an important component of the research needs.
LNK.3.1 EXAMINE EXISTING HUMAN TISSUE/SERUM BANKS FOR CORRELATIONS OF
EDCs AND HORMONE LEVELS. IDENTIFICATION OF EDCS THAT OCCUR AT
HIGH LEVELS IN ECOSYSTEMS.
Human tissue and serum banks could be examined for concentrations of specific
endocrine disrupting chemicals. Forthe contaminant information to be useful, some
knowledge about the pharmacokinetics and metabolism would be required, as it
would be possible to lead to false-negative conclusions if the dynamic relationship
between exposure and biological effect mediated via hormonal alterations is not
understood. With respect to measurement of hormone levels, the stability of the
hormone in serum and the age, sex, and health of the donor would need to be
considered in interpretation of any results.
Medium to low priority (Adjusted Score from Appendix Vl=53); Human Focus
LNK.3.2 EXAMINE EXISTING CANCER AND BIRTH DEFECT REGISTRIES FOR
INCIDENCES OF EDC-LIKE HEALTH EFFECTS IN HUMANS.
It has been suggested that the effects of EDC chemicals manifest themselves in the
human population in a predictable fashion as a direct consequence of the role of
hormones in reproductive development and in the regulation of some tumor types.
The existing human health information is quite weak, and it is difficult to determine
if effects are increasing as some have claimed. Studies are needed to evaluate
whether these outcomes (e.g., hypospadias, cryptorchidism, diminished semen
quality, endometriosis, breast, testicular, and prostatic cancers) are increasing or
decreasing overtime and to identify the true incidence of these effects in the human
population at the present time.
Medium Priority (Adjusted Score from Appendix Vl=34), Human Focus
LINKAGE ISSUE 4: DEVELOP RISK MANAGEMENT APPROACHES TO REDUCE OR
ELIMINATE ENVIRONMENTAL EXPOSURES TO EDCs.
LNK.4.1 CHARACTERIZATION OF THE SOURCES OF EDCs IN THE ENVIRONMENT
To develop effective risk management strategies for EDCs, the major sources of
EDCs entering the environment causing exposure of humans and the ecosystems
must be identified. Such a survey could be conducted by collecting existing data
from databases associated with the Toxic Release Inventory, hazardous waste
sites,
28
-------
ORD Research Plan for Endocrine Disrupters
pesticide production and use, incinerator effluent compositions, etc.
Medium priority (Adjusted Score from Appendix Vl=31), Risk management focus
LNK.4.2 DEVELOPMENT OF TOOLS FOR RISK MANAGEMENT OF EDCs
Based on the exposure studies and results from LNK.3.4, tools to manage the
unreasonable risks associated with EDCs will be needed. These tools may include
methods to induce biodegradation of EDCs at hazardous waste sites or in
contaminated sediments, or pollution prevention strategies for chemical plants that
employ or produce EDCs. These tools must significantly lower unreasonable risks
associated with EDCs at an affordable cost.
Medium priority (Adjusted Score from Appendix Vl=27), Risk management focus
29
-------
ORD Research Plan for Endocrine Disrupters
V. RESEARCH IMPLEMENTATION GUIDANCE
In accordance with the uncertainties associated with the endocrine-disruption hypothesis, the
research topics identified in this plan are quite broad in scope and are likely to exceed the
available resources. Implementation of this plan will therefore require extensive coordination and
communication among the research managers in ORD, assistance from external review panels,
and continued involvement of the ORD ED Research Planning Committee, to ensure that the most
relevant and defensible research projects are selected for funding. Targeting the research effort
is complicated by the fact that there is a considerable existing intramural research program in
addition to enhanced availability of extramural resources. Coordination within the intramural
program is especially important for the Linkage Studies. These combined field and laboratory and
effect and exposure projects will require close collaboration among nearly every component of
ORD.
It is presumed that investigator-initiated responses to Request for Applications (RFAs) derived
from this research plan will provide the basis upon which the expanded ORD research effort in
endocrine disruption will be built. From these submissions, projects will be selected for funding
on the basis of both scientific excellence and programmatic relevancy using criteria provided below.
A similar, parallel process will be used to target the RFAs in the STAR (Science To Achieve
Results) Program and to select grants for funding. Recognizing that integration of the intramural
research program with the extramural grants is crucial to effective resource utilization, intramural
and extramural RFAs will have to be targeted to achieve both the breadth and depth of balance
needed to address the problems. For example, when designing the RFA for the intramural
research program, consideration should be given to questions such as: (1) Do we have laboratories
capable of undertaking the research? (2) Do we have scientists currently working in these areas?
(3) What is scope of the effort needed to study the problem? and (4) Does the intramural program
have the capacity to accomplish goals in a timely manner? Answers to such questions will provide
an important element in determining how best to focus the intramural and the extramural RFAs.
While the particular processes vary, ORD maintains a high standard of external peer review
regardless of whether the intramural or extramural pathway is taken to resolve a scientific
uncertainty. Intramural project proposals are subject to external scientific review and internal
relevancy review at the initiation stage, as well as periodic programmatic reviews, and during the
tri-annual site reviews of individual research divisions by external scientific panels. Extramural
project proposals are subject to both study section review by external experts, and relevancy
reviews by Agency staff prior to funding.
