BBooaarrdd ooff SScciieennttiiffiicc CCoouunnsseelloorrss 

 

OOffffiicceeooffRReesseeaarrcchhaannddDDeevveellooppmmeenntt

UUnniitteeddSSttaatteessEEnnvviirroonnmmeennttaallPPrrootteeccttiioonnAAggeennccyy

Endocrine Disrupting Chemicals 

(EDC) Research Program Review

Final Report of the Subcommittee on 

Endocrine Disrupting Chemicals 

March 4, 2005 

Revised April 21, 2005 
ii 

This report was written by the Endocrine Disrupting Chemicals (EDC) 

Subcommittee of the Board of Scientific Counselors, a public advisory 

committee chartered under the Federal Advisory Committee Act (FACA) 

that provides external advice, information, and recommendations to the 

Office of Research and Development (ORD). This report has not been 

reviewed for approval by EPA, and therefore, the report’s contents and 

recommendations do not necessarily represent the views and policies of 

the EPA, or other agencies of the federal government. Further, the content 

of this report does not represent information approved or disseminated by 

EPA, and, consequently, it is not subject to EPA’s Data Quality Guidelines. Mention of trade names or commercial products does not constitute 

a recommendation for use. Reports of the Board of Scientific Counselors 

are posted on the Internet at http://www.epa.gov/osp/bosc. 
iii 

PROGRAM REVIEW REPORT

OF THE

BOARD OF SCIENTIFIC COUNSELORS

ENDOCRINE DISRUPTING CHEMICALS (EDC) 

RESEARCH PROGRAM

Office of Research and Development 

U.S. Environmental Protection Agency 

MARCH 4, 2005 

REVISED APRIL 21, 2005

SUBCOMMITTEE ON ENDOCRINE DISRUPTING CHEMICALS

Anna K. Harding (Chair)—Oregon State University 

George P. Daston (Vice-Chair)—The Proctor & Gamble Company 

Glen R. Boyd—Tulane University 

George W. Lucier—Consulting Toxicologist 

Stephen H. Safe—Texas A&M University 

Juarine Stewart—Morgan State University 

Donald E. Tillitt—USGS, Columbia Environmental Research Center 

Glen Van Der Kraak—University of Guelph 
iv 

TABLE OF CONTENTS 

I. EXECUTIVE SUMMARY ....................................................................................................................... 1 

Overall Goals and Charge............................................................................................................. 1 

Background for the EDC Research Program................................................................................ 2 

Structure of the Program Review.................................................................................................. 4 

Overarching Conclusions and Recommendations ........................................................................ 6 

Strengths and Challenges of Long-Term Goals............................................................................ 8 

Long Term-Goal 1............................................................................................................. 8 

Long Term-Goal 2 ........................................................................................................... 10 

Long Term-Goal 3 ........................................................................................................... 11 

Program Leadership..................................................................................................................... 12 

 Program Resources ...................................................................................................................... 13 

 Report Overview.......................................................................................................................... 14 

II. LONG-TERM GOAL 1 ....................................................................................................................... 15 

Introduction .................................................................................................................................. 15 

Program Design ............................................................................................................................ 15 

Relevance...................................................................................................................................... 18 

Program Progress.......................................................................................................................... 19 

Strengths and Challenges.............................................................................................................. 20 

III. LONG-TERM GOAL 2 ...................................................................................................................... 23 

Introduction .................................................................................................................................. 23 

Program Design ............................................................................................................................ 24 

Relevance...................................................................................................................................... 26 

Program Progress.......................................................................................................................... 27 

Strengths and Challenges.............................................................................................................. 29 

IV. LONG-TERM GOAL 3 ...................................................................................................................... 31 

Introduction .................................................................................................................................. 31 

Program Design ............................................................................................................................ 31 

Relevance...................................................................................................................................... 32 

Program Progress.......................................................................................................................... 32 

Strengths and Challenges.............................................................................................................. 34 

V. PROGRAM LEADERSHIP................................................................................................................... 37 

VI. PROGRAM RESOURCES ................................................................................................................... 39 

VII. APPENDIX A—CHARGE QUESTIONS........................................................................................... 42 

VIII. APPENDIX B—BIOGRAPHICAL SKETCHES OF THE 

 EDC SUBCOMMITTEE MEMBERS ............................................................................................. 45 

IX. APPENDIX C—LIST OF ACRONYMS.............................................................................................. 47
1 

I. EXECUTIVE SUMMARY 

 

Overall Goals and Charge 

The National Academy of Sciences has recommended independent expert review for evaluating 

federal research programs. The U.S. Environmental Protection Agency’s (EPA’s) Office of 

Research and Development (ORD) is committed to independent expert review of its 

environmental research programs for objective evaluation of research at the program level, to 

establish “best practices” in federal research program design, management, and evaluation, and 

to assist the Agency in preparing performance and accountability reports to Congress under the 

Government Performance and Results Act of 1993. 

The Board of Scientific Counselors (BOSC) Executive Committee agreed in May 2004 to 

undertake two pilot program reviews⎯the Endocrine Disrupting Chemicals (EDC) Program and 

the Global Change Program reviews. The BOSC formed a subcommittee to provide a program 

review of the EDC research program of EPA’s ORD. This subcommittee was charged with 

reviewing ORD’s EDC program and providing a report to the BOSC Executive Committee. The 

results of these pilot reviews will guide future BOSC program reviews. 

This pilot program review differs from previous Multi-Year Plan (MYP) reviews in that it 

includes a retrospective as well as a prospective evaluation, examining progress made to date 

and the future direction of the EPA research in this program. The program review is intended to 

provide guidance that will help ORD: (1) assess the progress and direction of the EDC research 

program; (2) plan, implement, and strengthen the program; (3) make research investment 

decisions over the next 5 years; (4) compare the program with programs designed to achieve 

similar outcomes in other parts of EPA and in other federal agencies; and (5) prepare EPA’s 

performance and accountability reports to Congress under the Government Performance and 

Results Act (GPRA) of 1993. 

The objective of the EDC program review was to review the relevance, quality, performance, 

scientific leadership, and resources of the program (see Appendix A). The subcommittee 

responded to a series of questions organized into five broad charge questions, which were 

framed to solicit comments on the program’s: (1) design; (2) relevance; (3) progress in 

addressing key scientific questions and impacting environmental decisionmaking; (4) 

contributions to scientific leadership; and (5) resource allocation. The subcommittee chose to 

organize the review around the three long-term goals presented in the MYP, commenting and 

responding to the questions and factors noted in the first three charge questions (i.e., program 

design, program relevance, program progress/performance) for each long-term goal. Charge 

questions four and five (leadership and resource allocation) were evaluated separately, as they 

crosscut the overall program. 
2 

Background for the EDC Research Program

In the early 1990s, a number of scientists began to synthesize information about the potential 

impacts of endocrine-mediated toxicity on humans and wildlife, arriving at the hypothesis that 

weakly endocrine-active compounds in the environment were having significant adverse effects 

on public and environmental health (Colborn and Clement, 1992)1

. In response, EPA convened 

two international workshops in 1995 (Kavlock, et al., 1996; Ankley, et al., 1997)2,3 at which 

uncertainties and research needs relative to future risk assessments for EDCs were highlighted. 

These workshops identified effects on reproductive, neurological, and immunological function 

and carcinogenesis as the major endpoints of concern and made a number of recommendations 

for research. The workshops served as the basis for establishing national research efforts that 

spanned the entire federal government, as well as international efforts. The Multi-Year Plan 

(FY2000-2012) for Endocrine Disruptors covers a considerable fraction of the research 

identified by the scientific community as being important for understanding the impact of 

endocrine disruptors. Collectively, chemicals with the potential to interfere with the function of 

endocrine systems are called endocrine disruptors or endocrine disrupting chemicals. 

A recent publication by experts in the field identifies 10 key areas of uncertainty that must be 

addressed to determine the significance of endocrine disruptors as public and ecological health 

threats (Daston, et al., 2003).4 The key uncertainties are: 

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 testing guidelines adequately evaluate potential endocrine-mediated effects? 

What extrapolation tools are needed? 

What are the effects of exposure to multiple EDCs, and will a Toxicity Equivalency Factors 

approach be feasible? 

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? 

What approaches are needed to assess risks to humans and wildlife? 

 

1 Colborn T., Clement C. 1992. Chemically-Induced Alterations in Sexual and Functional Development: The 

Wildlife/Human Connection. Princeton, NJ: Princeton Scientific Publishing Co. 

2 Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, Lucier G, Luster M, Mac MJ, Maczka 

C, et al. 1996. Research needs for the risk assessment of health and environmental effects of endocrine 

disruptors: a report of the U.S. EPA sponsored workshop. Environ Health Perspectives 104 (Suppl 4):715-740. 

3 Ankley GT, Johnson RD, Toth G, Folmar LC, Detenbeck NE, Bradbury SP. 1997. Development of a research 

strategy for assessing the ecological risk of endocrine disruptors. Rev Toxicol 1:71-106. 

4 Daston GP, Cook JC, Kavlock RJ. 2003. Uncertainties for endocrine disruptors: our view on progress. Toxicol 

Sci 74:245-252. 
3 

In 1996, EPA’s ORD identified endocrine disruptors as one of its top six research priorities. In 

the same year, through the enactment of the Food Quality Protection Act (FQPA), the U.S. 

Congress directed EPA to screen pesticides for estrogenic activity in humans using validated 

studies or other scientifically relevant information and gave the Agency discretionary authority 

to screen for other endocrine effects as well. The Safe Drinking Water Act (SDWA) 

Amendments passed in the same year, authorized EPA to screen drinking water contaminants for 

similar activities. To implement the legislation, a number of scientific questions needed to be 

addressed and resolved through research. As a result, EPA’s Endocrine Disruptors Research 

Program and the development and implementation of a mandated Endocrine Disruptor Screening 

Program (EDSP) by the Office of Prevention, Pesticides and Toxic Substances (OPPTS) are on 

parallel, yet highly interactive, tracks. 

The peer-reviewed blueprint for EPA’s research program was published in 1998 as ORD’s 

Endocrine Disruptors Research Plan (EDRP) and took into consideration the advice, provided to 

OPPTS, on the implementation of the legislation by an independent expert advisory panel. Since 

then, ORD has developed a Multi-Year Plan (FY2000-2012) for Endocrine Disruptors that 

identifies the elements of the EDRP that will be addressed intramurally over the next 5 to 10 

years across three national laboratories and one national center and extramurally through a 

competitive grants program. 

The purpose of the MYP is to provide a framework that: (1) integrates research across ORD’s 

laboratories and centers to produce scientifically credible results in accordance with the GPRA 

goals; and (2) supports the Agency’s mission to protect human health and the environment. 

ORD’s MYP identifies long-term goals (LTGs) and presents annual performance goals (APGs) 

and associated annual performance measures (APMs) for a planning window of approximately 

5-10 years. ORD’s MYP also fosters the integration of strategic risk-based environmental 

protection and anticipation of future environmental issues by communicating the research 

approach and timing for responding to environmental issues. ORD’s MYP is intended to be a 

living document that is updated every 2 years to reflect the current state of the science, resource 

availability, and Agency priorities. 

The MYP for EDCs is in its third iteration and reflects ORD’s most recent interpretation of 

Agency research needs in addressing key areas of uncertainty. The plan includes research 

activities implemented and planned for fiscal years (FY) 2000 through 2012. Resources for the 

implementation of these research activities for FY 2003 to 2005 have decreased from $12.7 

million to $8 million per year; the program includes approximately 55 full-time equivalent (FTE) 

personnel per year. 

In the MYP for EDCs, ORD has identified three LTGs that will provide the methods the Agency 

needs to implement the EDSP and the scientific underpinnings to interpret data from EDSP and 

incorporate them into risk assessments and Agency decisions. The LTGs are: 

 LTG 1: Provide a better understanding of science underlying the effects, exposure, 

assessment, and management of endocrine disruptors. 
4 

 LTG 2: Determine the extent of the impact of endocrine disruptors on humans, wildlife, and 

the environment. 

 LTG 3: Support EPA’s screening and testing program. 

In addition to the MYP for EDCs, which identifies the research directions for all of ORD’s 

laboratories and centers, some of the laboratories and centers have developed their own 

implementation plans. For example, ORD’s National Risk Management Research Laboratory 

(NRMRL) has developed a Risk Management Evaluation (RME), and the National Health and 

Environmental Effects Research Laboratory (NHEERL) has developed a Research 

Implementation Plan to guide that laboratory’s specific activities related to EDCs. These 

documents are consistent with the EDRP and the MYP. 

The magnitude of the scientific uncertainties about the causes, effects, exposures, and solutions 

in addressing the concerns relating to endocrine disruptors clearly require national and 

international coordination and communication. To facilitate efforts nationally, ORD chairs an 

interagency working group established under the auspices of the Committee on Environment and 

Natural Resources. This working group developed a national framework for research and an 

inventory of federal research programs, identified high priority research gaps, and serves as a 

vehicle through which to develop and issue multi-agency solicitations for research proposals to 

help fill in some of these gaps. At an international level, ORD is working with the European 

Union, the International Programme on Chemical Safety/World Health Organization (WHO), the 

Organization for Economic Cooperation and Development (OECD), and Japan’s Ministry of the 

Environment to promote collaboration among scientists and to develop validated assays. 

Structure of the Program Review

The EDC Subcommittee, chaired by Dr. Anna Harding from Oregon State University, had broad 

and considerable expertise in the area of EDC research. Dr. George Daston of The Proctor & 

Gamble Company served as Vice-Chair of the subcommittee. Other members included Drs. 

