Office of Research and EPA/600/R-98/042 

Development February 1998 

Washington, DC 20460 www.epa.gov 

Environmental Protection 

Agency 

United States 

Research Plan for 

Endocrine Disruptors 
Foreword 

The Strategic Research Plan for Endocrine Disruptors, one in a series of

research plans produced by EPA’s Office of Research and Development (ORD),

identifies and describes one of EPA’s high-priority research topics. This research 

topic was selected in accord with the ORD Strategic Plan, which identifies the

following as high-priority research areas for EPA: 

C broad-based fundamental research to improve human health and

ecosystem risk assessment, pollution prevention, and new technologies

for environmental protection; and 

C research targeted at specific pollution problems in safe drinking water,

high-priority air pollutants, and emerging environmental issues. 

In addition, ORD has included certain other key research program areas, such as

the Environmental Monitoring and Assessment Program (EMAP) and global

climate change. 

The Strategic Research Plan for Endocrine Disruptors is an outcome of ORD’s

research priority-setting process, which has employed human health and ecological

health research criteria, risk management research criteria, and methods/models

development criteria in order to set priorities among the many research topics

identified through input from all parts of EPA and from other government and

private sector organizations; the topics must also fit within EPA’s mission and 

goals. EPA’s program and regional offices—the Agency’s main research

clients—were consulted to ensure that the final version of this plan includes the 

research products they will need to fulfill their responsibilities. In addition, the

Strategic Research Plan for Endocrine Disruptors was subjected to rigorous

external peer review. 

Strategic research plans are important tools for measuring accountability

because they make clear the rationale for, and the intended products of, EPA’s

research. By specifying up front how EPA will manage its scientific data and

information products, EPA can effectively communicate the results of its research to

its clients, stakeholders, and the public. Research plans are also important budget

tools, enabling EPA to clearly track progress toward achieving its research goals as

required by the 1993 Government Performance and Results Act. 

An implementation 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, an implementation plan defines the research program that EPA is

pursuing. The research strategy, as an overarching view of research needs and 
priorities, thus provides a link between the ORD Strategic Plan and the

implementation plans of ORDs Laboratories and Centers which define the research

topics at the project level. 

Peer review is an important component of research plan development. The 

peer review history for the Strategic Research Plan for Endocrine Disruptors is as

follows: 

Initial Internal Agency Review: February, 1996 

ORD Science Council: Final Clearance, December, 1996 

Lead Reviewers: Rick Linthurst, NERL 

Jennette Wiltse, NCEA 

Submitted for Comments 

to the Endocrine Disruptor

Working Group of the

Committee on the 

Environment and 

Natural Resources April, 1997 

External Peer Review: July 8-9, 1997; Washington, DC. 

Reviewers: 

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, US Food and Drug Administration

Timothy Kubiak, US 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: March, 1998 
ORD Executive Lead: Larry Reiter, NHEERL 

List of Authors: 

Gerald Ankley, NHEERL

Elaine Francis, OSP

Earl Gray, NHEERL

Robert Kavlock, NHEERL, Chair

Sue McMaster, NHEERL

David Reese, NCERQA

Greg Sayles, NRMRL

Anne Sergeant, NCEA

Dan Vallero, NERL
ORD Strategic Research Plan for Endocrine Disruptors 

OFFICE OF RESEARCH AND DEVELOPMENT 

US ENVIRONMENTAL PROTECTION AGENCY 

RESEARCH PLAN FOR ENDOCRINE DISRUPTORS 1 

February, 1998 

1

ORD Research Planning Committee Members: Gerald Ankley, NHEERL; Elaine Francis, OSP; L Earl 

Gray Jr, NHEERL; Robert Kavlock (Chair), NHEERL; Sue McMaster, NHEERL; David Reese 

(NCERQA), Gregory Sayles, NRMRL; Anne Sergeant, NCEA; Dan Vallero, NERL 

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ORD Strategic Research Plan for Endocrine Disruptors 

TABLE OF CONTENTS 

I. INTRODUCTION......................................................................................................................3

II. REGULATORY BACKGROUND............................................................................................7

III. RESEARCH ISSUES............................................................................................................9 

IV. RESEARCH APPROACH AND ACTIVITIES.....................................................................13

Biological Effects Studies.....................................................................................15 

Issue 1. Chemical Classes and Potencies.......................................15

Issue 2. Testing Protocols.................................................................16

Issue 3. Dose Response Relationships............................................16

Issue 4. Endocrine Profiles in Wildlife..............................................18

Issue 5. Extrapolation to Populations...............................................20

Issue 6. Mixtures.................................................................................21

Exposure Studies ..................................................................................................23

Issue 1. Characterization Framework................................................23

Issue 2. Exposure Assessment Tools................................................24

Issue 3. Environmental Concentrations.............................................26

Linkage Studies......................................................................................................28

Issue 1. Risk Assessment Integration................................................29

Issue 2. Exposure Characterization...................................................29

Issue 3. Status and Trends..................................................................32

Issue 4. Risk Management Approaches..............................................33

V. RESEARCH IMPLEMENTATION GUIDANCE. ..................................................................34

VI. REFERENCES....................................................................................................................37

APPENDIX I. TIME LINES TO ADDRESS OVERARCHING QUESTIONS.............................38

APPENDIX II. SUMMARY DELIBERATIONS OF EPA WORKSHOPS...................................39

APPENDIX III. RESEARCH MATRIX FROM ORD STRATEGIC PLAN...................................42

APPENDIX IV. CROSS TABULATION OF ISSUES WITH RESEARCH QUESTIONS...........45

APPENDIX V. FOCAL AREAS, PRIORITY AND TIME FRAME FOR ISSUES......................48

APPENDIX VI. PRIORITY RANKING FACTORS....................................................................51

APPENDIX VII. GPRA ALIGNMENT........................................................................................53

I. INTRODUCTION

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ORD Strategic Research Plan for Endocrine Disruptors 

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 primarily been identified 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 that may have an endocrine-related basis (breast, prostate, testicular) 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 disruptors 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: 

The primary questions that need to be answered for endocrine disruptors 

% 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

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ORD Strategic Research Plan for Endocrine Disruptors 

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 the USEPA’s mandate to protect both public-health and the environment, it 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 which have the potential to act as 

endocrine disruptors, the Office of Research and Development of the USEPA held two workshops. 