The scope of the endocrine disrupter problem suggests that additional oversight of the ORD
effort may be required to maintain an appropriate balance among the various components of the
research plan and to ensure that the major data gaps are addressed. The danger in a program
developed largely through investigator-initiated activities, even within a defined topic such as
endocrine disruption, is that the individual components do not complement each other sufficiently
to achieve the overall goals as stated in the Introduction. To help avoid this potential problem,
ORD's Laboratories and Centers are expected to develop individual implementation plans for
addressing the research activities identified in this plan. These implementation plans should be
reviewed by the ORD Research Planning Committee for their ability to provide a useful and
integrated research output to the Program Offices. Annual reports of progress and presentation
of the upcoming research objectives from each Laboratory and Center will facilitate the exchange
of information within ORD, assist in the direction of work to the highest priority areas, help fine-tune
the research directions as new information from the program emerges, and communicate with
EPA's Program Offices on progress in understanding the nature and extent of the EDC problem.
30
-------
ORD Research Plan for Endocrine Disrupters
Interactions between the recipients of the STAR grants and the intramural investigators involved
in endocrine disrupter research through annual or bi-annual workshops are also encouraged.
The following decision-making criteria for use in setting priorities within the endocrine
disrupters research program have been developed:
Risk-Based Planning:
Scientific Excellence:
Programmatic Relevance:
Other Sources of Data:
Capabilities and Capacities:
Sequence of Research:
Research that addresses an element of the risk assessment
paradigm and is designed to reduce the greatest
uncertainties is of the highest priority.
The quality of the science selected for support is of critical
importance to both the regulatory application of the resulting
information and the overall credibility of the Agency.
The degree to which a research project addresses a specific
statutory requirement will be an important ranking factor.
It is important to determine whether research that will provide
equivalent or complementary information is underway or
planned elsewhere. A high priority will be given to projects
that leverage resources within or outside the Agency.
The likelihood that research can be implemented within a
reasonable period of time using existing facilities, expertise,
and available resources will be considered when ranking
competing projects. This criterion applies to work conducted
intramurally as well as in situations where in-house expertise
is needed to oversee the completion of work conducted
through a cooperative agreement, contract or grant.
The value of some research, regardless of its priority ranking
on other criteria, is dependent upon the completion of other
work. Research that is dependent upon completion of
otherwise equally ranked work will receive a lower priority.
Such time dependency requires that periodic review of
progress is made in order to move to the next stage.
As noted in the Introduction, an important component of the implementation of this plan will
be an in-depth review in three to four years to ensure that it remains appropriately focused and to
re-adjust priorities as needed. For example, research related to risk management was given only
a "medium" priority in this plan pending resolution of the extent the endocrine disruption problem.
Such efforts are likely to grow in importance and merit a higher priority for funding. Conversely,
other topics may fade in importance as the key uncertainties are addressed.
31
-------
ORD Research Plan for Endocrine Disrupters
VI. REFERENCES
Ankley, G.T., R.D. Johnson, G. Toth, L.C. Folmar, N.E. Detenbeck, and S.P. Bradbury (1997).
Development of a Research Strategy for Assessing the Ecological Risk of Endocrine Disrupters.
Reviews in Toxicology 1:71-106.
Ankley et al. (30 coauthors). 1998. Overview of a workshop on screening methods for detecting
(anti-) estrogenic/androgenic chemicals in wildlife. Environ. Toxicol. Chem. 17:68-87.
CENR (1996). The Health and Ecological Effects of Endocrine Disrupting Chemicals: A Framework
for Planning. Committee on Environment and Natural Resources, National Science and
Technology Council, Office of Science and Technology Policy. November 22,1996, Washington
DC.
CRS Report for Congress. Summaries of Environmental Laws Administered by the Environmental
Protection Agency. M.R. Lee, Coordinator. Congressional Research Service. The Library of
Congress. January 3, 1995.
Gray, L.E. Jr., W.R. Kelce, T. Wiese, R. Tyl, K. Gaido, J. Cook, G. Klinefelter, D. Deaulniers, E.
Wilson, T. Zacharewski, C. Waller, P. Faoster, J. Laskey, J. Reel, J. Geisy, S. Laws, J. McLachlan,
W. Breslin, R. Cooper, R. DiGuilio, R. Johnson, R. Purdy, E. Mihaich, S. Safe, C. Sonneschein, W.
Welshons, R. Miller, S. McMaster and T. Colborn (1997). Endocrine Screening Methods Workshop
Report: Detection of Estrogenic and Androgenic Hormonal and Antihormonal Activity for Chemicals
that Act Via Receptor or Steroidogenic Enzyme Mechanisms. Reproductive Toxicology 11 (5):719-
750.
Kavlock, R.J., G.P. Daston, C. DeRosa, P. Fenner-Crisp, L.E. Gray, S. Kaattari, G. Lucier, M.
Luster, M.J. Mac, C. Maczka, R. Miller, J. Moore, R. Rolland, G. Scott, D.M. Sheehan, T. Sinks, and
H.A. Tilson (1996). Research Needs for the Risk Assessment of Health and Environmental Effects
of Endocrine Disrupters: A Report of the U.S. EPA Sponsored Workshop. Environmental Health
Perspectives 104 (Supplement 4): 715-740.