Glen R. Boyd, Tulane University; George W. Lucier, private consultant; Stephen H. Safe, Texas 

A&M University; Juarine Stewart, Morgan State University; Donald E. Tillitt, U.S. Geological 

Survey (USGS) Columbia Environmental Research Center; and Glen Van Der Kraak, University 

of Guelph, Canada. The panel’s expertise included research specific to EDCs in the areas of 

developmental toxicology, fate and transport, wastewater treatment, hormone receptor 

mechanisms and receptor-mediated processes, risk assessment, molecular epidemiology, 

molecular biology and carcinogenesis, environmental toxicology, reproductive development in 

fish, aquatic ecosystems, and screening and testing. The subcommittee also has expertise in the 

areas of public health and xenobiotic metabolism in mammals. Biographical sketches of the 

subcommittee members are included in Appendix B. 

The subcommittee was sent ample review material in stages; the first package arrived 

approximately 7 weeks prior to the face-to-face meeting held December 13-15, 2004. A second 

mailing was received several weeks prior to the December meeting. Overall, the materials 

included the Research Plan for Endocrine Disruptors, the MYP for Endocrine Disruptors, 
5 

NHEERL’s Research Implementation Plan, a bibliography of publications by intramural and 

extramural researchers, proceedings and abstracts from recent EDC workshops (2002 Endocrine 

Disruptors Program Review Workshop Abstracts and the 2003 Proceedings of the Endocrine 

Disruptors Research Program Review Workshop), abstracts of the posters to be presented at the 

December meeting, and biographical sketches of the intramural and extramural researchers. 

Additional reports (WHO, Global Assessment of the State-of-the Science of Endocrine 

Disruptors; American Chemistry Council (ACC), Endocrine Issues Research Summary; 

Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), Endocrine 

Disruptor Screening and Testing Advisory Committee Final Report; and the CD-ROM, Effective 

Risk Management of Endocrine Disrupting Chemicals Workshop) were sent about 7 weeks prior 

to the face-to-face meeting. The subcommittee members also were sent the CD-ROM, 

Endocrine Disruptors Program Progress Review Workshop, held at Tulane University in 

October 2004, which included abstracts of the presentations from the Tulane conference, 

bibliographies of the presenters, and a summary of the panel discussion. Finally, the 

subcommittee members were provided a synopsis of EDC research and screening programs, 

including the logic model showing the interrelationship between the research program and the 

screening and testing program. At the December meeting, the subcommittee members received 

copies of the miniaturized posters, copies of the oral presentation slides, and summaries of the 

Science To Achieve Results (STAR) projects. 

The face-to-face meeting included a series of introductory/welcome presentations followed by a 

brief overview of the EDC Research Program and LTGs. The overview of each of the three 

LTGs was followed by a poster session of the research conducted by intramural and extramural 

researchers, program and regional office scientists, and grantees. The poster sessions were 

followed by a discussion period, in which the subcommittee members were given the 

opportunity to have one-on-one discussions with the principal investigators. Discussion and 

work sessions for the subcommittee were allotted throughout the 3-day face-to-face meeting. 

The meeting concluded with presentations that addressed the relevance of the research program 

from Agency program and regional offices that use the resulting science. Closing remarks were 

followed by a draft oral report from the BOSC EDC Subcommittee. The meeting also included 

an opportunity for public comment. 

Throughout the meeting, the presentations and posters were important to help clarify materials 

provided to the BOSC subcommittee. The presentations overviewing the goals and the posters 

presented by the investigators and grantees describing the research effort conducted under all of 

the LTGs were excellent. The enthusiasm, dedication, and excellence of the scientists within the 

program clearly were evident. The BOSC subcommittee thanked those who participated in these 

aspects of the face-to-face meeting, as they were critical for the BOSC’s evaluation of the EDC 

research program. 
6 

Overarching Conclusions and Recommendations

The subcommittee’s evaluation of the research plan and the MYP resulted in the conclusion that 

the goals and scientific questions are appropriate and represent an understandable and solid 

framework for setting research priorities for EDCs. The research plan was formalized in 1998 

following a series of workshops, interagency considerations, and meetings that embraced all 

relevant stakeholders. The program is recognized nationally and internationally as a 

multidisciplinary set of research areas for both human health and wildlife and it cuts across the 

risk assessment/risk management paradigm. Key research areas are aligned closely to the LTGs 

and to the APGs. 

The EDC program is a combination of “problem-driven” and core research and has stood the test 

of time; however, progress reviews are encumbered, to some extent, by the difficulty in defining 

the scope of activities considered to be part of endocrine disruptor research. There are a large 

number of toxic mechanisms that could be categorized as endocrine disruptors; therefore, EPA 

should clarify what is and what is not covered by the EDC program whenever the program is 

reviewed. Confusion regarding the classification and scope of endocrine disruptors is common 

in many assessments of these compounds. 

In general, the BOSC subcommittee is favorably impressed with the quality and relevance of the 

work and the progress to date, although it recognizes that much remains to be done. The APGs 

are highly ambitious and should be viewed as the time when significant progress should be 

evident but progress on those goals should, in most cases, continue well past the initial timeline. 

The subcommittee also is impressed with the enthusiasm of the investigators and their 

commitment to researching the difficult and controversial problems that surround EDCs. The 

poster presentations were exceptionally well done and served to consistently address potential 

problems raised by the reviewers after reading the written material. 

One of EPA’s main functions is providing risk assessment and risk management of chemicals in 

commerce and the environment. LTG 1 provides a solid scientific foundation for conducting 

risk assessments and making risk management decisions for endocrine disruptors. The research 

that falls under this goal covers the major questions in the key areas of the risk paradigm. 

Although there are many challenges to fully defining the nature of possible biological effects and 

the extent of exposure, the research being conducted under this LTG will put EPA in a strong 

position to make scientifically grounded decisions. 

EPA’s research program, relevant to the science questions contained in LTG 2 has been 

productive, of high quality, and relevant to the mission of EPA. Available resources have been 

used efficiently, and there is a high degree of enthusiasm for the projects by both the intramural 

and extramural investigators. In general, greater progress has been made on the ecological 

effects of EDCs compared to human health effects, although several appropriate human health 

projects are underway. 

The progress on LTG 3 within the EDC program has been excellent. Two mammalian tests 

already have been examined through a validation program administered by the OECD. These 

should be available for use by the EDSP very soon. Development of the other two tests 
7 

recommended by EDSTAC is in progress, and publications emanating from this work indicate 

that the work is on track. ORD has articulated clear goals for the development of screening and 

testing methods for endocrine disruptors and is fulfilling those goals in an admirable fashion. 

The research is directly relevant to legislation that EPA administers and is serving the program 

offices well. EPA’s research is well coordinated with that of other federal agencies and with 

international efforts on the standardization and validation of endocrine screening assays. 

In particular, Dr. Elaine Francis (EDC National Program Director) and Dr. Lawrence Reiter 

(Executive Lead for EDC and Director of NHEERL) have provided outstanding leadership 

necessary for this integrated program to thrive. The EDC program scientists are highly sought as 

consultants and provide technical assistance to EPA program offices, other federal agencies, and 

the broader scientific community. EDC scientists are engaged in intramural and extramural 

research within ORD, and program scientists have provided exemplary leadership in the field at 

the national and international levels. EDC scientists disseminate their research in top-tier 

scientific journals, a strong indicator of the quality of their research and respect among 

professional peers. The EDC researchers are a group of highly esteemed scientists who are at 

the forefront of EDC research in screening and testing methodologies for mammalian and 

ecological tests, source identification, effects on wildlife, and ecological health. 

EPA’s future success in meeting the specified goals of the EDC program will depend on a 

number of factors including continued funding, support from EPA management, 

multidisciplinary intramural research spanning ORD and other EPA entities, extramural grants, 

and continued interagency collaborations, especially with respect to identifying new sources of 

environmental and human exposure (e.g., National Institute of Environmental Health Sciences 

[NIEHS], Centers for Disease Control and Prevention [CDC], Food and Drug Administration 

[FDA], U.S. Department of Agriculture [USDA], USGS, and others). To date, ORD has been 

very astute in leveraging its EDC program resources by collaborating with other federal 

agencies, and these collaborations have extended the EDC research program. 

The continuation of the grants program is vital because it provides a mechanism for EPA to more 

efficiently evaluate new technologies and innovations for use in the risk assessment and risk 

management arenas. 

Recommendations: 

 Progress reviews are encumbered, to some extent, by the difficulty in defining the scope 

of activities considered “endocrine disruptor research.” There are a large number of 

toxic mechanisms that could be categorized as endocrine disruptors; therefore, EPA 

should clarify what is and is not covered by the EDC program whenever the program is 

reviewed. 

 The following are recommendations that would allow the Program Director to negotiate 

for needed research expertise from a position of strength and enhance the laboratories 

that participate in EDC program research: (1) hire additional personnel to share the 

workload of the participating laboratories; (2) elevate the position of the EDC Program 
8 

Director to the level of the Laboratory/Center Directors; and (3) provide the EDC 

Program Director budget authority. 

Strengths and Challenges of Long-Term Goals

Brief summaries of the overall strengths and challenges of each LTG are presented below. 

LONG-TERM GOAL 1

LTG 1: Provide a better understanding of science underlying the effects, exposure, 

assessment, and management of endocrine disruptors. 

The research being carried out under this LTG will strengthen the foundation of EPA’s risk 

assessment practices and risk management decisions for endocrine disruptors. The research plan 

plays to the strengths of EPA’s research laboratories, which are organized along risk assessment/ 

management themes. EPA already has been a leader in characterizing the effects of endocrine 

disruptors in mammalian systems and has expanded its capabilities in ecological toxicity by 

bolstering its laboratory capabilities and partnering with other agencies, and through judicious 

use of STAR grants to expand its expertise beyond its own walls. 

Strengths:

The scientific expertise available in ORD and some of the external STAR recipients is a primary 

strength. The research program structure and implementation are logical and well designed. 

Additionally, the models that are being characterized to evaluate EDCs under LTG 3 will 

complement the ongoing efforts in this area. 

The EDC program and scientists within ORD provide strong leadership in the design and 

execution of research efforts. The models, which have been designed or modified to evaluate 

endocrine disruption, will provide the data required to develop risk assessments. The models 

have been the subject of harmonization efforts to be compatible with OECD guidelines. 

The risk management program provides important information for the regulated community with 

regard to identifying and prioritizing EDCs of concern and leadership in developing risk 

management approaches. 

Challenges:

The complexity of endocrine systems, in conjunction with the diversity of potentially endocrineactive chemicals, makes evaluation of the combined effects of EDCs a daunting task. Even with 

a solid approach, good laboratory models, and adequate funding, it is likely that it will take some 

years for ORD to fully evaluate this question. 

Intramural scientific expertise for the areas of human and aquatic species (i.e., fish, invertebrates, 

and amphibians) is very good; however, this is not the case in the area of wildlife toxicology. 
9 

Consequently, much of the experimental research and expertise resides in the STAR grant 

recipients. It is advantageous to utilize the expertise of these scientists from outside the Agency; 

however, more expertise in the area of wildlife toxicology within the Agency may be required to 

fully attain the program’s goals. Application of the wildlife models that are being developed 

may require Agency personnel to meet the exact needs of regulatory concern. Also, the 

evaluations of EDCs on wildlife within a risk assessment paradigm, including evaluation of 

uncertainties, almost certainly would require full-time EPA personnel. It is not clear from the 

review of information presented to this subcommittee that adequate personnel exist to address 

wildlife concerns of EDCs. 

Recommendations: 

 To meet the program goals and fulfill the exact needs of regulatory concern, the BOSC 

recommends that the EDC program dedicate full-time EPA personnel to work in this 

area. 

 Because of the complexities in extrapolating among the many species in the 

environment that may be affected by endocrine disruptors, it will be important for 

ORD to continue to collaborate with other federal, academic, nongovernmental 

organization (NGO), and industry partners to characterize better the range of 

variability among species. 

A major challenge for risk assessment will be to form definitions of what constitutes an adverse 

effect, and what defines a biological indicator. This challenge does not reside exclusively within 

ORD, but ORD research will need to support decisions in this area. 

The development of analytical methods is a significant challenge and was not identified clearly 

as an APG and/or APM for this research. The subcommittee believes that this may be slowing 

down the progress of the risk management program. 

Selected water and wastewater treatment technologies have been studied by other investigators 

and reported in peer-reviewed literature but do not seem to be integrated into the EDC program. 

Recommendation: 

 Studies have been reported regarding the use of predictive tools that can be used to 

prioritize the focus of specific treatment technologies and compounds. These findings 

could be integrated into EPA’s EDC program. 

There is no current (i.e., as of 2004) ongoing research or specific plan for future research 

regarding natural processes in sediments. 

 
10 

LONG-TERM GOAL 2

LTG 2: Determine the extent of the impact of endocrine disruptors on humans, wildlife, and 

the environment. 

EPA’s research program relevant to the science questions contained in LTG 2 has been 

productive, of high quality, and relevant to the mission of EPA. Available resources have been 

used efficiently, and there is a high degree of enthusiasm for the projects by both the intramural 

and extramural investigators. In general, greater progress has been made on ecological effects of 

EDCs compared to human health effects, although several appropriate human health projects are 

underway. Several strengths and challenges were identified by the BOSC in the review of the 

projects listed under LTG 2, as indicated below. 

Strengths: 

Many of the models required for studying effects of EDCs on fish and invertebrates have been 

developed, modified and/or applied. Ongoing studies have set appropriate priorities for 

determining sources of EDC exposures including concentrated animal feedlot operations 

(CAFOs), combustion processes, and pulp mills. 