There, the opinions of international experts were sought to help formulate a national research plan 

for endocrine disrupting chemicals. 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 sole 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 USEPA-sponsored workshops, the scientific judgement of the 

ORD Research Planning Committee, and 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 Disruptor 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). The USEPA chairs this coordination effort and has 

been instrumental in establishing a communication network on endocrine disruptors 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 disruptor 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 participating 14 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 disruptor hypothesis, the 

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ORD Strategic Research Plan for Endocrine Disruptors 

overlapping concerns of federal agencies, and the resource constraints 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 are currently 

discussing issuing 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 USEPA’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 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 the Organization of Economic and Community Development to assemble international 

inventory and assessment of the endocrine disruptor issue. In addition, the National Research 

Council has also been commissioned by the USEPA’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 USEPA’s research plan, the committee noted that there are clearly important 

areas for which other federal agencies have the research lead (e.g., NCI and CDC for studies on 

environmental causes of breast cancer, NOAA for immunological effects in marine mammals, NSF 

and NIEHS 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 USEPA 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 USEPA activities (e.g., the Dioxin 

Reassessment and efforts to develop approaches for assessment of complex mixtures) will feed 

into the information base. 

This document was developed to serve several purposes, including: 

1. To provide a roadmap to guide the Agency’s efforts on endocrine disruptor, while 

at the same time remaining flexible enough to adjust to recommendations 

evolving from the CENR and NAS efforts; 

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ORD Strategic Research Plan for Endocrine Disruptors 

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. 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 the USEPA to perform a wide variety of activities with the underlying 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 to require 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 

the pesticide manufacturers submit in support of registration or reregistration to determine that a 

pesticide will not generally cause unreasonable adverse effects on the environment or to humans. 

Chemicals that are known or suspected of being endocrine disruptors 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 the USEPA to, within two 

years of enactment, develop 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 the USEPA develops. At joint 

workshops, cosponsored by USEPA, 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 EDSTAC (Endocrine Disruptor 

Screening and Testing Advisory Committee), an advisory committee to the USEPA on 

implementation of the FQPA and SDWA, is assembling a battery of assays both for screening and 

testing potential EDCs that 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 an ORD research planning perspective, the 

forthcoming EDSTAC recommendations will be critical because several of the non-mammalian tests 

proposed 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, therefore, needs the 

tools to be able to: 

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ORD Strategic Research Plan for Endocrine Disruptors 

1. Identify EDCs;

2. Evaluate their potential effects on human health and the environment;

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 large wealth of data available on some endocrine disruptors, much more 

research is needed in order for the Agency to carry out its large number of mandates. For this 

reason, the Agency is embarking on initiating a major research effort on endocrine disruptors. The 

objectives of the EDCs research program are to improve our knowledge and understanding of 

endocrine disruptors 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. 

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ORD Strategic Research Plan for Endocrine Disruptors 

III. RESEARCH ISSUES

Answering the questions posed of 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 unit. One function of the CENR 

Working Group on Endocrine Disruptors is to assist in a partitioning of 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 strong points of the USEPA research program. It is in these areas that we propose as 

our primary contributions to the overall federal effort on EDCs. 

Through the conduct of the research needs workshops of 1995, the USEPA and ORD have 

provided national leadership in the endocrine disruptor issue through collaboratively fostering the 

communicative environment across government, private industry, and the public. Several general 

comments about future research on endocrine disrupting chemicals emanated from the discussions 

at the aforementioned workshops. These include: 

1. The great advantage in bringing together a multi-disciplinary group of scientists 

representing both the 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 whether the effects are 

adverse or not. 

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. 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. 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 has mandated 

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ORD Strategic Research Plan for Endocrine Disruptors 

the USEPA to develop a chemical program for environmental estrogens and other endocrine 

disruptors as deemed necessary 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 significant roles in both prospective and retrospective 

assessments of the human health and ecological risks of EDCs. A key consideration, of course, 

in developing these types of methods/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 better defined. 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 are indicative both of exposure 

to EDCs and predictive of 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 (e.g., 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 to incorporate exposure 

during key developmental windows, and to ensure assessed 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 

the USEPA’s interim position (Crisp et al, 1997), 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, for example, carcinogenic, reproductive or developmental effects, routinely used in 

reaching regulatory decisions. 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, changes in community structure. Metrics considered at the 

individual level that infer likely trends in population dynamics most commonly are, or 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 directly translated into negative (i.e., 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 immediately manifested. Because of this, the need to 

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ORD Strategic Research Plan for Endocrine Disruptors 

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. 

Seldom, if ever, do organisms 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 environmental situations 

in terms of simultaneous (or sequential) exposure to multiple EDCs. While this is noted in only a 

single issue, it should be emphasized that the concern for mixtures transcends virtually ever other 

activity that is contained 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-teleost fish, 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. Without this, the 

usefulness of comparative endocrinology as a basis 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 there be a high degree of consistency in data collected. This becomes critical 

in terms of coordinating existing monitoring programs so that: 1) biological endpoints should include 

effects that are indicative of the impact of EDCS on individuals and populations, and 2) chemical 

characterization should include those xenobiotics suspected to exert toxicity through endocrine 

axes. Moreover, ideally there should be overlap of measurements made across different monitoring 

efforts. 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 waste water 

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 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. 