Reiter, L.W., C. DeRosa, R.J. Kavlock, G. Lucier, M.J. Mac, J. Melillo, R.L Melnick, T. Sinks and
B. Walton (1998). The U.S. Federal Framework for Research on Endocrine Disrupters and an
Analysis of Research Programs Supported during Fiscal Year 1996. Environmental Health
Perspectives. 106(2).
USEPA (1996a). Strategic Plan for the Office of Research and Development. Washington, DC,
EPA/600R-96/059, 60 pp.
USEPA (1996b). Environmental Endocrine Disruption: Effects Assessment and Analysis
Document. Risk Assessment Forum, December, 1996. Washington, DC.
32
-------
ORD Research Plan for Endocrine Disrupters
APPENDIX I. Time Lines for Major Research Questions.
OVERARCHING QUESTION
What effects are occurring in
exposed humans and wildlife
populations?
What are the chemical classes of
interest and their potencies?
What are the dose-response
characteristics in the low-dose
region?
Do our current testing guidelines
adequately evaluate potential
endocrine mediated effect?
What are the effects of exposure
to multiple EDCs, and will a TEF
approach be applicable?
How, and to what degree, are
humans and wildlife exposed to
EDCs?
What are the major sources and
environmental fates of EDCs?
How can unreasonable risks be
managed?
96
97
98
FISCAL YEAR
99
00
01
02
33
-------
ORD Research Plan for Endocrine Disrupters
APPENDIX II. SUMMARY DELIBERATIONS OF THE EPA WORKSHOPS
The premise of these workshops was given that environmental endocrine disrupting
chemicals (EDCs) have caused a variety of adverse biological effects in wildlife species, domestic
animals, and humans, there is a need to identify research that would assist the federal government
in making informed public health and regulatory decisions. An "environmental endocrine disrupter"
was broadly defined as "an exogenous agent that interferes with the production, release, transport,
metabolism, binding, action, or elimination of natural hormones in the body responsible for the
maintenance of homeostasis and the regulation of developmental processes." Importantly, this
definition reflects a growing awareness that the issue extends considerably beyond that of
"environmental estrogens" and includes anti-androgens and agents that act on other components
of the endocrine system such as the thyroid and pituitary glands.
The majority of the invited experts at the Raleigh workshop agreed that the endocrine
disrupter hypothesis was of sufficient concern to warrant a concerted research effort. In particular,
the study of potential effects on reproductive development at multiple phylogenetic levels was
deemed the most important area in need of attention. It was emphasized repeatedly that the
developing embryo, fetus, and neonate should not be viewed as small adults and that the
processes of development are especially vulnerable to brief periods of endocrine disruption.
However, for many of the effects reported in both wildlife and humans that have been attributed
to, or associated with, endocrine disruption, exposure assessment generally has been inadequate
for quantitative risk assessment. Because of this, some participants felt it was difficult to critically
evaluate and establish the level of priority relative to other research topics. Still other participants
reminded the workshop not to lose sight of the presence of natural occurring endocrine disrupters
(e.g., phytoestrogens) as the effects of man-made chemicals are studied.
The objectives of the ecological research strategy workshop were two-fold: to identify
research needs and approaches to determine the relative ecological risk of EDCs compared to
other stressors on populations and communities, both from a prospective and retrospective
standpoint, and to make recommendations for developing or modifying the requirements for testing
and evaluating chemicals and environmental samples so as to ensure that those exerting toxicity
through specific endocrine axes will be characterized adequately.
Several general comments pertaining to future research on endocrine disrupting chemicals
emanated from the discussions. These include the recognition that there was a great advantage
in bringing together a multi-disciplinary group of scientists representing both the human health and
ecological health viewpoints to help identify common issues and that this interaction must be
nurtured as the research agenda unfolds. The workgroup noted some key similarities and
differences exist between endocrine disrupters and other chemicals which can cause adverse
biological effects. Two of the key differences are: the presence of natural ligands within the body
that must interact at some level with the exogenous chemical; and that the concentrations of the
natural ligands within the body fluctuate during the life cycle and must be maintained within narrow
limits at key times during development. This latter point makes consideration of timing of exposure
a very significant factor in any assessment. While timing of exposure is important, many EDCs are
persistent in the environment and bioaccumulate, and exposures are widespread throughout the
entire globe. This can have important ramifications on a biological system that is geared to often
cyclical homeostatic control mechanisms such as many of the hormones of the endocrine system.
Lastly, the mechanistic basis of the interaction with biological systems presages the induction of
subtle effects at low doses that must be interpreted as adverse or not. As the level of organization
at which biological responses to endocrine disrupters are observed decreases (e.g. from
physiological to cellular to molecular), the challenge to describe the effects as adverse at the level
34
-------
ORD Research Plan for Endocrine Disrupters
of the individual and the population increases. In this regard, endocrine disrupters are not unlike
other types of chemicals for which toxicological information is amassed.
In general, it was felt that linking specific exposures to specific effects in the general
environment would often be difficult due to the complexities of exposure, the latency of the effects,
and the at times subtle nature of the outcomes. Therefore, to confirm the validity of the hypothesis
it is likely that there will be heavy reliance on the application of epidemiological criteria for causality
(strength of the association, presence of a dose-response relationship, specificity of the
association, consistency across studies, biological plausibility, and coherence of the evidence).