The ecological studies have effectively coupled field studies, biomarker measurements, 

analytical chemistry, laboratory studies with whole organisms, and cultures of hormoneresponsive cells with effluents suspected of possessing hormonal activity. 

EPA scientists have made good decisions on how best to use genomics in their EDC studies; the 

information that is being generated by the studies should produce important data that address 

critical knowledge gaps. There is a good balance between molecular toxicology and effects on 

aquatic species and experimental animals. 

Interactions between ORD and the regional offices are strong, effective, and frequent in regards 

to the EDC studies. Such interactions provide a good model for EPA to use in other areas. 

EPA’s research regarding LTG 2 is consistent with the overarching research plan developed by 

EPA and other agencies in 1998, and the research priorities reflect the high-priority goals 

identified by that plan. 

Challenges:

Although priorities for the chemicals studied have been appropriate, EPA should continue to 

improve its interactions with other agencies that have a strong interest in EDCs (i.e., CDC, 

NIEHS, National Toxicology Program [NTP], National Institute for Occupational Safety and 

Health [NIOSH], and FDA) to identify new sources of environmental and human exposures to 

EDCs. Moreover, EPA should mine data made available from the OECD High Production 

Volume (HPV) Program and work with FDA to investigate the role of pharmaceuticals in the 

environment as a source of endocrine disruptors. 
11 

Recommendation: 

 EPA should continue to improve its interactions with other agencies that have a strong 

interest in EDCs to identify new sources of environmental and human exposures, 

including investigating the role of pharmaceuticals as sources of EDCs. 

It was not feasible for scientists conducting epidemiologic studies to attend the face-to-face 

meeting. Although the EDC Subcommittee members were provided a CD-ROM of the Tulane 

conference and one of the subcommittee members attended the conference, the subcommittee 

members thought it would be helpful to include poster presentations by each of the scientists 

funded by this interagency program for subsequent program reviews. 

Recommendations: 

 It will be important for EPA to take a leadership role in the application of the “omics” 

technologies to address many of the science questions critical for evaluating 

environmental and human health effects of EDCs. This will require a strong 

commitment to a systems biology approach and computational toxicology as well as 

effective interactions with those generating much of the basic data. 

 EPA should continue to investigate the common ground between ecological and human 

health because the Agency is in a unique position to do so. 

LONG-TERM GOAL 3 

LTG 3: Support EPA’s screening and testing program. 

ORD has articulated clear goals for the development of screening and testing methods for 

endocrine disruption, and is fulfilling those goals in an admirable fashion. The research is 

directly relevant to legislation administered by EPA and is serving the program offices well. 

With regard to LTG 3, EPA’s research is well coordinated with that of other federal agencies and 

with international efforts on the standardization and validation of endocrine-screening assays. 

The progress on LTG 3 within the EDC program has been excellent. Two mammalian tests 

already have been through a validation program administered by OECD. These should be 

available for use by the EDSP very soon. Development of the other two tests recommended by 

EDSTAC is in progress, and publications emanating from this work indicate that the work is on 

track. 

Strengths:

ORD has clearly defined its objectives for research to support the development, standardization, 

and validation of alternative methods that can be used by the program offices. 
12 

ORD’s research is mechanistically driven, which provides a solid scientific foundation for the 

test methods that are developed. Because of this mechanistic focus, it is highly likely that the 

methods ORD develops will be valid, broadly applicable, and easily interpreted. 

ORD has used its leadership role in the fields of reproductive, developmental, endocrine, and 

aquatic toxicology to adapt and develop methods that have high relevance to the needs of the 

program offices and to the protection of public and environmental health. 

Challenges:

The major challenge that ORD has faced with regard to the screening and testing program is 

handing off its research to the program offices so that validation and implementation can occur 

in a timely way. It should be noted, however, that much of the delay in validation and regulatory 

acceptance is because this process takes place largely outside the Agency. 

ORD has a large number of research accomplishments within NHEERL that have contributed 

significantly to a basic understanding of the toxic responses to estrogens, anti-androgens (within 

the Reproductive Toxicology Division [RTD]) and thyroid toxicants (within Experimental 

Toxicology Division [ETD]), which in turn has led directly to the development of improved 

methods for endocrine disruptor detection. This research is not centralized and may not be 

captured adequately in the list of annual performance goals and accomplishments. It would be 

worthwhile to identify this research as important support for LTG 3. 

Recommendation: 

 ORD is beginning to develop core competencies in genomics and quantitative structure 

activity relationship (QSAR) methods, both of which hold promise in endocrine 

disruptor identification. Because these areas are so data intensive, it will be important 

for ORD to train or hire experts in bioinformatics to work with the life sciences experts 

already on staff. 

 

Program Leadership 

Dr. Lawrence Reiter serves as the Executive Lead for the EDC program and also is the Director 

of NHEERL. Dr. Reiter has been the Executive Lead since the inception of the program in 1995, 

and Dr. Elaine Francis serves as the National Program Director. She is extremely effective as 

the Program Director and has done an outstanding job of providing the leadership necessary for 

this integrated program to thrive. Her FTE and institutional support comes from the National 

Center for Environmental Research (NCER), and her role is to oversee the planning and 

execution of the intramural and extramural EDC research program. Dr. Francis works closely 

with Dr. Reiter to resolve EDC issues and reports to the NCER Director, Dr. Jack Puzak (Acting 

Director). Dr. Francis has responsibility for program oversight but does not have budgetary 

authority. 
13 

The EDC program is unique in that no other U.S. federal agency has such a program. The EDC 

program is not just an umbrella for a series of independent projects but is a fully integrated 

program across all ORD laboratories and centers (with the exception of the National Homeland 

Security Research Center). The program is recognized nationally and internationally as a 

multidisciplinary set of research areas for both human health and wildlife and it cuts across the 

risk assessment/risk management paradigm. 

EDC scientists are highly sought out as consultants to EPA program offices (such as the Office 

of Coordination and Science Policy and OPPTS), other federal agencies, and the broader 

scientific community. EDC scientists provide technical assistance to the program and regional 

offices. ORD supports research on EDCs in both its intramural and extramural programs, and 

scientists carrying out this research have provided leadership in the field at the national and 

international levels. These individuals are involved in organizing meetings on EDCs sponsored 

by governments and industry and scientific societies, and they also play an important role in 

these conferences by reporting their research on EDCs in terms of model development, 

mechanisms of action, and assay validation. The leadership of EPA scientists in the 

development of screening and testing methods for EDCs also is attributable in part to the long 

history within the Agency of studying the possible actions of chemicals as reproductive and 

developmental toxicants. The EDC researchers are a group of highly esteemed scientists who 

are at the forefront of research in EDC screening and testing methodologies for mammalian and 

ecological tests, source identification, effects on wildlife, and ecological health. EDC scientists 

are a tremendous resource and asset for the Agency.

Program Resources 

The EDC program was projected to have an average annual budget of $12 million. This includes 

the STAR grants program, which averages $4 million per year in those years it is funded. The 

average annual budget from FY 2003 to 2005 has ranged from $12.7 million enacted in FY 2003 

to the FY 2005 request of $8.0 million. The EDC Program Director does not have direct access 

to human or financial resources to carry out the program’s objectives; rather, the Director must 

negotiate with the Division Directors of the laboratories and centers (her peers) of ORD to 

recruit the time and effort of scientists with the needed expertise. 

The laboratories and center that contribute resources to the EDC program are NRMRL, NCER, 

NHEERL, and National Exposure Research Laboratory (NERL). Although the total budget for 

the program has decreased since FY 2003 (from $12.7 million to an $8.0 million request for FY 

2005), the percentage of resources provided by each of these laboratories has been relatively 

stable (except for NCER) during the past 2 years and is proportionate to the number and extent 

of tasks that they perform for the EDC program across the LTGs. The STAR grants program 

adds significant value to the research portfolio of the EDC program in that it assists in filling 

identified research gaps, brings in research expertise that is not found among intramural 

scientists, and assists ORD in responding to new issues that the laboratories and centers may not 

be able to readily address. 
14 

The manner in which this program is funded, though indirect and possibly cumbersome, does not 

appear to hinder the quality of the research conducted under the program. It is apparent that the 

EDC Program Director has had success in convincing Division Directors to loan scientist time to 

the EDC program. It does make it more difficult, however, for the Program Director to do 

forward planning or to plan the investigation of emerging issues. ORD has been very astute in 

leveraging the EDC program’s resources by collaborating with other federal agencies. The 

amount of research conducted by the EDC program has been expanded by collaboration with 

agencies such as NIOSH, NIEHS, and the National Cancer Institute (NCI); however, the 

fragmentation of scientists’ time without extra compensation raises concern about whether the 

productivity (e.g., number of published manuscripts, etc.) of these scientists is negatively 

impacted by participation in the EDC program. 

Recommendation: 

 The situations cited above (insufficient funding and the mechanism used to provide 

resources to the EDC program) can be remedied by several courses of action: (1) hire 

additional personnel to share the workload of the participating laboratories; (2) elevate 

the position of the EDC Program Director to the level of the Laboratory/Center 

Directors; and (3) give the EDC Program Director budget authority. 

 

These actions would allow the Program Director to negotiate for needed research expertise from 

a position of strength and will allow the Program Director to enhance the laboratories that 

participate in EDC program research. The subcommittee understands that ORD has plans to 

enact the latter two of these actions in the near future for all newly hired National Program 

Directors. The BOSC recommends the speedy implementation of that plan. 

Report Overview 

In addition to the Executive Summary, the progress review report contains five chapters and 

three appendices. Chapters II through IV focus on the three long-term goals of the program, and 

Chapters V and VI cover program leadership and program resources, respectively. These five 

chapters provide a more detailed account of the subcommittee’s deliberations. The three 

appendices include the charge questions to the EDC Subcommittee, biographical sketches of the 

subcommittee members, and a list of acronyms used in the report. 
15 

II. LONG-TERM GOAL 1 

Provide a better understanding of science underlying the effects, exposure, assessment, and 

management of endocrine disruptors. 

Introduction

LTG 1 of ORD’s EDRP strives to provide the science underlying the effects, exposure, risk 

assessment, and risk management of endocrine disruptors. The information generated under this 

LTG will help address key issues for the regulatory needs of EPA. The key issues and research 

questions to be answered are related to understanding: (1) characteristics of the dose-response 

relationships for EDCs, particularly in the low-dose region; (2) development of risk assessment 

approaches for EDCs, including interspecies extrapolations for EDCs; (3) the effects of multiple 

exposures of EDCs; (4) management of risks associated with EDCs; and (5) characterizing the 

nature and manifestations of latent effects from developmental exposures to EDCs. 

Program Design

The goals set forth in the EDRP and the MYP to address the underlying science needs for risk 

assessment and management of EDCs continue to be appropriate. The research and 

implementation plans to achieve these goals are well founded and provide a logical framework 

for attaining the EDRP goals. 

EPA’s MYP takes advantage of existing core competencies in reproductive toxicology, 

mechanistic toxicology, ecotoxicology, and risk assessment and risk management methodology 

to address these questions. The capabilities of these scientists are unique in breadth, depth, and 

scope within the federal government. No other federal agency is equipped to provide answers 

regarding both risk assessment and management of EDCs; however, the outcomes of the EDC 

program continue to be essential for other regulatory and resource management agencies, both 

federal and state, as well as external investigators and industry. 

The program also has relied on the STAR program to conduct research and provide expertise to 

achieve program-related outcomes. STAR grant recipients have provided important findings on 

interspecies differences in steroid receptors, avian and invertebrate models for EDC evaluations, 

and the effects of multiple EDC exposure. The EDC program also has utilized the skills and 

abilities of scientists from other federal agencies to complement some activities in this research 

area. Because the EDC program relies on this outside expertise, programs such as the STAR 

program are essential for the program to continue to meet its goals in this area. One example of 

the EDC program’s reliance on extramural expertise is in avian toxicology. This particular 

expertise and ability to conduct avian toxicology studies in the laboratory or in the field does not 

reside within EPA. 
16 

Dose Response. The most significant question in dose-response assessment is whether low doses 

(i.e., below the no-observed-effect level for traditional reproductive toxicity studies) of 

endocrine-active compounds produce qualitatively different responses than are observed at the 

exaggerated dose levels commonly used in hazard identification studies. There are reports in the 

literature of such low-dose effects, but these reports have not been corroborated in replicate 

studies. Unfortunately, because of the variability in the parameters being measured (e.g., organ 

weights) and the difficulty in controlling the many factors that may influence study outcomes, 

the participants in an NTP workshop (Melnick, et al., 2002)5 found that the possibility of lowdose effects could not be discounted (although it is believed that the weight of evidence weighed 

against the possibility). The issue is an important one because the presence of such effects 

would challenge the validity of our current approaches to hazard identification and risk 

assessment for endocrine disruptors. 

The MYP describes a number of research objectives that consider the low-dose question. The 

program is designed to evaluate effects on a number of target tissues at different life stages and 

with different model compounds. In addition to intramural research, a request for extramural 

grant proposals also was issued for this research. 

Risk Assessment. The identification and application of key risk assessment tools for humans and 

wildlife is one of the practical goals of the EDC program. The ability to obtain this goal is 

directly dependent on the success achieved in the other goals of the program. As the 

uncertainties of dose-response models and endpoints, interspecies differences, and cumulative 

effects of multiple exposures are clarified, the approaches required for risk assessment of EDCs 

will be elucidated. A key to attaining this goal is communication and cooperation among ORD 

personnel and staff in the regional and program offices. 