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ORD Strategic Research Plan for Endocrine Disruptors 

IV. RESEARCH APPROACH AND ACTIVITIES

Within this Chapter, specific research projects for biological effects and exposure research 

have been organized following the research strategy 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 StructureActivity Relationships) Models of EDC Modes of Action) is targeted at providing tools of equal utility 

for the prediction of both health and ecological effects, as well as the targeting of exposure 

assessment efforts. It is important to note that neither the Issues nor subissues are presented in 

priority order. 

For each “Issue” or activity, a brief description, a priority (high, medium or low, plus a priority 

score assigned by the planning committee (see below) , and the focal area of the research (health, 

ecological, exposure, or some combination) is provided. To place the activities into a hypothesisoriented context, each individual issue was evaluated according to which of the nine overarching 

questions stated in the Introduction it addressed. This cross walk, which is provided in Appendix 

IV, clearly demonstrates the areas of greatest uncertainty in our understanding of endocrine 

disruption, as two questions (What effects are occurring in exposed human and wildlife 

populations? and How and to what degree are humans and wildlife populations exposed to EDCs?) 

dominate in terms of the primary driving forces of the activities. The need to identify chemical 

classes of concern, to develop extrapolation tools, to understand the effects of multiple exposures 

and to understand the sources of exposure are most evident as secondary questions addressed 

by the issues, and 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 Vac, 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 nonweighted 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, there will be need to be selective in developing the actual implementation plans by the 

individual Laboratories and Centers. When doing this, it will be important to bear in mind that the 

most critical uncertainties lie in determining whether humans and wildlife populations are being 

impacted by levels of endocrine disruptors in the ambient environment, and what are the sources 

of those exposures. The final appendix that is presented (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). Under GPRA, each federal agency was 

required 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: 

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ORD Strategic Research Plan for Endocrine Disruptors 

C a comprehensive mission statement 

C general goals and objectives, including outcome-related goals and objectives 

C a description of how the goals and objectives are to be achieved 

C a description of the program evaluations used in establishing or revising general 

goals and objectives. 

On an annual basis, each agency is required, under GPRA to submit to OMB a performance plan 

covering each program activity set forth in the Agency’s budget that must be consistent with the 

strategic plan. ORD’s research on endocrine disruptors specifically 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 

Disruptors.” 

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BIOLOGICAL EFFECT 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 and/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/IN VIVO SCREENING METHODS AND 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 

types of assays should be calibrated against effects on integrated processes 

(development, reproduction) at the level of the individual. Quantitative structureactivity 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 VI=1) , Human Health and Ecological 

Focus 

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EFFECTS ISSUE 2. EVALUATE CURRENT TESTING AND MONITORING PROCEDURES FOR 

ADEQUACY OF ASSESSMENT OF THE EFFECTS OF EDCS. 

EFF.2.1 DEVELOPMENT, STANDARDIZATION AND UTILITY OF IN VITRO/IN VIVO TEST 

METHODS TO IDENTIFY ENDOCRINE DISRUPTING ACTIVITY. 

Present test methods used to assess toxicity provide little information on the mode 

of action of a chemical or the potential to produce latent effects after developmental 

exposure. For human health effects, the proposed improvements to the USEPA 

multi generational test will provide improved EDC detection for hazard ID and doseresponse, 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 for detection of EDC activity. Efforts should focus 

on those modes of action known to be exhibited by relevant environmental 

chemicals, including estrogenicity, anti-androgenicity, Ah-receptor binding, and antithyroidal activity. In addition to initial ligand receptor binding, endpoints should 

include EDC induced changes normal endocrine mediated transcriptional activation. 

Due to the USEPA’s Congressional mandate and the direct regulatory implications 

of this area, research planning should be done in coordination with the USEPA 

regulatory program offices. 

High priority (Adjusted Score from Appendix VI=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. 

For both between-chemical and between-species extrapolation, a more complete 

understanding of specific chemical MOA is required. Since many EDCs elicit toxicity 

through receptor-based interactions, these types of chemicals should be particularly 

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 tightly coupled not only with QSAR 

analyses, but also with comparative endocrinology and toxicology. The emphasis 

of this research should be on mechanisms that operate in the low end of the doseresponse curve, and the development of quantitative descriptions of rate limiting 

steps for later incorporation into formal BBDR (Biologically Base Dose-Response) 

Models. 

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High Priority (Adjusted Score from Appendix VI=23); Human and Ecological Focus; 

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 VI=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 VI=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 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 VI=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 

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CNS. 

Understanding the various steps in the pathogenesis of adverse effects is key to 

reducing the uncertainties in extrapolation of animal test data to humans. BBDR 

studies should be linked to the development of pharmacokinetic 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 VI=34); Human Focus; 

EFF.3.6 STUDIES ON THE MODES OF ACTION OF EDCS ON CELLULAR, MOLECULAR, 

NEUROENDOCRINE CNS FUNCTION IN PUBERTAL AND ADULT LABORATORY 

RODENTS. 

Steroid and thyroid hormones are important in the regulation of puberty in 

developing animals and in modulating CNS function in adults. Therefore, these 

processes are potentially 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 VI=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 seeming 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/toxicology studies. In any case, because of the 

commonality in endocrine function across (at least vertebrate) species, comparative studies are 

particularly important, because they help form the technical basis for extrapolation across species. 