Such considerations will have significant impact on the types of research activities necessary to
adequately confirm or refute the central hypothesis. Ten broad categories of research needs were
identified: basic research, biomarkers, database development, exposure determination, exposure
follow-up, mixtures, multi-disciplinary studies, risk assessment methods, hazard identification, and
sentinel species. Several workgroups noted the complexity in identifying whether effects of
xenobiotics on those systems were the result of primary or secondary aspects of endocrine
disruption. Workshop participants particularly noted that identification and characterization of
effects on the developing reproductive system were considered of high priority for additional
research due to the high sensitivity and frequent irreversibility of effects following even brief
exposures. More refined exposure assessments and research on the toxicology of mixtures were
also considered to be of high importance. Special emphasis was placed on consideration of the
unique challenges endocrine disrupters might pose to the risk assessment paradigm. Interestingly,
the fact that there is an understanding of the mechanisms underlying endocrine disruption induced
by some chemicals was seen as an advantage in that it may result in a common, biologically based,
human health risk assessment process for all effects (cancer and noncancer).
The following specific research strategies were suggested over the course of the Duluth
workshop to start to address the research recommendations listed above:
1) Review and compile available data on endocrine function and endocrine cycles in
species of concern (e.g., vulnerable species) to identify areas where additional
research is needed.
2) Consolidate and review data from ongoing monitoring programs (e.g., Environmental
Monitoring and Assessment Program, National WaterQuality Assessment Program,
National Status and Trends Program) to identify trends that may be associated with
effects of EDCs.
3) Modify existing monitoring programs to include information relevant to EDCs such as
measurement of relevant chemicals, information about sex ratios and endocrine
parameters.
4) Increase emphasis on research in comparative endocrinology and toxicology to allow
extrapolation among species.
5) Conduct focused research projects at a few selected sites with known endocrine
disrupter problems. Examine multiple species at several levels of organization to
establish linkages between endpoints measured in the laboratory at the
suborganismal/individual level and changes in the field at higher levels of
organization. Strategies and information developed from these projects could then
be used to assess or predict impacts of EDCs in other areas.
35
-------
Appendix III. Overview of Research Plan, Tasks, and Outputs for Endocrine Disruptors
Subtopic
Strategic Focus
Tasks
Products
Uses
Biological Defining the classes of
Effects chemicals that act as EDCs
and their potencies
Evaluating current testing
guidelines and monitoring
procedures for adequacy of
assessment of EDCs
Determining the shapes of
dose-response curves for
EDCs at relevant exposures
and the tissue levels
associated with adverse effects
Describing the normal
endocrine profiles in wildlife
species
Extrapolating effects at the
individual level to populations
for fish and wildlife
Develop in vitro and in vivo methods and
structure-activity models to screen for
EDC action
Enhance ability of existing test methods
(e.g., multi-generational studies in
mammals and life cycle tests in fish and
wildlife) to evaluate manifestations of
endocrine disruption and underlying
modes of action
Assess effects of EDC exposure on
neuroendocrine, immunological, and
reproductive function in developing and
adult animals in support of
pharmacokinetic and biologically based
dose-response models, with emphasis on
animal models of EDC-induced human
diseases
Provide baseline endocrine information for
wildlife populations and their laboratory
surrogates, with emphasis on comparative
endocrinology and developmental control
of sex differentiation, especially for
species with little historical attention
Translate results from measurement
endpoints at lower levels of biological
organization to impacts on populations
and communities through use of
microcosms and mesocosms
Identify appropriate sentinel species for
environmental monitoring
Methods to describe the hazard
potential of EDCs and likely
modes of action and potencies
Revised testing guidelines that
are more indicative of the most
sensitive life-stage, sex, and
target tissue for chemicals that
act through the endocrine system
Animal models of EDC-induced
health effects that provide
increased understanding of the
types and magnitudes of risks for
exposure to EDCs during various
phases of the life cycles
Databases of endocrine profiles
in species from multiple
phylogenetic levels and improved
understanding of the role of the
endocrine system in sex
differentiation
Models predicting population
level effects from studies at lower
levels of biological organization
Hazard
characterization to
support implementation
of the FQPAand the
SDWA
To improve regulatory
testing requirements
and data interpretation
To provide quantitative
dose-response
evaluation and reduced
uncertainties for
human health
extrapolations
To assess the impact
of EDCs in wildlife
populations
To facilitate ecological
risk assessment based