A number of products have resulted from ORD’s EDC program and ongoing efforts of the 

program will be used to develop risk assessment tools for EDCs in humans and wildlife. The 

structure of the program is well suited to develop information on mode of action, interspecies 

differences, multiple chemical exposures, critical life stages, dose response, evaluation of 

multiple levels of biological organization, establishment of linkages among assessment 

endpoints, and low-dose effects of EDCs, all required for risk assessments. Work on 

development of models (mammalian, fish, amphibian, and avian) is ongoing and the endpoints 

are appropriate to help identify and evaluate uncertainties for risk assessment of EDCs. Model 

compounds include traditional organochlorine pesticides and industrial compounds, positive 

controls (estrogens and androgens), current-use pesticides (e.g., atrazine), and thyroid-active 

agents. 

Multiple EDC Exposures. A key research need in the area of EDCs effect assessments is to 

develop a better understanding of potential impacts of multiple chemical exposures in both 

wildlife and humans. Unintentional environmental exposures to EDCs almost always involve 

more than one chemical. A better understanding of the interactions at the molecular, cellular, 

 

5 Melnick R, Lucier G, Wolfe M, Hall R, Stancel G, Prins G, Gallo M, Reuhl K, Ho SM, Brown T, et al. 2002. 

Summary of the National Toxicology Program’s report of the endocrine disruptors low-dose peer review. 

Environmental Health Perspectives 110:427-431. 
17 

and organism levels will provide the required information for risk assessment and risk 

management activities within EPA and across federal and state regulatory agencies. 

Additive, synergistic (i.e., “more than additive”), and antagonistic (i.e., “less than additive”) 

interactions are known to occur with EDCs. These interactions can occur through direct 

interactions with receptors (e.g., estrogen, androgen, thyroid, etc.), effects on metabolic 

pathways (i.e., steroid pathways), and signal transduction pathways (e.g., kinases or 

phosphorylases). The interactions of EDCs on endocrine function often are species-specific, 

life-stage specific, and tissue-specific, thereby increasing the potential complexity of these 

issues. Therefore, research efforts to address potential effects and population impacts of 

multiple EDC exposures must encompass a variety of animal models, measurement endpoints, 

and chemical classes. 

The program design within ORD to address this issue is appropriate given the state of knowledge 

and the funds available. The intramural EDC program incorporates aspects of QSAR models, 

computational toxicology, mechanistic laboratory models (in vitro and in vivo) with multiple 

endpoints, and field evaluations that address these issues. Some of the research that applies to 

this issue can be found under other LTGs (e.g., QSAR and computational chemistry), but there is 

good integration across research lines to ensure the appropriate application of the findings. 

Results from all of these lines of research will be required to address the scientific and regulatory 

issues of multiple chemical exposures. 

The models currently under active development or use to evaluate the effects of multiple 

exposures include mammalian models with endpoints of reproductive function and sexual 

differentiation, a short-term mammalian model evaluating thyroid function, in vitro approaches 

with cell culture, and a STAR grant to evaluate effects in a gastropod. Endpoints of the models 

include multiple levels of biological organization from genomic analysis to reproductive 

function. 

The 1996 FQPA mandated EPA to investigate the effects of multiple chemical exposures within 

the same class (mode of action) of chemical. Most of the research efforts within EPA on 

multiple chemical exposures have been testing chemical mixtures with a similar mode of action. 

 Major research efforts have been undertaken on Ah-R agonists (polychlorinated biphenyls 

[PCBs], dioxins, and furans), chlorotriazine pesticides, AR antagonist fungicides (viclozolin and 

procymidone), and phthalate esters. There also has been research on the effect of mixtures that 

contain chemicals with different modes of action. 

Risk Management. The risk management program aims to develop strategies for determining 

how unreasonable risks can be managed by minimizing exposure of humans and wildlife to 

suspected EDCs. Risk management strategies focus on modifying existing technologies for 

controlling the release of EDCs at the source and in developing new tools for mitigating 

exposure to EDCs. Risk management research is conducted in parallel with risk assessment 

research to identify and develop effective risk management approaches based on exposure and 

effects information as it becomes available. 
18 

Chemicals that currently are considered known or highly suspected endocrine disruptors and 

present in environmental situations associated with significant exposure to humans or wildlife 

are identified and discussed in the updated RME. The target compounds included in the current 

RME are alkylphenolics, PCBs, reproductive hormones, chlorinated dioxins and furans, and 

DDT and DDE. The risk management program relies on information generated by LTG 2 and is 

driven by three APGs with target completion dates of 2008 to 2009. 

Latent Effects From Developmental Exposures. Estrogens, androgens, and thyroid hormones are 

active during development and may produce effects that are organizational and permanent. 

Whereas some of these effects are obvious (e.g., structural malformations observable at birth), 

others are latent and are manifested as functional changes or increased susceptibility to disease 

states later in life. The research portfolio has a number of programs that evaluate the potential 

latent effects of developmental exposure to a variety of endocrine disruptors on a number of 

target tissues and functions. The program is a well-designed survey of the organ systems that are 

most likely to be affected by early life exposure. 

Relevance

The science conducted under this LTG is unique and provides the foundation required for future 

risk assessment and risk management activities required by EPA. Important models are being 

developed and characterized, and the choice of endpoints is relevant for the ecological risk 

assessment process. The choice of chemicals is timely and important relative to exposure. 

Important issues such as low-dose and latent effects are being addressed in a rigorous manner. 

Thus, a considerable amount of high-quality data is being developed under this LTG; these data 

will provide the foundation for environmental risk assessments and risk management of EDCs. 

Dose Response. This aspect of the LTG is directly relevant to a central mission of EPA, which is 

the appropriate assessment of hazard and risk of chemical substances. EPA’s entire chemical 

regulation framework is based on the presumption that as dose increases, so does the prevalence 

and severity of adverse effects. Hazard identification test designs and risk assessment practices 

to establish reference doses are based on this fact. The purported low-dose phenomenon 

challenges the existing paradigm. The program as described in the MYP is robust and directly 

addresses the key issue of whether these low-dose effects are real and does so with a 

combination of internal and external research. 

Risk Assessment. Research conducted under the EDC program is highly relevant to human and 

ecological risk assessments of EDCs. As stated above, many important models are being 

developed and characterized. The choice of endpoints is relevant for the ecological risk 

assessment process, and the choice of chemicals is timely and important relative to exposure. 

Important issues such as low-dose and latent effects are being addressed; thus, high quality data 

are being developed that will provide the foundation for environmental risk assessments of 

EDCs. 

Multiple EDC Exposures. The previous and ongoing work in this research area is very relevant, 

and the approach of first investigating interactions of chemicals within the same mode of action 
19 

is a sound approach. A thorough understanding of within-class interactions and development of 

predictive models stemming from within-class interactions are required before more complex 

interclass (i.e., across mode of action) effects of EDCs may be evaluated. The chemicals and 

classes represented in the ORD and STAR investigations are appropriate and timely based on the 

known concerns of exposure and observed effect. The research models encompass a variety of 

endocrine pathways and the evaluations have metrics at multiple levels of biological 

organization. 

Risk Management. The risk management program is unique in that it covers a breadth of 

research areas (i.e., water and wastewater treatment, septic systems, CAFOs, air quality, 

sediments, etc.) and aims to provide the foundation for developing approaches for pollution 

prevention and control. The program evaluates existing technologies (typical treatment 

operations and processes) and aims to develop new risk management approaches (e.g., treatment 

optimization, site remediation, chemical substitutes, and predictive computational tools) to 

reduce exposure to EDCs. The selection of target compounds is relevant based on available risk 

assessment and exposure data and information; thus, deliverables generated by this LTG will 

provide the foundation for developing effective environmental risk management approaches for 

EDCs. 

Latent Effects. EPA is charged with protecting the public from harmful chemical exposures. In 

so doing, it is necessary to identify the possible outcomes of toxicity that should be evaluated 

during the risk assessment process. The research goal on latent effects after developmental 

exposure evaluates the possibility that more needs to be done to test for latent effects of 

developmental exposures. 

 

Program Progress

The EDC program has developed important and relevant information on mode of action, 

interspecies differences, multiple chemical exposures, critical life stages, dose-response 

characteristics, effects at multiple levels of biological organization, linkages among assessment 

endpoints, and low-dose effects of EDCs. All of these findings are required for the appropriate 

evaluation and risk assessments of EDCs. Work on the development of models (mammalian, 

fish, amphibian, and avian) is ongoing and the endpoints are appropriate to help identify and 

evaluate uncertainties for risk assessment of EDCs. Model compounds include traditional 

organochlorine pesticides and industrial compounds, positive controls (estrogens and 

androgens), current-use pesticides (e.g., atrazine), and thyroid-active agents. 

Dose Response. Much of the work in this area has been completed; however, the extramural 

work is still in progress. This is a problem that has generated much interest and activity outside 

EPA, especially in the private sector. It may be time for EPA to evaluate the literature, along 

with its own progress, to determine whether there is enough information available to reduce the 

uncertainty associated with dose response, or to alter its research plans. 

Risk Assessment. Progress has been good on the basic research needs that are required to clarify 

uncertainties in risk assessment. Good models are being developed with endpoints important for 
20 

risk assessment needs. Progress and efforts to develop an integrated framework for human or 

environmental risk assessment of EDCs, however, appear to be limited. Some or most of this 

work may be the focus of other groups within EPA such as the Risk Assessment Forum. The 

model and framework for the development of critical information on EDCs for risk assessment is 

well established and progress is being made. Efforts now should focus on development of risk 

assessment paradigms for EDCs and application of the research findings. 

Multiple EDC Exposures. Although the challenges faced by ORD to address the issues of effects 

from multiple chemical exposures are tremendous, progress has been excellent. ORD has been 

methodically evaluating a number of relevant models and endpoints as well as relevant chemical 

classes. Moreover, the models that are being developed and validated in LTG 3 (e.g., fish 

reproduction, amphibian development, avian reproduction, etc.) will provide the foundation for 

testing and evaluation of combined effects in future years. 

Risk Management. Careful consideration must be paid to progress on risk management issues to 

meet the schedules provided in the MYP for the EDRP. An RME was prepared to identify EDCs 

of concern and major EDC sources and to develop a comprehensive risk management research 

program based on available risk assessment and exposure information to date. This RME is 

intended to identify opportunities of greatest need and greatest potential for making significant 

impacts on the reduction of EDC releases and exposures. Additional resources are needed to 

adequately consider the EDC compounds included in the current RME. Upcoming revisions of 

the RME are targeted for FY 2005 and FY 2008 based on information regarding new EDCs of 

concern. Future risk management research on new EDCs of concern will require additional 

resources to meet the schedules in the MYP. 

Latent Effects. Most of the milestones in this area have been achieved on time. 

Strengths and Challenges 

Strengths:

The scientific expertise available in ORD and through the STAR grants is a primary strength. 

The research program structure and implementation are logical and well designed. Additionally, 

the models, which are being characterized to evaluate EDCs under LTG 3, will complement the 

ongoing efforts in this area. 

The EDC Program and scientists within ORD provide strong leadership in the design and 

execution of research efforts in this area. The models, which have been designed or modified to 

evaluate endocrine disruption, will provide the data required to develop risk assessments. The 

models have been the subject of harmonization efforts to be compatible with OECD guidelines. 

The risk management program provides important information for the regulated community with 

respect to identifying and prioritizing EDCs of concern and leadership in developing risk 

management approaches. 
21 

Challenges:

The complexity of endocrine systems, in conjunction with the diversity of potentially endocrineactive chemicals, makes the evaluation of combined effects of EDCs a daunting task. Even with 

a solid approach, good laboratory models, and adequate funding, it is likely that it will be some 

years before ORD can fully evaluate this question. 

Scientific expertise in the areas of human and aquatic species (i.e., fish, invertebrates, and 

amphibians) is very good, but this is not the case in the area of wildlife toxicology. 

Consequently, much of the experimental research and expertise comes from STAR grant 

recipients. It is advantageous to utilize the expertise of these scientists from outside the Agency, 

but ORD will need more internal expertise in the area of wildlife toxicology to fully attain the 

program’s goals. Application of the wildlife models that are being developed may require 

Agency personnel to meet the exact needs of regulatory concern. Also, the evaluations of EDCs 

on wildlife within a risk assessment paradigm, including evaluation of uncertainties, almost 

certainly would require full-time EPA personnel. It is not clear from the review of information 

presented to this subcommittee that adequate personnel exist to address wildlife concerns of 

EDCs. Because of the complexities in extrapolating among the many species in the environment 

that may be affected by endocrine disruptors, it will be important for ORD to continue to 

collaborate with other federal, academic, NGO, and industry partners to better characterize the 

range of variability among species. 

A major challenge for risk assessment will be to settle on definitions of what constitutes an 

adverse effect and a biological indicator. This challenge does not reside exclusively within 

ORD, but ORD research will need to support decisions in this area. In addition, the development 

of analytical methods is a significant challenge and was not identified clearly as an APG and/or 

APM for this research. The subcommittee members believe that this may be slowing down the 

progress of the risk management program. 

Selected water and wastewater treatment technologies have been studied by other investigators 

and reported in peer-reviewed literature. These findings could be integrated into ORD’s work. 

Studies have been reported regarding the use of predictive tools that can be used to prioritize the 

focus of specific treatment technologies and compounds. 

As of 2004, there is no ongoing research or specific plan for future research regarding natural 

processes in sediments. 