For example, if it is possible to establish that a chemical that is estrogenic in one class of 

vertebrates also is likely to exert estrogenic effects in other classes, this is critical information in 

terms of screening. In fact, this is a major (but as yet generally unproven) supposition in the design 

of screening assays for EDCs by the EDSTAC. Thus, it is important that the technical 

underpinnings of the assumption of commonality in response across species be fully assessed. 

Although basic endocrinology research has been, and continues to be funded to some extent by 

other Federal agencies (e.g., NSF), 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 

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EDC-related research. 

EFF.4.1 DEFINITION OF "BASELINE" ENDOCRINE STATUS IN WILDLIFE POPULATIONS 

AND THEIR LABORATORY SURROGATES. 

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, and circulating hormone concentrations, developmental rates, 

and reproductive capacity, and population sex rations, and age structures. This type 

of information is critical not only to extrapolation in prospective risk assessments, 

but effective monitoring in retrospective analyses. 

High Priority (Adjusted Score from Appendix VI=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/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 VI=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 VI=36); Ecological Focus; 

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EFFECTS ISSUE 5. EXTRAPOLATE EFFECTS AT THE INDIVIDUAL LEVEL TO 

POPULATIONS FOR FISH WILDLIFE SPECIES. 

There is a need to identify/validate measurement endpoints that are indicative of the effects 

of EDCs, not only at individual and sub-organismal levels, but at the level of populations and 

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 

latter 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. The clear implication is that not all wildlife species can or will 

be considered in terms of ecological research with EDCs; this is logistically impossible. Therefore, 

there needs to be an emphasis on species selection which best enables extrapolation of potential 

EDC effects across animal species/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, monitoring environmental samples such as sediments, 

effluents, etc., 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 and/or EDC-specific effects. 

These tests should be modified where possible and/or new assays developed as 

needed. When selecting species/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 VI=26); Ecological Focus; 

EFF.5.2 EVALUATION OF EFFECTS AT POPULATION AND COMMUNITY 

LEVELS. 

To effectively utilize measurement endpoints collected at lower levels of biological 

organization (e.g., suborganismal, individual) in ecological risk assessments, it is 

necessary to translate these results 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 for this type of work include microcosms and mesocosms. 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 VI=22); Ecological and 

Exposure Focus; 

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, i.e., research planning should 

not be based upon selection of any particular class/species of animals, but on 

“problem” chemicals/sites or toxicological endpoints/issues. From that, appropriate 

animal models for research can be identified. Considerations for their selection 

should include: 1) representation of different life history strategies (both simple and 

complex); 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 VI=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 at the present 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 is impacts on many of the other issues 

identified in the this plan as evidence by cross walk of issues and overarching 

questions presented in Appendix IV. 

High Priority (Adjusted Score from Appendix VI=16); Human and Ecological Focus; 

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EXPOSURE ASSESSMENT STUDIES: 

The pathways between source and exposure to EDCs are complex. Many of the suspected 

EDC’s studied to date are organic compounds or organic forms of a few heavy metals that are 

persistent, can 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. 

For example, slight variations 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 in the Biological Effects section, 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 to 

predict exposure to these substances. 

At the outset, 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 

which are likely to be endocrine disruptors. In both of these areas, existing information in the 

public literature or in the USEPA data files will be evaluated to establish current capabilities, and 

to identify data gaps and uncertainties before new parameters and models are developed. 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 AND TO DIAGNOSE 

AND PREDICT ECOLOGICAL AND HUMAN EXPOSURE TO EDCs. 

EXP.1.1 IDENTIFICATION AND EVALUATION OF CLASSES OF SUSPECT EDCs TO 

WHICH HUMANS AND ECOSYSTEMS ARE LIKELY TO BE EXPOSED IN THE 

ENVIRONMENT. 

The physicochemical 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 suspect 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. Attributes 

categories will be updated as additional information becomes available under 

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Exposure Issue 3 and Effects Issue 1. 

High Priority (Adjusted Score from Appendix VI=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 VI=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 the USEPA, 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 today is the inability to monitor for non-volatile/non-extractable/thermally 

labile (unconventional) organic pollutants, which may often be the most prevalent types and 

amounts of compounds in many environmental samples. A true, rational assessment of ecological 

and human risk can be obtained only with the ability to characterize and monitor this problematic, 

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. 

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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 

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 under varying pH and ionic strength conditions. 

In addition to sorption kinetics, the biological relevance of EDCs should be better 

understood. 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 VI=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 weight of evidence, research is needed to improve sample extraction 

methods, extract preconcentration, chromatographic separation, and analyte 

detection. 

High Priority (Adjusted Score from Appendix VI=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, to improve exposure estimates in future epidemiological 

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studies, and to 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 

developed under EXP.1.2. 

High Priority (Adjusted Score from Appendix VI=21); Exposure and Ecological 

Focus; 

EXPOSURE ISSUE 3: DETERMINE THE TOTAL ECOSYSTEM AND HUMAN EXPOSURES TO 

EDCs OF CONCERN. 

The previously described exposure research, will substantially increase our understanding 

of the potential risks from EDCs. 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 water transport is the 

predominant factor in enhancing exposures to these compounds. 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 disruptor modes-of-action, 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 Exposure Issue. 

Medium Priority (Adjusted Score from Appendix VI=35); Exposure, Human Health 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 

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 EXP3.3. 

Medium Priority (Adjusted Score from Appendix VI=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 VI=22), Exposure and Human Focus, 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 develop a basis upon which to formulate an integrative 

effects/exposure program by crafting project areas in which both types of research must work 

together to accomplish the objectives. We also introduce, in a general sense, risk reduction 

issues. The importance of these projects are not in accordance with their position at the conclusion 

of the Research Issues Section, for it was felt that 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 that we utilize extramural 

resources to obtain the expertise needed to either augment our research capabilities (thus requiring 

cooperative agreements) or assume primary research responsibilities (through the grants program).