on effects in
individuals
36
-------
Appendix III. Overview of Research Plan, Tasks, and Outputs for Endocrine Disruptors
Subtopic
Strategic Focus
Tasks
Products
Uses
Characterizing the effects of
exposure to multiple EDCs
Systematically study the interactions of
EDCs at low, relevant dose levels to
understand potential for synergism
Assessment of the validity of the
additivity principal for EDCs and
predictive models for synergistic
interactions
To reduce uncertainties
associated with
assessment of
exposure to multiple
EDCs
Exposure
Studies
Developing a framework to
characterize and to diagnose
and predict ecological and
human exposure to EDCs
Providing adequate tools to
estimate exposure to EDCs
Determining total ecosystem
and human exposures to EDCs
of concern
Use physicochemical attributes to identify
transport, transformation, and
environmental fate characteristics
associated with exposure scenarios of
concern to biological organisms
Construct compartmental models to
predict environmental behaviors
Develop new methods, and refine existing
ones (e.g., analytical chemistry, sample
extraction, biomarkers) to acquire data for
compartmental models, with emphasis on
the transport and transformation in
sediments and tools for assessing
exposure in individuals
Examine multi generational transfer of
EDCs in ecosystems, including
biomagnification processes important to
higher vertebrates
Provide information on EDC exposure
distribution in the general human
population
Validated models to predict and
assess transport, fate and
exposure to EDCs from source to
receptor
Field and laboratory tools to
better quantitate EDCs in multi-
media
To conduct preliminary
environmental
exposure assessments
and set priorities for
additional focused
research
To improve
characterization of
exposure to EDCs
Exposure assessments for EDCs
in key wildlife species and the
general human population
To monitor the
environment for signals
of EDC exposure and
effects
Linkage of
Effects,
Exposure and
Risk
Management
Integrating human and
ecological effects research with
exposure research within the
risk assessment paradigm
Construct framework to identify,
characterize, prioritize and assess
potential and risks to EDCs and provide
database for preliminary risk
characterization
Coordinated process for
identifying exposure and effects
of concern for additional
intensive characterization of risk
To conduct preliminary
risk assessments and
assist research
prioritization
37
-------
Appendix III. Overview of Research Plan, Tasks, and Outputs for Endocrine Disrupters
Subtopic
Strategic Focus
Tasks
Products
Uses
Determining classes and
concentrations of EDCs
associated with observations of
endocrine disruption
Establishing status and trends
of human and wildlife
endocrine disruption and EDC
exposure
Developing risk management
approaches to reduce or
eliminate environmental
exposure to EDCs
Develop informational database for EDCs,
including biological effects, environmental
concentrations, and historical trends from
existing monitoring programs
Conduct integrated toxicology and
exposure studies in areas or human
populations with suspected contamination
or exposure to EDCs
Examine existing monitoring efforts and
exposure and effect registries for
relevancy to addressing EDC uncertainties
Identify major sources of EDCs entering
the environment
Develop tools for risk management such
as biodegradation processes or pollution
prevention strategies
Database on EDC levels in the
human environment and various
ecosystems associated with
biological effects of concern
Centralized Information
source for
environmental
monitoring of EDCs
Consolidated databases of status
and trends relevant to EDC
exposures and effects
Risk management tools for
elimination or prevention of
exposures to significant EDCs
For environmental
monitoring and
comparison of effects
with more intensive
exposures
To develop remedial
actions where adverse
effects of EDCs have
been documented
EDC = Endocrine Disrupting Chemical
FQPA = Food Quality Protection Act
SDWA = Safe Drinking Water Act
38
-------
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Activities Specified in the
Research Plan
ISSUE
EFF1
EFF2
EFF3
EFF4
Determine the classes of chemicals that act as EDCs and their potencies
Evaluate current testing and monitoring procedures for adequacy of assessment of the
effects of EDCs
Mode of action studies in laboratory animal models following developmental exposure.
Developmental and acute effects on immune function
Studies of EDC-induced human effects in animal models
Pharmacokinetic studies of highly relevant EDCs
Development of BBDR models for highly relevant EDCs
Mode of action studies in pubertal and adult laboratory models
Definition of baseline endocrine status in wildlife populations
Studies in comparative endocrinology and toxicology
Studies on the role of hormones in sexual differentiation
•a
CD
g>.
X f.
® 0
<= ~
— co
•i Q-
fc 0
zs a.
8 »
o —
CD —
CO ^
>CD CO
"CD c
CO
"co E
g Z!
/
/
/
/
/
//
/
/
o-
co •
CO
ra co
/
/
//
/
//
/
/
//
/
t>
ij=
"O
CD
-HJ T3
CO CD
cr E
CD CD
"O CZ
Ifl O
,~,
•- E
CD CD
•a
Z! CO
•^= "o
2 CD
o —
o g
Q CD
/
//
/
/
/
s
CD
•a
CD
CD
CD
&_
CO
o
o
cz
o
H— <
CO
o
Q.
CO
il
CD
CO
.C
/
/
//
//
/
/
//
//
_CD
CD -Q
AS
Z! Q-
F °-
C CO
° CD
CD^2
= 0
c^ co
o 2
CD Q.
M— CO
o u_
<5 UJ
0 |-
CD
E] — CO
CD =
CD g
CD
CD 0
.c Q
/
/
/
/
/
/
/
•a
cz _
« w
2 Q
E LJJ
-c 2
CD O
CD Q.
h, x
S5^
•a J5
_! , I—
cc P
.C "*IJ
0 0.