Recommendations:

 The model and framework for development of critical information on EDCs for risk 

assessment is well established and progress is being made. Efforts now should focus on 

the development of risk assessment paradigms for EDCs and application of the 

research findings. 
22 

 Studies have been reported regarding the use of predictive tools that can be used to 

prioritize the focus of specific treatment technologies and compounds. These findings 

could be integrated into EPA’s EDC program. 

 To meet the program goals and fulfill the exact needs of regulatory concern, the BOSC 

recommends that the EDC program dedicate full-time EPA personnel to work in the 

area of wildlife toxicity. 

 Because of the complexities in extrapolating among the many species in the 

environment that may be affected by endocrine disruptors, it will be important for 

ORD to continue to collaborate with other federal, academic, NGO, and industry 

partners to better characterize the range of variability among species. 
23 

III. LONG-TERM GOAL 2 

Determine the extent of the impact of endocrine disruptors on humans, wildlife, and the 

environment. 

Introduction

The BOSC EDC Subcommittee examined this goal in relation to the specific charge questions on 

design, relevance, and progress and the four specific research questions comprising this LTG. 

The key areas of uncertainty related to LTG 2 include: (1) how and to what degree human and 

wildlife populations are exposed to EDCs; (2) effects that are occurring in exposed human and 

wildlife populations; (3) chemical classes of interest and their potencies; and (4) major sources 

and environmental fates of EDCs. 

The subcommittee evaluation of the research plan and the MYP concluded that the goals and 

science questions are appropriate and represent an understandable and solid framework for 

setting research priorities for endocrine disruptors. The research plan was formalized in 1998, 

following a series of workshops, interagency considerations, and meetings that embraced all 

relevant stakeholders. This plan has stood the test of time and it is reflected appropriately in the 

MYP for LTG 2; however, progress reviews are encumbered, to some extent, by the difficulty in 

defining the scope of activities considered endocrine disruptor research. There are a large 

number of toxic mechanisms that could be categorized as endocrine disruption, so EPA needs to 

clarify what is and is not covered by the EDC program whenever the program is reviewed. 

Confusion regarding the classification and scope of endocrine disruptors is common to many 

assessments of these compounds. 

 In general, the subcommittee is favorably impressed with the quality and relevance of the work 

and the progress to date, although it is recognized that much remains to be done. The 

subcommittee also is impressed with the enthusiasm of the investigators and their commitment to 

understanding the difficult and controversial problems that surround EDCs. The poster 

presentations were exceptionally well done and helped to address issues raised by the reviewers 

after reading the written material provided for the review. 

EPA’s future success in meeting the specified goals of the EDC program will depend on a 

number of factors including continued funding, support from EPA management, multidisciplinary intramural research spanning ORD and other EPA entities, extramural grants, 

interagency collaborations (with NIEHS, CDC, USGS, FDA, USDA, and others), and 

partnerships with other government and industrial research funding agencies and groups. 

Continuation of the EPA-funded grants program is vital because it provides a mechanism for 

EPA to more efficiently evaluate new technologies and innovations for use in risk assessment 

and risk management arenas, and for resolving key scientific issues. 
24 

The APGs are highly ambitious and should be viewed at the time when significant progress 

should be evident, but progress on those goals should, in most cases, continue well past the 

initial timeline. 

The presentations and posters under LTG 2 appear to represent primarily issues of environmental 

and human exposures to actual and suspected EDCs and the spectrum of effects that might be 

produced from those exposures. There is obvious overlap with the other LTGs; for example, one 

of the key science questions in the MYP for LTG 2 is to “determine how and to what degree 

human and wildlife populations are exposed to EDCs.” This question also is relevant to LTG 1, 

which deals with dose response and exposure to mixtures of EDCs. This overlap is desirable if it 

is understood that the success of each of the LTGs is dependent on continued productive 

interactions among all the projects covered under the EDC umbrella as well as related activities 

in the human health, computational toxicology, risk assessment, and risk management programs 

and the needs of the regional offices. To date, EPA appears to have been successful in linking 

different components of the EDC program as evidenced by both the oral and poster 

presentations. 

Program Design

In the case of environmental releases and ecological effects, EPA has taken two approaches: (1) 

studying chemicals with known EDC activity; and (2) evaluating the endocrine activity of 

emissions and releases from different sources followed by attempts to identify the chemicals 

responsible for the observed activity. 

Both approaches are needed but EPA should not lose sight of the goal of determining chemical 

classes of interest and the sources of EDCs. The process for selecting chemicals studied under 

the EDC program should take advantage of the HPV program and other EPA activities and 

information obtained from NTP, FDA, CDC, NIOSH, and other relevant programs. It always is 

tempting to focus on chemicals that can be analyzed using validated methodologies; however, 

such an approach limits the ability of EPA to address some important science questions that 

define LTG 2. The BOSC recommends that EPA establish a procedure for determining which 

chemicals and/or exposure circumstances are of high priority for study. This procedure should 

incorporate material generated from CDC’s “report card”; recent results from the NTP, including 

data on the toxicity of herbal medicines; and information generated by the HPV Program on 

screening and emissions data. Consideration of studies on the release of pharmaceuticals and 

their metabolites into wastewater and other federal activities relevant to identifying chemical 

classes of interest also is recommended. It is clear that EPA is doing much of this on an ad hoc

basis; however, success in meeting the objectives of LTG 2 will require a more focused 

approach. 

Priority setting for chemical classes evaluated for human and ecological effects of EDCs should 

take into account newer methodologies that detect a wide range of endocrine-active compounds 

including dietary phytoestrogens. The consequences of human and wildlife exposures to 

environmental estrogens must be assessed in conjunction with parallel dietary exposures to 

phytoestrogens. 
25 

Research on the potencies of several chemical classes of EDCs is ongoing and is dependent on 

having adequately characterized experimental models. Many of the models required for 

mammalian, fish, invertebrate, and avian species models appear to have been developed or are 

under development. As the models are characterized and evaluated, it will be important for EPA 

to use these models to determine potencies of a wider range of chemicals. Current efforts using 

samples from the Ohio River and surface waters in California are tractable and address specific 

concerns. EPA needs to determine if the EDC program should systematically evaluate (in 

collaboration with FDA) releases of pharmaceutical compounds into the environment. 

Simple models of effects are required; however, EPA also should strive to develop models that 

permit evaluations across multiple levels of biological organization. In vitro models are valuable 

for obtaining detailed knowledge on discrete biological/molecular events important for endocrine 

disruption, but they do not capture and integrate the multiple events essential for normal as well 

as altered endocrine function. Therefore, the BOSC recommends that EPA continue to focus on 

systems biology approaches and develop biologically based models that identify hazards and 

reduce uncertainties in risk assessment. The development and refinement of reliable models will 

require a cohesive multidisciplinary approach involving EPA scientists and collaborators from 

other scientific agencies and organizations. 

Several sources of environmental releases of EDCs are being evaluated including CAFOs, 

wastewater treatment, combustion processes, and paper and pulp mills. These projects are well 

designed and should produce important data. The CAFO studies would benefit from collaborations with other agencies working on new technologies designed to minimize environmental 

discharges. For example, North Carolina has a well-funded effort to develop environmentally 

superior technologies for dealing with hog wastes from CAFOs; this includes testing new 

technologies on model farms to determine if toxic emissions and releases can be minimized in a 

cost-effective manner. The subcommittee was impressed with EPA’s priority setting for 

evaluating endocrine activity of environmental releases and the strong science emerging from the 

studies. 

The human health studies include a children’s exposure program, the National Children’s Study 

(interagency), and a series of epidemiology studies on known endocrine disruptors. The 

epidemiology studies represent a large and important component of the EDC program relevant to 

LTG 2. The epidemiology research was reviewed at the Tulane conference held in October 

2004. Given the travel expenses incurred by the researchers to attend that conference in New 

Orleans, it was not feasible for them to attend the BOSC’s EDC program review meeting in 

Research Triangle Park (RTP) 6 weeks later. As a result, a member of the EDC subcommittee 

was invited to attend the Tulane conference. To disseminate the epidemiology information to the 

subcommittee, each subcommittee member was given a CD-ROM with all of the abstracts of the 

presentations from the Tulane conference, bibliographies of the presenters, and a summary of a 

panel discussion. These are large studies that address reproductive and developmental effects as 

well as cancer. EPA is encouraged to continue these kinds of interagency activities and to use the 

exposure results to set priorities for future epidemiology studies so that the same substances are 

not tested repeatedly. 
26 

EPA also is encouraged to collaborate with the National Institutes of Health (NIH) and other 

agencies to ensure that appropriate markers of genetic predisposition are included in the 

epidemiology studies for the purpose of identifying sensitive subpopulations. With respect to 

human and rodent toxicogenomic studies, EPA should rely primarily on other groups to generate 

the basic human and rodent toxicogenomic data; however, EPA scientists could play a 

significant role in metabolomics. It will be important for EPA to take a leadership role in 

applying these data to hazard identification, systems biology, and computational toxicology 

strategies and the development of the next generation of biologically based models to estimate 

interindividual variation in risks. EPA should aggressively pursue ecogenomics through its 

extramural grants program and in-house research. 

Relevance

The major research questions covered under LTG 2 are: 

 How and to what degree are human and wildlife populations exposed to EDCs? 

 What effects are occurring in exposed human and wildlife populations? 

 What are the chemical classes of interest and their potencies? 

 What are the major sources and environmental fates of the EDCs? 

These questions are consistent with the overarching EDRP, and they are relevant to EPA’s scope 

of interests and responsibilities. The results emerging from studies addressing these goals have 

been essential in identifying EPA as a leader in the arena of endocrine disruption. The fact that 

EPA conducts research on both ecological and human health issues places the Agency in a 

unique position to study the common ground between ecological and human health. It is 

important that EPA continues to be vigilant in mining this common ground for environmental 

chemicals, pharmaceuticals, and substances administered to farm animals. 

Chemicals selected for testing and calibration of models for endocrine dysfunction represent 

important classes of EDCs based on their known or potential exposures. The proposed and 

ongoing human and wildlife studies are highly relevant to EPA’s mission and will be critical for 

future decisionmaking and regulatory measures for EDCs. Several studies address the 

endocrine-disrupting activities of trenbolone, a potent synthetic androgen used as a growth 

promoter in livestock. This is an excellent example of careful priority setting and wellconducted research relevant to the endocrine disrupting potential of CAFO emissions. 

The research presented at the review struck a good balance between molecular toxicology and 

ecological evaluations. This balance will be essential for EPA to continue to address the science 

questions covered under LTG 2. Good examples of this are the studies investigating aquatic 

invertebrates as indicators of EDC exposures in aquatic systems, in which diagnostic indicator 

data from multiple aquatic organisms are being integrated to characterize the intensity and 

duration of exposures to EDCs. The molecular profiles from this research may permit 

simultaneous monitoring of exposure to multiple classes of EDCs, and thereby provide data 

useful for determining cumulative risks and chemical interactions. 
27 

The relevance of the EDC to goals expressed in the research plan and MYP will require EPA to 

continue to improve interactions with federal and state agencies and the scientific community to 

leverage resources and to set appropriate priorities. Some suggestions were made previously 

under Charge Question 1 for LTG –2, including the need to mine data from programs such as the 

HPV Program, wherein industries are making available screening level toxicity data for 

chemicals that are produced or used in volumes greater than 1 million pounds per year in the 

United States. These data frequently reveal which chemicals are being released into the 

environment in substantial quantities and have the potential to be endocrine disruptors. This 

program is centered in OPPTS and should involve a systematic review by EPA for relevance to 

the EDC program. Although interactions between OPPTS and ORD have been strong regarding 

the congressional mandates of the FQPA and SDWA, improved interactions are needed in other 

areas relevant to the EDC program. Likewise, the ability of EPA’s EDC program to address 

emerging ecological and human health issues and to identify new classes of EDCs will require 

continued active interactions with CDC, NIEHS, NTP, NIOSH, FDA, and USGS.

The EPA-supported research is well connected to risk assessment and risk management needs 

and addresses local problems identified by the regional offices. This approach will clarify which 

classes of EDCs may adversely affect human health and the environment and thereby facilitate 

identification of sources and eliminate or reduce their release. The subcommittee was impressed 

by the effective interactions between ORD and the regional offices. These interactions seem to 

be working very well for the EDC program and as such may serve as a model for other programs 

within EPA. Specific examples include assistance in evaluating gender disruption in native 

fishes in the Arkansas River, assessment of endocrine disruption in fish in the Potomac River, 

and surface water monitoring programs in California that measure the magnitude of 

environmental estrogen signals in fish. 

Program Progress

Good progress has been made in both the intramural and extramural projects, and they appear to 

be complementary; therefore, the BOSC recommends that EPA continue to fund EDCs research 

through the STAR program and that regular meetings continue between the extramural and 

intramural investigators for the purpose of fostering collaborative research and maximizing the 

effectiveness of the available resources. 

Several highly relevant studies are underway on the potential adverse effects of various classes 

of chemicals in humans and ecological systems. These studies include evaluations of PCBs, 

polybrominated biphenyls (PBBs), pesticides, dioxin-like compounds, synthetic and steroidal 

androgens and estrogens, anti-androgens, thyroid-active agents, phthalate acid esters, and 

polybrominated diphenyl ethers (PBDEs). Whereas some of these compounds do not directly 

activate hormonal systems via hormone receptor mechanisms, they do modulate hormone 

pathways through other mechanisms, and adverse health effects are hormonally mediated. 