 Data bases that contain information about EDCs need to be identified and reviewed, and 

methods identified to improve coordination, reliability, and access by the scientific community. 

EXP.1.1 and LNK.1.1 will first prioritize potential hot spots and 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/exposure 

hypotheses, and in validating the compartmental, exposure, and effects models. Compartmental 

models and laboratory studies must be linked to field research by developing 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, i.e., 

site remediation, (2) pollution prevention to minimize the use, release, or production of EDCs, and 

(3) engineered controls, i.e., manipulation of exposure, 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. 

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ORD Strategic Research Plan for Endocrine Disruptors 

LNK.1.1 ESTABLISH FRAMEWORKS FOR COMPREHENSIVE EDC INVESTIGATIONS 

AND ASSESSMENTS 

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 

modes-of-action. Among other issues, this effort will consider how best to 

incorporate modes-of-action, multiple chemical exposure, critical life stages, criteria 

for adversity, dose-response relationships and inter-species comparisons. Such 

tools needed as the knowledge base on endocrine disruptors increases over the 

next few years. From a review of the current state of knowledge and databases for 

several suspect endocrine disruptors (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 collaboratively 

developed. 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 disruptors against 

potential exposure pathways and health outcomes. Such efforts should facilitate the 

evaluation of causality of reported adverse health effects. This database will also 

provide the basis for clearly identifying major gaps in both exposure and effects 

relative to endocrine disruptors, 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 VI=24); Exposure, Ecological and 

Human Focus; 

LINKAGE ISSUE 2. 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 database 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 into consideration potential sensitivities of specific populations given 

loading estimates, geographic distribution, and life history traits. These efforts will 

assist in hypothesis generation and identification of information gaps needed for 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 the 

Environmental Monitoring and Assessment Program (EMAP) of the USEPA, the 

National Status and Trends Program (BEST) 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 VI=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 SAR, toxicokinetics, bioenergetics, environmental chemistry, and 

population ecology, provide a means for testing effects and exposure screening 

tools, and will provide multimedia sample material for analytical methods 

development (EXP2.2). 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 VI=14); Ecological and Exposure 

Focus; 

LNK.2.3 EXAMINE HUMAN POPULATIONS FOLLOWING DEVELOPMENTAL EXPOSURE 

TO EDCs FOR ALTERATIONS IN CNS, 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 

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ORD Strategic Research Plan for Endocrine Disruptors 

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 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 VI=19), Human and Exposure Focus 

LNK 2.4 EPIDEMIOLOGICAL STUDIES OF HUMAN POPULATIONS EXPOSED AS 

ADULTS. 

Both cohort-based approaches searching for adverse health outcomes in EDC 

exposed populations, and case-control approaches focused 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 

occupationally exposed to EDCs (e.g., DDT, DDD, 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 VI=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 VI=41); Ecological and 

Exposure Focus; 

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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 systematically collect 

exposure and effects data 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. For the 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 VI=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, hence, 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 over time and to identify the true incidence of these effects 

in the human population at the present time. 

Medium Priority (Adjusted Score from Appendix VI=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 

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ORD Strategic Research Plan for Endocrine Disruptors 

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, pesticide production and use, incinerator effluent compositions, etc. 

Medium priority (Adjusted Score from Appendix VI=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 need to be developed. These tools 

may include, for example, 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 VI=27), Risk management focus, 

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ORD Strategic Research Plan for Endocrine Disruptors 

V. RESEARCH IMPLEMENTATION GUIDANCE 

In accordance with the breadth of uncertainties associated with the endocrine-disruption 

hypothesis, the research topics identified in this plan are quite broad in scope and are likely to 

outstrip 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 lab 

and effect and exposure projects will require close collaboration among nearly every component 

of ORD. 

It is presumed that investigator-initiated responses to 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? Answering such questions will provide an 

important element in determining how best to focus both 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 disruptor problem suggests that additional oversight of the ORD 

effort may be required to maintain an appropriate balance between 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, the 

individual National Laboratories and Centers are expected to develop 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 

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ORD Strategic Research Plan for Endocrine Disruptors 

the research directions as new information from the program emerges, and importantly, 

communicate with the USEPA’s Program Offices on progress in understanding the nature and 

extent of the EDC problem. Interactions between the recipients of the STAR grants and the 

intramural investigators involved in endocrine disruptor research through such mechanisms as 

annual or bi-annual workshops are also encouraged, as this would help exchange information and 

expand collaborations. 

The following decision-making criteria for use in priority setting within the endocrine disruptors 

research program have been developed with the above considerations in mind. 

Risk-Based Planning: Research that addresses an element of the risk assessment 

paradigm and is designed to reduce the greatest 

uncertainties is of the highest priority. 

Scientific Excellence: 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. 

Programmatic Relevance: The degree to which a research project addresses a specific 

statutory requirement will be an important ranking factor. 

Other Sources of Data: 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 and/or outside the Agency. 

Capabilities/Capacities: 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 

Sequence of Research: 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 readjust priorities as needed. For example, research related to risk management actions 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. 

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ORD Strategic Research Plan for Endocrine Disruptors 

VI. REFERENCES 

Ankley GT, Johnson RD, Toth G, Folmar LC, Detenbeck NE, and Bradbury SP (1997). 

Development of a Research Strategy for Assessing the Ecological Risk of Endocrine Disruptors. 