•^ o
"O o
CO ^
j. :=
6E
I S
/
/
•a
CO CJj
CO U
£1 LLJ
Z! M
O O
^ w
o -^
•=r CO
E "m
CD •£
35 CD
CD E
CO §
cc >
^? CD
/
•a
CD
O)
CO
CO
E
CD
.Q
CO
^
's_
CD
"o
CO
cz
o
CO
CO
cz
c
CO
o
>
o
I
/
/
39
-------
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Activities Specified in the
Research Plan
EFF5
EFF6
EXP1
EXP2
EXP3
LNK1
Bioassays for evaluating integrated effects
Evaluation of effects at populations and community levels
Determination of sentinel species
Studies of interactions of low, relevant dose levels of mixtures
Identification and evaluation of classes of suspect EDCs
Development and application of compartmental models
Abiotic Fate
Biotic Fate
Develop measurement methods and biomarkers for high throughput
Study inter-generational transfer in ecosystems
Study bioaccumulation in food webs
Obtain population based distributions of EDC exposures
Framework for comprehensive, multi-laboratory EDC investigations
•a
CD
8.C-
X f.
® 0
= :§
— co
05-5
•i Q-
fc 0
zs a.
8 »
O ~
CD —
CO ^
^ cc
ID c
cc
TO E
g Z!
/
//
//
/
/
/
/
/
/
O-
CD CD
CO ^
"0 32
— O
co a.
.f2 !_
E CD
CD ^~
(— •'••'
o -a
i= TO
u CD
Co CD
CC C
§ "o
/
/
/
/
o
O)
CD
CD
(/5
CD O
(/5 "a
8.0
(/5 —
CD CD
&_ (—
CD c
O
"O ^
CD "4=
CD 0>
CO ^
TO CO
/
/
•G
ij=
~o
_CD
-HJ T3
TO £
CT ^
CD CD
"C c
(/5 O
•El
CD CD
•a
Z! TO
•^= "o
B CD
j_ -HJ
O —
o g
Q CD
//
/
s
CD
•a
CD
CD
CD
lf>
O
o
cz
o
4— <
TO
O
a.
TO
il
CD
TO
.C
/
/
/
/
/
/
_CD
CD -C2
AS
zs a.
F °-
C TO
° CD
CD^2
= 0
0 |
X Q.
CD Q.
M— TO
o u_
<5 UJ
o H
CD
J^ TO
CD =
CD g
CD ^
TO y,
^50
^ Q
§UJ
//
/
/
/
•a
cz _
<* w
^ Q
E LJJ
-c 2
CD "O
TO («
CD O
CD a.
h, x
c?^
•a J5
_! , I—
CT3 P
_C "*IJ
o a.
•^ o
"O Q_
c
5. —
6E
I S
/
/
/
//
/
//
//
//
//
//
//
//
•a
CO CJj
v) O
CD Q
f£ LLJ
O O
^ w
O -^
•=r CO
E "m
CD "£
35 CD
CD E
TO §
cc >
^? CD
/
/
//
/
/
/
/
/
/
/
•a
CD
O)
TO
TO
E
CD
.Q
J2
's_
CD
o
TO
£Z
O
(/)
TO
CZ
c
TO
O
O
I
/
/
/
/
/
/
/
/
/
40
-------
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Activities Specified in the
Research Plan
LNK2
LNK2
LNK3
LNK4
Evaluation of existing data and programs for EDC monitoring
Integrated studies of wildlife at contaminated sites
Examine human populations exposed developmentally
Examine human populations exposed as adults
Studies of wildlife populations to establish relationships between EDCs and immune
function
Examine existing human tissue banks for correlations between EDCs and hormone
levels
Examine existing cancer and birth defect registries for incidences of EDC like effects
Characterization of the sources of EDCs in the environment
Development of risk management tools for EDCs
•a
CD
8.C-
X f.
® 0
= :§
— co
05-5
•i Q-
fc 0
•^ a.
8 »
O ~
CD —
CO ^
^ CO
ID c
co
TO E
f^
.C
/
//
//
//
//
s
//
/
/
o-
CD CD
CO ^
"o £
— O
co a.
.f2 s-
E CD
CD ^~
f— •'••'
o -a
^ TO
U CD
TO CD
TO C
§ "o
/
/
s
o
O)
CD
CD
(/5
CD O
(/5 "a
8.0
(/5 —
CD CD
&_ (—
CD c
O
"O "^
CD '^3
CD CD
CO
TO ro
/
/
t>
ij=
"O
_CD
TO^
CT ^
CD CD
"C c
(/5 O
•El
CD CD
•a
^ TO
•^= "o
2 CD
O —
o g
Q CD
/
s
CD
•a
CD
CD
CD
lf>
O
o
C.
o
H— <
TO
O
a.
TO
il
CD
TO
.C
/
_CD
CD -C2
AS
ZJ Q.
F °-
c TO
2 CD
CD^2
= 0
0 |
X Q.
CD Q.