Projects presented during the review are making reasonable progress, although it may be difficult 

to meet the designated timelines in all cases. The children’s health initiatives and the 

interagency epidemiology studies will take time to reach fruition. 
28 

The subcommittee notes that specific APGs have been met for the ecological studies, with 

timelines for significant accomplishments due by 2004. These APGs are to: (1) develop field 

methods to assess environmental exposures in tissues and environmental compartments; (2) 

determine the efficacy of various wildlife species as sentinels; and (3) evaluate several classes of 

chemicals suspected of being endocrine disruptors in field studies and ascertain the degree to 

which they are, or have the potential to, adversely affect wildlife at the population level. 

The subcommittee was impressed with the progress on studying CAFOs as a source of EDCs. 

These studies have demonstrated that estrogen conjugates are released into groundwater from 

swine operations, and the potential for release of trenbolone also has been demonstrated. The 

coupling of field studies to biomarker measurements (i.e., vitellogenin), analytical chemistry, 

and laboratory studies with whole organisms and hormone-responsive cells in effluents is 

yielding important results used to address specific problems identified by the regional offices. 

This strategy is a good model for EPA to follow in evaluating endocrine-disrupting activities in 

ecological systems at multiple levels of biological organization. In addition, good progress has 

been made on the identification of androgenic substances in pulp and paper mill discharges, the 

National Effluent EDC Screening Study, and the screening for emissions of EDCs from 

combustion processes. Progress has been made on developing assays to assess endocrine 

disrupting toxicity in invertebrates using a wide range of chemicals known or suspected to be 

EDCs. 

ORD also has made progress on the APG for evaluating several classes of chemicals suspected 

of being EDCs and determining their potencies in laboratory studies, especially with respect to 

ecological studies. Progress has been slower in mammalian systems based on the projects 

identified under LTG 2; however, some of the projects under LTG 1 are relevant to this APG. 

Likewise, the APG for determining the critical biological factors during development resulting in 

toxicities later in life are addressed in LTG 1. The APG for determining the extent to which 

exposures to EDCs contribute to the onset or increase the severity of diseases is an important 

goal that will require the collaboration of toxicologists, molecular biologists, and epidemiologists. It is not clear how EPA will address this APG, which stipulates the need for significant 

accomplishments by 2007. 

The deadline for the APG for determining whether adverse developmental/reproductive effects 

are occurring in human populations following exposures to EDCs is 2008. It was not feasible for 

scientists conducting the epidemiologic studies to attend the face-to-face meeting. Although the 

subcommittee members were provided with a CD-ROM of the Tulane conference and one of the 

subcommittee members did attend the conference, it was difficult for the subcommittee to 

critically review the progress in meeting this APG. The subcommittee determined that it would 

be helpful for subsequent reviews of this program to include poster presentations by each of the 

scientists funded by this interagency program. 

The deadline for the APG for determining sources of exposure and environmental fates of EDCs

also is 2008; nevertheless, good progress has been made for a wide range of chemical classes of 

EDCs. 
29 

It will be important for EPA to carefully review progress to determine when and how to take 

advantage of new methodologies and innovations such as gene arrays, proteomics, and 

metabolomics. The reviewers were pleased with the attention given the “omics” to date. 

It also will be important for EPA to make decisions regarding the ending of projects once goals 

have been achieved. 

Strengths and Challenges 

EPA’s research program relevant to the science questions contained in LTG 2 has been 

productive, of high quality, and relevant to the mission of EPA. Available resources have been 

used efficiently and there is a high degree of enthusiasm for the projects by both the intramural 

and extramural investigators. In general, greater progress has been made on ecological effects of 

EDCs compared to human health effects, although several appropriate human health projects are 

underway. Several strengths and challenges were identified by the subcommittee in the review 

of the projects listed under LTG 2, as indicated below. 

Strengths:

 Many of the models required for studying fish and invertebrate effects of EDCs have been 

developed, modified, and/or applied. Ongoing studies have set appropriate priorities for 

determining sources of EDC exposures including CAFOs, combustion processes, and pulp 

mills. 

 The ecological studies have effectively coupled field studies, biomarker measurements, 

analytical chemistry, and laboratory studies with whole organisms and hormone- responsive 

cells with effluents suspected of possessing hormonal activity. 

 EPA scientists have made good decisions on how to best use genomics, and the information 

generated should produce important data that address critical knowledge gaps. There is a 

good balance between molecular toxicology and effects on aquatic species and experimental 

animals. 

 Interactions between ORD and the regional offices on EDC problems are strong, effective, 

and frequent and provide a good model for EPA to use in other areas. 

 EPA’s research regarding LTG 2 is consistent with the overarching EDRP developed by EPA 

and other agencies in 1998, and research priorities reflect the high priority goals identified by 

that plan. 
30 

Challenges/Recommendations:

 Although priorities for chemicals studied have been appropriate, EPA should strive to 

continue to improve its interactions with other agencies that have a strong interest in 

EDCs such as the CDC, NIEHS, NTP, NIOSH, and FDA. This will facilitate identifying 

new sources of environmental and human exposures to EDCs. Moreover, EPA should 

mine data made available from the HPV Program and work with FDA to investigate 

the role of pharmaceuticals in the environment as a source of endocrine disruptors. 

 It was not feasible for scientists conducting epidemiologic studies to attend the face-toface program review meeting. Even though the subcommittee members were provided 

information from the Tulane conference and one of the subcommittee members 

attended the conference, the BOSC recommends that subsequent reviews of this 

program include poster presentations by each of the scientists funded by this 

interagency program. 

 It will be important for EPA to take a leadership role in the application of “omics” 

technologies to address many of the science questions critical for evaluating 

environmental and human health effects of EDCs. This will require a strong 

commitment to a systems biology approach and computational toxicology as well as 

effective interactions with those generating much of the basic data. 

 EPA should continue to investigate the common ground between ecological and human 

health, as no other agency is in a position to do this. 

 Progress reviews are encumbered, to some extent, by the difficulty in defining the scope 

of activities considered endocrine disruptor research. There is a large number of toxic 

mechanisms that could be categorized as endocrine disruptors; therefore, EPA should 

clarify what is and is not covered by the EDC program whenever the program is 

reviewed. 
31 

IV. LONG-TERM GOAL 3 

Support EPA’s screening and testing program. 

Introduction

EPA’s screening and testing program was established to comply with the FQPA and SDWA, 

both of which called for the establishment of screening programs for estrogenic activity and 

other endocrine activity that EPA deemed appropriate to evaluate. Principles for screening and 

testing of chemicals for potential endocrine-disrupting activity were developed by the EDSTAC, 

a federal advisory committee convened by EPA to provide recommendations on how to 

implement the endocrine disruptor assessment aspects of the FQPA and SDWA. EDSTAC 

recommended that the evaluation of chemicals proceed in a tiered manner: prioritization for 

assessment followed by screening for putative endocrine activity, which then would be 

confirmed by definitive testing. EDSTAC recommended that the screening encompass effects 

on estrogen, androgen, and thyroid hormone (EAT) function. 

EDSTAC developed a number of principles for screening and testing, including that these tiers 

evaluate every known mechanism of action that alters the EAT function, including binding to the 

estrogen or androgen receptor, interference with hormone synthesis or metabolism, and 

interference with hormonal action. EDSTAC also concluded that the screening and testing tiers 

be representative of the vertebrate classes known or suspected to be responsive to EAT 

disruptors. Because these recommendations cannot be accommodated in a single assay, a battery 

approach to screening and testing was recommended, and EDSTAC proposed a series of test 

methods with sufficient options. Although many of the assays in the proposed screening battery 

were in existence, there were no standardized, validated protocols for the purpose of EDC 

screening. Other assays had never been conducted, although the individual parameters of the test 

had been the subject of research. Most of the assays in the testing tier were already in use but 

required modification to include endpoints that were more sensitive to EAT activity. 

Regarding the prioritization tier of the screening program, EDSTAC recommended that 

consideration be given both to exposure and to the potential to cause biological effects. Because 

there is not a lot of existing information on the potential for biological effects, methods that are 

conducive to prioritization need to be developed. These methods may include QSAR approaches 

or high-throughput biological/ biochemical approaches. 

Program Design

EDSTAC’s recommendations have served as the basis for EPA’s EDSP. Given the state-of-theart at the time the recommendations were made, it became apparent that: (1) further methods 

development was required; (2) a better understanding of assay performance and reproducibility 

was needed; and (3) in some cases, additional studies of the mechanistic aspects of endocrine 

toxicity were needed to make the evaluation of endocrine disruptors more functional. ORD has 
32 

taken the appropriate steps through its MYP for endocrine disruptors to develop tools for 

prioritization, has standardized and validated assays for screening, and has added sensitive 

endpoints to traditional assessments of reproductive toxicity that enable a more complete 

understanding of the mechanisms of EDCs. 

ORD has been highly responsive to the needs of the EDSP and has provided technical expertise 

to the Office of Science Coordination and Policy (OSCP). ORD also has participated 

extensively with the OECD and other nations, notably Japan, in the harmonization of 

methodology for screening and testing methods. This has included the design of screening and 

testing methodologies through participation in the round-robin testing of proposed 

methodologies. ORD also has responded with the development of new approaches (e.g., the 

H295R adrenocortical tumor cell line for evaluating chemical effects on steroidogenesis) and by 

addressing technical issues via further experimentation (e.g., effects of loss of body weight on 

the applicability of the mammalian short-term reproduction assays and evaluation of additional 

endpoints for effects on the thyroid hormone axis). There also are several examples in which 

ORD has integrated some of the newer genomic and proteomic methodologies into the tests that 

are central to LTG 3 in an effort to define sensitive markers of response to different classes of 

EDCs. 

Relevance

The ORD research on screening and testing is essential to EPA’s mission and to the mandates 

given to EPA under the FQPA and SDWA. Virtually all of the short-term goals (i.e., those in the 

first several years) identified in the MYP are fully aligned with the recommendations of 

EDSTAC and EPA’s efforts to comply with the nature and timing of its FQPA/SDWA mandates. 

 Research support and expertise from ORD has been at the forefront of developing, 

standardizing, and validating screens for endocrine disruptors. 

The LTGs go beyond the explicit recommendations of EDSTAC but are highly relevant in that 

they anticipate and will take advantage of improvements in the science, especially in the realm of 

computational biology. EPA recently has launched a national, multilaboratory computational 

toxicology program, which stands to contribute significantly to endocrine disruptor screening, 

particularly through the development of QSAR models. 

Program Progress

There has been significant progress by ORD and its scientific partners in the development and 

validation of several relevant bioassays important for the screening and testing requirements for 

LTG 3. There were a number of mammalian assays proposed by EDSTAC as being useful for 

screening: the uterotrophic assay for estrogenic effects, the Hershberger assay for androgenic 

effects, and the pubertal male and female assays, which evaluate the attainment of puberty in 

rodents and are semi-apical in that they assess the integrated function of a number of 

mechanisms of action (i.e., hormone synthesis, hormone action, endocrine axes). Of these, only 

the uterotrophic protocol was sufficiently developed to be placed immediately into a 
33 

standardization and validation program. Therefore, ORD identified the need to further develop 

the other assays and included these as short-term goals in its MYP. 

The inclusion of new endpoints into traditional toxicity tests was another major recommendation 

of EDSTAC and it clearly has been the subject of research within ORD laboratories. This 

research is diffuse and is occurring in multiple divisions within NHEERL—development of 

sensitive markers of estrogenicity within the RTD and research on thyroid-mediated effects on 

development in the ETD and Neurotoxicology Division (NTD). Many of the accomplishments 

in these areas have been difficult to capture in the list of APGs. The BOSC recommends that 

EPA try to summarize this research and its relevance to EDC identification in subsequent reports 

and revisions of the MYP. 

In vitro assays for androgen receptor (AR) and estrogen receptor (ER) binding have been 

developed and validated. Moreover, in vitro AR- and ER-dependent transactivation assays in 

transformed cell lines now are available and these use both stable and transiently transfected 

cells. These assays, coupled with ongoing studies in other laboratories, suggest that this 

important screening component of LTG 3 is nearly complete. In addition, an in vitro assay for 

determining the effects of EDCs on steroidogenesis has been developed, and the approach will 

be capable of measuring both modulation of steroidogenic gene expression and activity. This 

bioassay seems highly promising and requires further validation using more extensive sets of test 

EDCs and possibly development of alternate cell lines to determine potential intercellular 

differences in response to EDCs. Excellent progress also has been made on validation of shortterm in vivo assays for the determination of estrogenic/antiestrogenic and androgenic/antiandrogenic chemicals using the rat as a model. 

Computational QSAR models also have been developed as part of the tier-I assays for the 

identification of EDCs. These approaches complement high-throughput screening assays, and 

their predictive nature will continually improve as new data on EDCs become available. It also 

is recommended that genomic/proteomic and metabolomic approaches for characterizing the 

various subtypes of EDCs be developed because this eventually should provide specific “omics” 

signatures for different structural and functional classes of EDCs. The bioinformatics expertise 

required for these approaches must be developed. 