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, LE Jr, WR 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 RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, Lucier G, Luster M, 

Mac MJ, Maczka C, Miller R, Moore J, Rolland R, Scott G, Sheehan DM, Sinks T, and Tilson 

HA (1996). Research Needs for the Risk Assessment of Health and Environmental Effects of 

Endocrine Disruptors: A Report of the US EPA Sponsored Workshop. Environmental Health 

Perspectives 104 (Supplement 4): 715-740. 

Reiter, LW, C DeRosa, RJ Kavlock, G Lucier, MJ Mac, J Melillo, RL Melnick, T Sinks and B 

Walton (1998). The US Federal Framework for Research on Endocrine Disruptors 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, 

USEPA/600R-96/059, 60 pp. 

USEPA (1996b). Environmental Endocrine Disruption: Effects Assessment and Analysis 

Document. Risk Assessment Forum, December, 1996. Washington, DC. 

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APPENDIX I. Time Lines for Major Research Questions. OVERARCHING QUESTION 

96 97 98 99 00 

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? >>>>>>>>>>>>>>>>>> 

FISCAL YEAR 

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APPENDIX II. SUMMARY DELIBERATIONS OF THE USEPA WORKSHOPS 

The premise of these workshops was given that environmental endocrine disruptors 

(EDs, or 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 disruptor” 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 

disruptor 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 repeatedly emphasized 

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 has generally 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 disruptors (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 and/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 adequately characterized. 

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 disruptors 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 

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ORD Strategic Research Plan for Endocrine Disruptors 

interpreted as to whether the effects are adverse or not. As the level of organization at which 

biological responses to endocrine disruptors are observed decreases (e.g. from physiological to 

cellular to molecular), the challenge to describe the effects as adverse at the level of the 

individual and the population increases. In this regard, endocrine disruptors 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 disruptors 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 (i.e., both 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 Water Quality 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 

para-meters. 

4) Increase emphasis on research in comparative endocrinology/toxicology to allow 

extrapolation among species. 

5) Conduct focused research projects at a few selected sites with known endocrine 

disruptor problems. Examine multiple species at several levels of organization to 

establish linkages between endpoints measured in the laboratory at the 

Page 39 
ORD Strategic Research Plan for Endocrine Disruptors 

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. 

Page 40 
Appendix III. Overview of Research Plan, Tasks and Outputs for Endocrine Disrup

Subtopic Strategic Focus Tasks Products Biological Defining the classes of Develop in vitro/in vivo methods and Methods to describe the hazar

Effects chemicals that act as EDCs and structure-activity models to screen for EDC potential of EDCs and likely 

their potencies. action modes of action and potencies 

Evaluating current testing Enhance ability of existing test methods Revised testing guidelines that 

guidelines and monitoring (e.g., multi generational studies in are more indicative of the most 

procedures for adequacy of mammals and life cycle tests in fish and sensitive life-stage, sex, and 

assessment of EDCs wildlife) to evaluate manifestations of target tissue for chemicals whi

endocrine disruption and underlying modes act through the endocrine systeof action 

Determining the shapes of Assess effects of EDC exposure on Animal models of EDC induced 

dose-response curves for EDCs neuroendocrine, immunological, and health effects that provide 

at relevant exposures and the reproductive function in developing and increased understanding of the 

tissue levels associated with adult animals in support of types and magnitudes of risks 

adverse effects pharmacokinetic and biologically based exposure to EDCs during vario

dose-response models, with emphasis on phases of the life cycles animal models of EDC-induced human diseases. 

Describing the normal Provide baseline endocrine information for Databases of endocrine profile

endocrine profiles in wildlife wildlife populations and their laboratory in species from multiple 

species surrogates, with emphasis on comparative phylogenetic levels and improv

endocrinology and developmental control understanding of the role of the of sex differentiation, especially for species endocrine system in sex with little historical attention differentiation 

Extrapolating effects at the Translate results from measurement Models predicting population le

individual level to populations endpoints at lower levels of biological effects from studies at lower for fish and wildlife organization to impacts on populations and levels of biological organization 

communities through use of microcosms and mesocosms Identify appropriate sentinel species for environmental monitoring 

Page 41 
Appendix III. Overview of Research Plan, Tasks and Outputs for Endocrine Disrup

Subtopic Strategic Focus Tasks Products 

Characterizing the effects of Systematically study the interactions of Assessment of the validity of th

exposure to multiple EDCs EDCs at low, relevant dose levels to additivity principal for EDCs an

understand potential for synergism predictive models for synergist

interactions 

Exposure Studies 

Developing a framework to characterize and to diagnose and predict ecological and human exposure to EDCs 

Use physicochemical attributes to identify transport, transformation and environmental fate characteristics associated with exposure scenarios of concern to biological organisms 

Validated models to predict anassess transport, fate and exposure to EDCs from source receptor 

Construct compartmental models to predict environmental behaviors 

Providing adequate tools to estimate exposure to EDCs 

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 

Field and laboratory tools to better quantitate EDCs in multimedia. 

Determining total ecosystem and human exposures to EDCs of concern 

Examine multi generational transfer of EDCs in ecosystems, including biomagnification processes important to higher vertebrates 

Exposure assessments for EDin key wildlife species and the general human population. 

Provide information on EDC exposure distribution in the general human population. 