M— TO
o u_
<5 LJJ
0 1-
CD
J^ TO
CD =
CD g
CD
^50
.c Q
§L1J
/
/
/
/
•a
c _
^? CD
/
/
//
/
•a
CD
O)
TO
TO
E
CD
.Q
^
's_
CD
o
TO
cz
o
(/)
TO
C
c
TO
O
O
I
/
/
/
/
//
41
-------
APPENDIX V.a. TASK SUMMARY AND PROPOSED SEQUENCE FOR EFFECT STUDIES
ISSUE
EFF.1.1
EFF.2.1
EFF.3.1
EFF.3.2
EFF.3.3
EFF.3.4
EFF.3.5
EFF.3.6
EFF.4.1
EFF.4.2
EFF.4.3
EFF.5.1
EFF.5.2
EFF.5.3
EFF.6.1
FOCUS1
HH
X
X
X
X
X
X
X
X
X
EE
X
X
X
X
X
X
X
X
X
X
X
EX
PRIORITY2
H(1)
H(13)
H(23)
H/M(27)
H(10)
H(24)
H/M(34)
M(37)
H(26)
M(33)
H(36)
H(26)
H/M(22)
H(26)
H(16)
PROPOSED TIME FRAME3
FY96
X
X
X
X
X
X
FY97
X
X
X
X
X
X
X
X
X
X
X
FY98
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FY99
X
X
X
X
X
X
X
X
X
X
X
X
X
FYOO
X
X
X
X
X
X
FY01
X
X
1 HH, Human Health, EE, Ecological Effect, EX, Exposure Assessment
2 As Priority (Priority Score). Priorities H (High), M Medium, (L) Low. See Appendix VI for basis of
prioritization score.
3 Assignment based on logical sequence of research, placing issues addressing the uncertainties of
most concern earlier in the implementation process.
42
-------
APPENDIX V.b. TASK SUMMARY AND PROPOSED SEQUENCE FOR EXPOSURE STUDIES
ISSUE
EXP.1.1
EXP.1.2
EXP.2.1
EXP.2.2
EXP.2.3
EXP.3.1
EXP.3.2
EXP.3.3
FOCUS1
HH
X
X
X
EE
X
X
X
X
X
EX
X
X
X
X
X
X
X
PRIORITY2
H(9)
H(28)
H(28)
H(10)
H(21)
M(35)
M(34)
H(22)
PROPOSED TIME FRAME3
FY96
X
X
X
FY97
X
X
X
X
X
X
X
FY98
X
X
X
X
X
X
X
FY99
X
X
X
X
X
X
X
FYOO
X
X
X
X
X
X
FY01
X
1 HH, Human Health, EE, Ecological Effect, EX, Exposure Assessment
2 As Priority (Priority Score). Priorities H (High), M Medium, (L) Low. See Appendix VI. for basis of
prioritization score.
3 Assignment based on logical sequence of research, placing issues addressing the uncertainties of most
concern earlier in the implementation process.
43
-------
APPENDIX V.c. TASK SUMMARY AND PROPOSED SEQUENCE FOR LINKAGE STUDIES
ISSUE
LNK.1.1
LNK.2.1
LNK.2.2
LNK.2.3
LNK.2.4
LNK.2.5
LNK.3.1
LNK.3.2
LNK.4.1
LNK.4.2
FOCUS1
HH
X
X
X
X
X
EE
X
X
X
X
EX
X
X
X
X
X
X
X
PRIORITY2
H(24)
H(29)
H(14)
H(19)
H/M(25)
M/L(41)
M/L(53)
M/L(34)
M(31)
M(27)
PROPOSED TIME FRAME3
FY96
X
X
FY97
X
X
X
X
X
X
FY98
X
X
X
X
X
X
X
X
FY99
X
X
X
X
X
X
X
X
X
FYOO
X
X
X
X
X
X
X
FY01
X
X
X
X
X
1 HH, Human Health, EE, Ecological Effect, EX, Exposure Assessment
2 As Priority (Priority Score). Priorities H (High), M Medium, (L) Low. See Appendix VI for basis of
prioritization score.
3 Assignment based on logical sequence of research, placing issues addressing the uncertainties of most
concern earlier in the implementation process.
44
-------
APPENDIX VI. Cumulative Priority Ranking Scores1
Issue
EFF1.1
EFF2.1
EFF3.1
EFF3.2
EFF3.3
EFF3.4
EFF3.5
EFF3.6
EFF4.1
EFF4.2
EFF4.3
EFF5.1
EFF5.2
EFF5.3
EFF6.1
EXP1.1
EXP1 .2
EXP2.1
EXP2.2
EXP2.3
EXP3.1
EXP3.2
EXP3.3
LNK1.1
LNK2.1
LNK2.2
Short Title
Chemical Classes
Testing Procedures
Modes of Action
Developmental Immune Effects
Animal Models of Diseases
Pharmacokinetics
BBDR Models
Adult neuroendocrine Effects
Endocrine Baselines
Comparative Endocrinology
Sexual Differentiation
Integrated Bioassays
Population Effects
Sentinel Species
Interactions
Classes of EDCs
Compartmental Models
Abiotic Fate
Biotic Fate
High Throughput
Intergeneratioanl Transfer
Trophic Dynamics
Population Distributions
Comprehensive Framework
Existing Monitoring
Integrated Wildlife Studies
Programmatic
Relevance
8
8
16
15
9
11
16
19
18
15
20
14
9
15
9
8
15
16
8
13
18
17
9
21
13
14
Biological
Concern
8
14
14
17
8
15
15
20
14
15
13
15
9
11
12
13
15
22