Considerable progress has been made in the development of tier-I screening methods for 

wildlife. This includes: (1) an in vivo test for examining thyroid physiology in Xenopus laevis; 

and (2) a short-term in vivo reproductive test with the fathead minnow. The former assay is 14 

days in duration and is sensitive to thyroid hormone synthesis inhibitors and exogenous thyroid 

hormones. The basic assay is being modified for the evaluation of molecular and biochemical 

endpoints of relevance to the thyroid axis in an effort to shorten the assay and develop diagnostic 

indicators of thyroid hormone system dysfunction. EPA has made considerable progress in the 

development and application of the short-term fathead minnow reproduction assay for testing 

chemicals that exert effects by diverse modes of action (estrogens, androgens, anti-androgens, 

and inhibitors of steroid metabolism). Both test methods have been developed through the stage 

of prevalidation and are ready for validation by OPPTS. Both methods also have been 

communicated in the peer-reviewed literature and made available to the OECD. 
34 

Considerable progress has been made with the development of tier-II test methodologies for 

wildlife species. An amphibian growth and reproduction test is under development to enable 

evaluation of the chronic effects of chemicals on the development and maturation of the 

amphibian HPG axis. This test involves X. tropicalis and takes advantage of the rapid maturity 

of this species (approximately 6 months). One negative issue is that the original intent was that 

this test would employ a native North American frog, but to date, no suitable candidate species 

has been identified. 

Two fish species have been identified for lifecycle testing. These take advantage of their short 

generation times and unique aspects of their life history that can be exploited. The sheepshead 

minnow is an estuarine species and represents an important link to the marine environment. 

Considerable progress has been made with respect to basic husbandry conditions and in 

establishing genomic and proteomic markers of response to EDCs. The second species is the 

medaka, which affords the possibility of using the DMY gene expression to determine genotypic 

sex and relate this to phenotypic sex. These tests respond to requests from the OPPTS and 

OECD for alternate test methods for fish reproduction and development. 

Considerable progress has been made in the development of tier-II tests for invertebrates. This 

includes the development and validation of a lifecycle test using mysids and a rapid bioassay 

using copepods. The latter test involves the rearing of a meiobenthic copepod in a 96-well 

microplate format. This method has been applied to the evaluation of molecular markers of 

response (vitellogenin and ecdysteroid production) and has application in population-based 

assessment through the use of the Leslie-Matrix population growth model. Both test methods 

represent an important link to invertebrates and the opportunity to look at modulators of 

endocrine disruption beyond the E, A, and T axes. 

There are a number of challenges associated with the delivery of the testing protocols to OPPTS. 

Some of the protocols have been in place for many years, yet the transfer to contract laboratories 

has been problematic. This has led to a substantial commitment by EPA staff to refine and 

troubleshoot assays. This also has had a negative effect on other core research activities that are 

the responsibility of EPA staff. A mechanism is needed to ensure the timely transition of 

protocols to OPPTS, or this will continue to be a major commitment of time and resources by 

ORD staff. This will become even more problematic when there is more emphasis on whole 

animal test methodologies. 

Strengths and Challenges 

The progress on LTG 3 within the EDC program has been excellent. Two mammalian tests 

already have been through a validation program administered by OECD. These should be 

available for use by the EDSP very soon. Development of the other two tests recommended by 

EDSTAC is in progress, and publications emanating from this work indicate that the work is on 

track. 

ORD has articulated clear goals for the development of screening and testing methods for 

endocrine disruption and is fulfilling those goals in an admirable fashion. The research is 
35 

directly relevant to legislation that EPA administers and is serving the program offices well. 

EPA’s research is well coordinated with that of other federal agencies and with international 

efforts on the standardization and validation of endocrine screening assays. 

Strengths:

ORD has clearly defined its objectives for research to support the development, standardization, 

and validation of alternative methods that can be used by the program offices. 

ORD’s research is mechanistically driven, which provides a solid scientific foundation for the 

test methods that are developed. Because of this mechanistic focus, it is highly likely that the 

methods ORD develops will be valid, broadly applicable, and easily interpreted. 

ORD has used its leadership role in the fields of reproductive, developmental, endocrine, and 

aquatic toxicology to adapt and develop methods that have high relevance to the needs of the 

program offices and to the protection of public and environmental health. 

Challenges:

The major challenge that ORD has faced is handing off its research to the program offices so that 

validation and implementation can occur in a timely way. In fairness, it should be noted that 

much of the delay in validation and regulatory acceptance is because this process takes place 

largely outside the Agency. 

Recommendation: 

 The transfer of protocols to contract laboratories has been problematic. This has led to 

a substantial commitment by EPA staff to refine and troubleshoot assays, and it has 

had a negative effect on other core research activities that are the responsibility of ORD 

staff. The BOSC recommends that there be a mechanism in place to ensure the timely 

transition of protocols to OPPTS. 

ORD has a large number of research accomplishments within NHEERL that have contributed 

significantly to a basic understanding of the toxic responses to estrogens, anti-androgens (within 

RTD), and thyroid toxicants (within ETD), which in turn has led directly to the development of 

improved methods for endocrine disruptor detection. 

Recommendation: 

 This research is diffuse and is occurring in multiple divisions within NHEERL, and 

many of the accomplishments in these areas have been difficult to capture in the list of 

APGs. The BOSC recommends that EPA try to summarize this research and its 

relevance to EDC identification in subsequent reports and revisions of the MYP. 
36 

ORD is beginning to develop core competencies in genomics and QSAR methods, both of which 

hold promise in endocrine disruptor identification. 

Recommendations: 

 It will be important for EPA to take a leadership role in the application of the “omics” 

technologies to address many of the science questions critical for evaluating the 

environmental and human health effects of the EDCs. This will require a strong 

commitment to a systems biology approach and computational toxicology as well as 

effective interactions with those generating much of the basic data. 

 Because these areas are so data-intensive, it will be important for ORD to train or hire 

experts in bioinformatics to work with the life sciences experts already on staff. 
37 

V. PROGRAM LEADERSHIP 

Dr. Lawrence Reiter serves as the Executive Lead for the Endocrine Disruptors Research 

Program and also the Director of NHEERL. As the lead senior administrator, he does not attend 

to the day-to-day activities, but does follow the issues and serves as a resource for the Program 

Director if problems arise. Dr. Reiter has been the Executive Lead since the inception of the 

Program in 1995. Dr. Elaine Francis is extremely effective as the National Program Director, 

and has done an outstanding job of providing the leadership necessary for this integrated 

program to thrive. Her FTE and institutional support comes from NCER, and her role is to 

oversee the planning and execution of the intramural and extramural research program. Dr. 

Francis works closely with Dr. Reiter on EDC issues and reports to the Acting NCER Director, 

Dr. Jack Puzak . With the current organizational arrangement for the National Program 

Directors, Dr. Francis has responsibility for program oversight but does not have budgetary 

authority. 

A new organizational structure has been proposed and presented to the BOSC Executive 

Committee at a meeting in 2004, in which the National Program Directors will be afforded 

stature within EPA comparable to the Laboratory and Center Directors. With the new 

organizational structure, National Program Directors will report to the Deputy Assistant 

Administrator for Science (the position currently held by Dr. William Farland) and the Deputy 

Assistant Administrator for Management. The new reporting structure might provide more 

management and budgetary authority. The proposed model probably would be more desirable 

than the current structure, which requires the EDC Program Director to negotiate with various 

Center and Laboratory Directors for FTEs and resources to work on the EDC program. Because 

the new organizational model appears to present advantages in program leadership that are 

absent in the current model, the BOSC recommends that EPA implement the new organizational 

paradigm for National Program Directors that was presented to the BOSC Executive Committee 

at the May and September 2004 meetings. 

The EDC program is unique in that no other U.S. federal agency has such a program. The EDC 

program is not just an umbrella for a series of independent projects but is a fully integrated 

program across all laboratories and centers (with the exception of the National Homeland 

Security Research Center). In addition, research partners from academia, other federal agencies, 

and industry participate in the program and contribute to a diverse set of talents to address 

various research questions. The program is recognized nationally and internationally as a 

multidisciplinary set of research areas for both human health and wildlife and it cuts across the 

risk assessment/risk management paradigm. 

There is ample evidence documenting the leadership EDC scientists provide both within EPA 

and external to the Agency. Examples of leadership internal to the Agency are: (1) service on 

national and international workgroups such as providing the lead in various aspects of the dioxin 

reassessment; (2) service as chairs and members on numerous laboratory steering committees; 

and (3) service on various validation and implementation groups. EDC scientists are highly 
38 

sought out as consultants to EPA program offices (such as OCSP and OPPTS), other federal 

agencies, and the broader scientific community. EDC scientists provide technical assistance to 

the program and regional offices. There also are numerous examples of EDC scientists 

providing scientific leadership external to the Agency. EDC scientists are recruited to lead 

national and international collaborative efforts, including organizing national and international 

conferences and symposia. They are invited speakers to international symposia, chair sessions at 

research symposia, serve on scientific review panels for other federal agencies and universities, 

and chair interagency working groups. 

EDC scientists also have been recognized for their leadership in the field through their 

contributions as elected officers and members of professional societies. The scientists serve as 

reviewers for an impressive number (well over 100 of peer-reviewed journals. EDC scientists 

boast impressive vitas, with publications in top-tier scientific journals, a strong indicator of the 

quality of their research and their respect among professional peers. In addition, EDC scientists 

have been successful in being awarded additional funding from other federal agencies (i.e., NIH, 

NSF, NIEHS, and National Oceanic and Atmospheric Administration [NOAA]), private 

industry, and research foundations, and also have received STAR grants. Scientists in the 

program serve as adjunct professors or research fellows in academia, Branch Chiefs, Division 

Directors, and Program Directors. They contribute to the pipeline of new scholars in the field by 

serving as mentors to and sponsors of postdoctoral fellows. Finally, EDC scientists are the 

recipients of numerous scientific and technical achievement awards, commendable service 

awards, publication awards, EPA bronze medals, and other research awards. The EDC 

researchers are a group of highly esteemed scientists who are at the forefront of research in EDC 

screening and testing methodologies for mammalian and ecological tests, source identification, 

effects on wildlife, and ecological health. EDC scientists are a tremendous resource and asset 

for the Agency. 
39 

VI. PROGRAM RESOURCES 

The EDC program was projected to have an average annual budget of $12 million. This includes 

the STAR grants for EDCs, which average $4 million per year in the years when the program is 

funded. In actuality, the average annual budget from FY 2003 to 2005 has ranged from $12.7 

million enacted in FY 2003 to the FY 2005 request of $8.0 million. 

The EDC Program Director does not have direct access to human or financial resources to carry 

out the program’s objectives. Instead, the Program Director must negotiate with the Division 

Directors of the laboratories and centers (her peers) to recruit the time and effort of scientists 

with the required expertise. The sum of the fractions of FTEs of individual scientists who are 

devoted to the EDC program then is calculated as the EDC budget. There are 55 FTEs devoted 

to the EDC program throughout ORD in the FY 2004 and FY 2005 budgets. 

Four ORD laboratories/centers contribute resources to the EDC program—NRMRL, NCER, 

NERL, and NHEERL. Although the total budget for the program has decreased since FY 2003 

(from $12.7 M to a $8.0 M request for FY 2005), the percentage of resources provided by each 

of these laboratories has been relatively stable (with the exception of NCER) over the past 2 

years and is in proportion to the number and extent of tasks that they perform for the EDC 

program across the LTGs. In FY 2003, NCER provided 44 percent and 48 percent of the total 

budgets for LTGs 1 and 2, respectively. These percentages were slightly decreased in FY 2004 

but were reduced drastically in the FY 2005 request. The FTEs contributed to the EDC program 

by NCER, however, have been relatively steady (one for LTGs 1 and 2 in FY 2003; one for LTG 

1, and two for LTG 2 in FY 2004 and the FY 2005 request). NCER has not made a significant 

contribution to LTG 3 in any year. Even with these variations, the distribution of tasks and 

resources across appropriate laboratories and centers and across the LTGs appears to be 

appropriate, although there was concern expressed that the total budget was not sufficient. 

The STAR grants program adds significant value to the research portfolio of the EDC program. 

The research sponsored by the STAR program assists in filling identified research gaps, brings in 

research expertise that is not found among intramural scientists, and assists ORD in responding 

to new issues that the laboratories and centers may not be able to readily address. The value of 

the STAR program to the EDC program was evident during this review because at least 25 

percent of the poster presentations selected to demonstrate the sound science done by the EDC 

program were from STAR grant recipients. The STAR grants program, however, is not always 

funded at a level that allows maximum utility by the EDC program. The consequences of these 

actions is that ORD has learned to forward-fund STAR recipients. This allows the funded STAR 

recipients to be confident in receiving funding for the entire period of their awards; however, it 

significantly reduces the number of awards that can be made. 

 The manner in which this program is funded, though indirect and possibly cumbersome, does 

not appear to hinder the quality of the research being conducted under the program; this could, 

however, make it more difficult for the Program Director to do forward planning or to plan the 

investigation of emerging issues. The Program Director currently must rely on the willingness 
40 

of Laboratory/Center Directors and Division Directors to “release” scientists to the EDC effort. 

Again, this does not diminish quality, but it may not be the best way to operate a program from 

which so much is expected. 

It should be noted that the scientists (both intramural and extramural) involved in the EDC 

program are some of the best in their respective fields. From the oral and poster presentations 

given and discussions with the investigators, it is apparent that scientists with the most relevant 

skills to EDC research are involved in this program. It also is apparent that the mix of skills on 

each project and in each subject area is appropriate for the research questions to be addressed. 

The EDC program has been very astute in leveraging its resources by collaborating with other 

federal agencies. The amount of research conducted by the EDC program has been expanded by 

collaboration with agencies such as NIOSH, NCI, and NIEHS. This leveraging of resources has 

allowed the EDC program to get involved in areas of research, such as epidemiological studies, 

that it does not have sufficient intramural expertise to handle and to increase the output in other 

research areas. 