Linkage of Integrating human and Construct framework to identify, Coordinated process for Effects, ecological effects research with characterize, prioritize and assess identifying exposure and effectExposure and exposure research within the potential and risks to EDCs and provide of concern for additional intensRisk risk assessment paradigm database for preliminary risk characterization of risk. Management characterization 

Page 42 
Appendix III. Overview of Research Plan, Tasks and Outputs for Endocrine Disrup

Subtopic Strategic Focus Tasks Products 

Determining classes and Develop informational database for EDCs, Database on EDC levels in the 

concentrations of EDCs including biological effects, environmental human environment and variou

associated with observations of concentrations and historical trends from ecosystems associated with 

endocrine disruption existing monitoring programs biological effects of concern 

Conduct integrated toxicology and exposure studies in areas or human populations with suspected contamination or exposure to EDCs 

Establishing status and trends Examine existing monitoring efforts and Consolidated databases of sta

of human and wildlife endocrine exposure and effect registries for relevancy and trends relevant to EDC 

disruption and EDC exposure to addressing EDC uncertainties. exposures and effects. 

Developing risk management Identify major sources of EDCs entering Risk management tools for 

approaches to reduce or the environment elimination or prevention of 

eliminate environmental exposures to significant EDCs

exposure to EDCs. Develop tools for risk management such 

as biodegradation processes or pollution prevention strategies 

EDC = Endocrine Disrupting Chemical FQPA = Food Quality Protection Act SDWA = Safe Drinking Water Act 

Page 43 
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Ac

Research Plan 

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 effects? 

What extrapolation tools are needed?

What are the effects of exposure to multiple

EDCs and will a TEF approach be applicable?

ISSUE EFF1 Determine the classes of chemicals that act as EDCs and their potencies TT

T T T

EFF2 Evaluate current testing and monitoring procedures for adequacy of assessment of 

the effects of EDCs 

T

T T TT T 

EFF3 Mode of action studies in laboratory animal models following developmental 

exposure. 

TT T T 

Developmental and acute effects on immune function 

T TT T T 

Studies of EDC induced human effects in animal models 

T

T TT T T 

Pharmacokinetic studies of highly relevant EDCs 

T

T T T

T 

Development of BBDR models for highly relevant EDCs 

T

T T T

T 

Mode of action studies in pubertal and adult laboratory models 

T TT T T 

EFF4 Definition of baseline endocrine status in wildlife populations 

T

T

T T 

Studies in comparative endocrinology and toxicology 

T

T TT

T 

Studies on the role of hormones in sexual differentiation 

T

T T T TT 

Page 44 
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Ac

Research Plan 

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 effects? 

What extrapolation tools are needed?

What are the effects of exposure to multiple

EDCs and will a TEF approach be applicable?

EFF5 Bioassays for evaluating integrated effects 

T

T TT

T 

Evaluation of effects at populations and community levels 

T

T T 

Determination of sentinel species TT

T T 

EFF6 Studies of interactions of low, relevant dose levels of mixtures 

T

T T T TT 

EXP1 Identification and evaluation of classes of suspect EDCs 

T

Development and application of compartmental models 

T

EXP2 Abiotic Fate 

Biotic Fate 

T

Develop measurement methods and biomarkers for high throughput 

T

EXP3 Study inter-generational transfer in ecosystems 

T

Study bioaccumulation in food webs 

T

T 

Obtain population based distributions of EDC exposures 

T

T T

LNK1 Framework for comprehensive, multi-laboratory EDC investigations 

T T

T

Page 45 
APPENDIX IV. Cross Tabulation of the Nine Overarching Research Questions with the Individual Research Ac

Research Plan 

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 effects? 

What extrapolation tools are needed?

What are the effects of exposure to multiple

EDCs and will a TEF approach be applicable?

LNK2 Evaluation of existing data and programs for EDC monitoring 

T

T 

Integrated studies of wildlife at contaminated sites TT T

T T 

Examine human populations exposed developmentally TT T T Examine human populations exposed as adults TT T Studies of wildlife populations to establish relationships between EDCs and immune function 

TT T T 

LNK3 Examine existing human tissue banks for correlations between EDCs and hormone 

levels. 

T

T 

Examine existing cancer and birth defect registries for incidences of EDC like effects TT 

LNK4 Characterization of the sources of EDCs in the environment 

T

Development of risk management tools for EDCs 

T T 

Page 46 
APPENDIX V.a. TASK SUMMARY AND PROPOSED SEQUENCE FOR EFFECT STUDIES. 

FOCUS1 PRIORITY2 PROPOSED TIME FRAME3 

ISSUE 

X X H(1) X X X X 

X X H( ) X X X X 

X X H( ) X X X X X 

EFF.3.2 X X X X X 

X H( ) X X X X 

X H( ) X X X X 

X H/M( ) X X X X 

EFF.3.6 X M(37) X X X 

EFF.4.1 X H(26) X X X 

EFF.4.2 X M(33) X X X 

EFF.4.3 X H(36) X X X 

EFF.5.1 X H(26) X X X 

EFF.5.2 X H/M(22) X X X 

EFF.5.3 X H(26) X X X 

EFF.6.1 X X X X X 

HH EE EX FY96 FY97 FY98 FY99 FY00 FY01 

EFF.1.1 

EFF.2.1 13

EFF.3.1 23

H/M(27) 

EFF.3.3 10

EFF.3.4 24

EFF.3.5 34

H(16) 

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 logical sequence of research, placing issues addressing the most uncertainties of 

most concern earlier in the implementation process. 

Page 47 
APPENDIX V.b. TASK SUMMARY AND PROPOSED SEQUENCE FOR EXPOSURE STUDIES. 

FOCUS1 PRIORITY2 PROPOSED TIME FRAME3 

ISSUE HH EE EX FY96 FY97 FY98 FY99 FY00 FY01 

EXP.1.1 X H(9) X X 

EXP.1.2 X H(28) X X X X 

EXP.2.1 X X H(28) X X X X 

EXP.2.2 X H(10) X X X 

EXP.2.3 X X X H(21) X X X X X 

EXP.3.1 X X X M(35) X X X X 

EXP.3.2 X X M(34) X X X X 

EXP.3.3 X X H(22) 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 logical sequence of research, placing issues addressing the most uncertainties of most 

concern earlier in the implementation process. 