9
15
12
13
15
9
14
8
Potential
Impact
8
14
9
15
9
14
9
15
13
15
13
8
9
15
9
8
13
8
15
9
13
14
8
11
19
8
Sequence
8
9
9
10
8
14
13
11
8
14
15
14
15
10
16
10
15
11
9
9
17
16
15
9
9
9
Technical
Success
10
9
16
11
17
11
22
13
14
15
16
16
21
16
11
11
11
12
10
16
16
15
16
15
15
16
Total Score
42
54
64
68
51
65
75
78
67
74
77
67
63
67
57
50
69
69
51
62
76
75
63
65
70
55
Adjusted Score
1
13
23
27
10
24
34
37
26
33
36
26
22
26
16
9
28
28
10
21
35
34
22
24
29
14
45
-------
APPENDIX VI. Cumulative Priority Ranking Scores1
LNK2.3
Issue
LNK2.4
LNK2.5
LNK3.1
LNK3.2
LNK4.1
LNK4.2
Human Development
Short Title
Human Adults
Wildlife Immunotoxicology
Tissue Banks
Registries
Sources of EDCs
Management of EDCs
14
Programmatic
Relevance
14
16
18
17
8
9
9
Biological
Concern
15
15
22
10
16
10
8
Potential
Impact
8
15
15
10
9
9
9
Sequence
10
15
16
15
22
24
20
Technical
Success
19
21
23
23
17
16
60
Total Score
66
82
94
75
72
68
19
Adjusted Score
25
41
53
34
31
27
1 Each member of the planning committee assigned a weight of 1 to 3 (1 being the highest) to each of five factors (Programmatic Relevance, Magnitude of
Biological Concern, Potential Impact of Research, Sequence of the Research, and Technical Feasibility of the Research). The values in the columns under each
of the five factors is the sum of the weights assigned by 8 individuals (thus, an issue would receive a highest possible score of 8, and the lowest a possible score
of 24). The column marked "Total Score" is the sum of weights for the five individual factors, while the Adjusted Score substracts the lowest total score, and
then adds one, such that the highest priority issue has a value of 1. This is the value used in the text and in Appendix Va-c.
46
-------
APPENDIX VII. Endocrine Disruptor Research Plan Arrayed Against the Government Performance and Results Act Structure
Agency Goals/Objectives/Sub-Objectives
EFFECTS
1
o
O
±s
CO
0)
f-
c
CO
0)
o
c
1
£
CO
£
O
ra
.0
c
£
J
UJ
w
§
&
CO
.1
"o
"o
w
.!2
c
03
O
0)
5
w
0)
-o
o
5
s
a.,
D)
C
-a
o
1
0
CL
o
'•s
3
S
03
O
B
"c
0)
|
|
c
Ul
c
(D
1
<
"3
w
"ro
gJ
w
o
a.
x
Ul
O
w
s
22
w
o
CL
x
UJ
RISK
ASSESSMENT
"E
0)
w
w
w
w
w
be
8
D)
O
8
UJ
•a
c
1
03
0)
I
8
c
CO
0
w"
o
£
w
1
"5
"E
w
w
<
"w
be
S
Q
•a
c
CO
§
CO
'5
•c
i.
Q.
W
o
w
w
<
"w
be
RISK MANAGEMENT
C
O
"co
.N
(D
1
03
O
_0)
0
CL
0
o
CO
w
o
1
c
o
"c
0)
1
CL
W
o
£
5
"o
"c
0
O
w
-a
o
1
c
0
'•§
o
U)
0)
^
c
_0
"co
1
0)
ce
c
o
'ra
O
^
1
1
O
o
c
fe
0)
0_
Q)
•i
C
£
>s
o
0
c
f-
o
(D
H
8: PROVIDE SOUND SCIENCE TO IMPROVE UNDERSTANDING OF ENVIRONMENTAL RISK AND DEVELOP AND IMPLEMENT INNOVATIVE APPROACHES
FOR CURRENT AND FUTURE ENVIRONMENTAL PROBLEMS
ORD Science Objective #3: Emerging Risk Issues: Establish
capability and mechanisms within EPA to anticipate and identify
environmental or other changes that may portend future risk,
integrate futures planning into ongoing programs, and promote
coordinated preparation for and response to change
ORD Science Sub-Objective #3.2: Endocrine Disrupters
MM-35
LNK.
2 2
3.1
MM-56
LNK.
2.1
MM-64
EFF.
1.1
2.1
MM-65
EFF.
5.1
MM-7
EFF.
5.1
5.3
LNK.
2.2
2.3
2.4
2.5
vlM-12
EFF.
3.1
3.2
3.3
3.4
3.5
3.6
vlM-30
LNK.
1.1
VSM-56
LNK.
2.1
MM-24
EFF.
4.1
4.2
4.3
MM-58
EFF.
6.1
MM-64
EFF.
1.1
2.1
VIM-23
EFF.
5.2
5.3
MM-66
EXP.
1.1
1.2
MM- 17
EXP.
2.1
2.2
2.3
MM-45
EXP.
3.1
3.2
3.3
MM-57
LNK.
2.1
MM- 8
EFF.
5.1
5.3
LNK.
2.2
2.3
2.4
2.5
MM-28
LNK.
1.1
MM-36
LNK.
2 2
3.1
VIM-63
LNK.
3.3
LNK.
2.3
2.4
2.5
3.2
MM-29
LNK.
1.1 "
MM-55
LNK.
2.1
•1M-18
LNK.
4.1
4.2
47
------- |