From the research progress made in the EDC program in the past 5 years, it is apparent that the 

EDC Program Director has had success in convincing Division Directors to lend scientists’ time 

to the program. It also is apparent that the Division Directors have been very cooperative in 

participating in the EDC program. The fragmentation of scientists’ time without compensation 

(e.g., the addition of a technician to the laboratory to either carry out the scientist’s originally 

assigned research or to perform the research necessary for the EDC program) raises concern 

about whether the productivity (e.g., number of manuscripts published) of these scientists is 

negatively impacted by participation in the EDC program. 

The situations cited above (insufficient funding and the mechanism used to provide resources to 

the EDC program) can be remedied by several courses of action: (1) hiring additional personnel 

to share the workload of the participating laboratories; (2) elevating the position of the EDC 

Program Director to the level of the Laboratory/Center Directors; and (3) giving the EDC 

Program Director budget authority. 

These actions would allow the Program Director to negotiate for needed research expertise from 

a position of strength and will allow the Program Director to enhance the laboratories that 

participate in EDC program research. 

The ORD has plans to enact the latter two of these ideas in the near future for all newly hired 

National Program Directors. The BOSC recommends the speedy implementation of that plan. 

It should be noted, however, that the BOSC’s recommendations about the hierarchal placement 

of the position of the National Program Director and the granting of budgetary authority to the 

holder of that position is based solely on its observations of the performance of the EDC 

Program Director. Dr. Elaine Francis has demonstrated the ability to work cooperatively with 

Laboratory/Center Directors and has used the resources provided to her in a responsible manner. 

 Thus, the BOSC’s recommendation is based solely on the exemplary model established by Dr. 

Francis. 
41 

The subcommittee subsequently discussed possible disadvantages to the elevation of the position 

of National Program Director. One disadvantage may be that giving the National Program 

Director the authority to unilaterally select ORD scientists to participate in the program may 

undermine the authority of the Laboratory/Center Directors. Another possible disadvantage may 

be that funds given directly to a National Program Director may further restrict the funding of a 

laboratory or center in times of fiscal retrenchment. The subcommittee is confident that ORD 

has worked through all possible problems involved in the elevation of the position. 

Recommendation: 

 

 The BOSC recommends the following courses of action: (1) hire additional personnel 

to share the workload of the participating laboratories; (2) elevate the position of the 

EDC Program Director to the level of the Laboratory/Center Directors; and (3) give the 

EDC Program Director budget authority. 
42 

VII. APPENDIX A—CHARGE QUESTIONS 

In your review of the Endocrine Disruptors Research Program, please use the Endocrine 

Disruptors Research Plan (EDRP), Multi-Year Plan (MYP), NHEERL’s Research 

Implementation Plan, and other submitted documents as background information. In your 

review, providing comments on the following areas would be very helpful in assessing the 

program’s relevance, performance, quality, and leadership, retrospectively, and its proposed 

directions, prospectively: 

CQ #1. Program Design 

A. Please comment on the goals and priorities of the EDRP and MYP, including whether the 

MYP’s long-term goals (LTGs) represent appropriate outcome measures for this 

program. 

B. Please comment on whether the research program has appropriately implemented the 

EDRP and MYP, tracking the key science questions closely and describing clearly the 

expectations for providing answers to the key science questions. 

3⁄4 Factors to consider: the appropriateness of the key science questions; the 

appropriateness of the LTGs in providing a logical framework for organizing the 

EDC Program to best meet the Agency’s needs; the degree of clarity to the path of 

annual research products aimed at accomplishing each of the LTGs; and the scientific 

soundness of the approaches used. 

 

 C. Please comment on whether the EDRP and MYP make it clear what ORD’s unique 

research niche is in the context of endocrine disruptors research being conducted across 

the federal government and internationally. Please comment on whether the rationale is 

sound for supporting the choices that ORD has made in the past and for the future 

regarding what to emphasize over the next 5 to 7 years. If it is not, what arguments need 

to be more clearly stated and what additional evidence and information need to be 

included? Have the potential public benefits of the program been clearly articulated? 

Also consider and comment on the interagency collaborations that should and can be 

improved to advance the Agency’s research agenda. To what extent has EPA established 

and utilized other agencies (inside and outside the government) in advancing EPA’s 

research agenda? What are the impediments to collaboration with other organizations? 

3⁄4 Factors to consider: research activities of other federal agencies, industry, academic 

institutions, and other countries; and the degree of collaboration and coordination 

with other research organizations. 

D. Please comment on whether the research products (annual performance measures 

[APMs]) and their sequencing and emphases over the next 5 to 7 years are appropriate, 

especially in light of needs for the Endocrine Disruptor Screening Program (EDSP) by 
43 

OPPTS. Does the program have a complete schedule with annual milestones for 

decisions and termination points, highlighting changes from previous schedules? 

3⁄4 Factors to consider: the appropriateness of the research products identified in the 

MYP to focus on the highest priority research for each LTG; and the 

adequacy/sufficiency/necessity of the sets of APMs under the annual performance 

goals (APGs) to accomplish the intended goals. 

E. Please comment on whether the MYP is sufficiently flexible to adapt to anticipated future 

science and policy direction changes. 

CQ #2. Program Relevance 

Please comment on the extent to which the research program, as evidenced by the EDRP, the 

MYP, the NHEERL Implementation Plan, and other submitted documentation plans to be 

responsive to Agency and other stakeholder needs and priorities. Please comment on the role the 

program scientists have had in providing technical support to Agency program and regional 

offices. 

3⁄4 Factors to consider: the degree to which the research is driven by EPA priorities; the 

degree to which this research program has had (or is likely to have) an impact on Agency 

decisionmaking; and the extent to which research program scientists participate on or 

contribute to Agency work groups and transfer research to program and regional 

customers. 

CQ #3. Program Progress in Addressing Key Scientific Questions and Impacting 

Environmental Decisionmaking 

The ORD MYP has identified three LTGs under which the key science questions are aligned. 

Please comment on the degree of progress that has been made in addressing each of the LTGs 

and associated key research questions. Please comment on the degree to which scientific 

products are being used in environmental decisionmaking. Has the research program met its 

APGs? 

3⁄4 Factors to consider: the scientific soundness of the approaches used; the degree to which 

scientific understanding of this problem has been advanced; the degree to which 

scientific uncertainty has been reduced; and the impact and use of research results in 

implementing the EDSP by other EPA program and regional offices and by other 

organizations. 

CQ #4. Program Contributions to Scientific Leadership 

Please comment on the leadership role the program and its scientists have in contributing to 

advancing the state of science on endocrine disruptors. 
44 

3⁄4 Factors to consider: the degree to which this program is identified as a leader in the field; 

the degree to which endocrine disruptor scientists serve/are asked to serve on 

national/international workgroups, officers in professional societies, and publication 

boards; the degree to which endocrine disruptor scientists lead national/international 

collaborative efforts, organize national/international conferences/symposia, and are 

awarded for their contributions/leadership; and benchmarking of scientific leadership 

relative to other programs, agencies, and countries. 

CQ #5. Program Resource Allocation 

The MYP was developed based on an assumption of level resources (approximately $12 M 

including approximately 55 full-time equivalent personnel) over the period covered by the plan. 

Please comment on: (1) the appropriateness of the relative allocation of resources across the 

LTGs based on a consideration of scientific and programmatic needs; and (2) the manner in 

which resources are allocated. Do these funding processes maintain program quality? 

3⁄4 Factors to consider: the degree to which resources are allocated across LTGs and across 

laboratories/centers; the appropriateness of the skill mix devoted to this program; 

intramural funds, allocated based upon ORD’s risk-based priority setting process; 

matching finite resources with finite in-house expertise; and extramural funds, allocated 

based upon competitive solicitation with only those achieving a rating of “excellent” or 

“very good” by an external peer panel considered for funding by an internal program 

panel. 
45 

VIII. APPENDIX B—BIOGRAPHICAL SKETCHES OF THE 

EDC SUBCOMMITTEE MEMBERS 

Anna K. Harding (Chair) is an Associate Professor in the Department of Public Health at 

Oregon State University. Dr. Harding received her Ph.D. in Public Health from Oregon State 

University in 1990. Dr. Harding’s research expertise is in environmental health, including water 

quality and public health outcomes, and the effects of environmental contamination on at-risk 

populations. Dr. Harding also serves as a member of EPA’s Board of Scientific Counselors 

(BOSC). 

George P. Daston (Vice-Chair) is a research fellow at the Proctor & Gamble Company in 

Cincinnati, Ohio. Dr. Daston has expertise in developmental biology, teratology, toxicology, 

and risk assessment. He received his Ph.D. in Developmental Biology and Teratology from the 

University of Miami in 1981. Dr. Daston also serves as a member of EPA’s BOSC. 

Glen R. Boyd is a registered professional engineer with a background in engineering consulting. 

Currently, he is an Assistant Professor in the Department of Civil and Environmental 

Engineering at Tulane University. Dr. Boyd’s research interests include occurrence and 

treatment of low-level EDC and pharmaceuticals and personal care products (PPCPs) in the 

environment, water quality in drinking water distribution systems, and remediation of dense 

nonaqueous phase liquid (DNAPL) contaminated groundwater. He received his Ph.D. in 

Environmental Systems Engineering from Clemson University in 1991. 

George Lucier is an environmental consultant who retired from the National Institute of 

Environmental Health Sciences (NIEHS) in 2000. While at NIEHS, he served as Director of the 

Environmental Toxicology Program and Associate Director of the National Toxicology Program 

(NTP). Dr. Lucier received his Ph.D. in Entomology in 1970 from the University of Maryland. 

He has expertise in hormonally active chemicals and risk assessment models. 

Stephen H. Safe is a Distinguished Professor in the Department of Veterinary Physiology and 

Pharmacology at Texas A&M University and the Director of its Center for Environmental and 

Genetic Medicine. He received his doctorate in 1965 from Oxford University. Dr. Safe’s 

research interests include: toxicology, molecular biology of estrogenic and antiestrogenic 

compounds, and molecular mechanisms of estrogen receptor and Ah receptor action. 

Juarine Stewart is the Interim Dean at Morgan State University’s School of Computer, 

Mathematical, and Natural Sciences. She received her Ph.D. in 1978 in Biomedical Sciences 

from the University of Tennessee. Her expertise includes chemistry, biochemistry, and 

management of research. Dr. Stewart also serves as a member of EPA’s BOSC. 

Donald E. Tillitt is the Branch Chief for the Biochemistry and Physiology Branch at the U.S. 

Geological Survey’s Columbia Environmental Research Center in Columbia, Missouri. He is 

also an Adjunct Assistant Professor in the Departments of Biochemistry and Fisheries and 
46 

Wildlife Sciences at the University of Missouri. Dr. Tillitt’s research interests include 

developmental and reproductive toxicology of environmental contaminants in fish and wildlife, 

techniques to assess the effects of complex mixtures on environmental contaminants, and 

biochemical effects on aquatic organisms. He received his Ph.D in Environmental Toxicology in 

1989 from Michigan State University. 

Glen Van Der Kraak is Associate Dean for Research of the College of Biological Science at the 

University of Guelph. He also is the Leader of the Reproductive and Endocrine Ecotoxicology 

Program, Canadian Network of Toxicology Centres. He received his Ph.D. from the University 

of British Columbia in 1984. Dr. Van Der Kraak’s current research includes the regulation of 

ovarian function in fish and evaluation of reproductive fitness in fish and amphibians. 
47 

IX. APPENDIX C—LIST OF ACRONYMS 

ACC American Chemistry Council 

APG Annual Performance Goal 

APM Annual Performance Measure 

AR Androgen Receptor 

BOSC Board of Scientific Counselors 

CAFO Concentrated Animal Feedlot Operation 

CDC Centers for Disease Control and Prevention 

DNAPL Dense Nonaqueous Phase Liquid 

EAT Estrogen, Androgen, and Thyroid Hormone 

EDC Endocrine Disrupting Chemical 

EDRP Endocrine Disruptors Research Plan 

EDSP Endocrine Disruptor Screening Program 

EDSTAC Endocrine Disruptors Screening and Testing Advisory Committee 

EPA U.S. Environmental Protection Agency 

ER Estrogen Receptor 

ETD Experimental Toxicology Division 

FDA U.S. Food and Drug Administration 

FQPA Food Quality Protection Act 

FTE Full-Time Equivalent 

FY Fiscal Year 

GPRA Government Performance and Results Act 

HPV High Production Volume 

LTG Long-Term Goal 

MYP Multi-Year Plan 

NCER National Center for Environmental Research 

NCI National Cancer Institute 

NERL National Exposure Research Laboratory 

NGO Nongovernmental Organization 

NHEERL National Health and Environmental Effects Research Laboratory 

NIEHS National Institute of Environmental Health Sciences 

NIH National Institutes of Health 

NIOSH National Institute for Occupational Safety and Health 

NOAA National Oceanic and Atmospheric Administration 

NRMRL National Risk Management Research Laboratory 

NTD Neurotoxicology Division 

NTP National Toxicology Program 

OECD Organization for Economic Cooperation and Development 

OPPTS Office of Prevention, Pesticides and Toxic Substances 

ORD Office of Research and Development 

OSCP Office of Science Coordination and Policy 

PBBs Polybrominated Biphenyls 

PBDEs Polybrominated Diphenyl Ethers 
48 

PCBs Polychlorinated Biphenyls 

PPCPs Pharmaceuticals and Personal Care Products 

RME Risk Management Evaluation 

RTD Reproductive Toxicology Division 

RTP Research Triangle Park 

SDWA Safe Drinking Water Act 

STAR Science To Achieve Results 

USDA U.S. Department of Agriculture 

USGS U.S. Geological Survey 

QSAR Quantitative Structure Activity Relationship 

WHO World Health Organization