Page 48 
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 PRIORITY2 PROPOSED TIME FRAME3 

HH 

X 

X 

X 

X 

X 

EE 

X 

X 

X 

X 

EX 

X 

X 

X 

X 

X 

X 

X 

H(24) 

H(29) 

H(14) 

H(19) 

H/M(25) 

M/L(41) 

M/L(53) 

M/L(34) 

M(31) 

M(27) 

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 

FY00 

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 logical sequence of research, placing issues addressing the most uncertainties of most 

concern earlier in the implementation process. 

. 

Page 49 
APPENDIX VI. Cumulative Priority Ranking Scores1 

Issue Short Title Programmatic Biological Potential Sequence Technical Total Score Ad

Relevance Concern Impact Success 

EFF1.1 Chemical Classes 8 8 8 8 10 42 EFF2.1 Testing Procedures 8 14 14 9 9 54 EFF3.1 Modes of Action 16 14 9 9 16 64 EFF3.2 Developmental Immune Effects 15 17 15 10 11 68 EFF3.3 Animal Models of Diseases 9 8 9 8 17 51 EFF3.4 Pharmacokinetics 11 15 14 14 11 65 EFF3.5 BBDR Models 16 15 9 13 22 75 EFF3.6 Adult neuroendocrine Effects 19 20 15 11 13 78 EFF4.1 Endocrine Baselines 18 14 13 8 14 67 EFF4.2 Comparative Endocrinology 15 15 15 14 15 74 EFF4.3 Sexual Differentiation 20 13 13 15 16 77 EFF5.1 Integrated Bioassays 14 15 8 14 16 67 EFF5.2 Population Effects 9 9 9 15 21 63 EFF5.3 Sentinel Species 15 11 15 10 16 67 EFF6.1 Interactions 9 12 9 16 11 57 EXP1.1 Classes of EDCs 8 13 8 10 11 50 EXP1.2 Compartmental Models 15 15 13 15 11 69 EXP2.1 Abiotic Fate 16 22 8 11 12 69 EXP2.2 Biotic Fate 8 9 15 9 10 51 EXP2.3 High Throughput 13 15 9 9 16 62 EXP3.1 Intergeneratioanl Transfer 18 12 13 17 16 76 EXP3.2 Trophic Dynamics 17 13 14 16 15 75 EXP3.3 Population Distributions 9 15 8 15 16 63 LNK1.1 Comprehensive Framework 21 9 11 9 15 65 LNK2.1 Existing Monitoring 13 14 19 9 15 70 LNK2.2 Integrated Wildlife Studies 14 8 8 9 16 55 

Page 50 
1 

LNK2.3 Human Development 14 9 8 9 

LNK2.4 Human Adults 14 15 8 

LNK2.5 Wildlife Immunotoxicology 16 15 15 15 21 82 

LNK3.1 Tissue Banks LNK3.2 Registries 17 10 10 15 23 75 

LNK4.1 Sources of EDCs 8 9 22 17 72 

LNK4.2 Management of EDCs 9 9 24 16 68 

APPENDIX VI. Cumulative Priority Ranking Scores

20 60 

10 19 66 

18 22 15 16 23 94 

16 

10 

1 Each member of the planning committee was asked to assign a weight of from 1 to 3 (1 being the highest) to each of five facto

Magnitude of Biological Concern, Potential Impact of Research, Sequence of the Research, and Technical Feasibility of the Res

under each of the five factors is the sum of the weights assigned by 8 individuals (thus, an issue would receive a highest possibpossible score of 24). The column marked “Total Score” is the sum of weights for the five individual factors, while the Adjusted 

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 

Page 51 
APPENDIX VII. Endocrine Disruptor Research Plan Arrayed Against the Government Performance and Results 

Agency Goals/Objectives/Sub-Objectives 

EFFECTS EXPOSURE RISK ASSESSMEN

Surveillance (human health/ecology)

Effects Indicators

Stressors

Mechanisms of Action

Predictive Models

Source/Exposure

Process Modeling (Physical, Chemical,

Environmental Characterization

Exposure Analysis/Assessment

Exposure Dose

Health and Ecological Risk Assessment

Risk Assessment Methods. Tools,

Risk Assessor Support (Guidance and

8: PROVIDE SOUND SCIENCE TO IMPROVE UNDERSTANDING OF ENVIRONMENTAL RISK AND DEVELOP AND IMPLEMENT 

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 Disruptors MM-35 LNK. 

2.2 3.1 

MM-56 

LNK. 

2.1 

MM-64 MM-7 

? 

MM12 

EFF. 

3.1 3.2 3.3 3.4 3.5 3.6 

MM30 

LNK. 

1.1 

MM56 

LNK. 

2.1 

MM-24 

EFF. 

4.1 4.2 4.3 

MM-58 

EFF. 

6.1 

MM-64 

EFF. 

1.1 2.1 

MM-23 MM-66 MM-17 MM-8 

? 

MM-28 

MM-63 MM-29 MM

EFF. 

1.1 2.1 

MM-65 

EFF. 

5.2 5.3 

EXP. 

1.1 1.2 

EXP. 

2.1 2.2 2.3 

MM-45 

LNK. 

3.3 

LNK. 

2.3 2.4 2.5 3.2 

LNK. 

1.1 

LN

2.

LNK. 

1.1 

EFF. MM-36

5.1 EXP. 

3.1 3.2 3.3 

MM-57 

LNK. 

2.2 3.1 

LNK. 

2.1